Olanzapine is an atypical antipsychotic similar in chemical structure and mechanism of action to clozapine, but with a lower incidence of side effects, including neutropenia. Atypical antipsychotics (excluding clozapine) are deemed to be the standard of care for schizophrenia and related disorders. Clinically, olanzapine is effective for the positive and negative symptoms of schizophrenia and for mood stabilization in patients with bipolar I disorder. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study evaluated the effectiveness of selected atypical antipsychotics and perphenazine in schizophrenic patients. The primary outcome measure was discontinuation of treatment for any cause, with secondary outcomes evaluating drug efficacy (determined via the PANSS and CGI scale), adverse event profiles, and reasons for drug discontinuation. For the primary outcome measure, 74% of patients discontinued study medication before 18 months. The olanzapine group demonstrated a slightly longer time to discontinuation of treatment for any cause compared to the quetiapine or risperidone groups. Secondarily, the duration of successful treatment was significantly longer in the olanzapine and risperidone groups, compared to other atypicals antipsychotics or perphenazine. The PANSS and CGI scores improved and were similar in all groups. Rates of hospitalizations were lowest in the olanzapine group (11%) vs. other treatment groups (15% to 20%). However, discontinuation of treatment due to adverse events was greater in the olanzapine group, primarily due to weight gain and metabolic effects. Compared to haloperidol or lithium, olanzapine is equally effective in achieving remission in bipolar mania. Olanzapine has been shown to be superior to valproate in a 3-week study of acute bipolar adult patients with mixed or manic episodes, but the decrease in the Hamilton Depression scores were similar. Olanzapine is FDA-approved for the treatment of schizophrenia and for manic or mixed episodes associated with bipolar I disorder (as monotherapy or in combination with lithium or valproate) in both adults and adolescents, and can be used for the maintenance treatment of bipolar I disorder as monotherapy. In adults, olanzapine is an effective adjunct to fluoxetine for treatment-refractory depression or for depressive episodes of bipolar I disorder. An intramuscular injection solution formulation (Zyprexa IntraMuscular) treats acute agitation associated with schizophrenia and bipolar disorder. An extended-release intramuscular depot formulation (Zyprexa Relprevv) is used for the maintenance treatment of schizophrenia in adults and is administered every 2 to 4 weeks. As with other atypical antipsychotics used for psychosis and as an adjunct to antidepressants, a boxed warning related to an increased risk of suicidality in children, adolescents, and young adults, as well as regarding increased mortality risk in elderly patients treated for dementia-related psychosis, is noted in the product labels.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May be administered without regard to meals.
Oral Solid Formulations
-Orally disintegrating tablets: Leave the disintegrating tablet in the foil package until ready to administer. Do not push the tablet through the blister pack. Peel open the package with dry hands and place the tablet on the patient's tongue. The tablet will dissolve rapidly and be swallowed in the saliva. The tablet may be administered with fluid if needed, but it is not necessary to do so.
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intramuscular Administration
Immediate-release intramuscular injection (Zyprexa IntraMuscular)
-Do not administer intravenously or intra-arterially.
-Dissolve the contents of the vial using 2.1 mL of Sterile Water for Injection to provide a solution containing approximately 5 mg/ml; refer to manufacturer table for injection volumes and corresponding doses.
-Dissolve contents of vial completely; resulting solution should be clear and yellow.
-Inject deeply into the gluteal muscle to minimize tissue irritation. Do not inject more than 5 mL into any one site.
-Use solution within 1 hour; discard any unused portion.
-Immediately after use, dispose of syringe in approved sharps box.
Extended-release intramuscular injection (Zyprexa Relprevv)
-Zyprexa Relprevv is available only through a restricted distribution program where the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the Zyprexa Relprevv Patient Care Program. To enroll, call 1-877-772-9390.
-For deep intramuscular gluteal injection only. Do not administer intravenously or subcutaneously.
-Use only the diluent provided in the Zyprexa Relprevv convenience kit for preparation of the suspension.
-The vial is for single-use only.
-Administer every 2 to 4 weeks by deep intramuscular gluteal injection using the 19-gauge, 1.5-inch needle contained in the convenience kit. For obese patients, a 2-inch, 19-gauge or larger needle may be used.
-See manufacturer insert entitled "Instructions to Reconstitute and Administer Zyprexa Relprevv" for information regarding the safe and effective use of the Hypodermic Needle-Pro syringe and needle.
-Zyprexa Relprevv must be administered in a registered healthcare facility with ready access to emergency response services.
-After each injection, a healthcare professional must continuously observe the patient at the healthcare facility for at least 3 hours for symptoms of Post-Injection Delirium/Sedation Syndrome (see Contraindications).
-Before administration of the injection, confirm that there will be someone to accompany the patient to their destination after the 3 hour observation period. If this cannot be confirmed, do not give the injection.
-Following the 3 hour observation period, the healthcare professional must confirm that the patient is alert, oriented, and free of any signs or symptoms of Post-Injection Delirium/Sedation Syndrome before releasing the patient.
Reconstitution of Zyprexa Relprevv
-It is advisable to wear gloves during reconstitution of the suspension to avoid irritation to the skin. Rinse skin with water if contact with preparation occurs.
-The diluent is a clear, colorless to slightly yellow solution in a glass vial; it should be noted that there is more diluent in the vial than is needed to reconstitute.
-210 mg vial: Use the 210 mg vial for a dose of 150 mg or 210 mg; reconstitute with 1.3 mL of the provided diluent.
-300 mg vial: Use the 300 mg vial for a dose of 300 mg; reconstitute with 1.8 mL of the provided diluent.
-405 mg vial: Use the 405 mg vial for a dose of 405 mg; reconstitute with 2.3 mL of the provided diluent.
-Loosen powder in the vial by lightly tapping the vial; withdraw appropriate diluent volume into the syringe using the Hypodermic Needle-Pro syringe/needle; inject diluent into the vial; pull back slightly on the syringe plunger to withdraw air to equalize the pressure in the vial; remove needle from the vial, holding the vial upright to prevent loss of material; engage needle safety device; pad a hard surface and tap the vial firmly on the surface until no powder is visible.
-Visually check reconstituted vial for clumps. Un-suspended powder appears as yellow, dry clumps on the vial surface.
-Shake reconstituted vial vigorously until the suspension appears smooth and consistent in color or texture. If foam forms, let vial stand until foam dissipates.
-The suspended product will be yellow and opaque.
-If the product is not used promptly after reconstitution, shake the vial vigorously to re-suspend at the time of injection; reconstituted suspension remains stable for up to 24 hours in the vial.
Intramuscular injection (Zyprexa Relprevv)
-After reconstitution of the product, attach a new safety needle to the syringe; slowly withdraw the desired amount into the syringe.
-To help prevent clogging, a 19-gauge or larger needle must be used.
-Select and prepare a site for injection in the gluteal area.
-The injection should be administered at a steady, continuous pressure.
-Do not massage the injection site.
-After the injection, engage the needle safety device and remove needle from syringe. Properly dispose of vials, needles, and syringes.
The most common adverse reaction observed in placebo-controlled trials of olanzapine is drowsiness (reported as somnolence). During clinical trials of orally administered olanzapine in adults, drowsiness was reported in 29% to 35% of those receiving active treatment. Results from one study indicate that drowsiness is dose-related, occurring in 20%, 30%, and 39% of patients who received olanzapine 5 mg/day, 10 mg/day, or 15 mg/day, respectively, . Drowsiness occurs at a higher frequency in adolescents than adults. During short-term clinical trials (6 weeks or less) in adolescents, sedation was reported in 39% to 48% of patients receiving olanzapine. In The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, drowsiness occurred in 24% to 31% of patients, with drowsiness being least in the ziprasidone group. Drowsiness was highest in the olanzapine and quetiapine groups (31% each). However, reported rates of insomnia ranged from 16% to 30%, and occurred least in the olanzapine group. Insomnia may have been a more important therapeutic outcome measure than drowsiness in the CATIE study. Other CNS effects reported more frequently in patients receiving oral olanzapine than placebo included: dizziness (7% to 18%), insomnia (12%), headache (17%), abnormal gait (6%), articulation impairment or dysarthria (2%), and fatigue (3% to 14%). Data from a dose comparison study indicate that fatigue is dose-related, having occurred in 1.5% of those receiving olanzapine 10 mg and 6.6% of those receiving 40 mg during the study. Data from a dose comparison study indicate that dizziness is dose-related, having occurred in 2.6% of those receiving olanzapine 10 mg and 6.6% of those receiving 40 mg during the study. Adverse events due to the immediate-release IM formulation also included somnolence (6% vs. 3%) and dizziness (4% vs. 2%). No patients experienced a serious adverse event after the administration of up to 3 doses. During a clinical trial of extended-release olanzapine injection, the following CNS effects were reported more frequently in patients receiving active drug than placebo: dizziness (1% to 4%), dysarthria (1% to 2%), fatigue (2% to 4%), headache (13% to18%), and drowsiness (8% to 13%). CNS effects occurring more often during combination therapy of olanzapine with lithium or valproate than the control groups included: dizziness (14%), drowsiness (52%), speech disorder (dysarthria 7%), incoordination (2%), and paresthesias (5%). CNS effects reported in 0.1% to 1% of patients receiving oral olanzapine during premarketing evaluation included ataxia, dysarthria, and stupor. Coma was reported rarely (less than 0.1%). The combination of olanzapine plus lithium or valproate resulted in a higher rate of discontinuation (11%) due to adverse events than if lithium or valproate were given as monotherapy (2%). The most common reason for discontinuation from clinical trials evaluating combination therapy was drowsiness (3%). Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine therapy include stuttering (dysphemia). The CATIE study evaluated the effectiveness of selected atypical antipsychotics and perphenazine in schizophrenic patients. The rate of treatment discontinuation due to intolerable side effects was highest for olanzapine group (18%) and lowest for risperidone (10%).
During a clinical trial of extended-release olanzapine injection, the following psychiatric effects were reported more frequently in patients receiving active drug than placebo: abnormal dreams (0-2% vs 0%), auditory hallucinations (0-3% vs 2%), restlessness (1-3% vs 2%), sleep disorder (0-2% vs 1%), and abnormal thinking (0-3% vs 1%). During clinical trials of oral olanzapine as monotherapy, personality disorder was reported in 8% of patients receiving active drug versus 4% of those receiving placebo. Restlessness was reported in 3% of olanzapine-treated adolescents versus 2% of placebo-treated patients. During clinical trials of combination therapy with olanzapine and lithium or valproate, depression (18% vs 17%), amnesia (5% vs 2%), apathy (4% vs 3%), confusion (4% vs 1%), and euphoria (3% vs 2%) were reported more frequently with active drug than placebo. Suicidal ideation (suicide attempt) was reported in 0.1-1% of patients receiving oral olanzapine during pre-marketing evaluation.
Dose-related extrapyramidal reactions are not frequent with olanzapine and occur at lower percentages than with haloperidol. Differences in EPS reactions with oral olanzapine treatment versus placebo were not evident in adult trials, with the exception of akathisia (3-5% vs 1-2%) , tremor (4-6% vs 3%), and hypertonia (3% vs 2%) During clinical trials with immediate-release olanzapine injection, tremor occurred in 1% of olanzapine-treated patients versus 0% of placebo-treated patients. In a controlled trial of extended-release olanzapine injection, tremor occurred in 0-3% of olanzapine-treated patients versus 1% of placebo-treated patients. Tremor was reported more frequently during combination treatment with olanzapine and lithium or valproate than in the control groups (23% vs 13%). In one fixed-dose study in adults comparing oral olanzapine 5 mg/day, 10 mg/day and 15 mg/day to placebo, the following EPS reactions were reported as assessed by formal rating scales: pseudoparkinsonism (12-14% vs 15%) and akathisia (16-27% vs 23%). In adolescent trials, the following EPS reactions were reported with oral olanzapine versus placebo as assessed by spontaneous reports: dystonic reaction (including dystonia, neck rigidity, oculogyric crisis, torticollis, 1% vs 0%), pseudoparkinsonism (1% vs 2%), akathisia (6% vs 4%), dyskinesia (1% vs 0%), nonspecific events (4% vs 0%), and any extrapyramidal event (10% vs 6%). In a fixed dose trial of immediate-release olanzapine injection (2.5 mg, 5 mg, 7.5 mg, 10 mg) compared to placebo, the following EPS reactions were reported as assessed by formal rating scales: pseudoparkinsonism (0-3% vs 0%) and akathisia (0-5% vs 0%). In a fixed dose trial of extended-release olanzapine injection (5 mg, 10 mg, 15 mg) compared to placebo, the following EPS reactions were reported as assessed by formal rating scales: pseudoparkinsonism (12-14% vs 15%) and akathisia (16-27% vs 23%). According to results from fixed-dose studies, akathisia appears to be dose-related. Dystonic reaction is a potential effect of all antipsychotics, and 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. Other EPS reactions may include pseudoparkinsonism (akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor), dyskinetic events (buccoglossal syndrome, choreoathetosis, dyskinesia), and residual events (movement disorder, myoclonia, twitching). The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study evaluated the effectiveness of selected atypical antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) and perphenazine in schizophrenic patients (see Atypical Antipsychotic Overview). In the secondary evaluation of adverse events and reasons for drug discontinuation, the rate of occurrence of any serious adverse effect was similar among groups. However, the discontinuation of treatment due to extrapyramidal symptoms (EPS) was low in the risperidone group (3%; 11/341) vs the perphenazine group (8%; 22/261). Olanzapine, quetiapine, and ziprasidone also had low incidences of EPS (2-4%).
Tardive dyskinesia is characterized by involuntary movements of the perioral region (tongue, mouth, jaw, eyelids, or face) or choreoathetoid movements in the extremities. It is observed more frequently in elderly women. The incidence of TD may be higher in those patients with bipolar disorder than those with schizophrenia. Some cases of TD may be irreversible. It has been suggested that the risk of developing TD increases with prolonged treatment and cumulative doses of antipsychotics. However, tardive dyskinesia has also been reported after short periods of treatment and with low dosages. Routine monitoring (e.g., AIMS testing) at 3- to 6-month intervals for movement disorders is considered the standard practice when using antipsychotics and should also be considered for olanzapine. If signs or symptoms of TD develop, discontinuation of olanzapine therapy should be considered.
During premarketing studies for oral olanzapine, 0.9% of olanzapine-treated patients developed seizures; however, confounding factors may have contributed to the occurrence of seizures in many of these cases. During clinical trials with the extended-release intramuscular injection, seizures occurred in 0.15% of patients. Despite the low incidence of seizures reported during clinical trials, several published case reports of seizures have been temporally associated with olanzapine use postmarketing, in the absence of other risk factors or etiologies.
Serious cardiovascular events with olanzapine treatment are infrequent. The most common vascular event is orthostatic hypotension, which occurred in 1-5% of patients treated with oral or IM olanzapine versus 0-2% of those receiving placebo in clinical trials. A large analysis of the vital sign data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine showed that orthostatic hypotension was recorded in at least 20% of the patients. Orthostatic hypotension may be associated with dizziness, tachycardia, bradycardia, and syncope, especially during initial dose titration. Syncope was reported in 0.1-1% of patients receiving immediate-release IM olanzapine during clinical trial evaluation. In patients receiving IM olanzapine, a significant decrease in systolic blood pressure (SBP) was defined as a SBP decrease >=30 mmHg. Three cases of hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved have been reported in normal subjects treated with IM or oral olanzapine. The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs. Complaints of dizziness are probably associated with orthostasis, particularly with the first dose of olanzapine or with the concomitant use of alcohol. Such reductions in blood pressure are rarely clinically significant with proper precautions. Sinus tachycardia (mean increase of 2.4 beats per minute in heart rate) is either related to the compensatory response to the blood pressure changes or the anticholinergic effects of olanzapine. Other cardiac effects that occurred more often with any olanzapine formulation than placebo during clinical trials included: sinus tachycardia (3% vs 1%), hypotension (2% vs 0%), hypertension (0-3% vs 0-1%), and chest pain (unspecified) (3% vs 1%). Hypertension (2% vs 1%) and chest pain (3% vs 2%) were reported more frequently during combination treatment with olanzapine and lithium or valproate than in the control group. Peripheral vasodilation was reported in 0.1-1% of patients during pre-marketing evaluation of oral olanzapine. The largest reported olanzapine ingestion during an overdose, 300 mg, did not produce ECG changes.
During a clinical trial with extended-release olanzapine injection, prolongation of the QTc interval was reported in 0-2% of patients receiving active drug treatment compared to 1% of patients receiving placebo. However, according to the package labeling, a comparison of extended-release olanzapine injection and oral olanzapine in a 24 week study revealed no significant differences on ECG changes. Additional information from the package labeling indicates that there were no significant differences between oral olanzapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters, QT, QTc (Fridericia corrected), and PR intervals in pooled studies of adults as well as pooled studies of adolescents. A manufacturer-funded study compared olanzapine to various conventional and atypical antipsychotics in a randomized controlled trial assessing the potential to cause QT prolongation. Thioridazine was found to have the greatest change in QTc (30.1 ms) and olanzapine the least (1.7 ms) of all the agents studied. Other data indicate that olanzapine may be associated with a prolongation of the QTc interval of > 75 ms. Case reports suggest that significant prolongation of the QTc interval can occur with olanzapine both at therapeutic doses and with high dose treatment . One case report documented a 76 ms increase following daily dosing of olanzapine 5 mg, and a similar increase upon re-challenge with the same dose.
During clinical trials of orally administered olanzapine as monotherapy, the following gastrointestinal (GI) effects occurred more frequently in patients receiving olanzapine than placebo: constipation (4% to 11%), xerostomia (4% to 22%), dyspepsia (3% to 11%), vomiting (4%), diarrhea (3%), and abdominal pain (6%). During premarketing evaluation, 0.1% to 1% of patients reported nausea with immediate-release IM olanzapine administration and nausea/vomiting with oral olanzapine. Tongue edema was reported in 0.1% to 1% of patients receiving oral olanzapine and ileus and intestinal GI obstruction occurred rarely (less than 0.1%). During clinical a trial of extended-release olanzapine injection, the following GI effects were reported more frequently in patients receiving active drug than placebo: abdominal pain (3%), diarrhea (2% to 7%), xerostomia (2% to 6%), flatulence (1% to 2%), nausea (4% to 5%), vomiting (1% to 6%), and toothache or dental pain (3% to 4%). Due to the antimuscarinic effects of olanzapine, xerostomia, constipation, or paralytic ileus may occur, which can be especially problematic in the elderly. Postmarketing reports have indicated that the risk for severe GI adverse reactions, including fatalities, was increased during coadministration of olanzapine with anticholinergic medications. Aspiration (including aspiration pneumonia) and esophageal dysmotility resulting in dysphagia have been associated with antipsychotic drug use; the elderly or patients with dementia might be at higher risk for aspiration and related complications. Hypersalivation has been reported during postmarketing use.
During pre-marketing use of oral olanzapine as monotherapy in approximately 2400 adult patients with a baseline ALT <= 90 International Units/L, 2% of patients experienced ALT elevations to > 200 International Units/L, whereas 0.8% of patients receiving injectable olanzapine (n = 1886) experienced similar increases. During monotherapy clinical trials of oral olanzapine in adults, clinically significant ALT elevations (change from less than 3 times the upper limit of normal (ULN) at baseline to at least 3 times the ULN) were reported in 5% of the olanzapine-treated patients compared to 1% of those receiving placebo. ALT elevations of at least 5 times the ULN occurred in 2% of patients in the active treatment group compared to 0.3% of those in the placebo group. Most patients receiving either oral or injectable olanzapine had changes that normalized or were decreasing despite continued treatment. During additional clinical trials in 2500 adult patients, approximately 1% discontinued olanzapine therapy due to elevated hepatic enzymes. Compared to adults, adolescents in clinical trials were more likely to have greater increases in hepatic transaminase concentrations. In monotherapy studies of oral olanzapine in adolescents, the following laboratory abnormalities were observed versus placebo: elevated ALT >= 3 times the ULN (12.1% vs. 2.3%), elevated AST (27.6% vs. 3.8%), low total bilirubin (22.1% vs. 6.7%), and elevated GGT (10.1% vs. 1.2%). ALT elevations of at least 5 times the ULN occurred in 4% of patients in the active treatment group compared to 1% of those in the placebo group. Approximately 3.4% of adolescents discontinued olanzapine therapy due to elevated transaminases. Increased alkaline phosphatase, hyperbilirubinemia, and hypoproteinemia were reported in 0.1-1% of patients receiving oral olanzapine during other pre-marketing evaluations. During pre-marketing studies, neither jaundice, liver necrosis nor failure was reported in any patients; however, liver fatty deposit was reported rarely (< 0.1%). During a clinical trial of extended-release olanzapine injection, elevated hepatic enzymes were reported in 1-4% of patients receiving active drug therapy versus 1% of those receiving placebo. Post-marketing reports indicate that jaundice has occurred and has been temporally related to administration of the drug. Causality is unknown. Rare cases of hepatitis or mixed liver injury have also been reported. The manufacturer recommends periodic liver function tests in those known to have pre-existing hepatic disease.
Clinical trial data and post-marketing reports indicate that leukopenia, neutropenia, and agranulocytosis have occurred during use of antipsychotic agents. Ecchymosis was reported in 5% of patients receiving oral olanzapine versus 3% of those receiving placebo during clinical trials. Leukopenia and thrombocytopenia were reported in 0.1 to 1% of patients during premarketing evaluation. Olanzapine has been reported to reduce neutrophil counts to less than 1,500/mm3 in roughly 2% of patients. In most cases the changes are transient and occur within the first 6 weeks of treatment. Neutropenia has been reported during the postmarketing use of olanzapine. Patients with a history of drug-induced leukopenia or neutropenia or a history of clinically significant low white blood cell (WBC) count should be carefully monitored while receiving an antipsychotic, including regular laboratory monitoring of the complete blood count (CBC) during the first few months of therapy. Consider discontinuing treatment if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Olanzapine should be discontinued in patients who develop severe neutropenia (ANC less than 1,000/mm3).
A potentially fatal symptom complex referred to as neuroleptic malignant syndrome (NMS) has been reported in association with administration of antipsychotics, including olanzapine. NMS is characterized by hyperthermia, severe extrapyramidal dysfunction, alterations in consciousness, altered mental status, and autonomic instability. Increased serum creatine phosphokinase (CPK), acute kidney failure, and leukocytosis also have occurred. 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 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 the 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). Olanzapine should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered. In an ISMP safety report, olanzapine was noted as 1 of the 19 overall drugs and one of the 3 antipsychotics having the strongest signals for serotonin syndrome with 14 cases reported over 1 year to the FDA Adverse Event Reporting System (FAERS). Serotonin syndrome, at its most severe, can resemble NMS. Serotonin syndrome rarely happens with single drug therapy, and more commonly is reported with interactions between multiple serotonergic drugs or accidental or intentional drug overdoses. The mechanism by which olanzapine might promote serotonergic excess is not clear, given its primary mode of action is a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonism.
During combination trials of olanzapine with lithium or valproate, dysmenorrhea was reported in 2% of patients in the olanzapine group and 0% in the placebo group. During pre-marketing evaluation of olanzapine, 0.1-1% of patients experienced amenorrhea, breast pain (mastalgia), impotence (erectile dysfunction), menstrual irregularity (increased or decreased menstruation), libido decrease, menorrhagia, and metrorrhagia. Many of these adverse reactions may be related to the prolactin-altering effects of olanzapine. Significant hyperprolactinemia occurs infrequently with olanzapine, due to a low affinity of olanzapine for the dopamine receptors of the tubero-infundibular tract. A dose-related effect has been observed in prolactin elevations. In a 24-week controlled trial with extended-release olanzapine injection, there was a significant difference between doses in the mean increase in prolactin from baseline as follows: 300 mg/2 weeks (+3.57 ng/mL), 405 mg/4 weeks (-2.76 ng/mL), and 150 mg/2 weeks (-5.61 ng/mL). Results from an 8-week clinical trial of oral olanzapine showed a dose-related mean change in incidence of prolactin > 24.2 ng/mL (female) or > 18.77 ng/mL (male) with significant differences between the 10 mg and 40 mg dose and the 20 mg and 40 mg dose: 10 mg/day (31.2%), 20 mg/day (42.7%), and 40 mg/day (61.1%). During short-term clinical trials in adults (<= 12 weeks), changes from normal to high prolactin concentrations occurred in 30% of olanzapine-treated patients versus 10.5% of those on placebo. Data from a pooled analysis (n = 8136) indicate that clinical manifestations of hyperprolactinemia possibly associated with olanzapine use in adults have included menstrual irregularity (2%, e.g., amenorrhea, hypomenorrhea, delayed menstruation, oligomenorrhea), sexual function-related events (2% of males and females, e.g., orgasm dysfunction reported as anorgasmia or abnormal orgasm, ejaculation dysfunction reported as delayed ejaculation, erectile dysfunction, libido decrease or loss of libido), and breast-related events (0.2% of males and 0.7% of females, e.g., breast discharge, breast enlargement or swelling, galactorrhea, gynecomastia, lactation disorder). During short-term clinical trials in adolescents (<= 6 weeks), changes from normal to high prolactin concentrations occurred in 47% of olanzapine-treated patients versus 7% of those on placebo. In data from a pooled analysis (n = 454), the percentages of adolescents who experienced clinical manifestations of hyperprolactinemia possibly associated with olanzapine use include: menstrual-related events (1%), sexual function-related events (0.7% of males and females), and breast-related events (2% of males and females). Data from an 8-week dose-comparison study in adults indicate that treatment-emergent prolactin elevations are dose-related, having occurred in 31.2% of those receiving olanzapine 10 mg/day and 61.1% of those receiving 40 mg/day. It should be noted that while hyperprolactinemia is associated with an increased incidence of mammary tumors in animals, no association of olanzapine use with the development of human breast carcinoma exists at this time.
During clinical trials of oral olanzapine as monotherapy, the following urogenital effects were reported more frequently in patients receiving olanzapine than placebo: urinary incontinence (2%) and urinary tract infection (2%). During clinical trials of combination therapy, vaginitis was reported in 2% of patients in the olanzapine group. Vaginal discharge was reported in 4% of patients receiving extended-release olanzapine injection. Urogenital effects reported in 0.1% to 1% of patients receiving oral olanzapine during premarketing evaluation included polyuria, increased urinary frequency, urinary retention, urinary urgency, and impaired urination. Urinary retention is a possible anticholinergic effect of olanzapine. Postmarketing reports have indicated that the risk for severe anticholinergic-related adverse reactions, including fatalities, was increased during coadministration of olanzapine with anticholinergic medications.
Priapism has been reported during post-marketing use of olanzapine. It is postulated that alpha-1 adrenergic antagonism by olanzapine may cause direct arteriodilation of the lacunar spaces of the cavernosa. The true incidence of priapism due to olanzapine is unknown.
During clinical trials with oral olanzapine as monotherapy, the following musculoskeletal effects were reported more frequently in patients receiving olanzapine than placebo: back pain (5%), extremity pain (5% to 6%), unspecified joint pain (5%), arthralgia (2%), and musculoskeletal pain/stiffness (2%). Back pain was also reported in 8% of patients receiving olanzapine combination therapy with lithium or valproate vs. 4% of patients receiving only lithium or valproate. During a clinical trial of extended-release olanzapine injection, the following musculoskeletal effects were reported more frequently in patients receiving active drug than placebo: arthralgia (3%), back pain (3% to 5%), muscle cramps or spasms (1% to 3%), and musculoskeletal pain/stiffness (1% to 4%). Osteoporosis was reported rarely (less than 0.1%) during premarketing evaluation. Increased creatine phosphokinase was reported in 0.1% to 1% of patients during premarketing evaluation of immediate-release IM olanzapine. Rhabdomyolysis and restless legs syndrome (RLS) have been reported during postmarketing use of olanzapine; however, the frequencies are unknown and causality to the drug has not been established.
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Diabetic ketoacidosis (DKA) and diabetic coma have been reported during postmarketing use of the drug. It is recommended that patients receiving olanzapine undergo baseline and periodic fasting blood glucose tests. Monitor patients for potential worsening of glucose control. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available; however, olanzapine appears to have a greater association with increased glucose concentrations than some other antipsychotics. Atypical antipsychotics may have effects on glucose metabolism that are independent of their effect on increases in weight; 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. A death due to DKA has been reported from a randomized, controlled trial in a patient with acute mania due to bipolar disorder receiving olanzapine. A pooled analysis of monotherapy studies in adults (median duration, 3 weeks) indicated that olanzapine was associated with a greater mean change in fasting blood glucose concentrations (2.76 mg/dL) vs. placebo (0.17 mg/dL). The mean blood glucose change was greater in patients with preexisting glucose dysregulation at baseline. During short-term studies (12 weeks or less) in adults, a change in fasting blood glucose from normal at baseline (less than 100 mg/dL) to high (126 mg/dL or more) occurred in 2.2% of olanzapine-treated patients vs. 3.4% of those on placebo. In long-term studies (48 weeks or more) 12.8% of olanzapine-treated patients had a change to high fasting blood glucose. In the same analysis, a change in baseline fasting glucose from borderline to high (at least 100 mg/dL and less than 126 mg/dL to 126 mg/dL or more) occurred in 17.4% of olanzapine-treated patients vs. 11.5% of those on placebo, while long-term studies showed this change in 26% of olanzapine-treated patients. A pooled analysis of monotherapy studies (3 to 6 weeks duration) in adolescents indicated olanzapine was associated with a greater mean change in fasting glucose levels (2.68 mg/dL) than those receiving placebo (-2.59 mg/dL). During other short-term studies in adolescents (12 weeks or less), a change in baseline in fasting glucose from normal to high occurred in 0% of olanzapine-treated patients and 1.9% of those on placebo, while long-term studies (48 weeks or more) showed this change in 0.9% of olanzapine-treated patients. In the same analysis, a change in baseline fasting glucose from borderline to high occurred in 14.3% of olanzapine-treated patients vs. 0% of those on placebos, while long-term studies showed a change in 23.1% of olanzapine-treated patients. Although increases in fasting blood glucose were similar in adolescents and adults treated with olanzapine, the difference between the olanzapine and placebo groups was greater in adolescents compared to adults. Temporal associations suggest that olanzapine therapy may precipitate or unmask diabetes mellitus; blood glucose concentrations normalize in most patients after discontinuation of olanzapine. A positive re-challenge has been demonstrated in some of these cases. The possibility of impaired glucose tolerance should be considered in patients that develop symptoms of hyperglycemia or diabetes, such as excess thirst, polyuria, polyphagia, and weakness. Dosage reduction, if clinically possible, may improve glycemic control. In patients with severe treatment-emergent hyperglycemia, discontinuation of olanzapine therapy should be considered.
Routine monitoring of weight is recommended during olanzapine therapy. Weight gain is a commonly occurring side effect of the drug, and consideration should be given to the potential medical consequences of weight gain prior to initiation of therapy. Discontinuation of therapy due to weight gain occurred in 2.2% of patients in clinical trials. A dose-related effect on weight has been observed. In a 24-week controlled trial with extended-release olanzapine injection, there was a significant difference between doses in the percentage of increase in weight as follows: 300 mg/2 weeks (1.7 kg), 405 mg/4 weeks (0.89 kg), and 150 mg/2 weeks (0.67 kg). Results from an 8-week clinical trial of oral olanzapine showed a dose-related mean change in weight with a significant difference between the 10 mg and 40 mg oral dose: 10 mg/day (1.9 kg), 20 mg/day (2.3 kg), and 40 mg/day (3 kg). During short-term monotherapy clinical trials of oral olanzapine in adults, weight gain occurred more frequently in those receiving olanzapine than placebo (5-6% vs 1-3%). Appetite stimulation also occurred more frequently within the active treatment groups compared to placebo (3% vs 2%). During a clinical trial with extended-release olanzapine injection, more patients receiving active treatment experienced weight gain (5-7% vs 5%) and appetite stimulation (1-6% vs 0%) than those receiving placebo. In adolescent clinical trials, a higher percentage of olanzapine-treated patients experienced weight gain (29-31% vs 4-9%) and appetite stimulation (17-29% vs 4-9%) compared to placebo-treated patients. The CATIE study noted that more patients stopped olanzapine therapy due to weight gain (or metabolic effects) vs. perphenazine, quetiapine, risperidone or ziprasidone (9% vs. 1-4%, respectively). Results from a combination therapy study indicated that weight gain occurred in 26% of patients receiving olanzapine in combination with lithium or valproate vs. 7% of patients receiving lithium or valproate alone, and that the percentage of patients in the combination groups with increased appetite (appetite stimulation) was higher than in those receiving either lithium or valproate alone (24% vs. 8%). In a pooled analysis of short-term monotherapy studies (median duration, 6 weeks) in adults, olanzapine-treated patients gained an average of 2.6 kg compared to an average weight loss of 0.3 kg by those on placebo. A weight gain of at least 7% from baseline was noted in 22.2% of those receiving active treatment versus 3% of those on placebo. A weight gain of at least 15% from baseline occurred in 4.2% of those receiving active treatment (median duration of olanzapine, 12 weeks) versus 0.3% of those on placebo. Clinically significant weight gain was noted in all baseline Body Mass index (BMI) categories, with 0.2% of olanzapine-treated patients discontinuing therapy due to weight gain versus none in the placebo groups. In a pooled analysis of long-term monotherapy studies in adults (>= 48 weeks), the mean weight gain was 5.6 kg (n = 2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline weight were 64%, 32%, and 12%, respectively. In a pooled analysis of short-term monotherapy studies in adolescents, the mean change in body weight from baseline in the olanzapine versus placebo-treated patients was 4.6 kg vs 0.3 kg (median exposure of 3 weeks). The percentage of olanzapine versus placebo-treated patients who gained at least 7% of baseline body weight was 40.6% vs 9.8% (median exposure of 4 weeks). The percentage of olanzapine versus placebo-treated patients who gained at least 15% of baseline body weight was 7.1% vs 2.7% (median exposure of 19 weeks). During long-term monotherapy studies in adolescents (median exposure of 201 days, n = 179), the mean weight gain from baseline was 11.2 kg. The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight were 89%, 55%, and 29%, respectively. The mean weight gain by baseline BMI category was as follows: normal = 11.5 kg (n = 106), overweight = 12.1 kg (n = 26), and obese = 12.7 kg (n = 17). Currently available data indicate that the mean increase in weight in adolescents is greater than adults. It should be noted that data on weight gain in adolescents beyond 6 months of treatment are limited.
During clinical trials of combination therapy of olanzapine with lithium or valproate, the following dermatologic effects occurred more frequently in the olanzapine group than the placebo group: hyperhidrosis (3% vs. 1%), acne vulgaris (2% vs. 0%), and xerosis (2% vs. 0%). During a clinical trial of extended-release olanzapine injection, acne was reported more frequently in patients receiving active drug than placebo (0% to 2% vs. 0%). During other pre-marketing evaluation, alopecia and photosensitivity were reported in 0.1% to 1% of patients receiving oral olanzapine.
Allergic reactions including anaphylactoid reactions, angioedema, pruritus, and urticaria have been reported during post-marketing use of olanzapine; rash (unspecified) has been reported in postmarket reports. The FDA issued a Medwatch alert in May 2016 after identifying and reviewing 23 reported cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with olanzapine worldwide since the initial approval of the drug in 1996; other unreported cases are likely. DRESS is a rare but potentially fatal syndrome typically characterized by a rash which may worsen or spread over time. One case of DRESS involved a patient receiving olanzapine who died; however, the patient was taking multiple medicines that could have been contributing factors. DRESS can include fever, lymphadenopathy, and facial swelling. Eosinophilia can cause inflammation and swelling, and organ involvement (e.g., liver, kidneys, lungs, heart, and pancreas) can lead to organ injury, and death in some cases. DRESS has a mortality rate of up to 10%. Olanzapine should be discontinued immediately if DRESS is suspected. There is no specific treatment for DRESS; management includes discontinuation of the offending agent as soon as possible, and supportive care. Patients should be advised to promptly report symptoms of rash, swollen lymph nodes, and/or fever.
During clinical trials of the extended-release intramuscular olanzapine formulation (Zyprexa Relprevv), 3.6% of patients receiving active drug treatment experienced an injection site reaction compared to 0% of placebo-treated patients. Injection site reactions included injection site pain, buttock pain, injection site mass, induration, and injection site induration. The most frequently reported adverse reaction was injection site pain, occurring in 2.3% of olanzapine-treated patients compared to 0% in the placebo groups. During clinical trials with the immediate-release intramuscular formulation (Zyprexa IntraMuscular), injection site pain was reported in at least 1% of patients receiving one or more doses of at least 2.5 mg per injection.
Extended-release intramuscular olanzapine (Zyprexa Relprevv) carries a specific warning related to post-injection delirium/sedation syndrome. Patients and/or their caregivers should be aware of the symptoms associated with this syndrome including sedation, coma, and/or delirium (e.g., confusion, disorientation, agitation, anxiety, and/or other cognitive impairment). Other symptoms that have been noted include extrapyramidal symptoms, dysarthria, ataxia, slurred speech, altered gait, difficulty ambulating, aggression, dizziness, weakness, hypertension, and seizures. During pre-marketing use of the drug, these events occurred in less than 0.1% of injections (total) and in about 2% of patients who received injections as prescribed for up to 46 months. All patients had largely recovered by 72 hours. In some cases, there was an unintentional increase in olanzapine serum concentrations above the therapeutic range; however, the mechanism by which this occurred is unknown. The risk of post-injection delirium/sedation syndrome is cumulative (i.e., increases with the number of injections). The likelihood of a reaction is highest during the first hour following the injection and most cases have occurred within 3 hours; however, there have been reports after 3 hours. Following each injection, the patient must remain under continuous observation by a healthcare professional at the healthcare facility for at least 3 hours. Following the 3 hour observation period, the healthcare professional must confirm that the patient is alert, oriented, and free of any signs or symptoms of post-injection delirium/sedation syndrome before release from the facility. Thereafter, the patient must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, the patient should not drive or operate heavy machinery. After leaving the healthcare facility, patients should ensure they have ready access to medical care in the event it is needed. Because the signs and symptoms of post-injection delirium/sedation syndrome are consistent with olanzapine overdose, suspected cases require close medical supervision in a medical facility capable of resuscitation. It should be noted that Zyprexa Relprevv is available only through a restricted distribution program where the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the Zyprexa Relprevv Patient Care Program. To enroll, call 1-877-772-9390.
Baseline and periodic lipid evaluations are recommended in patients receiving olanzapine. Hyperlipidemia, both hypercholesterolemia and hypertriglyceridemia, has occurred during olanzapine use. Severe elevations in triglycerides (> 500 mg/dL) have also been reported. A pooled analysis of short-term (<= 12 weeks) adult monotherapy studies indicated that olanzapine-treated patients experienced mean increases from baseline in fasting total cholesterol (5.3 mg/dL), LDL cholesterol (3 mg/dL), and triglycerides (20.8 mg/dL) compared to decreases in the placebo groups. Mean increases in lipid values were higher in patients without evidence of pre-existing dyslipidemia. Differences in fasting HDL cholesterol were not clinically significant between the groups. The percentage of olanzapine versus placebo-treated adults with a change from normal to high fasting total cholesterol (< 200 mg/dL to at least 240 mg/dL) was 2.8% vs 2.4%, with 21.6% vs 9.5% of patients experiencing an increase of at least 40 mg/dL. The percentage of olanzapine versus placebo-treated adults with a change from normal to high fasting triglycerides (< 150 mg/dL to at least 200 mg/dL) was 9.2% vs 4.4%, with 39.6% vs 26.1% experiencing an increase of at least 50 mg/dL. Increases of at least 30 mg/dL in fasting LDL cholesterol from baseline occurred in 23.7% of olanzapine-treated patients versus 14.1% of those on placebo. During studies evaluating chronic use (>= 48 weeks) of olanzapine in adults, patients experienced increases from baseline in mean fasting cholesterol (5.6 mg/dL), LDL cholesterol (2.5 mg/dL), and triglycerides (18.7 mg/dL) and a mean decrease from baseline in fasting HDL cholesterol (0.16 mg/dL). The percentage of patients with a change from normal to high fasting total cholesterol was 14.8%, with 32.9% of patients experiencing an increase of at least 40 mg/dL. The percentage of patients with a change from normal to high fasting triglycerides was 32.4%, with 61.4% of patients experiencing an increase of at least 50 mg/dL. The percentage of patients with a change from borderline fasting triglycerides (150 mg/dL to < 200 mg/dL) to high triglyceride levels (>= 200 mg/dL) was 70.7% and those with a change from borderline (>= 200 mg/dL to < 240 mg/dL) to high fasting total cholesterol (>= 240 mg/dL) was 55.2% after at least 48 weeks of exposure to the drug. Increases of at least 30 mg/dL in fasting LDL cholesterol from baseline occurred in 39.8% of patients. In patients who completed 12 months of therapy, the mean non-fasting total cholesterol did not increase further after about 4 to 6 months. A dose-related effect has been observed in fasting triglycerides. In a 24-week controlled trial with extended-release olanzapine injection, there was a significant difference between the low dose (150 mg/2 week) and high dose (300 mg/week) in the percentage of change from normal to high levels of fasting triglycerides: 300 mg/2 weeks (24.5%), 405 mg/4 weeks (9.8%), and 150 mg/2 weeks (6.5%). In a pooled analysis of short-term adolescent monotherapy studies (<= 6 weeks), olanzapine versus placebo-treated patients experienced the following mean increases from baseline: fasting total cholesterol (12.9 mg/dL vs 1.3 mg/dL), fasting LDL cholesterol (6.5 mg/dL vs 1 mg/dL), and fasting triglycerides (28.4 mg/dL increase vs 1.1 mg/dL decrease). Differences in fasting HDL cholesterol were not clinically significant between the groups. The percentage of olanzapine versus placebo-treated adolescents with a change from normal to high fasting total cholesterol (< 170 mg/dL to at least 200 mg/dL) was 6.9% vs 2.3%, with 14.5% vs 4.5% experiencing an increase of at least 40 mg/dL. The percentage of olanzapine versus placebo-treated adolescents with a change from normal to high fasting triglycerides (< 90 mg/dL to greater than 130 mg/dL) was 26.9% vs 10.7%, with 37% vs 15.2% experiencing an increase of at least 50 mg/dL. Increases of at least 30 mg/dL in fasting LDL cholesterol from baseline occurred in 17.5% of olanzapine-treated adolescents versus 11.1% of those on placebo. During studies evaluating chronic use (>= 24 weeks) of olanzapine in adolescents, patients experienced increases from baseline in mean fasting cholesterol (5.5 mg/dL), LDL cholesterol (5.4 mg/dL), and triglycerides (20.5 mg/dL) and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. The percentage of adolescents with a change from normal to high fasting total cholesterol was 7.7%, with 14.8% of patients experiencing an increase of at least 40 mg/dL. The percentage of adolescents with a change from normal to high fasting triglycerides was 36.4%, with 45.9% of patients experiencing an increase of at least 50 mg/dL. Increases of at least 30 mg/dL in fasting LDL cholesterol from baseline occurred in 22.3% of adolescents. The percentage of patients with a change from borderline fasting triglycerides (90-130 mg/dL) to high triglyceride levels (> 130 mg/dL) was 64.5% and those with a change from borderline (>= 170 mg/dL to < 200 mg/dL) to high fasting total cholesterol (>= 200 mg/dL) was 57.6% after at least 24 weeks of exposure to the drug. In addition, random cholesterol levels of at least 240 mg/dL and triglyceride levels of at least 1000 mg/dL have been reported during general post-marketing use.
A significantly greater incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in elderly patients with dementia-related psychosis receiving olanzapine in placebo-controlled trials. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Cerebrovascular accident is listed as an infrequent adverse event (occurring in 1/100 to 1/1000 patients) in the olanzapine package labeling. While the true incidence of stroke with atypical antipsychotics is unknown, some reports have associated stroke with the use of olanzapine or other selected atypical antipsychotics (e.g., risperidone) for behavioral symptoms in patients with dementia. The British Committee on Safety of Medicines (CSM) issued a statement in March 2004 recommending that olanzapine not be used for behavioral symptoms of dementia in the elderly, and those receiving treatment should be re-evaluated. Studies suggest a 3-fold higher incidence of stroke in treated control groups vs. placebo. It is the CSM's belief that the increased risk of stroke outweighs the likely benefits in the treatment of the behavioral symptoms of dementia. Individual stroke risk factors, such as smoking, hypertension, diabetes and conduction abnormalities should also be assessed in elderly dementia patients who may receive olanzapine.
During clinical trials of orally administered olanzapine, the following infectious or respiratory effects occurred more frequently in patients receiving olanzapine than placebo: rhinitis (7% vs 6%), increased cough (6% vs 0-3%), pharyngitis (4% vs 3%), nasopharyngitis (4% vs 2%), epistaxis (3% vs 0%), respiratory tract infection (3% vs 2%), sinusitis (3% vs 0%), and fever (6% vs 2%). During a clinical trial of extended-release olanzapine injection, the following effects were reported more frequently in patients receiving active drug than placebo: cough (3-9% vs 5%), nasal congestion (1-7% vs 3%), pharyngolaryngeal pain (2-3% vs 2%), sneezing (0-2% vs 0%), nasopharyngitis (1-6% vs 2%), tooth infection or dental caries (0-4% vs 0%), upper respiratory tract infection (1-4% vs 2%), viral infection (0-2% vs 0%), and fever (0-2% vs 0%). Pharyngitis (4% vs 1%) and dyspnea (3% vs 1%) were reported more frequently with active treatment than placebo during combination drug trials. During other pre-marketing evaluation, epistaxis was reported in 0.1-1% of patients receiving oral olanzapine and pulmonary edema occurred rarely (< 0.1%). During clinical trials of orally administered olanzapine as monotherapy, peripheral edema (3% vs 1%) occurred more frequently in patients receiving olanzapine than placebo. Peripheral edema (6% vs 4%) was reported more frequently during combination treatment with olanzapine and lithium or valproate than the control groups. Face edema was reported in 0.1-1% of patients receiving oral olanzapine during other pre-marketing evaluations. During a clinical trial of extended-release olanzapine injection, unspecified edema (2% vs 1%) occurred. Other post-marketing effects include pulmonary embolism and deep vein thrombosis (DVT).
During clinical trials of orally administered olanzapine as monotherapy, amblyopia occurred more frequently in patients receiving olanzapine than placebo (3% vs 2%). Amblyopia (9% vs 5%) and visual impairment (abnormal vision 2% vs 0%) were reported more frequently during combination treatment with olanzapine and lithium or valproate than the control groups. During other pre-marketing evaluations of oral olanzapine, abnormal accomodation and xerophthalmia were reported in 0.1-1% of patients. Mydriasis was reported rarely (< 0.1%). During a clinical trial of extended-release olanzapine injection, ear pain (otalgia) was reported more frequently in patients receiving active drug than placebo (1-4% vs 2%).
During clinical trials of orally administered olanzapine as monotherapy, the following general effects occurred more frequently in patients receiving olanzapine than placebo: asthenia (10-15% vs 6%) and accidental injury (12% vs 8%). Asthenia also occurred more often in patients receiving immediate-release IM olanzapine than placebo (2% vs 1%). Chills were reported in 0.1-1% of patients receiving oral olanzapine during other pre-marketing evaluations. Chills with fever, hangover effect, and sudden death occurred rarely (< 0.1%). During a clinical trial of extended-release olanzapine injection, the following general effects were reported more frequently in patients receiving active drug than placebo: unspecified pain (0-3% vs 0%) and procedural pain (0-2% vs 0%). Asthenia (18% vs 13%), and accidental injury (4% vs 2%) were reported more frequently during combination treatment with olanzapine and lithium or valproate than the control groups. A withdrawal reaction has been reported during post-marketing use. Other post-marketing effects include pancreatitis.
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). Alterations in serum sodium have been reported with olanzapine use during clinical trials, but the incidence is not known. During clinical trials with olanzapine for bipolar disorder, polydipsia (thirst) was reported more frequently during combination treatment with olanzapine and lithium or valproate than the control groups (10% vs. 6%).
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 olanzapine should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. 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 initiation of antipsychotic therapy or after dose increases. Of note, hypothermia may increase the risk of prolonging the QT interval when using olanzapine.
Olanzapine is contraindicated in patients with a previous hypersensitivity to olanzapine or any other component of the commercial product. Olanzapine has been associated with a risk of serious hypersensitivity reactions or anaphylaxis, including serious rash. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported; DRESS is a rare but potentially fatal syndrome typically characterized by a rash that can worsen or spread over time. DRESS can include pyrexia or elevated body temperature, lymphadenopathy, and facial swelling. Eosinophilia can cause inflammation and swelling, and organ involvement (e.g., liver, kidneys, lungs, heart, and pancreas) can lead to organ injury, and death in some cases. DRESS has a mortality rate of up to 10%. Olanzapine should be discontinued immediately if DRESS is suspected. There is no specific treatment for DRESS; management includes discontinuation of the offending agent as soon as possible and supportive care. Patients should be advised to promptly report symptoms of rash, swollen lymph nodes, and/or pyrexia or elevated body temperature.
Olanzapine should be used with caution in patients with hematological disease. Hematologic effects including leukopenia, neutropenia, and agranulocytosis have been associated with use of antipsychotics. A history of drug-induced leukopenia or neutropenia or pre-existing low white blood cell (WBC) count may increase the likelihood of these events. Monitor a complete blood count (CBC) frequently during the first few months of therapy in patients with a history of low WBC or drug-induced leukopenia/neutropenia. Consider discontinuing olanzapine at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (ANC less than 1,000/mm3) should discontinue the drug and have their WBC followed until recovery.
The sedative effects of olanzapine may be most evident during the initial days of treatment. Because olanzapine has the potential to impair cognitive and motor skills, patients should be advised to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how the drug affects them. 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, 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. Given the primary CNS effects of olanzapine, caution should be used during coadministration with other CNS depressants and alcohol. Ethanol ingestion may further impair cognitive and motor skills and patients should be advised to avoid use of alcoholic beverages. The extended-release intramuscular injection formulation (Zyprexa Relprevv) carries a specific boxed warning related to post-injection delirium/sedation syndrome (PDSS), which is the result of the drug entering the bloodstream too quickly and the development of sedation, delirium, and/or coma from significantly elevated olanzapine plasma concentrations. Patients must remain under continuous observation by a healthcare professional at the healthcare facility for at least 3 hours following the injection to help detect PDSS. After this time, the patient must be accompanied to their destination upon leaving the facility. For the remainder of the day of each injection, the patient should not drive or operate heavy machinery. Patients and/or their caregivers should be made aware of the symptoms associated with PDSS and what to do if symptoms occur. Following the 3-hour observation period, the confirm that the patient is alert, oriented, and free of any signs or symptoms of PDSS before release from the facility. Suspected PDSS cases require close medical supervision in a medical facility capable of resuscitation.
The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy. Olanzapine should be prescribed in the smallest quantity consistent with good management in order to reduce the risk of overdose. When olanzapine is prescribed in conjunction with fluoxetine for the treatment of depression, further considerations relative to antidepressant use are needed. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in children, adolescent, and young adult patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. The safety and efficacy of olanzapine injection suspension (i.e., Zyprexa Relprevv) have not been established in children or adolescents. Orally administered olanzapine is FDA approved for use in adolescents 13 years and older for the treatment of schizophrenia, the acute treatment of manic or mixed episodes associated with bipolar I disorder, and the maintenance treatment of bipolar I disorder; when oral olanzapine is used in conjunction with fluoxetine for depression, the boxed warnings regarding suicidal ideation for children and adolescents apply.
Olanzapine should be used cautiously in those patients with a history of seizure disorder or with conditions that may increase the risk of seizures. Like other antipsychotic drugs, olanzapine may lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.
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, olanzapine discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
Use oral and intramuscular olanzapine cautiously in patients with cardiac disease. Olanzapine may potentiate hypotension. Orthostatic hypotension, syncope, and cardiac events may be associated with aggressive dose titration. If olanzapine is prescribed, use a low initial dose followed by gradual dosage titration. Patients should remain recumbent if drowsy or dizzy after olanzapine injection solution or extended-release injection suspension til examination has indicated that they are not experiencing postural hypotension, bradycardia, and/or hypoventilation. Orthostatic hypotension could 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. Due to the potential orthostatic effects of olanzapine, caution is recommended in patients with cerebrovascular disease and those with risk factors for hypotension, such as hypovolemia or the use of antihypertensive agents. Similar to other antipsychotic agents, cases of ECG changes and serious cardiac or respiratory events have been reported with olanzapine therapy, but these events are infrequent. Limited data, including some case reports, suggest that olanzapine might be associated with a significant QT prolongation in rare instances. Torsade de pointes (TdP), a life-threatening arrhythmia, has not been reported with olanzapine. Use olanzapine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, cerebrovascular disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, older adults 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, abnormally low body temperature, 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) may also be at increased risk for QT prolongation.
Monitor patient weight prior to and during olanzapine therapy. Patients should also undergo fasting lipid profile testing at the beginning of treatment and periodically during treatment. Atypical antipsychotics have been associated with metabolic changes including dyslipidemia and weight gain. Use olanzapine with caution in patients with pre-existing obesity, hypercholesterolemia, hyperlipidemia, or hypertriglyceridemia. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risks.
Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Atypical antipsychotics have been associated with metabolic changes including hyperglycemia and diabetes mellitus. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risks. Assess the benefits of prescribing olanzapine versus the risks in patients with pre-existing diabetes mellitus or hyperglycemia. Monitor patients for hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness while receiving olanzapine.
Olanzapine exhibits anticholinergic effects and should be used with caution in those with a current diagnosis or history of conditions that may be aggravated by anticholinergic activity, such as closed-angle glaucoma, paralytic ileus, urinary retention, or clinically significant prostatic hypertrophy. The effects of olanzapine may be additive with other anticholinergic medications. Postmarketing reports have indicated that the risk for severe anticholinergic-related adverse reactions, including fatalities, was increased during coadministration of olanzapine with anticholinergic medications. Some of these events were severe gastrointestinal adverse reactions related to hypomotility, constipation, and intestinal GI obstruction.
Olanzapine should be used cautiously in patients with dysphagia. Esophageal dysmotility and aspiration have been associated with antipsychotic use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.
Antipsychotics can cause motor and sensory instability, which 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 diseases (e.g., neurological disease), conditions, or concurrent medication use that could exacerbate motor and sensory instability. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Olanzapine and other atypical antipsychotics should be used with caution in the patient with Parkinson's disease because of possible aggravation of EPS due to dopamine-receptor blockade.
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 olanzapine should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, dehydration).
As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported; fertility may also be affected. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients. Some human breast cancer may be prolactin-dependent and therefore most antipsychotics should be used cautiously in those who have a history of breast cancer.
Due to the fixed-dose and long-acting nature of the depot injection, a decision to use the extended-release intramuscular injection in patients with pre-existing hepatic disease or impairment should be carefully considered, and only after tolerability has been established via oral dosing titration. No dosage adjustment is usually needed for patients with hepatic disease receiving oral olanzapine therapy; a lower starting dose is recommended for these patients when used in combination with fluoxetine for the treatment of depression, with careful titration.
Geriatric patients may be more susceptible than younger adults to anticholinergic activity, orthostatic hypotension, movement disorders, and CNS depression with olanzapine. Geriatric patients may also be at increased risk for developing QT prolongation. Initiate olanzapine at a low dose, with longer intervals between dosage increases. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and use of olanzapine in this population should be avoided if possible due to an increase in morbidity and mortality in geriatric patients with dementia receiving atypical 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. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients except for treating schizophrenia, bipolar disorder, and nausea/vomiting during chemotherapy. The Beers panel recommends avoiding antipsychotics in geriatric patients with delirium, dementia, or Parkinson's disease. 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 for geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when olanzapine is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms due to mania or psychosis. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction, or rationale for continued use. Refer to the OBRA guidelines for complete information.
Evidence is insufficient to establish the safe use of olanzapine in humans during pregnancy. Because olanzapine is known to cross the placenta in animals, the drug is recommended for use during pregnancy only when the benefits outweigh the risks. Animal studies have not shown evidence of teratogenicity or mutagenicity. However, decreased viability or decreased birth weights have been observed in animals. Animal studies are not always predictive of human response. Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity and have ranged from self-limited to those requiring intensive care unit support and prolonged hospitalization. Neonates exhibiting signs or symptoms of extrapyramidal effects or withdrawal should be carefully monitored. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotic agents and requires further investigation. There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential prior to initiation of an antipsychotic. It is not known if antipsychotics, through their effect on prolactin, would affect labor or delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to olanzapine; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by calling 1-866-961-2388.
Olanzapine may pose a reproductive risk by increasing serum prolactin concentrations, which may lead to reversible infertility in females of reproductive potential.
Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in babies exposed to olanzapine through breast milk. There is no information on the effects of olanzapine on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for olanzapine and any potential adverse effects on the breastfed child from the drug or from the mother's underlying condition. Any infant exposed to olanzapine should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements). In a study in lactating women, the mean infant dose at steady-state was estimated to be 1.8% of the maternal olanzapine dose. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing olanzapine regimen if ongoing treatment is deemed necessary during breast-feeding. However, quetiapine may be considered as an alternate atypical agent. 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.
Tobacco smoking patients receiving olanzapine can have about a 40% higher clearance rate of the drug than nonsmokers, due to induction of hepatic microsomal enzymes by the hydrocarbons in tobacco. No specific dosage recommendations are recommended for smokers. The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations and certain individuals may require dose adjustments in treatment. Sudden smoking cessation may result in a reduced clearance of olanzapine, despite the initiation of nicotine replacement. Monitor patients carefully when changes in smoking status occur.
Olanzapine orally disintegrating tablets (ODT) contain aspartame, and the amounts of phenylalanine ingested should be considered in patients with phenylketonuria. The regular olanzapine tablets do not contain phenylalanine.
When discontinuing treatment with antipsychotic or antidepressant treatment, the clinician should recognize that abrupt discontinuation of immediate-release dose forms in some patients can cause adverse symptoms. While immediate discontinuation of an antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. With extended-release injections, rate-limited elimination of olanzapine occurs following any given dose.
Intramuscular olanzapine is for intramuscular administration only. Do not give via intravenous administration or via subcutaneous administration.
For the treatment of schizophrenia:
Oral dosage:
Adults: ADULTS NOT AT RISK FOR HYPOTENSION: 5 to 10 mg PO once daily initially, with a target dose of 10 mg/day PO within several days. Further dosage adjustments of 5 mg/day, if indicated, should occur at weekly intervals. Doses greater than 10 mg/day should be initiated only after clinical assessment. In clinical trials, doses greater than 10 mg/day PO were not more efficacious. Max: 20 mg/day. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH FACTORS FOR SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: Initially, 5 mg PO once daily; dose escalation should be performed cautiously.. Maintenance therapy may reduce relapse risk. Periodically reevaluate need for therapy; maintain at the lowest effective dosage.
Geriatric Adults: Initially, 5 mg PO once daily. Geriatric patients may be predisposed to hypotensive reactions, have risk factors for slower metabolism of olanzapine (age-related decline in hepatic or renal function), or may be more sensitive to the drug. Dose titration should be performed cautiously. In clinical trials, doses greater than 10 mg/day PO were not more efficacious. Max: 20 mg/day PO.
Adolescents: 2.5 or 5 mg PO once daily initially, with a target dose of 10 mg PO once daily. Dosage adjustments should be made in increments/decrements of 2.5 or 5 mg. During clinical trials, efficacy was established within a range of 2.5 to 20 mg/day, with a mean dose of 11.1 mg/day. Max: 20 mg/day PO. Continuation of therapy generally occurs in treatment responders. Use lowest dose necessary to maintain an adequate response. Periodically reevaluate the need for continued treatment.
Children* 6 to 12 years: 2.5 mg PO once daily is the initial recommended dose. Make adjustments of 2.5 mg/day, if indicated, at 4 to 7 day intervals. Effective dose range: 2.5 to 10 mg/day. Max: 20 mg/day PO. Atypical antipsychotics are not intended for use in pediatric patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders. The decision to prescribe atypical antipsychotic medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms; symptoms can be variable. Use lowest dose necessary to maintain an adequate response in treatment responders. Periodically reevaluate the need for continued treatment.
Intramuscular dosage (i.e., extended-release injectable suspension, Zyprexa Relprevv):
Adults: ADULTS NOT AT RISK FOR HYPOTENSION: Efficacy has been established within the range of 150 to 300 mg deep IM every 2 weeks or 405 mg IM administered every 4 weeks. Establish tolerability with the oral formulation prior to treatment. The recommended starting dose during the first 8 weeks is based upon a corresponding oral olanzapine dose as follows: target oral dose of 10 mg/day PO = 210 mg IM every 2 weeks or 405 mg IM every 4 weeks; target oral dose of 15 or 20 mg/day PO = 300 mg IM every 2 weeks. The recommended maintenance dose after 8 weeks of treatment is as follows: target oral dose of 10 mg/day PO = 150 mg IM every 2 weeks or 300 mg IM every 4 weeks; target oral dose of 15 mg/day PO = 210 mg IM every 2 weeks or 405 mg IM every 4 weeks; and target oral dose of 20 mg/day PO = 300 mg IM every 2 weeks. Extended-release IM doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been formally evaluated. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH FACTORS FOR SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR THOSE PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: 150 mg deep IM every 4 weeks initially; use caution with dose escalations. MONITORING: Zyprexa Relprevv must be administered in a registered healthcare facility with ready access to emergency response services. Monitor all patients after each injection at the facility for at least 3 hours. Confirm that someone will accompany patient after the 3-hour observation period.
Geriatric Adults: 150 mg deep IM every 4 weeks initially. Geriatric patients may be predisposed to hypotensive reactions, have risk factors for slower metabolism of olanzapine (age-related decline in hepatic or renal function), or may be more sensitive to the drug. Use caution with dose escalation. MONITORING: Zyprexa Relprevv must be administered in a registered healthcare facility with ready access to emergency response services. Monitor all patients after each injection at the facility for at least 3 hours. Confirm that someone will accompany patient after the 3-hour observation period.
For use in combination with fluoxetine for treatment-resistant depression:
Oral dosage:
Adults: ADULTS NOT AT RISK FOR HYPOTENSION: Initially, olanzapine 5 mg PO and fluoxetine 20 mg PO once daily in the evening. Dosage adjustments should be based upon efficacy and tolerability of individual components within the range of olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR THOSE PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: Initially, olanzapine 2.5 to 5 mg with fluoxetine 20 mg PO once daily in the evening. Subsequent dosage titrations should be done with caution and close monitoring. Usual effective adult dose range: olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg per day. Antidepressant efficacy was established within a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg. Max: 18 mg of olanzapine and 75 mg of fluoxetine per day.The need for continued treatment should be evaluated periodically. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus fluoxetine) compared to the fixed dose combination product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg. NOTE: Olanzapine is not FDA approved as monotherapy for treatment-resistant depression (major depressive disorder in patients who have not responded to 2 antidepressants of adequate dose and duration in the current episode).
Geriatric Adults: Initially, olanzapine 2.5 to 5 mg with fluoxetine 20 mg PO once daily in the evening. Subsequent dosage titrations should be done with caution and close monitoring. Effective adult dose range: olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg per day. Max: 18 mg of olanzapine and 75 mg of fluoxetine per day. The need for continued treatment should be evaluated periodically. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus fluoxetine) compared to the fixed dose combination product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg. Safety and efficacy in geriatric patients older than 65 years have not been established.
For the treatment of bipolar disorder (bipolar I disorder), including mania or mixed episodes:
Oral dosage:
Adults: 10 or 15 mg PO once daily, initially. Adjust dose by 5 mg/day every 24 hours or more based on clinical response and tolerability. Usual dose: 5 to 20 mg/day. The safety of doses above 20 mg/day has not been evaluated in clinical trials.
Adolescents: 2.5 or 5 mg PO once daily, initially. Adjust dose by 2.5 or 5 mg/day every 24 hours or more based on clinical response and tolerability to a target dose of 10 mg/day. Use the lowest dose necessary to maintain remission. Dose range: 2.5 to 20 mg/day. The safety of doses above 20 mg/day has not been evaluated in clinical trials.
For the treatment of acute agitation associated with schizophrenia or bipolar mania:
Intramuscular dosage (immediate-release):
Adults: 2.5 to 10 mg IM as a single dose. Usual dose: 10 mg/dose. Subsequent doses up to 10 mg may be given; however, the efficacy of repeat doses has not been evaluated. The safety of doses more than 30 mg/day or 10 mg/dose given more frequently than 2 hours after the initial dose and 4 hours after the second dose has not been evaluated in clinical trials.
Older Adults: 2.5 to 5 mg IM as a single dose. Usual dose: 5 mg/dose. Subsequent doses up to 10 mg may be given; however, the efficacy of repeat doses has not been evaluated. The safety of doses more than 30 mg/day or 10 mg/dose given more frequently than 2 hours after the initial dose and 4 hours after the second dose has not been evaluated in clinical trials.
Adolescents*: 0.1 mg/kg (Usual: 5 to 10 mg/dose) IM as a single dose. Consider one-fourth to one-half of the usual daily dose if the patient is currently taking an antipsychotic and it is not the usual dose time. Repeat dosing is generally not recommended; if needed, do not give a second dose more frequently than 2 hours after the initial dose or 4 hours after the second dose. Max: 10 to 30 mg/day, depending on previous antipsychotic exposure.
Children 6 to 12 years*: 0.1 mg/kg (Usual: 2.5 to 5 mg/dose) IM as a single dose. Consider one-fourth to one-half of the usual daily dose if the patient is currently taking an antipsychotic and it is not the usual dose time. Repeat dosing is generally not recommended; if needed, do not give a second dose more frequently than 2 hours after the initial dose or 4 hours after the second dose. Max: 10 to 30 mg/day, depending on previous antipsychotic exposure.
Oral dosage*:
Adolescents: 0.1 mg/kg (Usual: 5 to 10 mg/dose) PO as a single dose. Consider one-fourth to one-half of the usual daily dose if the patient is currently taking an antipsychotic and it is not the usual dose time. Repeat dosing is generally not recommended; if needed, may repeat in 30 to 45 minutes. Max: 10 to 30 mg/day, depending on previous antipsychotic exposure.
Children 6 to 12 years: 0.1 mg/kg (Usual: 2.5 to 5 mg/dose) PO as a single dose. Consider one-fourth to one-half of the usual daily dose if the patient is currently taking an antipsychotic and it is not the usual dose time. Repeat dosing is generally not recommended; if needed, may repeat in 30 to 45 minutes. Max: 10 to 30 mg/day, depending on previous antipsychotic exposure.
For the adjunct treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in combination with fluoxetine:
Oral dosage:
Adults: ADULTS NOT AT RISK FOR HYPOTENSION: Initially, olanzapine 5 mg PO and fluoxetine 20 mg PO once daily in the evening. DEBILITATED ADULTS, THOSE AT RISK FOR HYPOTENSION, THOSE WITH SLOWED DRUG METABOLISM (e.g., females, non-smokers), OR THOSE PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: Initially, olanzapine 2.5 to 5 mg and fluoxetine 20 mg, with cautious dosage titration thereafter. Dosage adjustments should be based upon efficacy and tolerability. Usual effective adult dose range: olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg per day. Max: 18 mg of olanzapine and 75 mg of fluoxetine per day. The need for continued treatment should be evaluated periodically. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus fluoxetine) compared to the fixed dose combination fluoxetine; olanzapine product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg. The dosage must be individualized according to the severity of symptoms exhibited. In all cases, the lowest effective dosage should be determined for each patient. Olanzapine is not FDA approved for the monotherapy treatment of depressive episodes associated with Bipolar I Disorder.
Geriatric Adults: Initially, olanzapine 2.5 to 5 mg PO with fluoxetine 20 mg PO once daily in the evening. Dosage adjustments may be necessary in patients who exhibit a combination of factors that may slow metabolism. Titrate dose with caution and close monitoring. Usual effective adult dose range: olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg per day. Max: 18 mg of olanzapine and 75 mg/day of fluoxetine per day. The need for continued treatment should be evaluated periodically. Safety and efficacy in geriatric patients older than 65 years have not been established. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus fluoxetine) compared to the fixed dose combination product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg.NOTE: Olanzapine is not FDA approved for the monotherapy treatment of depressive episodes associated with Bipolar I Disorder.
Children and Adolescents 10 years and older: Initially, 2.5 mg/day PO of olanzapine in combination with 20 mg/day PO of fluoxetine administered once daily in the evening. Thereafter, dose adjustments can be made according to efficacy and tolerability. Max: 12 mg/day PO of olanzapine with 50 mg/day PO of fluoxetine per day. Periodically reevaluate to assess the need for continued therapy. Approximate corresponding doses for the individual components of olanzapine and fluoxetine (Zyprexa plus Prozac) compared to the fixed dose combination fluoxetine; olanzapine product (Symbyax) are as follows: Symbyax 3 mg/25 mg = Zyprexa 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/25 mg = Zyprexa 5 mg/fluoxetine 20 mg; Symbyax 12 mg/25 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 20 mg; Symbyax 6 mg/50 mg = olanzapine 5 mg/fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Zyprexa 10 mg + 2.5 mg/fluoxetine 40 mg + 10 mg. Olanzapine is not FDA approved for the monotherapy treatment of depressive episodes associated with Bipolar I Disorder.
For the treatment of severe behavioral or psychological symptoms of dementia* (BPSD)*:
Oral dosage:
Geriatric Adults: Initially, 2.5 to 5 mg PO once daily. Further dosage adjustments of no more than 2.5 to 5 mg/day, if indicated, should occur at weekly intervals. Antipsychotics are not FDA-approved for the treatment of behavioral problems associated with dementia and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility (LTCF) residents with behavioral or psychological symptoms of dementia (BPSD). OBRA Max: 5 mg/day PO in residents meeting the OBRA criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility must attempt a gradual dose reduction (GDR) in 2 separate quarters, at least 1 month apart, within the first year of admission to the facility or after the facility has initiated an antipsychotic, unless clinically contraindicated. After the first year, a GDR must be attempted annually unless clinically contraindicated. The GDR may be considered clinically contraindicated if the target symptoms returned or worsened after the most recent GDR attempt within the facility and the physician has documented justification for why attempting additional dose reductions at that time would likely impair the resident's function or increase distressed behavior.
Intramuscular dosage (injection solution, e.g., Zyprexa IntraMuscular):
Geriatric Adults: Single and multiple doses of 2.5 to 5 mg IM have been studied. In one controlled trial, patients meeting the criteria for possible or probable Alzheimer's disease, vascular dementia, or a combination of both (n = 272) were randomized to receive up to 3 IM injections of olanzapine, lorazepam, or placebo within 24 hours. Significantly more patients who received olanzapine 5 mg did not require a second injection for the control of agitation (63.6%) compared to 41.8% of patients receiving placebo. The number of patients requiring only 1 injection of olanzapine 2.5 mg was not significantly greater than placebo. Significantly more patients in the placebo group (46.3%) required a third injection than in either of the olanzapine treatment groups. When required, the second injection was administered at least 2 hours after the first injection and the third injection was administered at least 1 hour after the second injection. Max: 12.5 mg/24 hours. Antipsychotics are not FDA-approved for the treatment of behavioral problems associated with dementia and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility residents; documentation of medical necessity is required according to OBRA guidelines.
For the treatment of breakthrough chemotherapy-induced nausea/vomiting*:
Oral dosage:
Adults: 10 mg PO once daily in patients who experience breakthrough nausea/vomiting despite optimal prophylaxis and who did not receive olanzapine prophylactically. Per the American Society of Clinical Oncology (ASCO), this recommendation is moderate with an intermediate quality of evidence and with benefits outweighing harms.
Children and Adolescents 3 to 17 years: 0.1 to 0.14 mg/kg/dose (Max: 10 mg/dose) PO once daily. Round dose to the nearest 1.25 or 2.5 mg increment. Alternatively, doses of 2.5 mg (patient weight 10 to 20 kg) or 5 mg (patient weight more than 20 kg) PO once daily has been evaluated. Complete response was significantly higher in the olanzapine arm for vomiting (72% vs. 39%) and nausea (59% vs. 34%) in a controlled trial evaluating 80 patients (age: 5 to 17 years) randomized to receive metoclopramide or olanzapine for the treatment of breakthrough chemotherapy-induced nausea/vomiting.
For chemotherapy-induced nausea/vomiting prophylaxis*:
Oral dosage:
Adults: 10 mg PO once daily on days 1 through 4 in patients receiving high-emetic-risk chemotherapy. Administer concomitantly with a neurokinin 1 (NK1) receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone. Use such regimens with initial chemotherapy treatment, rather than first assessing the emetic response of the patient with less effective treatment; per the American Society of Clinical Oncology (ASCO), this recommendation is strong with a high quality of evidence and with benefits outweighing harms. In 1 placebo-controlled trial in adults, the percentage of patients who reported no nausea was significantly higher in patients receiving an antiemetic regimen containing olanzapine than a regimen without olanzapine from 0 to 24 hours (74% vs. 45%), 24 to 120 hours (42% vs. 25%), and 0 to 120 hours (37% vs. 22%) after chemotherapy. Olanzapine also improved complete response during each time interval but increased sedation on day 2. A meta-analysis of olanzapine used in various regimens and settings also suggested that olanzapine reduces chemotherapy-induced nausea and vomiting.
Children and Adolescents 3 to 17 years: 0.1 to 0.14 mg/kg/dose (Max: 10 mg/dose) PO once daily during chemotherapy and for 3 to 4 days after the chemotherapy block. Round dose to the nearest 1.25 or 2.5 mg increment. Administer concomitantly with a 5-HT3 serotonin receptor antagonist, dexamethasone, and/or aprepitant/fosaprepitant. Olanzapine was well tolerated and significantly improved vomiting and nausea control (complete response 64% vs. 38% in the overall acute and delayed phase) when administered with ondansetron, dexamethasone, and aprepitant in a randomized, prospective, open label trial in pediatric patients (n = 231; age: 5 to 18 years) scheduled to receive highly emetogenic chemotherapy. Complete response was reported in 65% (83/128) of chemotherapy blocks (acute phase) in a retrospective review of 60 patients (age: 3 to 17 years) given olanzapine in addition to a 5HT3 receptor antagonist, dexamethasone, and/or aprepitant.
For the treatment of delirium* in the pediatric intensive care unit (PICU):
Oral dosage:
Children and Adolescents 3 to 17 years: Limited data available. An initial dose of 1.25 to 5 mg PO once or twice daily has been reported in a retrospective review (n = 31, mean age: 9.22 years); reserve larger doses for older, larger, or extremely agitated patients. As needed dosing ranged from half to equal the starting dose, available every hour, with a maximum of 4 doses per 24 hours. Routine daily dosing was then established based on total dose required during a 24-hour period to control symptoms. A mean initial dose of 4 mg/day (range: 0.625 to 30 mg/day) with a mean maximum dose of 10 mg/day (range: 1.25 to 60 mg/day) was reported in another small retrospective study (n = 78, mean age: 10.8 years, age range: 1 to 18 years). Patients received olanzapine for a mean of 26.5 days (range: 1 to 132 days).
Infants and Children 7 months to 2 years: Limited data available. An initial dose of 0.625 to 1.25 mg PO once or twice daily has been described in a retrospective review of patients (n = 16, age: 7 to 30 months) diagnosed with delirium. Mean average dose was 4.81 mg/day and mean maximum dose was 7.59 mg/day. Dosage ranged from 0.5 to 35 mg/day. Mean duration of therapy was 39 days (range: 2 to 151 days).
Maximum Dosage Limits:
-Adults
20 mg/day PO; 30 mg/day immediate-release IM; 300 mg every 2 weeks or 405 mg every 4 weeks extended-release IM.
-Geriatric
20 mg/day PO; 30 mg/day immediate-release IM; 300 mg every 2 weeks or 405 mg every 4 weeks extended-release IM.
-Adolescents
20 mg/day PO for bipolar I disorder or schizophrenia; 12 mg/day PO for bipolar depression. Safety and efficacy have not been established for other indications or injectable formulations; however, doses up to 0.14 mg/kg/day (Max: 10 mg/day) PO for chemotherapy-induced nausea/vomiting and 10 to 30 mg/day PO or IM (immediate-release) for acute agitation have been used off-label. Max doses for PICU delirium are not well-defined.
-Children
10 to 12 years: 12 mg/day PO for bipolar depression. Safety and efficacy have not been established for other indications or injectable formulations; however, doses up to 20 mg/day PO for schizophrenia, 0.14 mg/kg/day (Max: 10 mg/day) PO for chemotherapy-induced nausea/vomiting, and 10 to 30 mg/day PO or IM (immediate-release) for acute agitation have been used off-label. Max doses for PICU delirium are not well-defined.
6 to 9 years: Safety and efficacy have not been established; however, doses up to 20 mg/day PO for schizophrenia, 0.14 mg/kg/day (Max: 10 mg/day) PO for chemotherapy-induced nausea/vomiting, and 10 to 30 mg/day PO or IM (immediate-release) for acute agitation have been used off-label. Max doses for PICU delirium are not well-defined.
3 to 5 years: Safety and efficacy have not been established; however, doses up 0.14 mg/kg/day (Max: 10 mg/day) PO for chemotherapy-induced nausea/vomiting have been used off-label. Max doses for PICU delirium are not well-defined.
1 to 2 years: Safety and efficacy have not been established. Max doses for PICU delirium are not well-defined (mean reported Max: 7.59 mg/day PO).
-Infants
7 to 11 months: Safety and efficacy have not been established. Max doses for PICU delirium are not well-defined (mean reported Max: 7.59 mg/day PO).
1 to 6 months: Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Dosage may need modification depending on the indication for use, clinical response, and degree of hepatic impairment. Lower initial starting doses, e.g., 2.5 to 5 mg PO initially, with careful titration, have been recommended according to the labeling for adjunctive use of olanzapine in treatment-resistant depression or bipolar depression. Quantitative recommendations are not available for other indications; use caution with careful titration.
Patients with Renal Impairment Dosing
No dosage adjustments are required; olanzapine is not removed by hemodialysis.
*non-FDA-approved indication
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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Acetaminophen; Chlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Drugs that can cause CNS depression, including dichloralphenazone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness if used concomitantly with atypical antipsychotics.
Acetaminophen; Diphenhydramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Adagrasib: (Major) Concomitant use of adagrasib and olanzapine 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.
Aldesleukin, IL-2: (Moderate) Both aldesleukin, IL 2 and olanzapine can cause significant CNS depression. Use with caution and monitor patients for additive CNS depression.
Alfentanil: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Alfuzosin: (Moderate) Caution is advised when administering olanzapine with alfuzosin as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Alfuzosin may also prolong the QT interval in a dose-dependent manner.
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) Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs that have anticholinergic effects such as olanzapine, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus. Although specific recommendations are not available from the manufacturer, it would be prudent to avoid these drugs in patients taking alosetron.
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) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Amantadine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as olanzapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amiodarone: (Major) Concomitant use of olanzapine and amiodarone 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. 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 olanzapine. Amisulpride causes dose- and concentration- dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Amlodipine; Benazepril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amlodipine; Olmesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amlodipine; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Amoxapine: (Moderate) Use caution during coadministration of amoxapine and olanzapine. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics are given concurrently. CNS effects, orthostatic hypotension, anticholinergic effects, and lowering of seizure threshold are potential problems with the combined use of amoxapine and olanzapine.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Anagrelide: (Major) Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Monitor patients for cardiovascular effects during concurrent use. In addition, anagrelide has been shown to inhibit CYP1A2. Olanzapine is a CYP1A2 substrate. In theory, coadministration could lead to increases in the serum concentration of olanzapine and thus, adverse effects.
Angiotensin II receptor antagonists: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Angiotensin-converting enzyme inhibitors: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Anticholinergics: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Apomorphine: (Moderate) Coadministration of apomorphine and olanzapine may increase the risk for QT prolongation or sedation. Apomorphine and olanzapine may decrease the effectiveness of each other due to opposing effects on dopamine. Additive CNS effects are also possible. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. 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 during coadministration.
Aripiprazole: (Moderate) Coadministration may result in additive effects on the QT interval. Both aripiprazole and olanzapine have been associated with QT prolongation. In addition, 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.
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 olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and olanzapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased olanzapine 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 olanzapine should be avoided. Consider ECG monitoring if olanzapine must be used with or after artemether; lumefantrine treatment.
Articaine; Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should be avoided in combination with other agents also known to have this effect (e.g., olanzapine). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of olanzapine with asenapine 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.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like olanzapine 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: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Atenolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Atenolol; Chlorthalidone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and olanzapine 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: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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) Drugs that decrease GI motility, such as olanzapine, may produce additive effects with antidiarrheals, such as diphenoxylate/difenoxin, if used concomitantly.
Azilsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Azilsartan; Chlorthalidone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Azithromycin: (Major) Concomitant use of olanzapine and azithromycin 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.
Barbiturates: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with olanzapine. 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. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Belladonna; Opium: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Benazepril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with olanzapine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with olanzapine 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 olanzapine, reduce initial dosage and titrate to clinical response. If olanzapine is initiated a patient taking an opioid agonist, use a lower initial dose of olanzapine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Beta-adrenergic blockers: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Betaxolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Bethanechol: (Moderate) Drugs that possess antimuscarinic properties, such as olanzapine, are pharmacologic opposites of bethanechol (a direct agonist at muscarinic cholinergic receptors). 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.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and olanzapine 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 olanzapine 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 olanzapine may produce additive effects. (Moderate) Concomitant use of metronidazole and olanzapine 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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as olanzapine. 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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Brompheniramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Brompheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
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 olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine 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 olanzapine 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 olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine 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 olanzapine 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) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
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) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Butalbital; Acetaminophen; Caffeine: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Butorphanol: (Moderate) Other drugs that can cause CNS depression, such as butorphanol, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Cabergoline: (Moderate) Cabergoline should not be coadministered with olanzapine due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of olanzapine 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 olanzapine.
Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Calcium-channel blockers: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and olanzapine. Concurrent use may result in additive CNS depression.
Captopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Carbamazepine: (Moderate) Monitor for reduced olanzapine efficacy; dosage adjustments might be necessary in some patients for whom carbamazepine treatment is medically necessary. Carbamazepine (200 mg BID) increases olanzapine clearance by approximately 50% via potent induction of CYP1A2. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance. In addition, additive CNS effects (e.g., sedation) may occur, and antipsychotic therapy may also reduce the seizure threshold in some patients.
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) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Cariprazine: (Moderate) The risk of adverse effects may be increased during concurrent use of cariprazine with other antipsychotics, such as olanzapine. 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.
Carteolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Carvedilol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Celecoxib; Tramadol: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and olanzapine. Concurrent use may result in additive CNS depression.
Central-acting adrenergic agents: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Ceritinib: (Major) Avoid coadministration of ceritinib with olanzapine 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. Ceritinib causes concentration-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
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.
Charcoal: (Major) Concomitant administration of olanzapine and activated charcoal is not recommended and is not expected to occur under normal clinical use. The Cmax and AUC of olanzapine were reduced by 60% when co-administered with activated charcoal. Co-administration with activated charcoal may be appropriate in an olanzapine overdose situation, especially since peak olanzapine levels do not occur until 6 hours after an oral ingestion. However, patients should avoid dietary supplements containing activated charcoal.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorcyclizine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlordiazepoxide: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Chlordiazepoxide; Amitriptyline: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Chlordiazepoxide; Clidinium: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Chloroquine: (Major) Avoid coadministration of chloroquine with olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Chlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Dextromethorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpromazine: (Major) Concurrent use of olanzapine and chlorpromazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. 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. 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.
Chlorzoxazone: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants, such as olanzapine. Dosage adjustments of one or both medications may be necessary.
Cimetidine: (Minor) Inhibitors of CYP1A2, such as cimetidine, could potentially decrease the elimination of olanzapine.
Ciprofloxacin: (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP) including ciprofloxacin. Additionally, ciprofloxacin inhibits the activity of CYP1A2. Inhibitors of CYP1A2 could potentially reduce the elimination of olanzapine. However, since multiple enzyme pathways metabolize olanzapine, inhibition of only one isoenzyme may not appreciably decrease olanzapine clearance. One case study reported elevated olanzapine plasma concentrations during ciprofloxacin coadministration, possibly due to CYP1A2 inhibition of olanzapine metabolism. Ciprofloxacin inhibits the activity of CYP1A2. Inhibitors of CYP1A2 could potentially reduce the elimination of olanzapine. However, since multiple enzyme pathways metabolize olanzapine, inhibition of only one isoenzyme may not appreciably decrease olanzapine clearance. One case study reported elevated olanzapine plasma concentrations during ciprofloxacin coadministration, possibly due to CYP1A2 inhibition of olanzapine metabolism.
Cisapride: (Contraindicated) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Because of the potential for torsade de pointes (TdP), use of cisapride with olanzapine is contraindicated.
Citalopram: (Major) Concomitant use of olanzapine and citalopram 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.
Clarithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Clemastine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
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.
Clofazimine: (Moderate) Concomitant use of clofazimine and olanzapine 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.
Clonazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Clorazepate: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Clozapine: (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.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Codeine; Promethazine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
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.
Crizotinib: (Major) Avoid coadministration of crizotinib with olanzapine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Cyclobenzaprine: (Moderate) When cyclobenzaprine and olanzapine are used concurrently, an increase in anticholinergic side effects may occur. Cyclobenzaprine possesses antimuscarinic properties, which can cause dry mouth, urinary difficulties and slowing of gastrointestinal motility. If used with other drugs with antimuscarinic properties, such as olanzapine, anticholinergic side effects can be additive. Particular attention should be paid to GI problems because of the possible development of paralytic ileus.
Cyproheptadine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
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.
Darifenacin: (Moderate) Olanzapine exhibits anticholinergic effects that may be enhanced when combined with other drugs with anticholinergic activity like darifenacin. 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.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Dasatinib: (Moderate) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dasatinib and olanzapine should be used together cautiously. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Degarelix: (Major) Avoid coadministration of degarelix with olanzapine due to the risk of reduced efficacy of degarelix; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog. Additionally, androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Deutetrabenazine: (Moderate) Caution is advised when administering olanzapine with deutetrabenazine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. 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 olanzapine is a dopamine antagonist. The risk for parkinsonism, NMS, or akathisia may be increased with concomitant administration. Monitor for excessive sedation and somnolence during coadministration of olanzapine and deutetrabenazine. Concurrent use may result in additive CNS depression.
Dexchlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and olanzapine 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) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dextromethorphan; Quinidine: (Major) Quinidine and dextromethorphan; quinidine cause dose-dependent QT prolongation. These drugs should be avoided in patients receiving drugs that may prolong the QT interval and are metabolized by CYP2D6, such as olanzapine. The manufacturer recommends an ECG in patients taking these drugs together.
Diazepam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Dimenhydrinate: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
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) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Diphenhydramine; Ibuprofen: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Diphenhydramine; Naproxen: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Diphenhydramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Diphenoxylate; Atropine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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) Drugs that decrease GI motility, such as olanzapine, may produce additive effects with antidiarrheals, such as diphenoxylate/difenoxin, if used concomitantly.
Disopyramide: (Major) Olanzapine should be used cautiously and with close monitoring with disopyramide. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Additive anticholinergic effects are also possible; both drugs exhibit significant anticholinergic activity.
Dofetilide: (Major) Coadministration of dofetilide and olanzapine 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). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. 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 olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Donepezil: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Donepezil; Memantine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Dorzolamide; Timolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Doxazosin: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Doxylamine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Doxylamine; Pyridoxine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
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 olanzapine is contraindicated. Dronedarone is an inhibitor of CYP2D6. Olanzapine is a substrate for CYP2D6. Coadministration of dronedarone and olanzapine may result in elevated plasma concentrations of olanzapine. In addition, olanzapine has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. 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.
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 olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
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 CYP1A2 and CYP2D6 and should be used cautiously with atypical antipsychotics metabolized by CYP1A2 and CYP2D6 such as olanzapine. Plasma concentrations of atypical antipsychotics primarily metabolized via CYP1A2, such as olanzapine, may increase substantially during concurrent use. Decreased metabolism of olanzapine may lead to clinically important adverse reactions, such as orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with CYP1A2 and CYP2D6 inhibitors such as duloxetine.
Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Eliglustat: (Major) Coadminister olanzapine and eliglustat cautiously and with close monitoring; there may be an increased risk of QT prolongation and/or olanzapine-associated adverse effects. If coadministration is necessary, olanzapine dosage reduction may be considered but is not routinely recommended. Eliglustat is CYP2D6 inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Olanzapine is a minor substrate of CYP2D6 in vivo. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration of olanzapine and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of olanzapine, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
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 olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Enalapril, Enalaprilat: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Encorafenib: (Major) Avoid coadministration of encorafenib and olanzapine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
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 olanzapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
Eplerenone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Epoprostenol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Eprosartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Eribulin: (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with olanzapine 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) Concomitant use of olanzapine and erythromycin 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.
Escitalopram: (Moderate) Concomitant use of escitalopram and olanzapine 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.
Esketamine: (Major) Closely monitor patients receiving esketamine and olanzapine 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.
Esmolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Estazolam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
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.
Ethotoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Etrasimod: (Moderate) Concomitant use of etrasimod and olanzapine 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.
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.
Fenfluramine: (Moderate) Use fenfluramine and olanzapine with caution due to an increased risk of serotonin syndrome and additive CNS depression. Monitor for excessive sedation, somnolence, and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as olanzapine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of olanzapine during coadministration with fenofibric acid.
Fentanyl: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Fesoterodine: (Moderate) Coadministration of fesoterodine and other drugs with moderate to significant anticholinergic effects such as olanzapine may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention. Additive effects may be seen on GI smooth muscle, bladder function, the CNS, the eye, and temperature regulation.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Flavoxate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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: (Moderate) Concomitant use of flecainide and olanzapine 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.
Fluconazole: (Moderate) Concomitant use of fluconazole and olanzapine 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.
Fluoxetine: (Moderate) Concomitant use of fluoxetine and olanzapine 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.
Fluphenazine: (Moderate) Concurrent use of olanzapine and fluphenazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. 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, co-administration of olanzapine 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 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.
Flurazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated olanzapine concentrations during concurrent use of fluvoxamine and olanzapine. Caution is advisable. The manufacturer of olanzapine suggests that lower doses of olanzapine be considered in patients receiving fluvoxamine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a potent inhibitor of CYP1A2, which may result in decreased clearance of CYP1A2 substrates including olanzapine. Decreased metabolism of olanzapine may lead to excessive sedation, extrapyramidal symptoms, orthostatic hypotension, or QT prolongation. Fluvoxamine increases the mean olanzapine peak concentration by 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as olanzapine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosinopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Fosphenytoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Fostemsavir: (Moderate) Caution is advised when administering olanzapine with fostemsavir due to the potential for QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four 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 olanzapine. Concomitant use of gabapentin with olanzapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Galantamine: (Moderate) Atypical antipsychotics with significant anticholinergic effects, such olanzapine, 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. Monitor for decreased clinical efficacy of galantamine if olanzapine must be used concurrently.
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) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering olanzapine with gemifloxacin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; 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 olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and olanzapine is necessary. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Glasdegib: (Major) Avoid coadministration of glasdegib with olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
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.
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.
Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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: (Major) Avoid coadministration of goserelin with olanzapine due to the risk of reduced efficacy of goserelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Moderate) Use granisetron with caution in combination with olanzapine due to increased risk for QT prolongation and torsade de pointes (TdP). Granisetron has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with olanzapine. Halogenated anesthetics can prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
Haloperidol: (Moderate) Caution is advised when administering olanzapine with haloperidol as concurrent use may increase the risk of QT prolongation; additive antipsychotic-related adverse effects (e.g., drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures) may also occur. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. The likelihood of additive pharmacodynamic interactions varies based upon the individual properties of the coadministered 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.
Histrelin: (Major) Avoid coadministration of histrelin with olanzapine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Hydantoins: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine.
Hydromorphone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Hydroxychloroquine: (Major) Concomitant use of olanzapine and hydroxychloroquine 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.
Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with olanzapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, because hydroxyzine causes pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including olanzapine. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (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, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
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 olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. 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.
Iloprost: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with olanzapine due to the potential for additive QT 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
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.
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.
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.
Irbesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
Isoniazid, INH; Rifampin: (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
Itraconazole: (Moderate) Use itraconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and olanzapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Labetalol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with olanzapine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and olanzapine. Inform patients taking this combination of the risks and symptoms of excessive CNS depression and serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Lefamulin: (Major) Avoid coadministration of lefamulin with olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
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.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with olanzapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Leuprolide: (Major) Avoid coadministration of leuprolide with olanzapine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with olanzapine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Levobunolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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 olanzapine 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 olanzapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Levorphanol: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial dose of levorphanol by approximately 50% or more. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Lidocaine; Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Lithium: (Moderate) Olanzapine and lithium are associated with QT prolongation. Coadministration may increase the risk of QT prolongation; therefore, olanzapine and lithium should be coadministered with caution and close monitoring. Some atypical antipsychotics, including olanzapine, are indicated as 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., 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. Olanzapine does not influence the pharmacokinetics of lithium.
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: (Moderate) Monitor ECG if lofexidine is coadministered with olanzapine due to the potential for additive QT prolongation. 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 torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Loop diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Loperamide: (Moderate) Concomitant use of loperamide and olanzapine 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.
Loperamide; Simethicone: (Moderate) Concomitant use of loperamide and olanzapine 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.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
Lorazepam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Losartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Loxapine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and olanzapine. 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.
Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and olanzapine, 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) Similar to other antipsychotics, lurasidone administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The risk of these adverse effects may be increased during concurrent use of lurasidone with other antipsychotics. 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.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as olanzapine. 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Maprotiline: (Major) Coadministration may result in additive effects on the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, additive anticholinergic effects may be seen with coadministration. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
Mecamylamine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Meclizine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving olanzapine as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. There is also evidence that the use of halofantrine after mefloquine causes 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.
Meperidine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.
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 olanzapine, 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 olanzapine, 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; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Methohexital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Methscopolamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
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.
Metoprolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Metronidazole: (Moderate) Concomitant use of metronidazole and olanzapine 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: (Minor) Olanzapine is partially metabolized by CYP1A2. Mexiletine may inhibit CYP1A2 and may decrease the metabolism of olanzapine resulting in potential drug accumulation. Coadministration of olanzapine with mexiletine has not been studied.
Midazolam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Midostaurin: (Major) The concomitant use of midostaurin and olanzapine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There have been case reports of significant QT prolongation occurring with olanzapine therapy.
Mifepristone: (Moderate) Concomitant use of mifepristone and olanzapine 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.
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.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as olanzapine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Moderate) Concomitant use of mirtazapine and olanzapine 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.
Mobocertinib: (Major) Concomitant use of mobocertinib and olanzapine 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.
Moexipril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Molindone: (Major) Close monitoring is advisable during concurrent use of molindone with other antipsychotics. Because molindone shares certain pharmacological properties with other antipsychotics, additive cardiac effects (e.g., hypotension), CNS effects (e.g., drowsiness), anticholinergic effects (e.g., constipation, xerostomia), extrapyramidal effects, neuroleptic malignant syndrome, or seizures may occur. 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.
Monoamine oxidase inhibitors: (Major) Avoid concomitant use, or use in rapid succession, of monoamine oxidase inhibitors (MAOIs) and olanzapine. If concomitant use is necessary, monitor for signs and symptoms of serotonin syndrome, blood pressure, and for unusual drowsiness and sedation. Concomitant use increases the risk for serotonin syndrome and additive hypotension and CNS depression. If serotonin syndrome occurs, discontinue therapy.
Morphine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Moxifloxacin: (Major) Concurrent use of olanzapine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. 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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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.
Nebivolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Nebivolol; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Neostigmine; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Nirmatrelvir; Ritonavir: (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
Non-Ionic Contrast Media: (Major) Atypical antipsychotics may lower the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and olanzapine 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; Fluoxetine: (Moderate) Concomitant use of fluoxetine and olanzapine 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.
Oliceridine: (Major) Concomitant use of oliceridine with olanzapine may cause excessive sedation and somnolence. Limit the use of oliceridine with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Olmesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Ondansetron: (Major) Concomitant use of ondansetron and olanzapine 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) Olanzapine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of olanzapine may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like olanzapine 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) Monitor ECGs in patients receiving osilodrostat with olanzapine. Osilodrostat is associated with dose-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Osimertinib: (Major) Avoid coadministration of olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of olanzapine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Oxymorphone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxymorphone dosage by one-third to one-half. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking olanzapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis or serotonin syndrome. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension and serotonergic effects. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis or serotonergic effects. Olanzapine has also been associated with serotonin syndrome reports postmarketing, but the mechanism is not clear. Ozanimod may also 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. Olanzapine has been associated with a significant prolongation of the QTc interval.
Pacritinib: (Major) Concomitant use of pacritinib and olanzapine 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.
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 olanzapine. 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, tardive dyskinesia, or seizures. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Panobinostat: (Major) The co-administration of panobinostat with olanzapine is not recommended; QT prolongation has been reported with both drugs. Additionally, levels of olanzapine may be increased. If concomitant use of olanzapine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of olanzapine toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Olanzapine is a CYP2D6 substrate, and panobinostat is a CYP2D6 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Paroxetine: (Major) Concurrent use of paroxetine and olanzapine may result in additive anticholinergic effects, such as urinary retention, constipation, blurred vision, and xerostomia. In addition, paroxetine is a potent inhibitor of CYP2D6, which is a minor isoenzyme pathway for the metabolism of olanzapine. Adverse effects of olanzapine that may become evident include fatigue, dizziness, weight gain, prolactin elevation, orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with strong CYP2D6 inhibitors such as paroxetine.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with olanzapine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be avoided with pazopanib include olanzapine.
Peginterferon Alfa-2b: (Minor) Monitor for adverse effects associated with increased exposure to olanzapine, such as extrapyramidal symptoms, sedation, and orthostatic hypotension, if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 inhibitor, while olanzapine is a CYP1A2 substrate.
Pentamidine: (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Pentazocine: (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.
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) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
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 olanzapine.
Perindopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Perindopril; Amlodipine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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 olanzapine. Coadministration may also 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) 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 olanzapine. Coadministration may also 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.
Phenobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Phenoxybenzamine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Phenytoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
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 olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration may increase the risk for QT prolongation.
Pimozide: (Contraindicated) Olanzapine has a risk of QT prolongation and is contraindicated with pimozide. 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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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.
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.
Pitolisant: (Major) Avoid coadministration of pitolisant with olanzapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking olanzapine 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. Limited date, including some case reports suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Posaconazole: (Moderate) Use posaconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Potassium-sparing diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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.
Pregabalin: (Moderate) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and olanzapine. Concomitant use of pregabalin with olanzapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Prilocaine; Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
Primaquine: (Moderate) Exercise caution when administering primaquine in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Primidone: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Procainamide: (Major) Olanzapine should be used cautiously and with close monitoring with procainamide. Procainamide administration is associated with QT prolongation and torsades de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
Prochlorperazine: (Moderate) Both prochlorperazine and olanzapine are associated with a possible risk for QT prolongation; this risk may be increased during concurrent use. Coadministration of antipsychotics 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.
Promethazine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Promethazine; Dextromethorphan: (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Promethazine; Phenylephrine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Propafenone: (Major) Concomitant use of propafenone and olanzapine 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.
Propantheline: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Propranolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Pseudoephedrine; Triprolidine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Quazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Quetiapine: (Major) Concurrent use of quetiapine and olanzapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that both olanzapine and quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of quetiapine with olanzapine 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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Quinidine: (Major) Quinidine and dextromethorphan; quinidine cause dose-dependent QT prolongation. These drugs should be avoided in patients receiving drugs that may prolong the QT interval and are metabolized by CYP2D6, such as olanzapine. The manufacturer recommends an ECG in patients taking these drugs together.
Quinine: (Major) Concurrent use of quinine and olanzapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. 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, concentrations of olanzapine may be increased with concomitant use of quinine. Olanzapine is a CYP2D6 substrate and quinine is a CYP2D6 inhibitor.
Quizartinib: (Major) Concomitant use of quizartinib and olanzapine 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.
Ramelteon: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression including ramelteon.
Ramipril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include olanzapine.
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.
Relugolix: (Moderate) Caution is advised when administering olanzapine with relugolix. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Caution is advised when administering olanzapine with relugolix. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Remifentanil: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
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.
Ribociclib: (Major) Avoid coadministration of ribociclib with olanzapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with olanzapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Concomitant use may increase the risk for QT prolongation.
Rifampin: (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Risperidone: (Moderate) Use risperidone and olanzapine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (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. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ritonavir: (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
Rivastigmine: (Moderate) Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of rivastigmine. Consider the use of an antipsychotic with less prominent anticholinergic effects. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine.
Rolapitant: (Major) Monitor for olanzapine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to olanzapine may occur. Olanzapine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with olanzapine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a 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.
Sacubitril; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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: (Major) Concurrent use of olanzapine and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
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: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
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) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with olanzapine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
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) Concomitant use of sertraline and olanzapine 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. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
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.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
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 Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and olanzapine 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) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with olanzapine. Solifenacin has been associated dose-dependent prolongation of the QT interval. TdP has been reported with post-marketing use, although causality was not determined. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Sorafenib: (Major) Avoid coadministration of sorafenib with olanzapine 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. Sorafenib is associated with QTc prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
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 olanzapine 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.
Spironolactone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and could decrease the efficacy of some medications metabolized by these enzymes including olanzapine.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and olanzapine. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
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 olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. 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 olanzapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and olanzapine 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: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Telavancin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with olanzapine. Telavancin has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine also may be associated with a significant prolongation of the QTc interval in rare instances.
Telmisartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Telmisartan; Amlodipine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Temazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Terazosin: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, concurrent use of olanzapine and tetrabenazine should generally be avoided since the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, neuroleptic malignant syndrome, or extrapyramidal symptoms may be increased.
Thiazide diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes and is contraindicated with other drugs that prolong the QTc interval. Limited data, including some case reports, suggest that olanzapine may 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. 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.
Thiothixene: (Major) Caution is advisable during concurrent use of thiothixene and other antipsychotics. Thiothixene use may be associated with adverse events such as drowsiness, dizziness, hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of thiothixene and other antipsychotics. 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.
Timolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
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 smoking tobacco while taking olanzapine. Smoking tobacco has been observed to increase olanzapine clearance by 40% to 98% and may decrease efficacy.
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: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with olanzapine. Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. 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, olanzapine exhibits anticholinergic effects that may be clinically significant; additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly. 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.
Toremifene: (Major) Avoid coadministration of olanzapine 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. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Tramadol: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tramadol; Acetaminophen: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Trandolapril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Trandolapril; Verapamil: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Trazodone: (Major) Concomitant use of trazodone and olanzapine 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) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Triamterene: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Triazolam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and olanzapine 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) Olanzapine or tricyclic antidepressants, at elevated serum concentrations, may prolong the QTc interval. In addition, anticholinergic effects and sedation may be seen when tricyclic antidepressants are used with olanzapine.
Trifluoperazine: (Moderate) Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as olanzapine. 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: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. 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.
Triprolidine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Triptorelin: (Major) Avoid coadministration of triptorelin with olanzapine due to the risk of reduced efficacy of triptorelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; triptorelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
Trospium: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like trospium and olanzapine are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients.
Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Vandetanib: (Major) Avoid coadministration of vandetanib with olanzapine 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. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Vardenafil: (Moderate) Concomitant use of vardenafil and olanzapine 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.
Vasodilators: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as olanzapine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, olanzapine is a substrate of CYP1A2 and 2D6, while vemurafenib is an inhibitor of both of these enzymes. Therefore, concentrations of olanzapine could be increased with concomitant use. Monitor the patient for increase side effects.
Venlafaxine: (Moderate) Venlafaxine is associated with a possible risk of QT prolongation. Atypical antipsychotics associated with a risk for QT prolongation and TdP that should be used cautiously with venlafaxine include olanzapine. In addition, venlafaxine is a weak inhibitor of CYP2D6. Atypical antipsychotics with partial metabolism via CYP2D6 include olanzapine. Monitor patients for potential adverse effects if these drugs are co-prescribed.
Viloxazine: (Moderate) Monitor for olanzapine-related adverse effects, including sedation, anticholinergic effects, hypotension, and QT prolongation, if concomitant use of viloxazine is necessary. A dose reduction of olanzapine may be necessary. Concomitant use may increase olanzapine exposure. Direct glucuronidation and CYP metabolism via CYP2D6 and CYP1A2 are the primary metabolic pathways for olanzapine. Viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6.
Voclosporin: (Moderate) Concomitant use of voclosporin and olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Voriconazole: (Moderate) Caution is advised when administering voriconazole with olanzapine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Vorinostat: (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with olanzapine.
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) Olanzapine is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide. If altered consciousness occurs, consider treatment discontinuation.
Ziprasidone: (Major) Concomitant use of ziprasidone and olanzapine 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. Limited data, including some case reports, suggest that olanzapine may be associated with a 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.
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.
The exact mechanism of action of olanzapine in treating schizophrenia has not been determined. However, it is thought that atypical antipsychotics such as olanzapine reduce the positive and negative symptoms of schizophrenia through modulation of central dopaminergic and serotonergic activity. Available data suggest that the efficacy of olanzapine in treating schizophrenia is primarily attributable to a combination of dopamine and serotonin 5-HT2A antagonism. The mechanism of action in bipolar disorder is unknown.
Dopamine and serotonin mediate various effects in different portions of the brain. According to one hypothesis, a dopamine excess in the mesolimbic tract is thought to be responsible for the positive symptoms of schizophrenia. In the mesocortical tract, a reduction in dopamine activity may be responsible for the negative symptoms of schizophrenia. Reduced dopamine activity in the nigrostriatal tract may be related to decreased metabolic activity in the basal ganglia. Central serotonin hyperactivity may be associated with dopamine hypoactivity in the nigrostriatal and mesocortical tracts. Antipsychotics with a high affinity for serotonin receptors are thought to be more effective for treating the negative symptoms of schizophrenia than those with dopaminergic modulation as a primary mechanism. The tuberoinfundibular tract controls neuroendocrine and hypothalamic function (e.g., prolactin release). Antipsychotic-mediated dopamine receptor blockade in the tuberoinfundibular tract increases prolactin release, which can lead to adverse effects such as amenorrhea, gynecomastia, galactorrhea, decreased libido, and impotence.
Olanzapine has a high in vitro binding affinity at receptor sites including alpha-1, histamine H-1, dopamine D1 through D4, and serotonin 5-HT2A, 5-HT2C, and 5-HT6. Olanzapine moderately binds to muscarinic M1 through M5 and serotonin 5-HT3 receptors. Antagonism at muscarinic receptors, H-1 receptors, and alpha-1 receptors correlates with various side effects of olanzapine, including anticholinergic effects, somnolence, and orthostatic hypotension, respectively. The 5-HT2C receptor is involved in the regulation of food intake, which may explain the larger increase in weight associated with olanzapine compared to many other atypical antipsychotics. Olanzapine binds weakly to GABA-A, benzodiazepine, and beta-adrenergic receptors.
Olanzapine is administered orally or intramuscularly by immediate-release or extended-release injection. Protein binding is about 93%, primarily to albumin and alpha-1-acid glycoprotein. Olanzapine is primarily metabolized by glucuronidation and CYP450 oxidation via CYP1A2 and CYP2D6. Oxidation via CYP2D6 seems to be a minor metabolic pathway in vivo; the clearance of olanzapine is not decreased in adults with a deficiency of this enzyme. The flavin-containing mono-oxygenase system also appears to be involved in olanzapine oxidation. The major circulating metabolites are the 10-N-glucuronide and 4-N-desmethyl olanzapine; neither metabolite has any pharmacological activity. The elimination half-life averages 30 hours for immediate-release dosage forms of olanzapine with a range of 21 to 54 hours. Excretion is 30% fecal and 57% renal.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP1A2, CYP2D6, UGT
Olanzapine is a major substrate for CYP1A2 and a minor substrate for CYP2D6. Concurrent use with a CYP1A2 inhibitor or inducer (e.g., smoking) can result in clinically significant interactions. Inducers of glucuronyl transferase (UGT) can increase olanzapine clearance. In vitro data suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, olanzapine is well absorbed. Food does not affect oral absorption. There is extensive first-pass metabolism, with about 40% of the dose being metabolized before reaching the systemic circulation. The onset of action is 20 to 30 minutes; action peaks at 6 hours and persists for 24 hours. Steady-state concentrations are reached in approximately 1 week of continuous dosing. Pharmacokinetic studies showed that olanzapine tablets and olanzapine orally disintegrating tablets (i.e., Zyprexa Zydis) are bioequivalent. Based on a pharmacokinetic study in healthy volunteers, a 5 mg IM dose produces, on average, a maximum plasma concentration roughly 5 times higher than the maximum plasma concentration produced by a 5 mg oral dose. The area under the curve achieved after an IM dose is similar to that achieved after oral administration of the same dose. Metabolic profiles after IM administration are qualitatively similar to metabolic profiles after oral administration. About 57% and 30% of an orally administered dose is recovered in the urine and feces, respectively.
Intramuscular Route
Immediate-release injection (Zyprexa IntraMuscular)
Intramuscular (IM) administration results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based on a pharmacokinetic study in healthy volunteers, a 5 mg IM dose produces, on average, a maximum plasma concentration roughly 5 times higher than the maximum plasma concentration produced by a 5 mg oral dose. The AUC achieved after an IM dose is similar to that achieved after oral administration of the same dose. In clinical trials, IM olanzapine was superior to placebo at 2 hours post-injection for the treatment of agitation in patients with schizophrenia or bipolar disorder. Metabolic profiles after IM administration are qualitatively similar to metabolic profiles after oral administration.
Extended-release injection (Zyprexa Relprevv)
Slow dissolution from the injection site results in prolonged systemic olanzapine plasma concentrations for weeks to months. A 2- to 4-week injection within the therapeutic dose range provides similar plasma concentrations to those achieved by therapeutic daily doses of oral olanzapine. The effective half-life is about 30 days compared to a half-life of 30 hours for the oral formulation. Peak plasma concentrations are attained within the first week and are at trough levels just prior to the next injection. The peak-to-trough fluctuation is comparable to that of once-daily oral dosing. A Zyprexa Relprevv dose of 300 mg IM every 2 weeks corresponds to about 20 mg/day of the oral formulation and a Zyprexa Relprevv dose of 150 mg IM every 2 weeks corresponds to about 10 mg/day of the oral formulation. When switching from the oral formulation to the extended-release injection, approximately 3 months of dosing is needed to re-establish steady-state conditions. Although plasma concentrations from the injectable formulation may initially be lower than the oral formulation, olanzapine concentrations remained within a therapeutic range, and supplementation with oral olanzapine was generally not needed during clinical trials.
-Special Populations
Hepatic Impairment
Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically significant (Childs Pugh Class A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine.
Renal Impairment
Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied. Olanzapine is not removed by hemodialysis.
Pediatrics
Infants, Children, and Adolescents
Postmenstrual age and body weight are influential covariates for describing developmental changes in olanzapine clearance. A parabolic relationship between half-life and postnatal age was observed in a pediatric pharmacokinetic study (n = 45, age range: 2 months to 19 years). Longer half-lives were observed in infants younger than 5 months and children 6 years and older. Shorter half-lives were observed for children 6 months to 5 years. Median half-life was 18.56 hours in patients younger than 2 years, 13.36 hours in patients 2 to 5 years, 26.92 hours in patients 6 to 11 years, and 28.93 hours in patients 12 years and older. Typical clearance and Vd (scaled to 70 kg) were 16.8 L/hour and 663 L, respectively.
Geriatric
The half-life of olanzapine is 1.5 times longer in the elderly versus younger adults.
Ethnic Differences
In vivo studies indicate that exposure to olanzapine after administration of equivalent doses is similar among Japanese, Chinese, and White patients.
Other
Smoking
Smoking induces CYP1A2, a primary metabolic path for olanzapine. Olanzapine clearance is about 40% higher in smokers than nonsmokers, although dosage adjustments are not generally recommended based upon smoking status. The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences between patients.
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