Clozapine is an oral dibenzodiazepine-derived atypical antipsychotic. Clozapine is structurally related to the antipsychotic loxapine but differs in efficacy and adverse effects. Approximately 35 mg of clozapine is equivalent to 100 mg of chlorpromazine (CPZ EQ), the prototype typical antipsychotic. Compared to traditional antipsychotics, clozapine has greater limbic system specificity and a low incidence of extrapyramidal side effects. Clozapine had the distinction of being the first atypical antipsychotic that was proven effective in treating patients with schizophrenia refractory to other medications. Guidelines recommend clozapine use in the following patients: patients with treatment-resistant schizophrenia, patients with schizophrenia where the risk for suicide attempts or suicide remains substantial despite other treatments, and patients with schizophrenia where the risk for aggressive behavior remains substantial despite other treatments. The prescribing information contains a boxed warning regarding the potential for life-threatening severe neutropenia (agranulocytosis); clozapine should be reserved for patients who have failed treatment with two or more trials of other schizophrenia drugs or who are at risk for recurrent suicidal behavior. Clozapine therapy requires special monitoring and surveillance due to its potential for causing fatal agranulocytosis in about 1% of exposed patients per year; surveillance programs have been effective at reducing the incidence of clozapine-induced agranulocytosis to roughly 0.4% during postmarket use. The Clozapine REMS Program includes the requirements for monitoring, prescribing, dispensing, and receiving clozapine, and the required management of therapy and monitoring for neutropenia. Prescribers or their designated agents must enroll each patient into the Clozapine REMS Program prior to patient eligibility to receive the drug. All prescribers and dispensing pharmacies of clozapine are required to be certified by the program. More information is available at https://www.clozapinerems.com.
Since its initial inception, the clozapine REMS program has undergone numerous changes and updates to ensure patients are monitored safely and appropriately for signs of neutropenia. However, these updates have been associated with difficulties in patient, provider, and pharmacy enrollment in the REMS program, leading to delays in access to clozapine. These delays can result in significant complications for patients, including symptom relapse, rehospitalization, and dangerous side effects when the medication is restarted after a period of abrupt discontinuation. In order to prioritize continuity of care for patients, the FDA issued a statement in November 2022 highlighting the importance of inpatient pharmacies dispensing an appropriate amount of clozapine to patients who are being discharged from an inpatient facility. The FDA alert states that the FDA will not object to these inpatient pharmacies dispensing a multiple day supply of clozapine that aligns with the patient's current monitoring frequency (e.g., a patient with weekly lab monitoring would be given a 7-day supply, while a patient with twice monthly monitoring should receive a 14-day supply. Patients with monthly lab monitoring could receive a 30-day supply). This FDA alert is the most recent in a series of drug safety and availability updates for clozapine. Previous alerts from 2021 addressed both distribution and outpatient pharmacy dispensing of clozapine and stated the FDA would not object to wholesalers shipping clozapine to pharmacies or health care settings without a confirmed REMS enrollment nor would it object if a pharmacist dispensed clozapine without a REMS dispense authorization (RDA) in order to provide continuity of care for patients. The FDA encourages health care providers to use their clinical judgement to prescribe or dispense clozapine to patients with acceptable ANC values while experiencing delays with the REMS program and to avoid abrupt discontinuation of the medication unless medically warranted.
General Administration Information
For storage information, see specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May administer without regard to meals.
-If a patient experiences an interruption in treatment, the dosage of clozapine should be reduced and then retitrated to minimize the risk of hypotension, bradycardia, and syncope. The dosage reduction needed is dependent on the days of treatment missed or interrupted.
Oral Solid Formulations
Oral disintegrating tablets (ODT) (e.g., FazaClo):
-Keep the ODT in the unopened blister until the time of use. Just prior to use, peel the foil from the blister and gently remove the ODT. Do not push the ODT through the foil, because this could damage the tablet.
-Place tablet on the tongue, allow to dissolve, then swallow. Alternatively, the tablets may be chewed and swallowed.
-May be swallowed with saliva. No water is necessary for administration.
Oral Liquid Formulations
Oral Suspension (e.g., Versacloz):
-Each box contains one 1 mL oral syringe, one 9 mL oral syringe, and 1 bottle adaptor along with the suspension bottle. For each new bottle, push the provided adaptor into the bottle until the top of the adaptor is lined up with the top of the bottle.
-Prior to each use, shake well for 10 seconds.
-Fill the oral syringe (1 mL or 9 mL depending upon dose) with air and insert into the adaptor, dispelling the air into the bottle.-If the dose is 1 mL (50 mg) or less, use the 1 mL oral syringe.
-If the dose is greater than 1 mL (50 mg), use the 9 mL oral syringe.
-Fill syringe with the prescribed dose and administer immediately. Do not save the dose in the oral syringe for later administration.
-Administer slowly into 1 side of the mouth with the patient's lips closed tightly around the syringe. The dose should be swallowed slowly.
-After use, the oral syringe may be washed with warm water and air dried in preparation for the patient's next dose.
-Close the bottle with its cap; the bottle adaptor can remain in place.
-Storage of opened bottle: The suspension is stable for 100 days after initial opening. Store at or below 25 degrees C (77 degrees F). Do not refrigerate or freeze.
Close monitoring of WBC count must be undertaken in all patients receiving clozapine. Clozapine use is associated with an established risk of hematologic effects, including severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/mcL. To improve and standardize understanding, the term severe neutropenia replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis in the product labels. Severe neutropenia increases the risk for serious infectious diseases and death. Epidemiologic data suggest that the risk of neutropenia is greatest during the first 18 weeks on treatment and then declines. In general, weekly ANC monitoring is required for all patients during the first 6 months of treatment. If the ANC of the patient is 1,500/mcL or greater for the first 6 months of treatment, monitoring frequency may be reduced to every 2 weeks for the next 6 months. If the ANC remains 1,500/mcL or greater for the second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once every 4 weeks thereafter. The mechanism by which clozapine causes neutropenia is unknown and is not dose-dependent. Patients generally recover from clozapine-induced severe neutropenia within 7 to 28 days after the clozapine is stopped. Patients who have developed agranulocytosis from treatment with clozapine are at increased risk of subsequent episodes. Do not rechallenge with clozapine if a patient has experienced severe neutropenia unless the prescriber determines benefits outweigh risks; the prescribing label gives guidance on such scenarios. During clinical trials, the following hematologic effects were reported in at least 1% of patients receiving clozapine: leukopenia/decreased WBC count/neutropenia (3%), agranulocytosis or severe neutropenia (1%), and eosinophilia (1%). Hematologic effects occurring in less than 1% of patients during premarketing evaluation of clozapine included anemia, epistaxis, and leukocytosis. Postmarketing, hematologic events include cases of elevated hemoglobin/hematocrit, increased erythrocyte sedimentation rate, thrombocytosis, and thrombocytopenia. Moderate leukopenia (WBC count 2,000 to 3,000/mcL) has been reported to be a risk factor for agranulocytosis/severe neutropenia with clozapine therapy. A report from the Clozaril National Registry during the period of 1990 to 1994 showed that use of clozapine in 99,502 U.S. patients according to package labeling requirements was associated with a total of 382 cases of agranulocytosis (0.38%) and 12 deaths attributed to complications of agranulocytosis. A hematologic risk analysis was conducted based upon the available information in the Clozapine National Registry for U.S. patients. Utilizing data up to April 30, 1995, the incidence rates of agranulocytosis based upon a weekly monitoring schedule rose steeply during the first 2 months of therapy, peaking in the third month. Among clozapine patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell a substantial degree. After 6 months, the weekly incidence of agranulocytosis declined still further; however, it never reached zero.
Central nervous system (CNS) adverse events are common with clozapine therapy and may lead to therapy discontinuation in some patients. Excessive sedation or drowsiness is an extremely common initial adverse effect of clozapine administration. During clinical trials, the following centrally-mediated effects were reported in at least 1% of patients receiving clozapine: drowsiness/sedation (39%), dizziness/vertigo (19%), headache (7%), disturbed sleep/nightmares (4%), fatigue (2%), insomnia (2%), hyperkinesis (1%), weakness/asthenia (1%), lethargy (1%), ataxia (1%), and slurred speech (1%). During a comparative trial between clozapine and olanzapine, the following CNS effects occurred in patients receiving clozapine versus olanzapine: drowsiness (46% vs. 25%), dizziness (27% vs. 12%), and insomnia (20% vs. 33%). CNS effects occurring in less than 1% of patients during premarketing evaluation of clozapine include loss of speech, tics, poor coordination, stuttering, dysarthria, and numbness. CNS events observed during postmarketing use include paresthesias, restless legs syndrome (RLS), and possible mild cataplexy. In rare instances, intensification of dream activity has occurred during clozapine therapy; Rapid eye movement (REM) sleep has been found to increase to 85% of total sleep time and the onset of REM sleep begins almost immediately after falling asleep. After the initial dosage titration, giving most or the entire dose at bedtime can prevent problems due to continuing sedation. If morning sedation is a problem, then dividing doses, with the majority administered at bedtime, can be helpful. Sedative effects can diminish with continued use of the drug. Because somnolence may lead to falls with the potential for fractures and other injuries, a fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate somnolence. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy.
Clozapine lowers the seizure threshold, and seizures may develop. During clinical trials, seizures were reported in 3% of patients and epileptiform movements/myoclonic jerks were reported in 1% of patients. Status epilepticus, myoclonia, and EEG changes have been observed during postmarketing use. Clozapine was associated with a cumulative seizure incidence at one year of approximately 5% during premarketing evaluation. Rapid dose increases and high daily dosages (more than 600 mg/day) are associated with a greater likelihood of seizure activity. Slow upward or downward titration of dosage can usually help to prevent seizures. If seizures develop, dosage reduction or discontinuation of the drug may be indicated if the patient has not obtained significant benefit from clozapine. In patients whose illness has improved substantially while taking clozapine, the benefits and risks of continuing clozapine with a concomitant anticonvulsant must be considered.
Long-term therapy with antipsychotics can result in tardive dyskinesia, an involuntary dyskinetic movement disorder. Tardive dyskinesia is less likely to occur with clozapine therapy than with traditional antipsychotics. To date, no confirmed cases of tardive dyskinesia have been associated with clozapine in the absence of previous treatment with other antipsychotics. Clozapine is often used in patients who develop tardive dyskinesia to traditional antipsychotics (e.g., haloperidol, phenothiazines). Many patients with pre-existing tardive dyskinesia have significant improvement in their symptoms following therapy with clozapine. However, the condition is irreversible in some cases, so patients receiving long-term therapy should be monitored for possible symptoms, such as involuntary movements of the tongue, face, mouth, or jaw, and if any signs develop, the drug should be immediately withdrawn. Geriatric patients and females appear to be more prone to development of this syndrome. All patients treated with an antipsychotic should receive informed consent and be monitored at 3 to 6 month intervals for the possible appearance of abnormal movements.
During clinical trials, the following extrapyramidal effects or related symptoms were reported in at least 1% of patients receiving clozapine: tremor (6%), restlessness (4%), hypokinesia/akinesia (4%), rigidity (3%), and akathisia (3%). Extrapyramidal effects or similar symptoms occurring in less than 1% of patients during premarketing evaluation of clozapine include involuntary movement, shakiness, and pseudoparkinsonism. Dystonic reaction is a potential effect of all antipsychotics including clozapine which may occur in susceptible individuals during the first few days of treatment. This effect is observed more commonly in males, younger age groups, and with high potency antipsychotics. Dystonic reactions may manifest as torticollis with or without throat tightness, difficulty swallowing or breathing, oculogyric crisis, trismus, or protrusion of the tongue. The possible development of a dystonic reaction is much lower with clozapine therapy than with traditional antipsychotic drugs because of its low propensity for causing extrapyramidal effects.
A potentially fatal symptom complex referred to as neuroleptic malignant syndrome (NMS) has been reported in association with antipsychotic administration. NMS is characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac dysrhythmia). Increased serum creatine phosphokinase (CPK), rhabdomyolysis, and acute renal failure may also occur. There have been fewer reports of NMS with clozapine therapy than with traditional antipsychotics, but NMS has occurred in several patients treated with clozapine. In a comparison of 15 cases of clozapine-induced NMS to 115 cases of traditional antipsychotic-induced NMS, clozapine cases had fewer problems with rigidity and tremor, smaller increases in CPK, or a less significant increase in temperature. Clozapine-induced cases also were less likely to have EPS before the onset of NMS, but they were more likely to have autonomic features (e.g., pyrexia, elevated blood pressure, increased sweating, tachycardia, cardiac dysrhythmias). The cause of NMS is not completely understood; however, dopamine receptor blockade is one of the mechanisms by which NMS is thought to occur. A primary risk factor for developing NMS appears to be the initiation or increase in dose of an antipsychotic. High potency and depot antipsychotics carry the greatest risk. Environmental risk factors include conditions that inhibit heat dissipation such as an elevated ambient room temperature, prolonged heat exposure, the use of patient restraints, or dehydration. NMS occurs more frequently in young adults, which is most likely the result of age of first exposure rather than an age-related risk. NMS occurs more frequently in men, which is thought to be related to the higher likelihood of male versus female exposure to the causative agent. Risk factors for recurrent NMS include a personal history of NMS, increasing age, and certain medical co-morbidities (e.g., electrolyte imbalances, dehydration). Combined use of clozapine and lithium increases the risk of NMS. Clozapine should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered.
Peripheral vascular effects, including phlebitis, thrombophlebitis, and cyanosis, occurred in less than 1% of patients receiving clozapine during premarketing evaluation. During postmarketing use, deep vein thrombosis (DVT) and pulmonary embolism have been reported; although the frequencies are unknown. In an analysis of the Swedish national pharmacovigilance register from the year 2000, 12 cases of venous thromboembolism (VTE) with 5 fatal outcomes were identified during clozapine treatment. Based on the available data, it was estimated that at least 1 patient per every 2,000 to 6,000 clozapine-treated patients experienced a VTE. Although some surveillance programs and meta-analyses have found an increased VTE risk for clozapine compared to many other antipsychotics, further study is needed to control for potential confounders, such as disease-specific or patient-specific factors. Therefore, whether pulmonary embolus can be attributed to clozapine or some characteristic(s) of the patients is not clear. Until more information becomes available, the possibility of pulmonary embolism should be considered in any patient receiving clozapine who presents with deep vein thrombosis, chest pain, acute shortness of breath, or other respiratory signs and symptoms. An increased risk of cerebrovascular events (e.g., stroke) has been observed in patients with dementia receiving some atypical antipsychotics. Clozapine should be used cautiously in patients with dementia or risk factors for stroke.
Orthostatic hypotension frequently occurs during therapy with clozapine, especially during initial titration or dosage increase. Other cardiovascular effects noted in 1% or more of patients receiving clozapine in clinical trials include sinus tachycardia (25%), hypotension (9%), chest pain (unspecified) or angina (1%), ECG changes/cardiac abnormality (1%), syncope (6%), and hypertension (4%). Less common cardiovascular effects (occurring in less than 1% of patients) have included edema, palpitations, premature ventricular contractions (PVCs), and bradycardia. Many of these cardiac effects, particularly hypotension, syncope, and bradycardia, are most common during initiation of the medication or with rapid dose titrations. Patients who are restarting clozapine after missing 2 or more days of treatment are also at risk of these cardiac effects and should be titrated slowly from the manufacturer recommended starting doses. Patients taking clozapine are also at risk of other rare but significant cardiac events and should be screened and monitored closely if cardiac changes occur. Myocarditis is a rare but serious complication associated with clozapine use. If untreated, this reaction can be fatal. The possibility of myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, shortness of breath, tachypnea, pyrexia, chest pain, palpitations, tachycardia, other signs or symptoms of heart failure, or ECG findings such as ST-T wave changes or cardiac arrhythmias, particularly during the first month of therapy. If these symptoms occur, close monitoring for other signs and symptoms of myocarditis is warranted. Clozapine should be discontinued promptly if myocarditis is suspected and patients with a history of clozapine-related myocarditis should not be re-challenged with clozapine. While the overall incidence rate of myocarditis is unknown, postmarketing surveillance data from 4 countries that employ hematological monitoring of clozapine-treated patients revealed that the rate of myocarditis in clozapine-treated patients appears to be 17 to 322 times greater than the general population and is associated with an increased risk of fatal myocarditis that is 14 to 161 times greater than the general population. The total number of myocarditis cases for 4 countries (U.S., U.K., Canada, and Australia) was 82 of which 51 cases (62%) occurred within the first month of clozapine treatment, 25 (31%) occurred after the first month of therapy and 6 (7%) were unknown. The median duration of treatment before myocarditis onset was 3 weeks. Of 5 patients re-challenged with clozapine, 3 had a recurrence of myocarditis. Of the 82 reports, 31 (38%) were fatal and 25 of these deaths had evidence of myocarditis at autopsy. These data also suggest that the incidence of fatal myocarditis may be highest during the first month of therapy. In addition to myocarditis, cases of clozapine-related cardiomyopathy have been reported postmarketing. Palpitations, atrial fibrillation, arrhythmia exacerbation, ventricular fibrillation, periorbital edema, heart failure, pericarditis, pericardial effusion, ventricular tachycardia, QT prolongation, torsade de pointes, myocardial infarction, cardiac arrest, and mitral valve incompetence have been reported. The incidence of clozapine-induced cardiomyopathy has been estimated at 8.9 per 100,000 patient-years according to a 1999 national survey of hospital discharges. In this study, many cases (65%) occurred after 6 months of treatment. Cardiomyopathy should be considered in patients experiencing symptoms such as exertional shortness of breath, fatigue, orthopnea, paroxysmal nocturnal shortness of breath, and peripheral edema. Other rare but serious adverse effects associated with clozapine use that have been reported postmarketing have included polyserositis (e.g., inflammation of several membranes at the same time, including pericarditis, peritonitis, and pleuritis) and pseudopheochromocytoma (symptomatic paroxysmal hypertension, which presents as severe hypertension).
In pooled analyses comparing the lipid profiles of clozapine and chlorpromazine, the following mean changes in baseline lipid parameters occurred in the clozapine and chlorpromazine groups, respectively: increase in total cholesterol (13 mg/dl vs 15 mg/dl) and increase in fasting triglycerides (71 mg/dl vs 39 mg/dl). The percentages of patients with categorical changes from baseline in total cholesterol in the clozapine and chlorpromazine groups, respectively, were as follows: increase by >= 40 mg/dl (33% vs 25%), from < 200 mg/dl to >= 240 mg/dl (8% vs 2%), and from 200-239 mg/dl to >= 240 mg/dl (38% vs 41%). The percentages of patients with categorical changes from baseline in fasting triglycerides in the clozapine and chlorpromazine groups, respectively, were as follows: increase by >= 50 mg/dl (50% vs 43%), increase from < 150 mg/dl to >= 200 mg/dl (0% vs 33%), and increased from >= 150-199 mg/dl to >= 200 mg/dl (100% vs 0%). The proportion of patients with increases in total cholesterol and fasting triglycerides increased with duration of clozapine exposure. During post-marketing use of clozapine, hypertriglyceridemia and hypercholesterolemia have been reported; however, the frequencies are unknown. Atypical antipsychotics have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk over time, including dyslipidemia.
Due to its potent anticholinergic effects, clozapine commonly causes constipation due to reduced gastrointestinal (GI) motility, and less commonly fecal impaction, megacolon, GI obstruction, ischemia, infarction, perforation, paralytic ileus, or bowel necrosis. Such reactions can lead to hospitalization or fatalities if such serious bowel conditions are not diagnosed and treated quickly. Evaluate the patient's bowel function prior to initiating clozapine. Consider prophylactic laxative treatment in patients with a history of constipation or bowel obstruction. Monitor patients for symptoms consistent with GI hypomotility such as nausea, abdominal distention or pain, and vomiting, and inquire about the frequency and quality of bowel movements throughout treatment. Advise patients frequently about the significant risk of constipation and potentially fatal bowel complications that can occur while taking clozapine and the need to stay hydrated. Patients should contact their health care provider immediately if they experience constipation while taking clozapine or develop other signs and symptoms of GI hypomotility. During clinical trials, the following gastrointestinal (GI) effects were reported in at least 1% of patients receiving clozapine: constipation (14% to 25%), nausea (3% to 17%), abdominal discomfort or pyrosis (heartburn) (4%), vomiting (3% to 17%), diarrhea (2%), hypersalivation (31% to 48%), dyspepsia (14%), xerostomia (6%), and sore/numb tongue (1%). GI effects occurring in less than 1% of patients during the premarketing evaluation of clozapine included abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric peptic ulcer, bitter taste (dysgeusia), eructation, and dry throat. Gastrointestinal effects reported during postmarketing use include colitis, dysphagia, fecal impaction, intestinal GI obstruction, megacolon, intestinal ischemia (bowel ischemia) or infarction, and salivary gland swelling. Hypersalivation and drooling can be excessive and troublesome during sleep. The reduction of clozapine dosage occasionally improves hypersalivation and should be attempted if tolerated. While the administration of an anticholinergic agent is reported to be helpful in reducing saliva, anticholinergics that can cause GI hypomotility should be avoided.
During clinical trials, the following genitourinary (GU) effects were reported in at least 1% of patients receiving clozapine: urinary abnormalities (2%), urinary incontinence (1%), ejaculation dysfunction (1%), increased urinary frequency or urinary urgency (1%), and urinary retention (1%). GU effects occurring in less than 1% of patients during premarketing evaluation of clozapine include dysmenorrhea, impotence (erectile dysfunction), mastalgia, and vaginal itch/infections. GU events observed during postmarketing use include acute interstitial nephritis, renal failure (unspecified), nocturnal enuresis (nocturia), retrograde ejaculation, and priapism. Priapism is a potentially serious adverse reaction and can occasionally result in permanent impairment of erectile function or impotence.
Hyperglycemia, in some cases extreme and associated with diabetic ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine. These events may occur even in patients with no prior history of hyperglycemia. Glucose levels normalize in most patients after discontinuation of clozapine. A positive rechallenge has been demonstrated in some patients. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available; but temporal associations of clozapine therapy with the precipitation or aggravation of diabetes mellitus have been reported. Atypical antipsychotics may have effects on glucose metabolism that are independent of their effect on weight gain; one study noted that patients taking atypical agents (e.g., clozapine, olanzapine, quetiapine) were 9% more likely to have a new diagnosis of diabetes mellitus than patients taking older therapies. In one pooled analysis comparing clozapine to chlorpromazine, the mean change in fasting glucose was +11 mg/dL for clozapine and +4 mg/dL for chlorpromazine. A larger percentage of clozapine-treated patients demonstrated the following baseline increases in fasting glucose concentrations compared to chlorpromazine-treated patients: normal to high concentrations (from less than 100 mg/dL to at least 126 mg/dL) (27% vs. 10%) and from borderline to high fasting glucose concentrations (from 100 to 125 mg/dL to at least 126 mg/dL) (42% vs. 28%). Polydipsia was observed during premarketing evaluation of clozapine (less than 1%); hyperglycemia and new onset diabetes have occurred during postmarketing use although the incidences are unknown. Patients with diabetes who are started on clozapine should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with clozapine should undergo fasting blood glucose testing at the beginning of treatment and periodically throughout treatment. The possibility of impaired glucose tolerance should be considered in patients receiving clozapine who develop symptoms of hyperglycemia or diabetes, such as excessive thirst, polyuria, polyphagia, and weakness. In patients with severe treatment-emergent hyperglycemia, discontinuation of clozapine therapy should be considered.
During clinical trials, the following infections and/or respiratory conditions/symptoms were reported in at least 1% of patients receiving clozapine: throat irritation/discomfort (1%), dyspnea (1%), and nasal congestion (1%). Less than 1% of patients during premarketing evaluation of clozapine reported cough, pneumonia, pneumonia-like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, sneezing, malaise, chills, and chills with febrile illness. Events observed postmarketing include aspiration, pleural effusion, sleep apnea, and sepsis. Pneumonia and lower respiratory tract infection have also been reported and, in some instances, may be fatal.
During clinical trials, the following psychiatric effects were reported in at least 1% of patients receiving clozapine: agitation (4%), confusion (3%), depression (1%), and anxiety (1%). Psychiatric effects occurring in less than 1% of patients during pre-marketing evaluation of clozapine include amentia, delusions, hallucinations, amnesia/memory loss, histrionic movements, paranoia, irritability, libido increase, and libido decrease. Psychiatric events observed during post-market use include delirium, exacerbation of psychosis, overdose, and obsessive-compulsive symptoms.
During clinical trials, the following dermatologic effects were reported in at least 1% of patients receiving clozapine: rash (unspecified) (2%) and hyperhidrosis (6%). Dermatologic effects occurring in less than 1% of patients during pre-marketing evaluation of clozapine include pruritus, pallor, atopic dermatitis, erythema, bruise (hematoma), dermatitis, petechiae, urticaria, and hot flashes. Hypersensitivity reactions observed during post-market use include photosensitivity, vasculitis, leukocytoclastic vasculitis, angioedema, erythema multiforme, and Stevens-Johnson syndrome (SJS). Skin pigmentation disorder, resulting in skin hyperpigmentation, has also occurred during post-market use.
During clinical trials, the following musculoskeletal effects were reported in at least 1% of patients receiving clozapine: myasthenia (1%), back pain/neck pain/leg pain (1%), muscle cramps or spasm (1%), and myalgia (1%). Musculoskeletal effects occurring in less than 1% of patients during pre-marketing evaluation of clozapine include twitching and joint pain. Events observed during post-market use include myasthenic syndrome, elevated creatine phosphokinase, lupus-like symptoms consistent with systemic lupus erythematosus, and rhabdomyolysis.
During clinical trials, visual impairment (unspecified) was reported in 5% of patients receiving clozapine. Adverse reactions involving special senses which occurred in less than 1% of patients during pre-marketing evaluation of clozapine include mydriasis, ear disorder (unspecified), eyelid disorder (unspecified), bloodshot eyes (conjunctival hyperemia), and nystagmus. Narrow-angle glaucoma (ocular hypertension) has been reported during post-market use.
General effects not listed elsewhere that have been observed during postmarketing use of clozapine include hyperuricemia.
During clinical trials, the following changes in appetite and weight were reported in at least 1% of patients receiving clozapine: anorexia (1%) and weight gain (4%). Appetite stimulation was reported in less than 1% of patients. Weight loss has occurred during post-marketing use. In a pooled analysis with active comparators, weight gain of at least 7% of body weight from baseline was reported in 35% of patients receiving clozapine for a mean duration of 609 days, 46% of patients receiving olanzapine for a mean duration of 728 days, and 8% of patients receiving chlorpromazine for a mean duration of 42 days.
Abrupt discontinuation of clozapine is not recommended, unless required by the patient's medical condition (e.g., leukopenia). If abrupt discontinuation is necessary, the patient should be carefully observed for the recurrence of psychotic symptoms or withdrawal symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting or diarrhea.
Thirst and polydipsia have occurred during treatment with antipsychotics. Polydipsia may be psychogenic in nature or a result of antipsychotic-induced metabolic complications such as diabetes; therefore, careful evaluation is recommended. Hyponatremia can develop from polydipsia which can progress to water intoxication, with symptoms such as confusion, lethargy, psychosis, and in severe cases, seizures or death. Some data suggest that antipsychotic-induced hyponatremia is most likely the result of syndrome of inappropriate antidiuretic hormone (SIADH). Hyponatremia has been reported during postmarketing use of clozapine.
Severe, life-threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported during postmarketing use of clozapine. Patients should be monitored for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, hyperbilirubinemia, coagulopathy, and hepatic encephalopathy; permanent discontinuation of treatment should be considered if hepatitis or elevated hepatic enzymes combined with other systemic symptoms are due to clozapine. Other hepatobiliary effects reported during postmarketing use include cholestasis, jaundice, hepatic steatosis, hepatic fibrosis, hepatic cirrhosis, mixed liver injury, and acute pancreatitis. During clinical trials, elevated hepatic enzymes were reported in 1% of patients.
During clozapine therapy, patients have experienced transient, clozapine-related fever. During clinical trials fever was reported in 5% of treated patients. The peak incidence of clozapine-related fever is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. Carefully evaluate patients with fever to rule out severe neutropenia, infection, or other serious conditions. Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving clozapine should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Hypothermia was reported in less than 1% of patients during premarket evaluation of clozapine. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during the initiation of antipsychotic therapy or after dose increases.
Clozapine is contraindicated for use in patients with a previous hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of the product. Eosinophilia, defined as a blood eosinophil count of greater than 700/microL, has also occurred with clozapine treatment. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with organ involvements such as cardiac. pancreatic, hepatic, renal, and colon inflammation. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). If eosinophilia develops during clozapine treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, and organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue clozapine immediately. If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, being infected with a parasite, and specific neoplasms), treat the underlying cause and continue clozapine. Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue clozapine under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt clozapine therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.
Clozapine is available only through a restricted program called the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program. All prescribers of clozapine, prescriber designees, and dispensing pharmacies must be certified in the Clozapine REMS program. Because clozapine can cause severe neutropenia (agranulocytosis), which can lead to infection and death, there is a minimum baseline neutrophil count required to initiate therapy and all patients receiving clozapine must be enrolled by the prescriber or the prescriber's designee in the clozapine REMS program. More information, including enrollment and certification requirements for providers and pharmacies, is available at: https://www.clozapinerems.com. To improve and standardize understanding, severe neutropenia replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis in the clozapine product labels. The ANC is the only test result accepted in the Clozapine REMS Program to monitor for neutropenia. The mechanism by which clozapine causes neutropenia is not known, and it is not dose-dependent. Clozapine dose cannot be used as a reliable indicator for severe neutropenia risk. The risk of neutropenia generally appears greatest during the first 18 weeks and then declines, but may occur at any time. Conditions that may mcL or more before treatment can be initiated. Weekly ANC monitoring is required for all patients during the first 6 months of treatment, with modifications made to the ANC monitoring requirements after that for each individual based on clinical status, BEN status, and previous laboratory results, as outlined in the Clozapine REMS program. Treatment exclusions occur when the absolute neutrophil count (ANC) falls below the required minimum ANC as outlined in the monitoring requirements. In general, patients who develop severe neutropenia (ANC less than 500/mcL) with clozapine should not be re-challenged, unless the prescriber determines that the benefit outweighs the risks. The prescriber must take into account the recommended ANC thresholds, the patient's medical/psychiatric history, the severity of the neutropenic episode, and should discuss the benefits and risks of clozapine re-challenge with the patient or his/her caregiver. Patients should report the appearance of fever, sore throat, lethargy, weakness, or other signs of bone marrow suppression or infection to their health care provider immediately. Risk factors for developing severe neutropenia from clozapine therapy, other than initial bone marrow suppression, are not known. Patients with a Jewish background, those undergoing the first 4 to 10 weeks of drug therapy, female sex, older patients, cachectic patients, or those with serious underlying medical illness may theoretically be at greater risk for severe neutropenia, but definitive data are not available. It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., chemotherapy) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased ANC monitoring and consult the treating hematologist/oncologist.
Clozapine can cause somnolence, CNS depression, and impairment of cognitive and motor performance; these reactions may be particularly evident during treatment initiation and following dosage increases. Clozapine-induced somnolence may be dose-related; a dose reduction may be required in some cases. Somnolence could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions or diseases that could exacerbate somnolence, including coadministration with other CNS depressants or ethanol ingestion. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Patients should be cautioned about driving or operating machinery or performing other tasks requiring mental alertness until they know how clozapine affects them.
Clozapine should be used cautiously in patients with a history of seizure disorder or those with risk factors that may predispose them to seizures (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Clozapine lowers the seizure threshold in a dose-dependent manner, particularly at doses greater than 600 mg/day. Dosage increases in patients with a pre-existing seizure disorder should be cautious. Clozapine may induce EEG changes, myoclonic jerks or generalized seizures. Because of the substantial risk of seizure associated with clozapine use, patients should be cautioned about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving, operating complex machinery, swimming, climbing). Clozapine may potentially decrease the effectiveness of anticonvulsants in the treatment of seizure disorders. Additionally, anticonvulsants that are inducers of CYP3A4 or CYP1A2 may reduce the efficacy of clozapine, which is a substrate of CYP3A4 and CYP1A2. If seizures occur, the clozapine dosage should be reduced or discontinued, and, if necessary, anticonvulsant treatment initiated.
Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics. Regular evaluation for movement disorders is recommended (e.g., AIMS, DISCUS). Factors associated with a greater susceptibility to tardive dyskinesia include an age above 55 years, female gender, white or African ethnicity, presence of a mood disorder, intellectual disability, CNS injury, prior or current akathisia, significant parkinsonism, or acute dystonic reaction. The rate of tardive dyskinesia in adults treated with a first generation antipsychotic appears to be at least 3 times that observed with second generation antipsychotics. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotics administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may arise after drug discontinuation. Antipsychotics may suppress the signs and symptoms of tardive dyskinesia and thereby mask the underlying process; however, the syndrome may also remit partially or completely if the antipsychotic is withdrawn. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. If signs and symptoms of tardive dyskinesia appear, clozapine discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
ECG repolarization changes and serious cardiac events, such as QT prolongation, ventricular arrhythmias, torsade de pointes (TdP), cardiac arrest, and sudden death, have been reported with clozapine. Clozapine should be used cautiously in patients with conditions that may increase the risk of QT prolongation, such as congenital long QT syndrome, bradycardia, AV block, heart failure, myocardial infarction, cerebrovascular accident, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications that prolong the QT interval or cause electrolyte imbalances. Other risk factors for QT prolongation may include females, patients age 65 years and older, sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis). ECG should be obtained prior to starting treatment and monitored periodically for changes; treatment should be discontinued if the QT interval measurement exceeds 500 milliseconds. Electrolytes (such as potassium and magnesium) should also be assessed at baseline and any imbalances should be corrected prior to initiating treatment. Orthostatic hypotension, syncope, and cardiac arrest have occurred during clozapine treatment and are consistent with neurally mediated reflex bradycardia. The risk of these serious cardiac effects is highest during the initial titration period and particularly with rapid titration. These effects can also occur with the first dose, with low doses, or in patients who are restarting treatment after a brief interruption in treatment. It is imperative that the manufacturer dosing titration guidelines are followed carefully to minimize the risk of serious cardiac effects. Orthostatic hypotension could also lead to falls with the potential for fractures and other injuries. Complete a fall risk assessment upon antipsychotic initiation in patients with conditions, diseases, or taking concurrent medications that could exacerbate orthostasis and recurrently during long-term therapy in at-risk patients. Use clozapine cautiously in patients with cardiac disease (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities), cerebrovascular disease, or other conditions that could provoke hypotension (e.g., concurrent use of antihypertensives, dehydrated state, or hypovolemia). Prescribers should carefully evaluate symptoms of dizziness, syncope, or palpitations to determine if these are clozapine-related or due to underlying cardiac disease.
Cardiomyopathy or myocarditis, sometimes fatal, has occurred during clozapine use. Stress-related cardiomyopathy may increase the risk of clozapine associated QT prolongation. Discontinue clozapine and obtain a cardiac evaluation if either cardiomyopathy or myocarditis are suspected. Myocarditis most frequently presents within the first 2 months of treatment and cardiomyopathy symptoms usually occur after 8 weeks of treatment. Cardiomyopathy or myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or ECG findings such as ST-T wave abnormalities or cardiac arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. In patients who are diagnosed with cardiomyopathy while taking clozapine, mitral valve incompetence has been reported. These cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography. In patients with suspected cardiomyopathy, consider a 2D-echo Doppler exam to identify mitral valve incompetence. Tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis as, while tachycardia may occur secondary to hypotension, it has been noted as a presenting sign in patients with myocarditis. In general, patients with clozapine-related myocarditis or cardiomyopathy should not be re-challenged with clozapine. However, if the benefit of treatment with clozapine is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, rechallenge with clozapine may be considered in consultation with a cardiologist, after a complete cardiac evaluation, and with close monitoring.
Use clozapine with caution in patients with a history of thromboembolism or thromboembolic disease. Pulmonary embolism and deep-vein thrombosis (DVT) have occurred in patients treated with clozapine. Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and DVT can be attributed to clozapine or some characteristic(s) of patients is not clear.
Patients with significant hepatic disease or impairment may require a clozapine dosage reduction, as increased drug exposure is likely with usual doses. Dose reduction may also be necessary for CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients because clozapine is almost completely metabolized and then excreted. Clozapine may cause hepatotoxicity. Severe, life-threatening, and in some cases fatal liver injury, including hepatic failure, hepatic necrosis, and hepatitis, have been reported. Monitor for signs and symptoms of hepatotoxicity (e.g., fatigue, malaise, anorexia, nausea, jaundice, hyperbilirubinemia, coagulopathy, hepatic encephalopathy) and perform liver function tests (LFTs) if hepatotoxicity is suspected. Consider permanent treatment discontinuation if the cause of the liver injury is due to clozapine.
Dose reduction may be necessary in patients with significant renal impairment; use particular caution in patients with renal failure. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted.
Clozapine exhibits potent anticholinergic effects, which can result in central or peripheral anticholinergic toxicity. Because of this, clozapine commonly causes constipation. Less common but more severe gastrointestinal (GI) reactions include fecal impaction, megacolon, GI obstruction, ischemia, infarction, GI perforation, paralytic ileus, ulceration, or necrosis. Such reactions can lead to hospitalization, surgery, or death if they are not diagnosed and treated quickly. Evaluate bowel function before treatment initiation. Consider prophylactic laxative treatment in patients with a history of constipation or bowel obstruction. Monitor for symptoms consistent with GI hypomotility such as nausea, abdominal distention or pain, and vomiting, and inquire about the frequency and quality of bowel movements throughout treatment. Avoid concurrent use of clozapine with other anticholinergic medications that can cause GI hypomotility. Advise patients frequently about the significant risk of constipation and potentially fatal bowel complications that can occur while taking clozapine and the need to stay hydrated. Advise patients to contact their health care provider immediately if they experience constipation or develop other signs and symptoms of GI hypomotility. Also, use clozapine with caution in patients that have other conditions that may be exacerbated by anticholinergic activity, including closed-angle glaucoma, prostatic hypertrophy, urinary retention, or other conditions in which anticholinergic effects can lead to significant adverse reactions.
Antipsychotics can cause motor and sensory instability, which may lead to falls with the potential for fractures and other injuries. Complete a fall risk assessment upon antipsychotic initiation in patients with conditions, diseases (e.g., neurological disease), or taking concurrent medications that could exacerbate motor and sensory instability and recurrently during long-term therapy in at-risk patients. In general, antipsychotics should be avoided in patients with Parkinson's disease due to the potential for dopamine antagonists to exacerbate the symptoms of Parkinson's disease. Although clozapine appears less likely to precipitate worsening of Parkinson's disease than most other antipsychotics, caution and close monitoring are recommended.
Antipsychotics have been associated with esophageal dysmotility and aspiration of gastric contents, which may increase the incidence of aspiration pneumonia in certain patient populations, such as patients with advanced Alzheimer's disease. Dysphagia and aspiration have been reported during postmarketing use of clozapine. Aspiration pneumonia has occurred in the setting of clozapine overdose. Patients with dysphagia or who are at risk for aspiration pneumonia should be closely monitored while receiving clozapine.
Atypical antipsychotics, including clozapine, have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk over time, including loss of blood glucose control, dyslipidemia, and weight gain. Monitoring of weight and evaluation of lipids at baseline and periodically throughout treatment are recommended. Patients with risk factors for diabetes mellitus (e.g., obesity, pre-diabetes, family history) should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Treatment with clozapine should be undertaken with caution in patients with pre-existing conditions such as obesity, pre-diabetes, or hyperlipidemia (e.g., hypercholesterolemia or hypertriglyceridemia). Hyperglycemia and diabetes mellitus, in some cases associated with diabetic ketoacidosis, hyperosmolar hyperglycemic state (HHS) with coma or death, have been reported in patients treated with atypical antipsychotics including clozapine. Epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics, although precise risk estimates are not available. An increased risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus, in general, complicates this concern. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, weakness). Patients with established diabetes mellitus should be monitored regularly for worsening of glucose control. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing. In some cases, hyperglycemia had resolved when the antipsychotic was discontinued; however, some patients required continuation of the anti-diabetic medication(s) despite discontinuation of the suspect drug.
During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. Carefully evaluate patients with fever to rule out severe neutropenia, infection, or other serious conditions. Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving clozapine should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration).
Tobacco smoking may increase the clearance of clozapine, resulting in reduced plasma concentrations and the potential loss of efficacy. Tobacco smokers may require higher clozapine doses. Tobacco smoke contains hydrocarbons that moderately induce CYP1A2, one of the isoenzymes responsible for clozapine metabolism. The effect on CYP1A2 is not related to the nicotine component of tobacco, and sudden smoking cessation may result in a reduced clozapine clearance, despite nicotine replacement. Monitor patients carefully when changes in smoking status occur.
Abrupt discontinuation of clozapine is not recommended (due to the potential for cholinergic rebound and recurrence of psychotic symptoms) unless required by the patient's medical condition (e.g., moderate to severe neutropenia). Otherwise, discontinuation should occur through a gradual dose reduction over 1 to 2 weeks. Carefully observe patients for the recurrence of psychotic symptoms or cholinergic rebound (e.g., headache, nausea, vomiting, diarrhea) during drug discontinuation. For abrupt clozapine discontinuation unrelated to neutropenia, continuation of the existing absolute neutrophil count (ANC) monitoring is recommended for general population patients until their ANC is 1,500/microL or higher and for benign ethnic neutropenia (BEN) patients until their ANC is at least 1,000/microL or above their baseline. For abrupt discontinuation due to moderate to severe neutropenia, obtain ANCs as specified in the ANC monitoring section of the product labeling. Patients who are eligible to restart clozapine and have missed 2 or more days of medication should undergo titration according to the manufacturer's dosing titration guidelines to minimize the risk of serious and potentially fatal cardiac effects, such as orthostatic hypotension, syncope, and cardiac arrest.
Geriatric adults may be more susceptible to the side effects of clozapine, including orthostatic hypotension, tachycardia, tardive dyskinesia, and anticholinergic effects. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric adults; avoid use of clozapine if possible due to an increase in morbidity and mortality in elderly patients with dementia receiving antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections (primarily pneumonia). An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. A low starting dose with careful titration is recommended for the geriatric adult if clozapine is used. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in geriatric adults and use should be avoided except for treating schizophrenia, bipolar disorder, or as part of antiemetic regimens during chemotherapy. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary in those with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk reduction strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored at initiation and after dose changes. The U.S. Omnibus Budget Reconciliation Act (OBRA) regulates antipsychotic use in residents of long-term care facilities (LTCFs) and use must be supported by an appropriate clinical indication that is thoroughly documented within the medical record. When used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the antipsychotic as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. Indications, dosages, and the duration of antipsychotic treatment in the geriatric adult should be in accordance with prescribing labels, published literature recommendations, and expert guidelines. "As needed" (PRN) use for acute behavioral/medical situations in the LTCF must be limited to 14 days, and any use beyond this duration requires that the attending physician/prescribing practitioner evaluate the patient prior to continued use.
There are no adequate trials of the effect of clozapine in human pregnancy. Animal studies have produced no evidence of adverse fetal effects; however, the use of clozapine during pregnancy should be undertaken only when needed because animal data may not be indicative of a human response. Clozapine is known to have serious adverse effects that may compromise maternal health and influence pregnancy status. Neonatal effects have been reported with the use of antipsychotics during pregnancy. Extrapyramidal symptoms and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates exposed to antipsychotics during the third trimester of pregnancy. These complications have varied in severity, with some neonates recovered within hours or days without specific treatment and others requiring prolonged hospitalization. Monitor neonates for extrapyramidal and withdrawal symptoms and manage symptoms appropriately. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotics and requires further investigation. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential before initiation of an antipsychotic. It is not known if antipsychotics, through their effect on prolactin, would affect labor or obstetric delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to clozapine; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry or by calling 1-866-961-2388.
A decision should be made whether to discontinue breast-feeding or to discontinue clozapine, taking into account the importance of the drug to the mother. Anecdotal evidence suggests that clozapine accumulates in human breast milk. An antipsychotic agent other than clozapine would be preferred due to the possibility of clozapine-induced agranulocytosis or other adverse events in the nursing infant; guidelines support that lactating women taking clozapine should not breastfeed. Although elevations in prolactin associated with clozapine are minimal relative to many other antipsychotics, interference with proper lactation is possible. Alternate medications for consideration during breast-feeding include atypical antipsychotic agents such as olanzapine or quetiapine. Data related to the safety of antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events.
The safety and efficacy of clozapine use in children and adolescents have not been established. Limited data on the use of clozapine for resistant schizophrenia exists for children older than 9 years of age. Due to the potential for serious adverse effects, including agranulocytosis, only consider clozapine use in children who are refractory to other antipsychotic medications. Routine cardiovascular monitoring has been suggested for children receiving psychotropic medications due to the potential of these agents to produce adverse cardiac effects. There is no known use of clozapine in infants. Additionally, adverse effects have been reported after delivery in newborns exposed to antipsychotics during the third trimester and some cases have included intensive care unit stays and prolonged hospitalization.
Oral disintegrating clozapine tablets (e.g., FazaClo) may contain aspartame and should be used cautiously in patients with phenylketonuria. Phenylalanine is a component of aspartame. Each 25 mg orally disintegrating tablet of FazaClo contains 3.1 mg of aspartame (1.74 mg of phenylalanine), and each 100 mg oral disintegrating tablet of FazaClo contains 12.4 mg of aspartame (6.96 mg of phenylalanine).
For the treatment of refractory schizophrenia that has failed to respond adequately to appropriate courses of standard antipsychotic agents; also to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder:
All patients receiving clozapine must be enrolled in the Clozapine REMS program by the prescriber.
Oral dosage:
Adults: 12.5 mg PO once or twice daily on the first day. Then, may titrate by 25 to 50 mg/day over 2 weeks, if well tolerated, to a dose of 300 to 450 mg/day PO, given in divided doses. Then, titrate no more than once or twice weekly, in increments of no more than 100 mg, to efficacy and tolerability. Proper titration and divided dosing minimizes the risk of orthostatic hypotension, bradycardia, and syncope. Max: 900 mg/day PO. Doses more than 600 mg/day and rapid dose escalation may increase risk for seizures or other side effects. Due to the potentially serious side effects, avoid extended use in those failing to show an acceptable level of clinical response. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions. Debilitated or older adults and CYP2D6 poor metabolizers may need reduced dosages. DISCONTINUATION: Use gradual reduction over 1 to 2 weeks unless clinical circumstances (e.g., neutropenia) require abrupt discontinuation. If abruptly discontinued, monitor for recurrence of psychosis or cholinergic rebound (e.g., headache, nausea, vomiting, diarrhea). RE-INITIATION OF HELD TREATMENT: If 1 day's dosing has been missed, resume treatment at 40% to 50% of the established dosage. If 2 days have been missed, resume at approximately 25% of the established dosage. For longer interruptions, re-initiate with 12.5 mg once or twice daily. If these dosages are well tolerated, the dosage may be increased to the previous dose more quickly than recommended for initial treatment.
Children* and Adolescents* 9 years and older: Safety and efficacy have not been established; limited data for off-label use reported. One study used 6.25 to 12.5 mg PO per day initially; mean effective dosages after titration were 200 to 300 mg/day PO, given in divided doses. Slowly titrate due to risk for hypotension, bradycardia or syncope. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. CYP2D6 poor metabolizers may need reduced dosage. DISCONTINUATION: Gradually reduce over 1 to 2 weeks unless clinical circumstances (e.g., neutropenia) require abrupt discontinuation. If abruptly discontinued, monitor for recurrence of psychosis or cholinergic rebound. RE-INITIATION OF HELD TREATMENT: If 1 day's dosing has been missed, resume treatment at 40% to 50% of the established dosage. If 2 days dosing has been missed, resume at approximately 25% of the established dosage. For longer interruptions, re-initiate with suggested initial doses and follow the recommended titration thereafter.
For the treatment of bipolar disorder*:
Oral dosage:
Adults: Limited data are available describing the use of clozapine in the initial management of acute bipolar disorder; data are from studies in non-elderly adults. In one review, the mean dose of clozapine after titration at follow-up was 325.6 +/- 161.9 mg/day in 21 patients with bipolar disorder. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. It may be necessary to reduce the dose in poor metabolizers of CYP2D6 (CYP2D6 PMs). Clozapine has been evaluated as treatment in refractory bipolar I disorder. A small, 3-week, open label trial (n = 27) compared the effectiveness of clozapine (mean dose 166 mg/day) to chlorpromazine (mean dose 310 mg/day); both agents were in combination with lithium for treatment of refractory bipolar mania. At 2 weeks, reduction YMRS scores (Young Mania Rating Scale) were significantly lower in the clozapine group, indicating a more rapid response to clozapine, but at 3 weeks no difference was noted in YMRS. As add-on treatment in a 12-month study, clozapine was effective for mood stabilization at a mean doses of 156 +/- 77 mg/day. Overall, depressive symptoms were not improved. Clozapine has been shown to be effective in a 12-month study as maintenance therapy for patients refractory to combined conventional mood stabilizers (e.g., lithium, divalproex, carbamazepine). Thirty-nine patients were randomly assigned to adjunctive clozapine (mean dose 234 mg/day PO; range 50 to 403 mg/day PO) or treatment as usual. No significant effect was noted on depression scores.
For the treatment of refractory, severe behavioral or psychological symptoms of dementia* (BPSD)*, particularly in patients with Parkinson's disease psychosis* or dementia with Lewy bodies*:
NOTE: Due to concerns of agranulocytosis and other potential adverse effects, clozapine is often reserved for use in patients refractory to other available treatments.
Oral dosage:
Adults: 6.25 mg at bedtime, initially. Then, may slowly titrate by 12.5 mg twice a week up to 50 mg/day, if needed. Use the lowest effective dosage. May further titrate by 12.5 mg twice a week if the 50 mg dose is not effective. Mean effective range: 50 to 72 mg/day per published studies; a few patients have required up to 100 mg/day. Clozapine, along with quetiapine, has been an alternative choice for BPSD due to Parkinson's disease psychosis or Lewy Body dementia due to better tolerance vs. other atypical antipsychotics in these patients, and is approved for these indications in some countries outside the U.S. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions and CYP2D6 metabolizer status.
Therapeutic Drug Monitoring:
General Information
-Because of the risk of severe neutropenia, all patients receiving clozapine must be enrolled in the Clozapine REMS Program, and all prescribers and dispensing pharmacies of clozapine are required to be certified in the Clozapine REMS Program. The requirements to monitor, prescribe, dispense, and receive all clozapine medications are incorporated into the Clozapine REMS Program. Only prescribers or their designated agents may enroll patients into the REMS program.
-The absolute neutrophil count (ANC) is the only test result accepted in the Clozapine REMS Program to monitor for neutropenia. In order to dispense clozapine, the certified pharmacy should establish processes and procedures to verify the patient's ANC is in the acceptable range according to the clozapine prescribing information and aligned with the patient's ANC monitoring frequency or that the prescriber has authorized the continuation of clozapine treatment for patients with an ANC that falls below the acceptable range when the prescriber determines the benefits exceed the risks of developing severe neutropenia. More information is available at https://www.clozapinerems.com.
-It is generally recommended not to combine clozapine with other antipsychotics. If clozapine is initiated in a patient currently receiving another antipsychotic, it is recommended that the dose of the other antipsychotic be decreased or discontinued by a gradual taper. The prescriber should decide whether to discontinue the other antipsychotic before initiating treatment with clozapine.
Frequency of monitoring based on the stage of therapy, symptoms, or results from ANC counts:
-Initiation of therapy: A complete blood count (CBC), including the ANC value, should be obtained before initiating treatment with clozapine to ensure a normal baseline neutrophil count (ANC) of at least 1,500/mcL for the general population (i.e., non-Benign Ethnic Neutropenia patients). Patients with documented Benign Ethnic Neutropenia (BEN) must have at least 2 baseline ANC levels of at least 1,000/mcL before treatment can be initiated. Weekly ANC monitoring is required for all patients during the first 6 months of treatment. If the ANC remains at least 1,500/mcL for the first 6 months of treatment in the general population or at least 1,000/mcL for BEN patients, monitoring frequency may be reduced to every 2 weeks for the next six months. If the ANC remains at 1,500/mcL or greater in the general population or at least 1,000/mcL for BEN patients for the second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once every 4 weeks after that.
-Monitoring if neutropenia occurs during treatment:-Mild neutropenia: If mild neutropenia (ANC 1,000 to 1,499/mcL) develops during clozapine treatment in the general population, continue treatment and obtain an ANC 3 times weekly until the ANC is 1,500/mcL or greater, then return to the patient's last "normal range" ANC monitoring interval if clinically appropriate.
-Moderate neutropenia: For moderate neutropenia (ANC 500 to 999/mcL) during clozapine treatment in the general population, recommend hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. Obtain ANC values daily until the ANC is at least 1,000/mcL, then resume treatment and check the ANC 3 times weekly until the ANC reaches 1,500/mcL or more. Then, measure the ANC weekly for 4 weeks, with a subsequent return to the patient's last "normal range" ANC monitoring interval if clinically appropriate. For BEN neutropenia (ANC 500 to 999/mcL), obtain a hematology consult and continue treatment. Obtain an ANC 3 times weekly until the ANC is 1,000/mcL or greater, or is at least at the patient's baseline. Then, the ANC should be checked weekly for 4 weeks, with a subsequent return to patient's last "normal BEN range" ANC monitoring interval if clinically appropriate.
-Severe neutropenia: For severe neutropenia (ANC less than 500/mcL) during clozapine treatment in the general population, recommend a hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. Obtain ANC values daily until the ANC is at least 1,000/mcL, then 3 times weekly until the ANC is 1,500/mcL or greater. If a general population patient is re-challenged after having severe neutropenia, resume treatment as a new patient under "normal range" monitoring when the ANC is at least 1,500/mcL. In BEN severe neutropenia (ANC less than 500/mcL), obtain hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. The ANC should be checked daily until the ANC is 500/mcL or more, then 3 times weekly until the ANC is at least to the patient's baseline. If a BEN patient is re-challenged after having severe neutropenia, resume treatment as a new patient under "normal range" monitoring once the ANC is at least 1,000/mcL or at the patient's baseline.
-Treatment interruption or discontinuation: When the ANC is within the normal range and treatment is interrupted for less than 30 days, continue monitoring as before; if treatment is interrupted for 30 days or more, monitor as if a new patient. For abrupt treatment discontinuation for a reason unrelated to neutropenia, the continuation of the existing ANC monitoring is recommended for general population patients until their ANC is 1,500/mcL or more, and for BEN patients until their ANC is at least 1,000/mcL or is above their baseline.
-Fever or Infection: Interrupt clozapine as a precaution in any patient who develops a fever of at least 38.5 degrees C (101.3 degrees F) and obtain an ANC; assess for neutropenia, and continue to monitor the fever, and for other conditions associated with fever (e.g., neuroleptic malignant syndrome). If fever occurs in any patient with an ANC less than 1,000/mcL, initiate appropriate workup and treatment for infection, refer to the manufacturer's guidelines for ANC monitoring, and consider hematology consult. Patients should report the appearance of fever, sore throat, lethargy, weakness, or other signs of bone marrow suppression or infection to their health care provider immediately.
Maximum Dosage Limits:
-Adults
900 mg/day PO.
-Geriatric
900 mg/day PO.
-Adolescents
Safety and efficacy have not been established; however, doses up to 300 mg/day PO have been reported for the treatment of refractory schizophrenia off-label.
-Children
9 to 12 years: Safety and efficacy have not been established; however, doses up to 300 mg/day PO have been reported for the treatment of refractory schizophrenia off-label.
Less than 9 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Use clozapine with caution in patients with hepatic disease. Modify dosage depending on clinical response and degree of hepatic impairment. If a patient develops signs or symptoms of liver problems during treatment, liver function tests (LFTs) should be measured. If LFTs are significantly elevated or if jaundice is present, treatment should be discontinued.
Patients with Renal Impairment Dosing
It may be necessary to reduce the dose of clozapine in patients with significant renal impairment; however, quantitative guidelines for adjustments are not available.
Intermittent hemodialysis
Hemodialysis, forced diuresis, hemoperfusion, or other methods are unlikely to be of benefit in clozapine removal.
*non-FDA-approved indication
Abiraterone: (Moderate) Monitor for an increase in clozapine-related adverse reactions if coadministration with abiraterone is necessary; consider reducing the dose of clozapine if clinically appropriate. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. If abiraterone is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Clozapine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor.
Acarbose: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Acebutolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
Acetaminophen; Caffeine; Pyrilamine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Chlorpheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Diphenhydramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, this drug combination may result in additive effects on intestinal motility or bladder function. Prior to concurrent use of oxycodone in patients taking clozapine, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower clozapine dose. Monitor patients for sedation and respiratory depression.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Acetazolamide: (Moderate) Caution is advisable during concurrent use of clozapine and acetazolamide as electrolyte imbalance caused by diuretics may increase the risk of QT prolongation with clozapine.
Acyclovir: (Moderate) Consider a clozapine dose reduction if coadministered with acyclovir and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate; acyclovir is a weak CYP1A2 inhibitor.
Adagrasib: (Major) Avoid concomitant use of adagrasib and clozapine due to the potential for increased clozapine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for clozapine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clozapine is a CYP3A and CYP2D6 substrate, adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation.
Ado-Trastuzumab emtansine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Alemtuzumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Alfentanil: (Moderate) Concomitant use of alfentanil with other CNS depressants, including clozapine, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. Combining alfentanil with clozapine may also lead to additive effects on intestinal motility or bladder function. A dose reduction of one or both drugs may be warranted.
Alfuzosin: (Moderate) Use caution when administering alfuzosin with clozapine due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. Treatment with clozapine has been associated with QT prolongation, torsade de pointes, cardiac arrest, and sudden death.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine.
Allopurinol: (Moderate) Consider a clozapine dose reduction if coadministered with allopurinol and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate; allopurinol is a weak CYP1A2 inhibitor.
Alogliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alogliptin; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like clozapine, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
Alpha-glucosidase Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alprazolam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Amantadine: (Moderate) Medications with significant anticholinergic activity, such as clozapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
Amifampridine: (Major) Carefully consider the need for concomitant treatment with atypical antipsychotics and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Atypical antipsychotics may increase the risk of seizures.
Amiloride: (Moderate) Monitor blood pressure and adjust amiloride dose accordingly as clozapine may enhance the hypotensive effects of antihypertensive agents.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Monitor blood pressure and adjust amiloride dose accordingly as clozapine may enhance the hypotensive effects of antihypertensive agents.
Amiodarone: (Major) Concomitant use of amiodarone and clozapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase clozapine exposure and the risk for clozapine-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider a clozapine dose reduction and take steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Clozapine is a CYP3A, CYP2D6, and CYP1A2 substrate; amiodarone is a weak CYP3A, CYP2D6, and CYP1A2 inhibitor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with clozapine. Amisulpride causes dose- and concentration- dependent QT prolongation. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Amitriptyline: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Amlodipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Amlodipine; Atorvastatin: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Amlodipine; Benazepril: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Amlodipine; Celecoxib: (Moderate) A dosage adjustment may be warranted for clozapine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of clozapine. Celecoxib is a CYP2D6 inhibitor, and clozapine is a CYP2D6 substrate. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Amlodipine; Olmesartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Amlodipine; Valsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Amobarbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Amoxapine: (Moderate) Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when clozapine is given concurrently. In addition, additive anticholinergic effects and sedation are possible, as well as lowering of the seizure threshold.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Anagrelide: (Moderate) Caution is advisable during concurrent use of anagrelide and clozapine. Anagrelide is an inhibitor of CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor to clozapine treatment, monitor for adverse reactions and consider reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Angiotensin II receptor antagonists: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Angiotensin-converting enzyme inhibitors: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Anticholinergics: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Antimetabolites: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Apalutamide: (Major) Coadministration of clozapine with apalutamide is not recommended due to decreased plasma concentrations of clozapine. If concomitant use is unavoidable, the patient should be monitored for loss of efficacy; consider increasing the clozapine dose if necessary. When apalutamide is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
Apomorphine: (Moderate) Coadministration of apomorphine and clozapine may increase the risk for QT prolongation or sedation. Apomorphine and clozapine may decrease the effectiveness of each other due to opposing effects on dopamine. Additive CNS effects are also possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. In general, atypical antipsychotics are less likely to interfere with Parkinson's disease treatments than traditional antipsychotics. Monitor for movement disorders, unusual changes in moods or behavior, sedation, fast, irregular heartbeat, and diminished effectiveness of either agent if coadministration cannot be avoided.
Aprepitant, Fosaprepitant: (Major) Use caution if clozapine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in clozapine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Clozapine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of clozapine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Clozapine is an atypical antipsychotic with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with aripiprazole. In addition, caution is advisable when aripiprazole is given in combination with other CNS depressants such as other atypical antipsychotics. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.
Armodafinil: (Moderate) Caution is advisable during concurrent use of modafinil or armodafinil with clozapine. Modanil and armodafinil have potential to induce CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Patients receiving clozapine in combination with a CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. An interaction between modafinil and clozapine has been reported in a case report that resulted in clinical side effects. After the addition of modafinil to the drug regimen of a patient stabilized on clozapine, the patient became symptomatic with dizziness, problems with gait, and sinus tachycardia. Clozapine serum concentrations were found to be elevated. All symptoms resolved and the patient's clozapine levels returned to normal on modafinil discontinuation. The mechanism of the interaction is unclear, but may be related to changes in clozapine metabolism by modafinil. Concomitant therapy of modafinil and clozapine should be approached with close monitoring of the patient's clinical status.
Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include clozapine. In addition, it is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and clozapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased clozapine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as clozapine, should be avoided. Consider ECG monitoring if clozapine must be used with or after artemether; lumefantrine treatment.
Articaine; Epinephrine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
Asciminib: (Moderate) Consider a clozapine dose reduction if coadministered with asciminib and monitor for adverse reactions. If asciminib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Asciminib is a weak CYP3A inhibitor.
Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Coadministration of asenapine with clozapine may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Aspirin, ASA; Butalbital; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Aspirin, ASA; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like clozapine and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
Aspirin, ASA; Omeprazole: (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, this drug combination may result in additive effects on intestinal motility or bladder function. Prior to concurrent use of oxycodone in patients taking clozapine, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower clozapine dose. Monitor patients for sedation and respiratory depression.
Atazanavir: (Moderate) Caution is advisable during concurrent use of atazanavir and clozapine. Atazanavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Atazanavir; Cobicistat: (Moderate) Caution is advisable during concurrent use of atazanavir and clozapine. Atazanavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Atenolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Atenolol; Chlorthalidone: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Atropine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Atropine; Difenoxin: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Diphenoxylate decreases GI motility. Other drugs that also decrease GI motility, such as clozapine, may produce additive effects with diphenoxylate if used concomitantly.
Avacopan: (Moderate) Consider a clozapine dose reduction if coadministered with avacopan and monitor for adverse reactions. If avacopan is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A; avacopan is a weak CYP3A inhibitor.
Azilsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Azilsartan; Chlorthalidone: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Azithromycin: (Major) Avoid coadministration of azithromycin with clozapine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Baclofen: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with clozapine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Belinostat: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Belladonna; Opium: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Pain medications such as opiate agonists, should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
Belumosudil: (Moderate) Consider a clozapine dose reduction if coadministered with belumosudil and monitor for adverse reactions. If belumosudil is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Belumosudil is a weak CYP3A inhibitor.
Belzutifan: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with belzutifan. Consideration should be given to increasing the clozapine dose if necessary. When belzutifan is discontinued, reduce the clozapine dose based on clinical response. Belzutifan is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Benazepril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Bendamustine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with clozapine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with clozapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking clozapine, reduce initial dosage and titrate to clinical response. If clozapine is initiated a patient taking an opioid agonist, use a lower initial dose of clozapine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benzodiazepines: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Benztropine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Berotralstat: (Moderate) Consider a clozapine dose reduction if coadministered with berotralstat and monitor for adverse reactions. If berotralstat is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP2D6 and CYP3A substrate and berotralstat is a moderate CYP2D6 and moderate CYP3A inhibitor.
Beta-adrenergic blockers: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Betaxolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Bethanechol: (Moderate) Drugs that possess antimuscarinic properties, such as clozapine, are pharmacologic opposites of bethanechol. These agents should not be used with bethanechol except when the specific intent is to counteract excessive actions of one or the other.
Bexagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Bexarotene: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Bicalutamide: (Moderate) Consider a clozapine dose reduction if coadministered with bicalutamide and monitor for adverse reactions. If bicalutamide is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. Bicalutamide is a weak CYP3A4 inhibitor.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bismuth Subsalicylate: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of clozapine may produce additive effects.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of clozapine may produce additive effects. (Moderate) Concomitant use of metronidazole and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bisoprolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Blinatumomab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Bortezomib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Bosentan: (Moderate) Concomitant use of clozapine and bosentan can increase the risk and severity of hypotension by potentiating the effect of bosentan; monitor for hypotension. In addition, bosentan is an inducer of CYP3A4 and clozapine is partially metabolized by this isoenzyme. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Bosutinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Brentuximab vedotin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as clozapine. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.
Brimonidine; Timolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Bromocriptine: (Moderate) The effectiveness of bromocriptine may be reduced by most of the atypical antipsychotics, via their action as dopamine antagonists. Monitor the patient for reduced response to bromocriptine. The atypical antipsychotics elevate prolactin to various degrees. Atypical antipsychotics may also aggravate diabetes mellitus and cause metabolic changes including hyperglycemia; use caution if bromocriptine is taken for diabetes. If bromocriptine is taken for diabetes, monitor for worsening glycemic control.
Brompheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Brompheniramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Brompheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Bupivacaine; Epinephrine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of clozapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clozapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of clozapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of clozapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clozapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of clozapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Bupropion: (Major) Monitor for evidence of clozapine-related adverse reactions and consider a clozapine dose reduction if necessary when coadministered with bupropion. If bupropion is discontinued after dose adjustments are made, monitor for lack of clozapine affect and consider increasing the clozapine dose if necessary. Concurrent use may result in increased clozapine exposure due to inhibition of CYP2D6 metabolism by bupropion. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. Furthermore, bupropion is associated with a dose-related risk of seizures; this risk may be increased by antipsychotics.
Bupropion; Naltrexone: (Major) Monitor for evidence of clozapine-related adverse reactions and consider a clozapine dose reduction if necessary when coadministered with bupropion. If bupropion is discontinued after dose adjustments are made, monitor for lack of clozapine affect and consider increasing the clozapine dose if necessary. Concurrent use may result in increased clozapine exposure due to inhibition of CYP2D6 metabolism by bupropion. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. Furthermore, bupropion is associated with a dose-related risk of seizures; this risk may be increased by antipsychotics.
Buspirone: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant atypical antipsychotic and buspirone use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Butalbital; Acetaminophen: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Butalbital; Acetaminophen; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as clozapine, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
Cabergoline: (Moderate) Cabergoline should not be coadministered with clozapine due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of clozapine may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as clozapine. It should be noted that the effect of clozapine on prolactin is generally not clinically relevant.
Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Caffeine; Sodium Benzoate: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Canagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Candesartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Cannabidiol: (Moderate) Consider a clozapine dose reduction if coadministered with cannabidiol and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor. Also monitor for excessive sedation and somnolence during coadministration of cannabidiol and clozapine; additive CNS depression may occur.
Capivasertib: (Moderate) Consider a clozapine dose reduction if coadministered with capivasertib and monitor for adverse reactions. If capivasertib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6 and CYP3A and capivasertib is a moderate CYP2D6 and weak CYP3A inhibitor.
Capmatinib: (Moderate) Consider a clozapine dose reduction if coadministered with capmatinib and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate. Capmatinib is a moderate CYP1A2 inhibitor.
Capsaicin; Metaxalone: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
Captopril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Carbamazepine: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as carbamazepine, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Carbamazepine may also increase the metabolism of clozapine through induction of CYP1A2. Both agents have myelosuppressive properties; patients should be monitored for and instructed about symptoms of infection. Lastly, close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of carbamazepine in treating seizures may be reduced. Dosage adjustments may be necessary and close monitoring is warranted when carbamazepine is used with clozapine.
Carbidopa; Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Carbidopa; Levodopa; Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease. (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Carbinoxamine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Carboplatin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Carfilzomib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cariprazine: (Moderate) The risk of adverse effects may be increased during concurrent use of cariprazine with other antipsychotics, such as clozapine. Similar to other antipsychotics, cariprazine administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. The incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, but the risk appears to be increased.
Carisoprodol: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
Carmustine, BCNU: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Carteolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Carvedilol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Celecoxib: (Moderate) A dosage adjustment may be warranted for clozapine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of clozapine. Celecoxib is a CYP2D6 inhibitor, and clozapine is a CYP2D6 substrate.
Celecoxib; Tramadol: (Moderate) A dosage adjustment may be warranted for clozapine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of clozapine. Celecoxib is a CYP2D6 inhibitor, and clozapine is a CYP2D6 substrate. (Moderate) Concurrent use of tramadol and clozapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that clozapine has CYP2D6 inhibitory effects and may increase plasma concentrations of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by clozapine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and clozapine.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and clozapine. Concurrent use may result in additive CNS depression. Additionally, monitor for loss of clozapine effectiveness if coadministered with cenobamate. Consideration should be given to increasing the clozapine dose if necessary. When cenobamate is discontinued, reduce the clozapine dose based on clinical response. Cenobamate is a moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Central-acting adrenergic agents: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Ceritinib: (Major) Avoid coadministration of ceritinib with clozapine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Additionally, consider a clozapine dose reduction and monitor for adverse reactions; if ceritinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Clozapine is partially metabolized by CYP3A4 and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use.
Cetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Cetirizine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Cetrorelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Chlophedianol; Dexbrompheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlorambucil: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Chloramphenicol: (Moderate) Caution is advisable during concurrent use of chloramphenicol and clozapine. Chloramphenicol is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Chlorcyclizine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorcyclizine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlordiazepoxide: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Chlordiazepoxide; Amitriptyline: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin. (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Chlordiazepoxide; Clidinium: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Chloroquine: (Major) Avoid coadministration of chloroquine with clozapine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Chlorothiazide: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine.
Chlorpheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlorpheniramine; Codeine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
Chlorpheniramine; Dextromethorphan: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlorpheniramine; Hydrocodone: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlorpheniramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlorpheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Chlorpromazine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). In addition, coadministration of clozapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Chlorthalidone: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine.
Chlorzoxazone: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants, such as clozapine. Dosage adjustments of one or both medications may be necessary.
Cimetidine: (Moderate) Caution is advisable during concurrent use of cimetidine and clozapine. Cimetidine is an inhibitor of CYP3A4, CYP2D6, and CYP1A2, the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, 2D6, or 3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4, CYP2D6, or CYP1A2 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cinacalcet: (Moderate) Consider a clozapine dose reduction if coadministered with cinacalcet and monitor for adverse reactions. If cinacalcet is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6 and cinacalcet is a moderate CYP2D6 inhibitor.
Ciprofloxacin: (Major) If co-administration of clozapine and a potent inhibitor of CYP1A2 such as ciprofloxacin is necessary, the manufacturer of clozapine recommends using one-third of the usual clozapine dose. If the inhibitor is discontinued, increase the clozapine dose based on clinical response. One study of 7 schizophrenic patients has shown that concurrent therapy with ciprofloxacin (250 mg twice daily) versus placebo resulted in increased clozapine plasma concentrations (29%) and N-desmethylclozapine plasma concentrations (31%). One case study has reported elevated clozapine plasma concentrations (by 80%) during ciprofloxacin coadministration at doses of 500 mg twice daily. In addition, rare cases of QT prolongation and torsade de pointes (TdP) have been reported with both ciprofloxacin and clozapine. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP3A4, or CYP2D6 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. If quinolone administration is indicated during clozapine therapy, an alternative fluoroquinolone with minimal inhibitory effects on CYP1A2, CYP2D6, or CYP3A4 should be considered.
Cisapride: (Contraindicated) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Because of the potential for TdP, use of cisapride with clozapine is contraindicated.
Cisplatin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Citalopram: (Major) Concurrent use of clozapine and citalopram should be avoided if possible. Citalopram causes dose-dependent QT interval prolongation and clozapine is associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. According to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. However, if concurrent therapy is considered essential, ECG monitoring is recommended. In addition, citalopram is a weak inhibitor of CYP2D6, and increased plasma concentrations of antipsychotics partially metabolized via CYP2D6, such as clozapine, may occur. A reduced dosage of clozapine should be considered when clozapine is combined with CYP2D6 inhibitors, due to a decrease in clozapine metabolism and a potential for clozapine-related adverse effects, such as orthostatic hypotension, seizures, or adverse cardiac effects.
Cladribine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Clarithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Clemastine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as clemastine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Clobazam: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Clofarabine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Clofazimine: (Moderate) Concomitant use of clofazimine and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Clomipramine: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Clonazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Clonidine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Clorazepate: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Cobicistat: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
Codeine; Guaifenesin: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
Codeine; Phenylephrine; Promethazine: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
Codeine; Promethazine: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
COMT inhibitors: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Conivaptan: (Moderate) Consider a clozapine dose reduction if coadministered with conivaptan and monitor for adverse reactions. If conivaptan is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Conivaptan is a moderate CYP3A inhibitor.
Crizotinib: (Major) Avoid coadministration of crizotinib with clozapine due to the risk of QT prolongation; exposure to clozapine may also increase. If concomitant use is unavoidable, consider a clozapine dose reduction. Monitor ECGs for QT prolongation and monitor electrolytes; also monitor for clozapine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. If crizotinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Clozapine is partially metabolized by CYP3A4, and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Cyclobenzaprine: (Moderate) Additive anticholinergic effects may be seen when clozapine is used concomitantly with other drugs with antimuscarinic activity such as cyclobenzaprine. Antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Particular attention should be paid to GI problems because of the possible development of paralytic ileus. Additive sedation may also occur.
Cyproheptadine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as cyproheptadine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Dacomitinib: (Moderate) Consider a clozapine dose reduction if coadministered with dacomitinib and monitor for adverse reactions. If dacomitinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
Dalfopristin; Quinupristin: (Moderate) Consider a clozapine dose reduction if coadministered with dalfopristin; quinupristin and monitor for adverse reactions. If dalfopristin; quinupristin is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor.
Danazol: (Moderate) Caution is advisable during concurrent use of danazol and clozapine. Danazol is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Dantrolene: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
Dapagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Daridorexant: (Moderate) Consider a clozapine dose reduction if coadministered with daridorexant and monitor for adverse reactions. If daridorexant is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A; daridorexant is a weak CYP3A inhibitor.
Darifenacin: (Moderate) Consider a clozapine dose reduction if coadministered with darifenacin and monitor for adverse reactions including anticholinergic effects. If darifenacin is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6. Darifenacin is a moderate CYP2D6 inhibitor. Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with other drugs with moderate to significant anticholinergic effects including clozapine.
Darunavir: (Moderate) Caution is advisable during concurrent use of darunavir and clozapine. Darunavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Darunavir; Cobicistat: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of darunavir and clozapine. Darunavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of darunavir and clozapine. Darunavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Dasatinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, in vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Clozapine therapy may lead to S-T segment depression and flattening or inversion of T waves. In theory, concurrent use of dasatinib and clozapine could produce clinically significant prolongation of the QTc interval.
Deferiprone: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as clozapine; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Delavirdine: (Moderate) Caution is advisable during concurrent use of delavirdine and clozapine. Delavirdine is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Desflurane: (Major) Concomitant use of clozapine and halogenated anesthetics increases the risk of QT/QTc prolongation, torsade de pointes (TdP), excessive sedation and respiratory depression, and neuroleptic malignant syndrome (NMS). Avoid concomitant use if possible, especially in patients with additional risk factors for these adverse effects. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary and monitor for signs and symptoms of NMS and prolonged sedation and respiratory depression.
Desipramine: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Deutetrabenazine: (Major) Use clozapine with caution in combination with deutetrabenazine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and clozapine is a dopamine antagonist. Additionally, monitor for excessive sedation and somnolence during coadministration of clozapine and deutetrabenazine. Concurrent use may result in additive CNS depression.
Dexamethasone: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with dexamethasone. Consideration should be given to increasing the clozapine dose if necessary. When dexamethasone is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A substrate and dexamethasone is a weak CYP3A inducer.
Dexbrompheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Dexchlorpheniramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Dextromethorphan; Bupropion: (Major) Monitor for evidence of clozapine-related adverse reactions and consider a clozapine dose reduction if necessary when coadministered with bupropion. If bupropion is discontinued after dose adjustments are made, monitor for lack of clozapine affect and consider increasing the clozapine dose if necessary. Concurrent use may result in increased clozapine exposure due to inhibition of CYP2D6 metabolism by bupropion. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. Furthermore, bupropion is associated with a dose-related risk of seizures; this risk may be increased by antipsychotics.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Dextromethorphan; Quinidine: (Contraindicated) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include clozapine.
Diazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Diazoxide: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Dicyclomine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Digoxin: (Moderate) Because clozapine is highly protein bound, other highly protein bound medications such as digoxin can displace clozapine from its binding sites, predominantly alpha1-acid glycoprotein. Clozapine, in turn, can increase the serum concentrations of digoxin.
Diltiazem: (Moderate) Caution is advisable during concurrent use of diltiazem and clozapine. Diltiazem is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Dimenhydrinate: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as dimenhydrinate. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Dinutuximab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Diphenhydramine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Diphenhydramine; Ibuprofen: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Diphenhydramine; Naproxen: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Diphenhydramine; Phenylephrine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Diphenoxylate; Atropine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Diphenoxylate decreases GI motility. Other drugs that also decrease GI motility, such as clozapine, may produce additive effects with diphenoxylate if used concomitantly.
Disopyramide: (Major) Clozapine should be used cautiously and with close monitoring with disopyramide. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Additive anticholinergic effects are also possible; both drugs exhibit significant anticholinergic activity.
Disulfiram: (Moderate) Caution is advisable during concurrent use of disulfiram and clozapine. Disulfiram is an inhibitor of CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor to clozapine treatment, monitor for adverse reactions and consider reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Dofetilide: (Major) Coadministration of dofetilide and clozapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with clozapine as concurrent use may increase the risk of QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Donepezil: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than clozapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Clozapine exhibits considerable anticholinergic activity, and is more likely than other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
Donepezil; Memantine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than clozapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Clozapine exhibits considerable anticholinergic activity, and is more likely than other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
Dorzolamide; Timolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Doxazosin: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Doxepin: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Doxylamine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Doxylamine; Pyridoxine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Dronabinol: (Moderate) Drugs that can cause CNS depression such as dronabinol, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Dronedarone: (Contraindicated) Concomitant use of dronedarone and clozapine is contraindicated. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death and dronedarone is associated with dose-related increases in the QTc interval. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation; concomitant use is contraindicated. In addition, dronedarone is an inhibitor of CYP2D6 and CYP3A, two of the isoenzymes responsible for the metabolism of clozapine. Coadministration of dronedarone and clozapine may result in elevated plasma concentrations of clozapine, which may potentially increase the risk of life-threatening arrhythmias or other adverse effects. According to the manufacturer of clozapine, concomitant use of clozapine and substrates or inhibitors of CYP2D6 may require lower doses of either drug.
Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include clozapine.
Dulaglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Duloxetine: (Moderate) Duloxetine is an inhibitor of CYP2D6 and CYP1A2, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP1A2, CYP3A4, or CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Duvelisib: (Moderate) Consider a clozapine dose reduction if coadministered with duvelisib and monitor for adverse reactions. If duvelisib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4 and duvelisib is a moderate CYP3A4 inhibitor.
Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with clozapine as concurrent use may increase the risk of QT prolongation; decreased clozapine exposure may also occur. Monitor for loss of clozapine efficacy and consider increasing the clozapine dose if necessary. QTc prolongation has been observed with the use of efavirenz. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is an and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with clozapine as concurrent use may increase the risk of QT prolongation; decreased clozapine exposure may also occur. Monitor for loss of clozapine efficacy and consider increasing the clozapine dose if necessary. QTc prolongation has been observed with the use of efavirenz. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is an and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with clozapine as concurrent use may increase the risk of QT prolongation; decreased clozapine exposure may also occur. Monitor for loss of clozapine efficacy and consider increasing the clozapine dose if necessary. QTc prolongation has been observed with the use of efavirenz. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is an and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Elagolix: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with elagolix. Consideration should be given to increasing the clozapine dose if necessary. When elagolix is discontinued, reduce the clozapine dose based on clinical response. Elagolix is a weak to moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with elagolix. Consideration should be given to increasing the clozapine dose if necessary. When elagolix is discontinued, reduce the clozapine dose based on clinical response. Elagolix is a weak to moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Elbasvir; Grazoprevir: (Moderate) Administering clozapine with grazoprevir may result in elevated clozapine plasma concentrations. Clozapine is a substrate of CYP3A4 and grazoprevir is a weak CYP3A inhibitor. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and clozapine concurrently. Ivacaftor is an inhibitor of CYP3A and clozapine is partially metabolized by CYP3A. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Eliglustat: (Major) Coadministration of clozapine and eliglustat may result in increased plasma concentrations of clozapine and an increased risk of QT prolongation. If coadministration is necessary, use great caution and monitor closely. Consider reducing the dosage of clozapine and titrating to clinical effect. In addition, if eliglustat is discontinued while the patient is taking clozapine, monitor for a lack of antipsychotic efficacy, and increase the clozapine dose as clinically necessary. Clozapine is a CYP2D6 substrate associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Eliglustat is a CYP2D6 inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Empagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Linagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Enalapril, Enalaprilat: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Enasidenib: (Moderate) Monitor for a reduction in clozapine efficacy or an increase in clozapine-related adverse effects if clozapine is coadministered with enasidenib; adjust the clozapine dose as necessary based on response. Concurrent use may alter clozapine exposure although the net effect is unknown. Clozapine is a CYP3A and CYP2D6 substrate and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Encorafenib: (Major) Avoid concurrent use of encorafenib with clozapine due to the risk for decreased clozapine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is required, monitor for altered response to clozapine and increase the clozapine dose if necessary. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clozapine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Entrectinib: (Major) Avoid coadministration of entrectinib with clozapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Enzalutamide: (Major) Coadministration of clozapine with enzalutamide is not recommended due to decreased plasma concentrations of clozapine. If concomitant use is unavoidable, the patient should be monitored for loss of efficacy; consider increasing the clozapine dose if necessary. When enzalutamide is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
Epinephrine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
Eplerenone: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Epoprostenol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Eprosartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Ergotamine; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Eribulin: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with clozapine include eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Ertugliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Erythromycin: (Major) Concurrent use of erythromycin and clozapine should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death and erythromycin has an established risk of QT prolongation and TdP. A case report has documented increased serum clozapine concentrations and the occurrence of a seizure when erythromycin was added to a stable dose of clozapine. Erythromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Escitalopram: (Moderate) Consider a clozapine dose reduction if coadministered with escitalopram and monitor for adverse reactions, inlcuding QT prolongation. If escitalopram is discontinued, monitor for lack of clozapine effect, and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine and increased risk of QT prolongation may occur during concurrent use. Clozapine is partially metabolized by CYP2D6 and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Escitalopram is a moderate CYP2D6 inhibitor that has been associated with a risk of QT prolongation and TdP.
Esketamine: (Major) Closely monitor patients receiving esketamine and clozapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Eslicarbazepine: (Moderate) Eslicarbazepine is an inducer of CYP3A4, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary. In addition, clozapine can lower the seizure threshold, potentially reducing the effectiveness of eslicarbazepine in treating seizures. Monitor for increased seizure activity during concurrent use.
Esmolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Estazolam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Estramustine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Eszopiclone: (Moderate) A reduction in the dose of eszopiclone should be considered during co-administration of other CNS depressants, such as antipsychotics, to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Antipsychotics with a higher incidence of sedation, such as olanzapine, clozapine, quetiapine, lurasidone, chlorpromazine, and thioridazine, are more likely to interact with eszopiclone. In one evaluation, concurrent use of eszopiclone and olanzapine reduced psychomotor function as measured by the Digit Symbol Substitution Test (DSST).
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethiodized Oil: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ethotoin: (Moderate) Ethotoin may increase the metabolism of clozapine through CYP1A2 and/or CYP3A4 induction, leading to increased clearance of clozapine. When initiating clozapine or adding a weak to moderate CYP1A2 or CYP3A4 inducer to pre-existing clozapine treatment, monitor for decreased effectiveness and consider increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions and consider reducing the clozapine dose if necessary. In addition, clozapine lowers the seizure threshold and may reduce the effectiveness of ethotoin in treating seizures. Monitor for increased seizure activity and consider alternative treatment or make dose adjustments accordingly.
Etomidate: (Moderate) Clozapine can potentiate the actions of other CNS depressants such as the general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Etrasimod: (Moderate) Concomitant use of etrasimod and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Etravirine: (Moderate) Caution is advisable during concurrent use of etravirine and clozapine. Etravirine is an inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. According to the manufacturer, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Everolimus: (Moderate) Consider a clozapine dose reduction if coadministered with everolimus and monitor for adverse reactions. If everolimus is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is metabolized by CYP3A4 and CYP2D6. Everolimus is a weak CYP3A4 inhibitor and a CYP2D6 inhibitor.
Exenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Fedratinib: (Moderate) Consider a clozapine dose reduction if coadministered with fedratinib and monitor for adverse reactions. If fedratinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4 and CYP2D6. Fedratinib is a moderate inhibitor of CYP3A4 and CYP2D6.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and clozapine. Concurrent use may result in additive CNS depression.
Fenoldopam: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Fentanyl: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as clozapine, can potentiate the effects of fentanyl on respiration, CNS depression, sedation, and hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
Fesoterodine: (Moderate) Coadministration of fesoterodine and other drugs with moderate to significant anticholinergic effects such as clozapine may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention.
Fexinidazole: (Major) Concomitant use of fexinidazole and clozapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Also consider a clozapine dose reduction and monitor for adverse reactions. If fexinidazole is discontinued, monitor for lack of clozapine effect and increase the dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 and CYP3A substrate and fexinidazole is a CYP1A2 and CYP3A inhibitor.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with clozapine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Flavoxate: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Flecainide: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Flecainide should be used cautiously and with close monitoring with clozapine. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Contraindicated) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, like clozapine, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of clozapine, causing an increased risk for adverse events such as QT prolongation.
Flucytosine: (Moderate) Because of the ability of flucytosine to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants, including clozapine.
Fludarabine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Fluoxetine: (Moderate) Consider a clozapine dose reduction if coadministered with fluoxetine and monitor for adverse reactions including QT prolongation. If fluoxetine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of fluoxetine. Clozapine is a CYP2D6 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Fluoxetine is a strong CYP2D6 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
Fluphenazine: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of clozapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.
Flurazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and clozapine. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death, especially at high dosages. In addition, if coadministration of clozapine and a potent inhibitor of CYP1A2 such as fluvoxamine is necessary, the manufacturer of clozapine recommends using one-third of the usual clozapine dose. If the inhibitor is discontinued, increase the clozapine dose based on clinical response. In one study, the mean concentrations of clozapine and its metabolites were increased about 3-fold compared to baseline values. Up to a 10-fold increase in plasma concentrations of clozapine and its metabolites have been noted in other evaluations. Fluvoxamine is also a moderate CYP3A4 inhibitor and a mild CYP2D6 inhibitor. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP3A4, or CYP2D6 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects.
Food: (Major) Advise patients to avoid cannabis use during clozapine treatment due to decreased exposure of clozapine which may alter its efficacy. Concomitant use may also increase the risk for additive CNS depression and other adverse reactions. Cannabis use induces CYP1A2 and clozapine is a CYP1A2 substrate. The induction potential of cannabis is greatest with chronic inhalation. Other routes of administration or sporadic use may have less of an effect.
Fosamprenavir: (Moderate) Consider a clozapine dose reduction if coadministered with fosamprenavir and monitor for adverse reactions. If fosamprenavir is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A and fosamprenavir is a moderate CYP3A inhibitor.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as clozapine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosinopril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Fosphenytoin: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as fosphenytoin converted to phenytoin, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Fosphenytoin may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of fosphenytoin in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring is warranted.
Fostamatinib: (Moderate) Consider a clozapine dose reduction if coadministered with fostamatinib and monitor for adverse reactions. If fostamatinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. Fostamatinib is a weak CYP3A4 inhibitor.
Fostemsavir: (Moderate) Use clozapine and fostemsavir together with caution due to the potential for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and clozapine. Concomitant use of gabapentin with clozapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Galantamine: (Moderate) The anticholinergic activity of clozapine may interfere with the action of cholinergic medications such as galantamine. Atypical antipsychotics with significant anticholinergic effects, such clozapine, are more likely than other atypical antipsychotics to diminish the therapeutic action of galantamine in treating dementia. Use of an alternative antipsychotic should be considered. Galantamine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Consider the use of an antipsychotic with less prominent anticholinergic effects.
Ganirelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
Gemifloxacin: (Moderate) Gemifloxacin should be used cautiously with clozapine as concurrent use may increase the risk of QT prolongation. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and clozapine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Gilteritinib: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and clozapine is necessary. Gilteritinib has been associated with QT prolongation. Clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Coadministration has the potential for additive QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with clozapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Glimepiride: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glipizide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glyburide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glycerol Phenylbutyrate: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with glycerol phenylbutyrate. Consideration should be given to increasing the clozapine dose if necessary. When glycerol phenylbutyrate is discontinued, reduce the clozapine dose based on clinical response. Glycerol phenylbutyrate is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Glycopyrrolate: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Glycopyrrolate; Formoterol: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Granisetron: (Moderate) Use clozapine with caution in combination with granisteron. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Granisetron has been associated with QT prolongation.
Green Tea: (Major) Some, but not all, green tea products contain caffeine. Caffeine may inhibit clozapine metabolism via CYP1A2. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2 may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Clozapine clearance has been decreased by roughly 14% during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption including consumption from beverages or food should be minimized during clozapine treatment.
Guanfacine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Guanidine: (Minor) Bone marrow suppression is associated with guanidine therapy. Avoid concomitant use of other drugs known to cause bone marrow suppression such as clozapine.
Halogenated Anesthetics: (Major) Concomitant use of clozapine and halogenated anesthetics increases the risk of QT/QTc prolongation, torsade de pointes (TdP), excessive sedation and respiratory depression, and neuroleptic malignant syndrome (NMS). Avoid concomitant use if possible, especially in patients with additional risk factors for these adverse effects. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary and monitor for signs and symptoms of NMS and prolonged sedation and respiratory depression.
Haloperidol: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Haloperidol is also associated with a possible risk for QT prolongation and TdP. In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. Clozapine is metabolized by CYP1A2, CYP3A4, and CYP2D6. Antipsychotic drugs known to inhibit the activity of CYP2D6 include haloperidol. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP3A4, or CYP2D6 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Homatropine; Hydrocodone: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
Hydralazine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
Hydromorphone: (Moderate) Concomitant use of hydromorphone with other central nervous system (CNS) depressants can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Examples of drugs associated with CNS depression include clozapine. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
Hydroxychloroquine: (Major) Avoid coadministration of clozapine and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Hydroxyurea: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Hydroxyzine: (Major) Caution is recommended if hydroxyzine is administered with clozapine due to the potential for additive QT prolongation, increased risk of torsade de pointes (TdP), significant sedation, and anticholinergic effects. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Hyoscyamine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Ibritumomab Tiuxetan: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Ibrutinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, this drug combination may result in additive effects on intestinal motility or bladder function. Prior to concurrent use of oxycodone in patients taking clozapine, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower clozapine dose. Monitor patients for sedation and respiratory depression.
Ibutilide: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with clozapine, a CYP3A substrate, as clozapine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. In addition, it is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clozapine. In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Imatinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, clozapine is a CYP2D6 substrate and imatinib, STI-571 is a potent inhibitor of CYP2D6, Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Imipramine: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Indacaterol; Glycopyrrolate: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Indinavir: (Moderate) Caution is advisable during concurrent use of indinavir and clozapine. Indinavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with clozapine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Insulin Aspart: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Degludec: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Detemir: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Glargine: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Glulisine: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Lispro: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin, Inhaled: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulins: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Interferon Alfa-2b: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., certain antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Interferon Alfa-n3: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., certain antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Iodixanol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iohexol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iomeprol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iopamidol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Iopromide: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ioversol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ipilimumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Irbesartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Isavuconazonium: (Moderate) Consider a clozapine dose reduction if coadministered with isavuconazonium and monitor for adverse reactions. If isavuconazonium is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Isavuconazonium is a moderate CYP3A inhibitor.
Isocarboxazid: (Moderate) Monitor blood pressure and for unusual drowsiness and sedation during coadministration of monoamine oxidase inhibitors (MAOIs) and clozapine due to the risk for additive hypotension and CNS depression.
Isoflurane: (Major) Concomitant use of clozapine and halogenated anesthetics increases the risk of QT/QTc prolongation, torsade de pointes (TdP), excessive sedation and respiratory depression, and neuroleptic malignant syndrome (NMS). Avoid concomitant use if possible, especially in patients with additional risk factors for these adverse effects. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary and monitor for signs and symptoms of NMS and prolonged sedation and respiratory depression.
Isoniazid, INH: (Moderate) Consider a clozapine dose reduction if coadministered with isoniazid and monitor for adverse reactions. If isoniazid is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Isoniazid is a weak CYP3A inhibitor.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as rifampin, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Rifampin may also increase the metabolism of clozapine through induction of CYP1A2. (Moderate) Consider a clozapine dose reduction if coadministered with isoniazid and monitor for adverse reactions. If isoniazid is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Isoniazid is a weak CYP3A inhibitor.
Isoniazid, INH; Rifampin: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as rifampin, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Rifampin may also increase the metabolism of clozapine through induction of CYP1A2. (Moderate) Consider a clozapine dose reduction if coadministered with isoniazid and monitor for adverse reactions. If isoniazid is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Isoniazid is a weak CYP3A inhibitor.
Isophane Insulin (NPH): (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Isosulfan Blue: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Isradipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Istradefylline: (Moderate) Consider a clozapine dose reduction if coadministered with istradefylline 40 mg daily and monitor for adverse reactions. If istradefylline is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Itraconazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clozapine. Both clozapine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with clozapine (a CYP3A4 substrate) may result in elevated clozapine plasma concentrations and an increased risk for adverse events, including QT prolongation. Consider a clozapine dose reduction if necessary. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Ivacaftor: (Moderate) Use caution when administering ivacaftor and clozapine concurrently. Ivacaftor is an inhibitor of CYP3A and clozapine is partially metabolized by CYP3A. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with clozapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Ketamine: (Moderate) Clozapine can potentiate the actions of other CNS depressants such as the general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and clozapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of clozapine, thereby further increasing the risk for adverse events. Clozapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
Labetalol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Lamotrigine: (Major) One report has described an interaction between lamotrigine and clozapine. A 3-fold increase in clozapine concentrations occurred in a patient after lamotrigine was added to the drug regimen. The patient experienced drowsiness and dizziness that were clinically significant. Measurement of clozapine plasma concentrations during the time of the interaction and after lamotrigine was discontinued indicated a probable interaction, although the mechanism of the interaction is not certain. Clozapine may interact with anticonvulsants in several ways; therefore concurrent use of clozapine in patients on antiepileptic medications is not recommended if seizures are not controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures. Dosage adjustments of clozapine should be cautious.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Lapatinib: (Moderate) Consider a clozapine dose reduction if coadministered with lapatinib and monitor for adverse reactions. Also, monitor for evidence of QT prolongation and torsade de pointes (TdP). If lapatinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Lapatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
Larotrectinib: (Moderate) Consider a clozapine dose reduction if coadministered with larotrectinib and monitor for adverse reactions. If larotrectinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Larotrectinib is a weak CYP3A inhibitor.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and clozapine. Concurrent use may result in additive CNS depression.
Lefamulin: (Major) Avoid coadministration of lefamulin with clozapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and atypical antipsyhotics. Dosage adjustments of lemborexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
Lenacapavir: (Moderate) Consider a clozapine dose reduction if coadministered with lenacapavir and monitor for adverse reactions. If lenacapavir is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Lenacapavir is a moderate CYP3A inhibitor.
Lenalidomide: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Leniolisib: (Moderate) Consider a clozapine dose reduction if coadministered with leniolisib and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate and leniolisib is a weak CYP1A2 inhibitor.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with clozapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Treatment with clozapine has also been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Letermovir: (Moderate) Consider a clozapine dose reduction if coadministered with letermovir and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Clozapine is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Androgen deprivation therapy may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Androgen deprivation therapy may prolong the QT/QTc interval.
Levamlodipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Levobunolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Levocetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and clozapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of clozapine, thereby further increasing the risk for adverse events. Clozapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
Levorphanol: (Moderate) Concomitant use of levorphanol with other CNS depressants such as clozapine can potentiate the effects of levorphanol on respiration, blood pressure, and alertness. Severe hypotension, respiratory depression, profound sedation, or coma may occur. Prior to concurrent use of levorphanol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment with levorphanol with another CNS depressant is necessary, reduce the dose of 1 or both drugs. The initial dose of levorphanol should be reduced by approximately 50% or more when levorphanol is used with another drug that may depress respiration.
Lidocaine; Epinephrine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
Linagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Liraglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Lisinopril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Lithium: (Major) Some atypical antipsychotics are considered first-line adjunctive therapy to mood stabilizers such as lithium. However, it is advisable to monitor patients for neurotoxicity during co-administration. Neuroleptic malignant syndrome (NMS) has been observed occasionally during concurrent use of lithium and either atypical or conventional antipsychotics. Additive extrapyramidal effects have also been noted. Early case reports described an encephalopathic syndrome consisting of delirium, tremulousness, dyskinesia, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevations in laboratory values (e.g., liver function tests, blood urea nitrogen, fasting blood sugar) and, in some cases, irreversible brain damage, during use of lithium and conventional antipsychotics, particularly haloperidol. Subsequent rare reports of NMS or NMS-like reactions have been described during co-administration of lithium and atypical antipsychotics (e.g., aripiprazole, risperidone, olanzapine, clozapine). Following resolution of NMS, there are isolated instances of re-emergence of symptoms following re-initiation of lithium as monotherapy. Lithium may be a risk factor for antipsychotic-induced NMS; however, this hypothesis has not been confirmed. In many reported cases, confounding factors have been present (e.g., previous history of NMS, high dose therapy). The ability of antipsychotics alone to precipitate NMS and the rarity of the condition further complicate assessment of lithium as a risk factor. Furthermore, lithium has been associated with QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation.
Lixisenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with clozapine due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Lomustine, CCNU: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Lonafarnib: (Moderate) Consider a clozapine dose reduction if coadministered with lonafarnib and monitor for adverse reactions. If lonafarnib is discontinued, monitor for lack of clozapine effect, and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4; lonafarnib is a strong CYP3A4 inhibitor.
Loperamide: (Major) Loperamide should be used cautiously and with close monitoring with clozapine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. In addition, both drugs may decrease gastrointestinal (GI) motility; concurrent use could produce additive GI effects and induce toxic megacolon. If these drugs are given together, monitor for prolongation of the QT interval and for signs of impaired intestinal motility.
Loperamide; Simethicone: (Major) Loperamide should be used cautiously and with close monitoring with clozapine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. In addition, both drugs may decrease gastrointestinal (GI) motility; concurrent use could produce additive GI effects and induce toxic megacolon. If these drugs are given together, monitor for prolongation of the QT interval and for signs of impaired intestinal motility.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with clozapine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. (Major) Consider a clozapine dose adjustment if coadministered with ritonavir and monitor for efficacy and adverse reactions. If ritonavir is discontinued, monitor for lack of clozapine effect and adverse effects and adjust dose if necessary. A clinically relevant increase or decrease in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4, CYP2D6, and CYP1A2. Ritonavir is a strong CYP3A4 and weak CYP2D6 inhibitor and a moderate inducer of CYP1A2.
Lorazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Lorlatinib: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with lorlatinib. Consideration should be given to increasing the clozapine dose if necessary. When lorlatinib is discontinued, reduce the clozapine dose based on clinical response. Lorlatinib is a moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Losartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Loxapine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and clozapine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of clozapine by decreasing its systemic exposure; concomitant use is not recommended. If coadministration cannot be avoided, monitor for a lack of antipsychotic efficacy and consider increasing the clozapine dosage if necessary. Upon discontinuation of lumacaftor; ivacaftor, reduce the clozapine dosage based on clinical response. Clozapine is primarily metabolized by CYP3A4, CYP1A2, and CYP2D6. Lumacaftor is a strong CYP3A inducer. (Moderate) Use caution when administering ivacaftor and clozapine concurrently. Ivacaftor is an inhibitor of CYP3A and clozapine is partially metabolized by CYP3A. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of clozapine by decreasing its systemic exposure; concomitant use is not recommended. If coadministration cannot be avoided, monitor for a lack of antipsychotic efficacy and consider increasing the clozapine dosage if necessary. Upon discontinuation of lumacaftor; ivacaftor, reduce the clozapine dosage based on clinical response. Clozapine is primarily metabolized by CYP3A4, CYP1A2, and CYP2D6. Lumacaftor is a strong CYP3A inducer.
Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and clozapine, may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from antipsychotic combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Lurasidone: (Major) Co-administration of clozapine with lurasidone may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as clozapine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Maprotiline: (Major) Caution is recommended during concurrent treatment of clozapine with heterocyclic antidepressants including amoxapine or maprotiline. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Amoxapine and maprotiline have a possible risk of QT prolongation and TdP. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Additive anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like amoxapine or maprotiline. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. In addition, clozapine is metabolized by CYP1A2 and CYP2D6 isoenzymes; maprotiline is also metabolized via CYP2D6 and could compete for the same metabolic pathway.
Maribavir: (Moderate) Consider a clozapine dose reduction if coadministered with maribavir and monitor for adverse reactions. If maribavir is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A and maribavir is a weak CYP3A inhibitor.
Mavacamten: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with mavacamten. Consideration should be given to increasing the clozapine dose if necessary. When mavacamten is discontinued, reduce the clozapine dose based on clinical response. Mavacamten is a moderate inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Mecamylamine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Meclizine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as meclizine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. There is also evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
Meglitinides: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Melphalan Flufenamide: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Melphalan: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Meperidine: (Moderate) Meperidine should be combined cautiously with clozapine due to the potential for additive depressant effects, respiratory depression, or hypotension. Combining clozapine with opiate agonists may also lead to reduced intestinal motility or bladder function.
Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.
Mercaptopurine, 6-MP: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Meropenem: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with meropenem. Consideration should be given to increasing the clozapine dose if necessary. When meropenem is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP1A2 and CYP3A substrate and meropenem is a weak CYP1A2 and weak CYP3A inducer.
Meropenem; Vaborbactam: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with meropenem. Consideration should be given to increasing the clozapine dose if necessary. When meropenem is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP1A2 and CYP3A substrate and meropenem is a weak CYP1A2 and weak CYP3A inducer.
Metaxalone: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as clozapine, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, concomitant use of methadone with another CNS depressant, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; ; in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Consider a lower dose of the CNS depressant. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
Methazolamide: (Moderate) Caution is advisable during concurrent use of clozapine and methazolamide as electrolyte imbalance caused by diuretics may increase the risk of QT prolongation with clozapine. In addition, clozapine, in combination with methazolamide, has been reported to cause agranulocytosis. As with clozapine-induced agranulocytosis, the agranulocytosis that occurs with carbonic anhydrase inhibitors is neither dose related or predictable, but is reversible.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Methocarbamol: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
Methohexital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Methotrexate: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Methscopolamine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Methyldopa: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Metoclopramide: (Contraindicated) Avoid metoclopramide in patients receiving atypical antipsychotics. There is a potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Some manufacturer labels for metoclopramide contraindicate the use of these drugs together, while others state avoidance is necessary. If these agents must be used together, monitor closely for movement disorders and additive CNS effects. There also may be additive sedation. Discontinue these medications at the first signs of dyskinesia.
Metolazone: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine.
Metoprolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Metronidazole: (Moderate) Concomitant use of metronidazole and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Mexiletine: (Moderate) Consider a clozapine dose reduction if coadministered with mexiletine and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate. Mexiletine is a moderate CYP1A2 inhibitor.
Midazolam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Midostaurin: (Major) The concomitant use of midostaurin and clozapine may lead to additive QT interval prolongation. If these drugs are used together, obtain electrocardiograms to monitor the QT interval. Electrolyte imbalances should be corrected prior to initiating treatment with clozapine. Baseline assessments of serum potassium and magnesium levels should be performed, as well as periodic evaluation during treatment, in patients at risk for electrolyte imbalances. The drug should be discontinued if the QT interval exceeds 500 milliseconds. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Treatment with clozapine has been associated with QT prolongation, torsade de pointes, cardiac arrest, and sudden death.
Mifepristone: (Moderate) Avoid use together when possible. Use extreme caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine, such as mifepristone, which may do both. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Mifepristone has also been associated with QT prolongation. Mifepristone is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through inhibition of CYP3A4 may potentially increase the risk of life-threatening arrhythmias or other clozapine-related adverse effects such as sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Miglitol: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Minoxidil: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Mirabegron: (Moderate) Patients receiving clozapine in combination with a CYP2D6 inhibitor such as mirabegron should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Mirabegron is a moderate inhibitor of CYP2D6, and clozapine is a CYP2D6 substrate. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects.
Mirtazapine: (Moderate) Concomitant use of mirtazapine and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Mitapivat: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with mitapivat. Consideration should be given to increasing the clozapine dose if necessary. When mitapivat is discontinued, reduce the clozapine dose based on clinical response. Mitapivat is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Mitotane: (Moderate) The concomitant use of mitotane with clozapine is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of clozapine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and clozapine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of clozapine. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with clozapine.
Mitoxantrone: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Mobocertinib: (Major) Concomitant use of mobocertinib and clozapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, monitor for loss of clozapine efficacy if coadministered with mobocertinib. Concurrent use may decrease clozapine exposure. Clozapine is a CYP3A substrate and mobocertinib is a weak CYP3A inducer.
Modafinil: (Moderate) Caution is advisable during concurrent use of modafinil or armodafinil with clozapine. Modanil and armodafinil have potential to induce CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Patients receiving clozapine in combination with a CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. An interaction between modafinil and clozapine has been reported in a case report that resulted in clinical side effects. After the addition of modafinil to the drug regimen of a patient stabilized on clozapine, the patient became symptomatic with dizziness, problems with gait, and sinus tachycardia. Clozapine serum concentrations were found to be elevated. All symptoms resolved and the patient's clozapine levels returned to normal on modafinil discontinuation. The mechanism of the interaction is unclear, but may be related to changes in clozapine metabolism by modafinil. Concomitant therapy of modafinil and clozapine should be approached with close monitoring of the patient's clinical status.
Moexipril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Molindone: (Major) Close monitoring is advisable during concurrent use of molindone and clozapine. Because molindone shares certain pharmacological properties with other antipsychotics, additive cardiac effects (e.g., hypotension), CNS effects (e.g., drowsiness), or anticholinergic effects (e.g., constipation, xerostomia) may occur.
Monoamine oxidase inhibitors: (Moderate) Monitor blood pressure and for unusual drowsiness and sedation during coadministration of monoamine oxidase inhibitors (MAOIs) and clozapine due to the risk for additive hypotension and CNS depression.
Morphine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include clozapine. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
Morphine; Naltrexone: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include clozapine. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
Moxifloxacin: (Major) Concurrent use of clozapine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Nabilone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Nadolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Nalbuphine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and nalbuphine. Concurrent use may result in additive CNS depression.
Nateglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Natural Antineoplastics: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Nebivolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Nebivolol; Valsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Nefazodone: (Major) Caution is advisable during concurrent use of nefazodone and clozapine. Nefazodone is a potent inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. In one case report, nefazodone 300 mg/day was started in a patient receiving clozapine who subsequently developed dizziness, elevated anxiety, and hypotension. Clozapine and norclozapine plasma concentrations were 75% and 89% higher, respectively, after starting nefazodone. Lowering the nefazodone dose to 200 mg/day resolved the adverse effects, and the serum concentrations of clozapine declined. In contrast, other studies have not shown an interaction between clozapine and nefazodone. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary.
Nelarabine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Nelfinavir: (Moderate) Caution is advisable during concurrent use of nelfinavir and clozapine. Nelfinavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Neostigmine; Glycopyrrolate: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Nevirapine: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with nevirapine. Consideration should be given to increasing the clozapine dose if necessary. When nevirapine is discontinued, reduce the clozapine dose based on clinical response. Nevirapine is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Nicardipine: (Moderate) Caution is advisable during concurrent use of nicardipine and clozapine. Nicardipine is an inhibitor of CYP3A4 and CYP2D6, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 or CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
NIFEdipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Nilotinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. In addition, coadministration of clozapine and nilotinib may result in increased risk of QT prolongation.
Niraparib; Abiraterone: (Moderate) Monitor for an increase in clozapine-related adverse reactions if coadministration with abiraterone is necessary; consider reducing the dose of clozapine if clinically appropriate. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. If abiraterone is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Clozapine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor.
Nirmatrelvir; Ritonavir: (Major) Avoid concurrent use of ritonavir-boosted nirmatrelvir and clozapine; consider an alternative COVID-19 therapy. If concurrent use is necessary, consider reducing the clozapine dose and monitoring for adverse reactions. Coadministration may increase clozapine exposure resulting in increased toxicity. Clozapine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) Consider a clozapine dose adjustment if coadministered with ritonavir and monitor for efficacy and adverse reactions. If ritonavir is discontinued, monitor for lack of clozapine effect and adverse effects and adjust dose if necessary. A clinically relevant increase or decrease in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4, CYP2D6, and CYP1A2. Ritonavir is a strong CYP3A4 and weak CYP2D6 inhibitor and a moderate inducer of CYP1A2.
Nirogacestat: (Moderate) Consider a clozapine dose reduction if coadministered with nirogacestat and monitor for adverse reactions. If nirogacestat is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A; nirogacestat is a moderate CYP3A inhibitor.
Nisoldipine: (Major) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Nitroprusside: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Nortriptyline: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Obeticholic Acid: (Moderate) Consider a clozapine dose reduction if coadministered with obeticholic acid and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate; obeticholic acid is a weak CYP1A2 inhibitor.
Obinutuzumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Odevixibat: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with odevixibat. Consideration should be given to increasing the clozapine dose if necessary. When odevixibat is discontinued, reduce the clozapine dose based on clinical response. Odevixibat is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Ofatumumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Olanzapine: (Major) Concurrent use of olanzapine and clozapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Some case reports describe the re-induction of bone-marrow suppression by olanzapine when the patient is known to have a history of clozapine-induced blood dyscrasias. When olanzapine therapy follows clozapine therapy in such patients, monitoring of complete blood counts is recommended.
Olanzapine; Fluoxetine: (Major) Concurrent use of olanzapine and clozapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Some case reports describe the re-induction of bone-marrow suppression by olanzapine when the patient is known to have a history of clozapine-induced blood dyscrasias. When olanzapine therapy follows clozapine therapy in such patients, monitoring of complete blood counts is recommended. (Moderate) Consider a clozapine dose reduction if coadministered with fluoxetine and monitor for adverse reactions including QT prolongation. If fluoxetine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of fluoxetine. Clozapine is a CYP2D6 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Fluoxetine is a strong CYP2D6 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
Olanzapine; Samidorphan: (Major) Concurrent use of olanzapine and clozapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Some case reports describe the re-induction of bone-marrow suppression by olanzapine when the patient is known to have a history of clozapine-induced blood dyscrasias. When olanzapine therapy follows clozapine therapy in such patients, monitoring of complete blood counts is recommended.
Oliceridine: (Major) Concomitant use of oliceridine with clozapine may cause excessive sedation and somnolence. Limit the use of oliceridine with clozapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Olmesartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Olutasidenib: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with olutasidenib. Consideration should be given to increasing the clozapine dose if necessary. When olutasidenib is discontinued, reduce the clozapine dose based on clinical response. Olutasidenib is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Omacetaxine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Omaveloxolone: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with omaveloxolone. Consideration should be given to increasing the clozapine dose if necessary. When omaveloxolone is discontinued, reduce the clozapine dose based on clinical response. Omaveloxolone is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Omeprazole: (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with rifabutin. Consideration should be given to increasing the clozapine dose if necessary. When rifabutin is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Omeprazole; Sodium Bicarbonate: (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Ondansetron: (Major) Concomitant use of ondansetron and clozapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Opicapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Oritavancin: (Moderate) Clozapine is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of clozapine may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like clozapine and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
Osilodrostat: (Moderate) Consider a clozapine dose reduction and monitor for adverse reactions if coadministered with osilodrostat; concurrent use may increase clozapine exposure. Additionally, consider more frequent ECG monitoring due to the risk of additive QT prolongation. If osilodrostat is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Clozapine is a CYP1A2 and CYP3A4 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Osilodrostat is a moderate CYP1A2 and weak CYP3A4 inhibitor that is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of clozapine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Oxaliplatin: (Major) Monitor ECGs and electrolytes in patients receiving oxaliplatin and clozapine concomitantly; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. Treatment with clozapine has also been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Oxazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Oxcarbazepine: (Major) Clozapine has an established risk of seizures, which may compromise the effectiveness of oxcarbazepine in the treatment of seizure disorders. In addition, concurrent use of clozapine and oxcarbazepine may decrease the therapeutic effects of clozapine since oxcarbazepine is an inducer of CYP3A4 and clozapine is a substrate for this isoenzyme. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary. Monitor for additive CNS effects.
Oxybutynin: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, this drug combination may result in additive effects on intestinal motility or bladder function. Prior to concurrent use of oxycodone in patients taking clozapine, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower clozapine dose. Monitor patients for sedation and respiratory depression.
Oxymorphone: (Moderate) Concomitant use of oxymorphone with other CNS depressants may produce additive CNS depressant effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants include clozapine. Prior to concurrent use of oxymorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxymorphone, a reduced dosage of oxymorphone (1/3 to 1/2 of the usual dose) and/or the CNS depressant is recommended. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, it is recommended to use an initial dosage of 5 mg PO every 12 hours. Monitor for sedation or respiratory depression.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking clozapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Pacritinib: (Major) Concomitant use of clozapine and pacritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase clozapine exposure and the risk for other clozapine-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concurrent use is necessary, consider a dosage reduction of clozapine and monitor for adverse reactions. If pacritinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clozapine is a substrate of CYP3A4 and CYP1A2; pacritinib is a weak CYP3A4 and CYP1A2 inhibitor.
Palbociclib: (Moderate) Monitor for an increase in clozapine-related adverse reactions if coadministration with palbociclib is necessary, including seizures, orthostasis, sedation, and QT prolongation; clozapine-related neutropenia is not concentration-dependent. Consider a dosage reduction of clozapine. Palbociclib is a weak time-dependent inhibitor of CYP3A while clozapine is a CYP3A4 substrate.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clozapine. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include clozapine. In addition, it is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Paroxetine: (Moderate) Consider a clozapine dose reduction if coadministered with paroxetine and monitor for adverse reactions. If paroxetine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6 and paroxetine is a strong CYP2D6 inhibitor.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with clozapine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Pazopanib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, in vitro studies have shown that pazopanib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Clozapine therapy may lead to S-T segment depression and flattening or inversion of T waves. In theory, concurrent use of pazopanib and clozapine could produce clinically significant prolongation of the QTc interval. Pazopanib is also a weak inhibitor of CYP3A4. Coadministration of pazopanib and clozapine, a CYP3A4 substrate, may cause an increase in systemic concentrations of clozapine. Elevated plasma concentrations of clozapine may increase the risk for QT prolongation, torsade de pointes (TdP), sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Pegaspargase: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Peginterferon Alfa-2b: (Major) Peginterferon alfa-2b is a CYP1A2 and CYP2D6 inhibitor and clozapine is a substrate of these enzymes; therefore, coadministration may lead to increased clozapine concentrations. According to the manufacturer of clozapine, patients receiving clozapine in combination with a CYP1A2 and CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. In addition, it is unclear if concurrent use of other drugs known to cause neutropenia (e.g., certain antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Peginterferon beta-1a: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., certain antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Pentamidine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with clozapine include pentamidine.
Pentazocine; Naloxone: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
Pentobarbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Pentostatin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as clozapine.
Perindopril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Perindopril; Amlodipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Perphenazine: (Moderate) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as clozapine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Perphenazine; Amitriptyline: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin. (Moderate) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as clozapine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Pertuzumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Pertuzumab; Trastuzumab; Hyaluronidase: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Pexidartinib: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with pexidartinib. Consideration should be given to increasing the clozapine dose if necessary. When pexidartinib is discontinued, reduce the clozapine dose based on clinical response. Pexidartinib is a moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Phenelzine: (Moderate) Monitor blood pressure and for unusual drowsiness and sedation during coadministration of monoamine oxidase inhibitors (MAOIs) and clozapine due to the risk for additive hypotension and CNS depression.
Phenobarbital: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as phenobarbital, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Phenobarbital may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of phenobarbital in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring of clinical and/or adverse effects is warranted when phenobarbital is used with clozapine. Additive sedation may be noted with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as phenobarbital, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Phenobarbital may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of phenobarbital in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring of clinical and/or adverse effects is warranted when phenobarbital is used with clozapine. Additive sedation may be noted with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Phenoxybenzamine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Phenytoin: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as phenytoin, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Phenytoin may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of phenytoin in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring of clinical and/or adverse effects is warranted when phenobarbital is used with clozapine.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Due to the risk of additive QT prolongation and potential for serious arrhythmias, the concurrent use of pimozide with clozapine is contraindicated. Concurrent use of pimozide with atypical agents may increase the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Pindolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pioglitazone; Glimepiride: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pioglitazone; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pirtobrutinib: (Moderate) Consider a clozapine dose reduction if coadministered with pirtobrutinib and monitor for adverse reactions. If pirtobrutinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Pirtobrutinib is a weak CYP3A inhibitor.
Pitolisant: (Major) Avoid coadministration of pitolisant with clozapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Pomalidomide: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking clozapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Posaconazole: (Contraindicated) Concurrent use of posaconazole and clozapine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of clozapine. These drugs used in combination may result in elevated clozapine plasma concentrations, causing an increased risk for clozapine-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as clozapine.
Pralatrexate: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Pramipexole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or pramipexole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and pramipexole may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with pramipexole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Pramlintide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Prazosin: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and clozapine. Concomitant use of pregabalin with clozapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Prilocaine; Epinephrine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
Primaquine: (Moderate) Exercise caution when administering primaquine in combination with clozapine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Primidone: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as primidone, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Primidone may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of primidone in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring is warranted when primidone is used with clozapine. Additive sedation may be noted with concurrent use of clozapine and primidone; enzyme induction by primidone may take several days to become clinically apparent.
Procainamide: (Major) Clozapine should be used cautiously with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Prochlorperazine: (Moderate) Prochlorperazine, a phenothiazine, is associated with a possible risk for QT prolongation and clozapine has a possible risk of QT prolongation and torsade de pointes. Coadministration of prochlorperazine and clozapine may increase the risk of adverse effects such as QT prolongation, torsade de pointes, drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Promethazine: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary.
Promethazine; Dextromethorphan: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary.
Promethazine; Phenylephrine: (Major) Coadministration of promethazine and clozapine may increase the risk of QT prolongation and other adverse effects. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, and seizures. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary.
Propafenone: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as propafenone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, propafenone is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary.
Propantheline: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Propofol: (Moderate) Clozapine can potentiate the actions of other CNS depressants such as the general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Propranolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Protriptyline: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Pseudoephedrine; Triprolidine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as triprolidine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Purine analogs: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Quazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Quetiapine: (Major) Concurrent use of quetiapine and clozapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of quetiapine with clozapine may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Quinapril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Quinidine: (Contraindicated) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include clozapine.
Quinine: (Major) Both clozapine and quinine are associated with a possible risk for QT prolongation and torsade de pointes (TdP). Avoid concurrent use if possible. In addition, quinine is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through inhibition of CYP2D6 or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer of clozapine, monitor for adverse reactions and consider reducing the clozapine dose during concomitant use of inhibitors of CYP2D6 or CYP3A4. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Quizartinib: (Major) Concomitant use of quizartinib and clozapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Radium-223 Dichloride: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Ramipril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Ramucirumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Ranolazine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as ranolazine. Additionally, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as clozapine. Elevated plasma concentrations of clozapine may increase the risk for QT prolongation, torsade de pointes (TdP), sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Rasagiline: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or rasagiline during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rasagiline may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with rasagiline than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Regular Insulin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Regular Insulin; Isophane Insulin (NPH): (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Relugolix: (Moderate) Use clozapine with caution in combination with relugolix. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Use clozapine with caution in combination with relugolix. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Remifentanil: (Moderate) Remifentanil should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Combining clozapine with opiate agonists may also lead to reduced intestinal motility or bladder function.
Remimazolam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Repotrectinib: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with repotrectinib. Consideration should be given to increasing the clozapine dose if necessary. When repotrectinib is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer.
Ribociclib: (Major) Avoid coadministration of ribociclib with clozapine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of clozapine may also be increased resulting in an increase in clozapine-related adverse reactions. Clozapine is a CYP3A4 substrate that has also been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with clozapine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of clozapine may also be increased resulting in an increase in clozapine-related adverse reactions. Clozapine is a CYP3A4 substrate that has also been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
Rifabutin: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with rifabutin. Consideration should be given to increasing the clozapine dose if necessary. When rifabutin is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Rifampin: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as rifampin, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Rifampin may also increase the metabolism of clozapine through induction of CYP1A2.
Rifapentine: (Major) Coadministration of clozapine with rifapentine is not recommended due to decreased plasma concentrations of clozapine. If concomitant use is unavoidable, the patient should be monitored for loss of efficacy; consider increasing the clozapine dose if necessary. When rifapentine is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Risperidone: (Moderate) Because both clozapine and risperidone have a possible risk for QT prolongation and/or torsade de pointes (TdP), caution is advisable during concurrent use. Reports of QT prolongation and TdP during risperidone therapy are noted primarily in the overdosage setting. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. If coadministration is required, the patient's underlying medical conditions and additional potential risk factors should be considered. Patients with known risk factors for cardiac disease or arrhythmia should be closely monitored. In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, or seizures. Chronic administration of clozapine and risperidone may decrease the clearance of risperidone.
Ritlecitinib: (Moderate) Consider a clozapine dose reduction if coadministered with ritlecitinib and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 and CYP3A substrate; ritlecitinib is a moderate CYP1A2 and CYP3A inhibitor.
Ritonavir: (Major) Consider a clozapine dose adjustment if coadministered with ritonavir and monitor for efficacy and adverse reactions. If ritonavir is discontinued, monitor for lack of clozapine effect and adverse effects and adjust dose if necessary. A clinically relevant increase or decrease in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4, CYP2D6, and CYP1A2. Ritonavir is a strong CYP3A4 and weak CYP2D6 inhibitor and a moderate inducer of CYP1A2.
Rivastigmine: (Moderate) Concurrent use of rivastigmine and clozapine should be avoided if possible. Clozapine exhibits considerable anticholinergic activity, and is more likely than other atypical antipsychotics to diminish the therapeutic action of rivastigmine. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Consider the use of an antipsychotic with less prominent anticholinergic effects.
Rolapitant: (Moderate) Use caution if clozapine and rolapitant are used concurrently, and monitor for clozapine-related adverse effects, including QT prolongation. Clozapine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration. Elevated plasma concentrations of clozapine may increase the risk for QT prolongation, torsade de pointes (TdP), sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Romidepsin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Antineoplastic agents with a possible risk of QT prolongation and TdP (torsade de pointes) include romidepsin. In theory, coadministration could produce clinically significant prolongation of the QTc interval.
Ropinirole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or ropinirole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and ropinirole may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with ropinirole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Rotigotine: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, excess sedation, and diminished effectiveness of the atypical antipsychotic or rotigotine during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rotigotine may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with rotigotine than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Rucaparib: (Moderate) Monitor for an increase in clozapine-related adverse reactions (e.g., sedation, orthostasis, seizures, and QT prolongation) if coadministration with rucaparib is necessary; consider reducing the dose of clozapine if needed. If rucaparib is discontinued, monitor for a lack of efficacy, increasing the clozapine dose if necessary. Clozapine is a CYP1A2 and CYP3A4 substrate. Rucaparib is a moderate CYP1A2 inhibitor as well as a weak CYP3A4 inhibitor. Coadministration may increase plasma concentrations of clozapine.
Ruxolitinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Sacubitril; Valsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Safinamide: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or safinamide during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and safinamide may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with safinamide than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Saquinavir: (Contraindicated) Concurrent use of clozapine and saquinavir is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Scopolamine: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Secobarbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Selegiline: (Moderate) Monitor for loss of selegiline efficacy, signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, and unusual drowsiness and sedation during concomitant atypical antipsychotic and selegiline use. Dopamine antagonists, such as atypical antipsychotics, may diminish the effectiveness of selegiline. Concomitant use may increase the risk for serotonin syndrome or additive CNS depression. If serotonin syndrome occurs, discontinue therapy.
Selpercatinib: (Major) Consider a clozapine dose reduction if coadministered with selpercatinib and monitor for adverse reactions, including QT prolongation. Monitor ECGs more frequently during coadministration. If selpercatinib is discontinued, monitor for lack of clozapine effect, and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine and increased risk of QT prolongation may occur during concurrent use. Clozapine is a CYP3A4 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Selpercatinib is a weak CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner.
Semaglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sertraline: (Moderate) Use caution and monitor patients for QT prolongation when administering clozapine with sertraline. Treatment with clozapine has been associated with QT prolongation, torsade de pointes, cardiac arrest, and sudden death. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure). In addition, concurrent use of clozapine, a CYP2D6 substrate, with a CYP2D6 inhibitor, such as sertraline, can increase clozapine plasma concentrations and lead to adverse effects, such as seizures or orthostatic hypotension. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of sertraline. A case denoting sudden cardiac death has been described in the literature when clozapine was combined with sertraline, but causality was not established.
Sevoflurane: (Major) Concomitant use of clozapine and halogenated anesthetics increases the risk of QT/QTc prolongation, torsade de pointes (TdP), excessive sedation and respiratory depression, and neuroleptic malignant syndrome (NMS). Avoid concomitant use if possible, especially in patients with additional risk factors for these adverse effects. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary and monitor for signs and symptoms of NMS and prolonged sedation and respiratory depression.
SGLT2 Inhibitors: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Siltuximab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving clozapine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Treatment with clozapine has been associated with QT prolongation, torsade de pointes, cardiac arrest, and sudden death.
Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with taurursodiol. Consideration should be given to increasing the clozapine dose if necessary. When taurursodiol is discontinued, reduce the clozapine dose based on clinical response. Clozapine is a CYP3A and CYP1A2 substrate and taurursodiol is a weak CYP3A and CYP1A2 inducer.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Solifenacin: (Moderate) Use clozapine with caution in combination with solifenacin as concurrent use may increase the risk of QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with clozapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Sorafenib is also associated with QTc prolongation.
Sotagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sotalol: (Major) Concomitant use of sotalol and clozapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with sotorasib. Consideration should be given to increasing the clozapine dose if necessary. When sotorasib is discontinued, reduce the clozapine dose based on clinical response. Sotorasib is a moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Spironolactone: (Moderate) Consider a clozapine dose reduction if coadministered with spironolactone and monitor for adverse reactions. If spironolactone is discontinued, monitor for lack of clozapine effect, and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Spironolactone is a weak CYP3A inhibitor. Additionally, monitor blood pressure and adjust spironolactone dose accordingly as clozapine may enhance the hypotensive effects of antihypertensive agents.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Consider a clozapine dose reduction if coadministered with spironolactone and monitor for adverse reactions. If spironolactone is discontinued, monitor for lack of clozapine effect, and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Spironolactone is a weak CYP3A inhibitor. Additionally, monitor blood pressure and adjust spironolactone dose accordingly as clozapine may enhance the hypotensive effects of antihypertensive agents.
St. John's Wort, Hypericum perforatum: (Major) Concomitant use of clozapine, a CYP3A4 substrate, with strong CYP3A4 inducers, including St. John's Wort, Hypericum perforatum, is not recommended; however, if this combination is necessary, monitor for decreased effectiveness with consideration for increasing the clozapine dose if clinically warranted. St. John's Wort is also a CYP1A2 inducer, which may further increase the elimination of clozapine.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and clozapine. CNS depressants can potentiate the effects of stiripentol.
Streptogramins: (Moderate) Consider a clozapine dose reduction if coadministered with dalfopristin; quinupristin and monitor for adverse reactions. If dalfopristin; quinupristin is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor.
Sufentanil: (Moderate) Sufentanil should be combined cautiously with clozapine due to the potential for additive depressant effects, respiratory depression, or hypotension. Combining clozapine with opiate agonists may also lead to reduced intestinal motility or bladder function.
Sulfonylureas: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Sunitinib can prolong the QT interval.
Suvorexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of suvorexant and atypical antipsyhotics. Dosage adjustments of suvorexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with other CNS depressants.
Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with clozapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Tapentadol: (Moderate) Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants. Severe hypotension, profound sedation, coma, or respiratory depression may occur. Prior to concurrent use of tapentadol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with tapentadol, a reduced dosage of tapentadol and/or the CNS depressant is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
Telavancin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with clozapine. Telavancin has been associated with QT prolongation, while treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Telmisartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Telmisartan; Amlodipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Telotristat Ethyl: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with telotristat. Consideration should be given to increasing the clozapine dose if necessary. When telotristat is discontinued, reduce the clozapine dose based on clinical response. Telotristat is a weak inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Temazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Terbinafine: (Moderate) Consider a clozapine dose reduction if coadministered with terbinafine and monitor for adverse reactions. If terbinafine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6 and terbinafine is a strong CYP2D6 inhibitor.
Teriflunomide: (Moderate) Caution is advisable during concurrent use of teriflunomide with clozapine. Teriflunomide induces CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Patients receiving clozapine in combination with a CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions and consider reducing the clozapine dose if necessary.
Tetrabenazine: (Major) Concurrent use of tetrabenazine and clozapine should be avoided if possible. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer of tetrabenazine recommends against concurrent use of tetrabenazine with other drugs known to prolong QTc. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. In addition, tetrabenazine is a selective, reversible, centrally-acting dopamine depleting drug and clozapine is a central dopamine antagonist. The risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, neuroleptic malignant syndrome, or extrapyramidal symptoms may be increased.
Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and clozapine concurrently. Ivacaftor is an inhibitor of CYP3A and clozapine is partially metabolized by CYP3A. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Thalidomide: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Thiazide diuretics: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine.
Thioguanine, 6-TG: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Thioridazine: (Contraindicated) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Because thioridazine has an established risk of QT prolongation and TdP, concurrent use with clozapine is considered contraindicated. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. Clozapine is metabolized by CYP1A2, CYP3A4, and CYP2D6. Antipsychotic drugs known to inhibit the activity of CYP2D6 include thioridazine. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP3A4, or CYP2D6 may potentially increase the risk of life-threatening arrhythmias or other adverse effects.
Thiothixene: (Major) Co-administration of clozapine with thiothixene may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Timolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Tipranavir: (Moderate) Caution is advisable during concurrent use of tipranavir and clozapine. Clozapine is a substrate for CYP1A2, CYP2D6, and CYP3A4; tipranavir is a potent inhibitor of CYP3A4 and CYP2D6, and a moderate inducer of CYP1A2. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Use with a CYP1A2 inducer may result in a loss of effectiveness of clozapine. According to the manufacturer, patients receiving clozapine in combination with inhibitors or inducers of CYP2D6, CYP3A4, or CYP1A2 should be monitored for adverse reactions or loss of effectiveness, respectively. Consideration should be given to adjusting the clozapine dose as clinically warranted.
Tirzepatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Tobacco: (Major) Advise patients to avoid tobacco products while receiving clozapine. Tobacco smoking may decrease the plasma concentration of clozapine; monitor for decreased effectiveness. Consider increasing the clozapine dose if necessary. Smoking tobacco induces CYP1A2 and clozapine is a CYP1A2 substrate.
Tolcapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Tolterodine: (Major) Depending on the specific agent, additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly with other antimuscarinics. Other commonly used drugs with moderate to significant anticholinergic effects include clozapine. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent. In addition, tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Drugs that are also associated with QT prolongation and have antimuscarinic properties that should be used cautiously and with close monitoring with tolterodine include clozapine.
Toremifene: (Major) Avoid coadministration of clozapine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Treatment with clozapine has also been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Tramadol: (Moderate) Concurrent use of tramadol and clozapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that clozapine has CYP2D6 inhibitory effects and may increase plasma concentrations of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by clozapine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and clozapine.
Tramadol; Acetaminophen: (Moderate) Concurrent use of tramadol and clozapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that clozapine has CYP2D6 inhibitory effects and may increase plasma concentrations of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by clozapine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and clozapine.
Trandolapril: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Trandolapril; Verapamil: (Moderate) Caution is advisable during concurrent use of verapamil and clozapine. Verapamil is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Tranylcypromine: (Moderate) Monitor blood pressure and for unusual drowsiness and sedation during coadministration of monoamine oxidase inhibitors (MAOIs) and clozapine due to the risk for additive hypotension and CNS depression.
Trazodone: (Major) Concomitant use of trazodone and clozapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Treprostinil: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Tretinoin, ATRA: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Triamterene: (Moderate) Monitor blood pressure and adjust triamterene dose accordingly as clozapine may enhance the hypotensive effects of antihypertensive agents.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Monitor blood pressure and adjust triamterene dose accordingly as clozapine may enhance the hypotensive effects of antihypertensive agents.
Triazolam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Tricyclic antidepressants: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Trifluoperazine: (Moderate) Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as clozapine. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Trihexyphenidyl: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Trimipramine: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, trimipramine, and doxepin.
Triprolidine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as triprolidine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving clozapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Trofinetide: (Moderate) Consider a clozapine dose reduction if coadministered with trofinetide and monitor for adverse reactions. If trofinetide is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Trofinetide is a weak CYP3A inhibitor.
Trospium: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like trospium are used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including clozapine.
Tucatinib: (Moderate) Consider a clozapine dose reduction if coadministered with tucatinib and monitor for adverse reactions. If tucatinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4; tucatinib is a strong CYP3A4 inhibitor.
Valproic Acid, Divalproex Sodium: (Moderate) Until more data become available, it is advisable to monitor for effectiveness of clozapine as well as evidence of side effects during concurrent use of valproic acid. One study documented an average decrease in clozapine concentrations of 41% during combined use, while others report minor increases in clozapine serum concentrations. The mechanism by which this apparent pharmacokinetic interaction occurs is not clear, since valproic acid is not an established inhibitor or inducer of the primary CYP isoenzymes responsible for clozapine metabolism, and the protein binding characteristics of the two agents differ. No adverse outcomes were reported in association with these studies; however, further investigation is needed to establish clinical relevance. In a separate case, one patient experienced sedation, confusion, disorientation, and slurred speech when clozapine was added to a regimen of valproic acid and lithium; discontinuation of valproic acid with subsequent re-initiation produced similar symptoms. The authors suggest the CNS properties of valproic acid and clozapine as one possible explanation; however, the exact cause of the reaction cannot be determined with the available information. Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, have occurred when clozapine was coadministered with valproic acid or divalproex sodium. Although clozapine is associated with a well-established risk of seizures, the benefits and risks of continuing clozapine with anticonvulsant therapy must be considered in a patient whose psychiatric sypmtoms have improved substantially while taking clozapine. Clinicians should also monitor for weight gain and sedation during combination therapy with clozapine and valproic acid. In addition, the risk for adverse hematologic effects such as neutropenia may theoretically be increased during concomitant use of these agents.
Valsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution is advisable during concurrent use of clozapine and thiazide diuretics as concurrent use may increase the risk and severity of hypotension. In addition, electrolyte imbalance caused by thiazide diuretics may increase the risk of QT prolongation by clozapine. (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Vandetanib: (Major) Avoid coadministration of vandetanib with clozapine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Treatment with clozapine has also been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Vardenafil: (Moderate) Concomitant use of vardenafil and clozapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Vasopressin, ADH: (Moderate) Monitor hemodynamics and adjust the dose of vasopressin as needed when used concomitantly with drugs suspected of causing diabetes insipidus, such as clozapine. Use together may decrease the pressor and antidiuretic effects of vasopressin.
Vemurafenib: (Major) Vemurafenib is a moderate CYP1A2 inhibitor and the manufacturer of vemurafenib recommends avoiding use with medications that are CYP1A2 substrates and that have a narrow therapeutic index. In addition, vemurafenib is a weak inhibitor of CYP2D6 and a substrate/inducer of CYP3A4 while clozapine is a substrate of CYP1A2, 2D6, and 3A4. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. Vemurafenib is also associated with a possible risk for QT prolongation and torsade de pointes (TdP), It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. If concurrent use of vemurafenib and clozapine is necessary, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor, CYP2D6 inhibitor, or CYP3A4 inhibitor to clozapine treatment, the manufacturer of clozapine recommends monitoring for adverse reactions and reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Venlafaxine: (Major) Venlafaxine is associated with a possible risk of QT prolongation and clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. In addition, venlafaxine is a weak inhibitor of CYP2D6. Clozapine is a substrate of CYP1A2, CYP2D6, or CYP3A4 and elevated plasma concentrations of clozapine occurring through CYP inhibition may increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Post-marketing reports have indicated there may be the potential for seizure activity if venlafaxine is added to established clozapine therapy. Clozapine serum concentrations have risen temporally following the addition of venlafaxine.
Verapamil: (Moderate) Caution is advisable during concurrent use of verapamil and clozapine. Verapamil is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Viloxazine: (Major) Reduce the clozapine dose to one-third of the original dose when coadministered with viloxazine and monitor for adverse reactions. If viloxazine is discontinued, monitor for lack of clozapine effect and increase the clozapine dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use, resulting in adverse reactions. Clozapine is a CYP1A2, CYP2D6, and CYP3A substrate; viloxazine is a strong CYP1A2, weak CYP2D6, and weak CYP3A inhibitor.
Vinblastine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Vincristine Liposomal: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Vincristine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Vinorelbine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Vismodegib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Voclosporin: (Moderate) Concomitant use of voclosporin and clozapine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Vonoprazan: (Moderate) Consider a clozapine dose reduction if coadministered with vonoprazan and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A and vonoprazan is a weak CYP3A inhibitor. If vonoprazan is discontinued, monitor for lack of clozapine effect and increase dose if necessary.
Vonoprazan; Amoxicillin: (Moderate) Consider a clozapine dose reduction if coadministered with vonoprazan and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A and vonoprazan is a weak CYP3A inhibitor. If vonoprazan is discontinued, monitor for lack of clozapine effect and increase dose if necessary.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Consider a clozapine dose reduction if coadministered with vonoprazan and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A and vonoprazan is a weak CYP3A inhibitor. If vonoprazan is discontinued, monitor for lack of clozapine effect and increase dose if necessary.
Voriconazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clozapine. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with clozapine (a CYP3A4 substrate) may result in elevated clozapine plasma concentrations and could increase the risk for adverse events, including QT prolongation. Consider reducing the clozapine dose if necessary. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorinostat: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, clozapine therapy may lead to S-T segment depression and flattening or inversion of T waves. Vorinostat therapy is associated with a risk of QT prolongation. In theory, coadministration could produce clinically significant prolongation of the QTc interval.
Voxelotor: (Moderate) Consider a clozapine dose reduction if coadministered with voxelotor and monitor for adverse reactions. If voxelotor is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Moderate) The protein binding of clozapine is 97%; highly protein-bound medications can displace clozapine from its binding sites, predominantly alpha-1-acid glycoprotein. Clozapine, in turn, can increase the serum concentrations of digoxin or warfarin. Closely observe patients on other highly protein-bound drugs for an increased incidence of adverse effects.
Zafirlukast: (Moderate) Caution is advisable during concurrent use of zafirlukast and clozapine. Zafirlukast is an inhibitor of CYP3A4 and CYP1A2, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 or CYP1A2 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Zaleplon: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Ziconotide: (Moderate) Clozapine has CNS depressant effects and may increase drowsiness, dizziness, and confusion that are associated with ziconotide if coadministered.
Zileuton: (Moderate) Consider a clozapine dose reduction if coadministered with zileuton and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate. Zileuton is a weak CYP1A2 inhibitor.
Ziprasidone: (Major) Concomitant use of ziprasidone and clozapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. At elevated serum concentrations, clozapine may produce clinically significant prolongation of the QTc interval. In addition, coadministration of atypical antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Ziv-Aflibercept: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Zolpidem: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zolpidem due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Limit the dose of Intermezzo sublingual tablets to 1.75 mg/day.
Zonisamide: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
Zuranolone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Clozapine is an atypical antipsychotic. Although the exact mechanism of action of clozapine is unknown, the therapeutic effect is thought to occur in part from inhibition of central dopamine-2 (D2) and serotonin 5-HT2A receptors. While the efficacy of conventional antipsychotics in treating the positive symptoms of schizophrenia occurs primarily from central D2 antagonism in the limbic area of the brain, clozapine has a high affinity for 5-HT2A receptors (ki = 5.4 nM) compared to D2 receptors (ki = 160 nM), which may contribute to its efficacy in treating both positive and negative symptoms of schizophrenia. Negative symptoms are thought to occur from decreased dopamine activity in the mesocortical tract of the brain where antagonism of serotonin receptors is hypothesized to lead to an increase in dopamine release thereby reducing negative symptoms. Clozapine also has an inhibitory binding affinity at 5-HT6, muscarinic-1 (M1), 5-HT7, and 5-HT2C receptors, and to a lesser extent at alpha-2, 5-HT3, 5-HT1A, D1, D3, D4, and D5 receptors; however, the exact contribution of the receptor binding profile of clozapine as it relates to the safety and efficacy of the drug has not been fully defined. Clozapine exhibits potent inhibitory binding affinity at histamine-1 (H1) and alpha-1 receptors. The orthostatic effects observed with clozapine are likely due to its alpha-1 receptor activity and the sedative properties occur largely from its antihistaminic action. Clozapine often causes problematic anticholinergic effects, however, paradoxically, it can cause sialorrhea. Full agonist activity at the M4 muscarinic receptor is thought to contribute to sialorrhea. In contrast to some antipsychotics, clozapine produces little to no hyperprolactinemia. The lower incidence of extrapyramidal symptoms associated with clozapine compared to other antipsychotics may be related to reduced affinity for dopamine receptors in the nigrostriatal pathway of the brain.
Clozapine is administered orally. The onset of antipsychotic effect can take several weeks, but maximal effects can require several months. There is a wide variation in the clinically effective dose between individuals and the relationship between the dose of clozapine and the resulting serum concentration is weak. Therapeutic drug monitoring is not routinely performed or recommended; however, it has been suggested that a therapeutic response in treatment-refractory schizophrenia is associated with plasma concentrations above 350 ng/mL. Clozapine is 97% bound to serum proteins, and has the potential for interactions with other highly protein bound drugs. Metabolism is extensive and occurs primarily via CYP1A2, CYP2D6 and CYP3A4. Norclozapine, the desmethyl metabolite, has limited pharmacological activity while the hydroxylated and N-oxide derivatives are inactive. In one study, the mean elimination half-life after a single oral 75 mg dose was 8 hours (range: 4 to 12 hours) compared to 12 hours (range: 4 to 66 hours) after achieving steady state with 100 mg PO twice daily dosing. Clozapine is almost completely metabolized prior to excretion; only trace amounts of unchanged drug are detected in the urine and the feces. About 50% of a dose is excreted in the urine and 30% in the feces, mostly as metabolites.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2D6, CYP3A4
Clozapine metabolism occurs primarily through CYP1A2, CYP2D6 and CYP3A4. A dosage reduction of clozapine is necessary during concurrent use of strong CYP1A2 inhibitors. Patients receiving weak to moderate CYP1A2 inhibitors, CYP2D6 or CYP3A4 inhibitors, weak to moderate CYP3A4 inducers, or weak to moderate CYP1A2 inducers should be monitored with consideration of a dose adjustment based upon response or adverse reactions. Concurrent use of strong CYP3A4 inducers is not recommended.
-Route-Specific Pharmacokinetics
Oral Route
Clozapine is administered orally as tablets, orally disintegrating tablets, and oral suspension. The orally disintegrating tablets and oral suspension are bioequivalent to the oral tablets and may be substituted on a milligram-for-milligram basis. The average oral bioavailability ranges from 50% to 60%, although bioavailability data vary significantly between studies (range: 22% to more than 90%). Food does not appear to affect the systemic bioavailability of clozapine; therefore, all formulations may be administered with or without food. After administration of 100 to 800 mg/day of the oral suspension, steady-state peak plasma concentrations were attained in an average of 2.2 hours (range: 1 to 3.5 hours). Steady-state concentrations can be attained within 1 week of twice daily dosing.
-Special Populations
Hepatic Impairment
No pharmacokinetic studies have been conducted to evaluate the effects of hepatic impairment on clozapine exposure, although higher plasma concentrations are expected in patients with significant hepatic impairment, as clozapine is extensively metabolized before excretion. It may be necessary to reduce the dose of clozapine in patients with significant hepatic impairment.
Renal Impairment
No pharmacokinetic studies have been conducted to evaluate the effects of renal impairment on clozapine exposure, although higher plasma concentrations are expected in patients with significant renal impairment. It may be necessary to reduce the dose of clozapine in patients with significant renal impairment. There are conflicting data from case reports evaluating plasma concentrations of clozapine and norclozapine during hemodialysis; therefore, well-controlled studies are needed to determine the effect, if any, of dialysis on the pharmacokinetics of clozapine.
Pediatrics
Pharmacokinetic data are not available for pediatric patients.
Geriatric
There have not been sufficient numbers of geriatric patients to determine if they have different pharmacokinetic data vs. younger adults. However, geriatric patients may need a slower titration due to age-related susceptibilities to anticholinergic effects and orthostatic hypotension.
Other
Poor Metabolizers of CYP2D6 (CYP2D6 PMs)
Poor metabolizers of CYP2D6 may develop higher than expected plasma concentrations of clozapine when receiving usual doses.
Smoking
Tobacco smoke increases the clearance of clozapine, which may result in a reduction in clozapine plasma concentrations. Tobacco smoke is a moderate inducer of CYP1A2, one of the isoenzymes responsible for clozapine metabolism. In one study, the average plasma clozapine level of smokers was 81.8% of the clozapine levels of non-smokers (p = 0.022). In the same study, the plasma clozapine levels in male smokers were 67.9% of those of non-smokers (p = 0.0083). A separate study found that non-smokers had 3.2-fold higher plasma clozapine levels compared to smokers. Smokers should be monitored for decreased effectiveness of clozapine. Consider increasing the clozapine dose if necessary. Dosage adjustments may be required if smoking is discontinued.