Carbidopa; levodopa; entacapone is a combination product for the treatment of idiopathic Parkinson's disease in adult patients who experience the end-of dose 'wearing off' effect of levodopa. Carbidopa; Levodopa and Entacapone have been used together successfully as separate dosage formulations. Carbidopa; levodopa; entacapone is indicated as a substitution (with equivalent strengths) for patients previously taking these drugs separately, and is also indicated to replace immediate-release carbidopa/levodopa therapy when entacapone-naive patients experience the end-of dose 'wearing off' effect. Three 24-week pivotal trials demonstrated increased 'on' time, reduced 'off' time, improved motor function and improved activities of daily living with carbidopa; levodopa; entacapone. Patients who receive carbidopa; levodopa; entacapone should have previously been receiving levodopa 600 mg/day or less and have no associated dyskinesias. The FDA granted approval for carbidopa; levodopa; entacapone as a combination product in 2003.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer tablets whole. Do not split, crush or chew the tablets.
-May administer with or without food. However, a high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours. A change to a high-protein diet may also result in delayed absorption.
-Only 1 tablet of carbidopa-levodopa-entacapone should be administered at each dose. Combining multiple tablets or portions of tablets to achieve a higher levodopa dose may lead to an overdose of the entacapone component.
-Advise patients that dark coloration (red, brown, or black) may appear in saliva, urine, or sweat. The color change is not harmful, but garments may become discolored.
This monograph discusses the combination product Carbidopa; Levodopa; Entacapone. Clinicians may wish to consult the individual monographs for more information about each agent.
Rare cases of a symptom complex resembling neuroleptic malignant syndrome have been reported following abrupt discontinuation or dose reduction of carbidopa; levodopa, especially in patients receiving antipsychotic agents concomitantly. Therefore, patients should be observed carefully when the dosage of carbidopa; levodopa; entacapone is abruptly reduced or discontinued. The early diagnosis of this condition is important for the appropriate management of these patients. Patients should be observed closely for manifestations of this symptom complex, which include tachycardia, muscular rigidity, elevation of body temperature (fever or hyperthermia), mental status changes (e.g., confused state), increased sweating, tachypnea, and increases in serum creatinine levels. Altered consciousness, elevated CPK levels, leukocytosis, myoglobinuria, and increased serum myoglobin have also been reported. Rapid re-emergence of Parkinson's disease symptoms may occur on entacapone withdrawal, and concurrent dopaminergic therapies may need an upward dosage adjustment.
Dyskinesia is the most common adverse effect of carbidopa; levodopa; entacapone therapy and includes dystonic reaction (e.g., oculogyric crisis), choreiform movements, or other involuntary movements. These involuntary movements occur in up to 80% of patients receiving levodopa therapy for >= 3 years and may necessitate dosage reduction. Carbidopa and entacapone allow more levodopa to reach the brain and more dopamine to be formed. Entacapone may cause and/or exacerbate preexisting dyskinesia, especially during the first 8 weeks of therapy. Therefore, in patients naive to entacapone it may be prudent to titrate the patient with separate dosage forms of levodopa; carbidopa and entacapone, and then switch to the fixed dosage combination (Stalevo) once the optimal response is reached. Although decreasing the dose of levodopa may lessen levodopa dosage-induced side effects, patients may continue to experience frequent dyskinesias despite levodopa dosage reduction. During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, the following movement disorders occurred more frequently in the entacapone treatment group than the placebo treatment group: dyskinesia (25% vs 15%), hyperkinesis (10% vs 5%), and hypokinesia (9% vs 8%).
'Bradykinetic episodes' or 'on-off' phenomena, including akinesia, sudden return of effectiveness, and akinesia paradoxica, can occur during levodopa therapy and is likely due to both disease progression and excessive levodopa dosage. The bradykinetic episode, a sudden lack of effectiveness with concomitant akinesia, can last from 1 minute to an hour. Bradykinesia may be followed by a sudden return of effectiveness, and the cycle may occur many times a day. Increasing the frequency of carbidopa; levodopa administration can minimize this effect in some patients by providing less dose-to-dose variation in CNS levodopa levels. Akinesia paradoxica or freezing is an abrupt hypotonic reaction resulting in a short-lived interruption of motor function. Akinesia paradoxic is most problematic if it occurs when the patient is walking, and may cause a fall. The etiology of the freezing episodes is not well understood. The response to levodopa decreases over time and many patients develop 'wearing-off' fluctuations of their symptoms. Wearing-off occurs during the day and consists of a gradual onset of parkinsonian symptoms before the next levodopa dose takes effect, usually 1-3 hours after the last dose. Hypokinesia (9%) has also been reported during treatment with carbidopa; levodopa; entacapone.
Mild to severe diarrhea and colitis can occur during treatment with entacapone, and may be associated with loss of weight, dehydration, and hypokalemia. During clinical trials, diarrhea occurred in 10% of those in the levodopa/dopa decarboxylase inhibitor + entacapone group versus 4% of those in the levodopa/dopa decarboxylase inhibitor + placebo group. In the entacapone group, diarrhea was considered mild to moderate in 8.6% of patients and severe in 1.3% of patients. Treatment was discontinued in 1.2% of those with mild to moderate diarrhea and 0.5% of those with severe diarrhea, and 2 patients were hospitalized. During post-marketing use, drug-induced microscopic colitis, primarily lymphocytic colitis, has been reported. Symptoms of entacapone-induced colitis generally consist of moderate to severe, watery, non-bloody diarrhea which may be associated with dehydration, abdominal discomfort, loss of weight, and hypokalemia. Diarrhea and colitis-related symptoms usually resolve or improve significantly upon discontinuation of the drug. Diarrhea commonly presents within 4-12 weeks of beginning entacapone treatment, but it may appear as early as the first week and as late as many months after the initiation of therapy. If prolonged diarrhea is thought to be related to carbidopa; levodopa; entacapone treatment, the drug should be discontinued. If symptoms persist, diagnostic measures such as colonoscopy and biopsy should be considered.
Gastrointestinal adverse effects are common with both carbidopa; levodopa and entacapone therapy. Nausea/vomiting is a common, but often transient adverse reaction seen with carbidopa; levodopa; entacapone. Anorexia and weight loss may also occur. Although levodopa; carbidopa; entacapone can be administered with food to offset nausea, it should be noted that foods, especially high-protein or high-fat foods, could interfere with levodopa absorption. Peripheral dopa decarboxylase is saturated by carbidopa at approximately 70-100 mg/day; patients receiving less than this amount are more likely to experience nausea and vomiting. Xerostomia may be a beneficial effects of carbidopa; levodopa; entacapone in some patients as sialorrhea is often a Parkinson's disease effect due to excess acetylcholine. During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, the following adverse gastrointestinal (GI) effects occurred more frequently in the entacapone treatment group than the placebo treatment group: nausea (14% vs 8%), diarrhea (10% vs 4%), abdominal pain (8% vs 4%), constipation (6% vs 4%), vomiting (4% vs 1%), xerostomia (3% vs 0%), dyspepsia (2% vs 1%), flatulence (2% vs 0%), gastritis (1% vs 0%), dysgeusia (1% vs 0%), and GI disorders NOS (1% vs 0%). Diarrhea due to colitis has also been reported. Adverse GI effects reported during treatment with levodopa alone or carbidopa; levodopa formulations include dark saliva, GI bleeding, peptic ulcer, anorexia, vomiting, constipation, dyspepsia, xerostomia, dysgeusia, GI pain, dysphagia, sialorrhea, teeth grinding (bruxism), burning sensation of the tongue, pyrosis (heartburn), hiccups, weight gain, and weight loss.
Cases of rhabdomyolysis have been reported with entacapone use in combination with levodopa. It is not known what role entacapone had in these events, but rhabdomyolysis has been associated with other drugs that increase dopaminergic activity. Severe prolonged motor activity may account for the rhabdomyolysis; however, at least one case involved fever and altered consciousness, suggesting that rhabdomyolysis may also be the result of a symptom complex resembling neuroleptic malignant syndrome which has been reported during rapid dose reduction or withdrawal of other dopaminergic drugs.
Hyperhidrosis can be seen during carbidopa; levodopa; entacapone therapy, although drenching sweats may be a sign of Parkinson's disease. In pivotal trials, when either entacapone or placebo was added to current carbidopa; levodopa therapy, the incidence of hyperhidrosis was 2% vs. 1%, respectively. Lowering the levodopa dosage may be effective or, if medically appropriate, a beta-blocker may be used to decrease hyperhidrosis. Dermatologic effects that have been reported during use of levodopa alone or carbidopa; levodopa combinations include rash (unspecified), hyperhidrosis, alopecia, flushing, and dark sweat. Hypersensitivity reactions have included angioedema, urticaria, pruritus, and bullous rash/lesions (including pemphigus-like reactions). Because levodopa may activate malignant melanoma, carbidopa; levodopa; entacapone is contraindicated in patients with a history of melanoma, or in patients with suspicious, undiagnosed pigmented lesions.
During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, the following centrally-mediated effects occurred more frequently in the entacapone treatment group than the placebo treatment group: dizziness (8% vs 6%) and drowsiness (2% vs 0%). Somnolence (2%) was among the most common causes of discontinuation of carbidopa; levodopa; entacapone therapy during clinical trials. There have been reports of patients receiving dopaminergic agents who have fallen asleep while performing activities of daily living, including driving. Excessive drowsiness has, in some cases, occurred as late as one year after the initiation of treatment. In some cases, sudden sleep onset has resulted in auto accidents or other harmful events in the course of daily living. Symptoms of excessive drowsiness may not be preceded by warning signs. Patients should be cautioned about driving or operating machinery, working at heights, or performing other tasks that require alertness while receiving carbidopa; levodopa; entacapone. Those who have experienced somnolence or a sudden episode of sleep while taking the drug should avoid these activities. Reassessment for oversedation is suggested throughout therapy; patients should notify their prescriber if they fall asleep during normal activities. The use of concomitant CNS depressant medications or sleep disorders may increase the risk of falling asleep while taking this medication; patients should be assessed for these risk factors prior to initiation of the drug and be advised of the additive risks for somnolence. Carbidopa; levodopa; entacapone should generally be discontinued in patients who experience episodes of falling asleep while engaged in activities of daily living. It is not known if a reduction in dosage will subsequently reduce or eliminate excessive somnolence or sudden episodes of sleep. Nocturnal effects may be improved by reducing or stopping the last evening dose or giving the last dose earlier in the evening. Adverse CNS effects reported during treatment with levodopa alone or carbidopa; levodopa formulations include dizziness, drowsiness, dream abnormalities (e.g., nightmares), insomnia, paresthesias, headache, libido increase, ataxia, extrapyramidal disorder, gait abnormalities, decreased mental acuity, memory impairment, trismus, tremor, numbness, muscle twitching, activation of latent Horner's syndrome, and peripheral neuropathy. Seizures have also occurred; however, causality to carbidopa; levodopa has not been established.
Elevated hepatic enzymes and hyperbilirubinemia have been reported with carbidopa; levodopa; entacapone. Laboratory test alterations reported during treatment with levodopa alone or carbidopa; levodopa combinations include: a false positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria; false negative tests with the use of glucose-oxidase methods of testing for glucosuria; abnormalities in alkaline phosphatase, AST, ALT, or lactic dehydrogenase; abnormal bilirubin or blood urea nitrogen (BUN); decreased serum potassium; increased serum creatinine or uric acid; and protein and glucose in the urine. Commonly, the levels of BUN, creatinine, and uric acid are lower during administration of carbidopa; levodopa; entacapone combinations than with levodopa alone.
Hematologic adverse events and infections have been reported during treatment with carbidopa; levodopa; entacapone. During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, the following hematologic effects or infections occurred more frequently in the entacapone treatment group than the placebo treatment group: purpura (2% vs 1%) and bacterial infection (1% vs 0%). Leukopenia, non-hemolytic and hemolytic anemia, agranulocytosis, and thrombocytopenia have been reported during therapy with levodopa alone or carbidopa; levodopa and warrant temporary discontinuance of the drug. Urinary tract infection, decreased hemoglobin and hematocrit, decreased white blood cell count, white blood cells, bacteria, and blood in the urine, and abnormalities in the Coombs' test have also been reported during use of levodopa or carbidopa; levodopa combinations. Henoch-Schonlein purpura has been reported as a hypersensitivity reaction to carbidopa; levodopa.
The most common cardiovascular effect of levodopa therapy is orthostatic hypotension and occurs even with therapeutic dosages. Tolerance usually develops within a few months. Due to enhancement of the dopaminergic effects of levodopa, entacapone has also been associated with hypotension or syncope (1.2%) in patients also receiving carbidopa; levodopa or its equivalent during clinical trials. Reports of syncope were generally more frequent in patients who had a previously documented episode of orthostatic hypotension. Cardiac effects (e.g., arrhythmias, hypertension, orthostatic hypotension, phlebitis, chest pain (unspecified), myocardial infarction, and palpitations) have been reported during treatment with levodopa alone or carbidopa; levodopa therapy. In 2010, the FDA required a study of the potential for cardiovascular risk with the entacapone component of carbidopa; levodopa; entacapone (Stalevo) to determine whether entacapone was associated with an increased risk of cardiovascular events including myocardial infarction, stroke, and cardiovascular death. This mandate followed possible cardiovascular safety issues observed in the Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) trial (i.e., 7 myocardial infarctions and one cardiovascular death in the carbidopa; levodopa; entacapone group vs. none in the carbidopa; levodopa group) and in a meta-analysis that combined the cardiovascular-related findings from 15 clinical trials comparing Stalevo to carbidopa/levodopa, an extensively used drug combination without an increased cardiovascular risk. Following a review of the new data, the FDA found no clear evidence of an increased risk of heart attacks, stroke, or other cardiovascular events associated with the use of entacapone for the treatment of Parkinson's disease. It should be noted that STRIDE-PD was not designed to assess cardiac safety, and previous trials have not shown a difference in myocardial infarctions, stroke, or cardiovascular death between carbidopa; levodopa; entacapone and carbidopa; levodopa alone.
Saliva, sweat, or urine discoloration may be noted during carbidopa; levodopa; entacapone therapy. The dark color (red, brown, or black) appears to be clinically insignificant, but may stain garments and other fabrics. During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, urine discoloration occurred in 10% of patients in the entacapone treatment group and no patients in the placebo treatment group. Genitourinary (GU) effects that have been reported during treatment with levodopa alone or carbidopa; levodopa include urinary tract infection, increased urinary frequency, urinary retention, urinary incontinence, priapism, and urine discoloration.
During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, the following general adverse effects occurred more frequently in the entacapone treatment group than the placebo treatment group: fatigue (6% vs 4%) and asthenia (2% vs 1%). General effects reported during treatment with levodopa alone or carbidopa; levodopa formulations include asthenia, abdominal pain and distress, edema, fatigue, bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, and sense of stimulation.
Four cases of pulmonary fibrosis were reported during clinical development of entacapone; three of these patients were also treated with pergolide and one with bromocriptine. The duration of treatment with entacapone ranged from 7-17 months. Fibrotic-related complications, such as retroperitoneal fibrosis, pulmonary fibrosis, pleural effusion, and pleural thickening, have been reported in some patients receiving ergot-derived dopaminergic agents (e.g., bromocriptine). Although these events are thought to be associated with the ergoline structure of such compounds, the possibility that non-ergot derived drugs such as entacapone or levodopa can cause them cannot be excluded.
Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, or other intense urges. Causality due to dopaminergic agents has not been established; however, in some cases the urges stopped after the dose was reduced or the drug was discontinued. Practitioners should inquire periodically about new or worsening impulse control symptoms in patients receiving carbidopa; levodopa; entacapone. Likewise, patients should be instructed to report such changes while receiving carbidopa; levodopa; entacapone. Dose reduction or discontinuation should be considered in those who experience these effects.
During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, back pain was reported in 2% of patients in the entacapone treatment group and 1% of patients in the placebo treatment group. Adverse musculoskeletal effects reported during treatment with levodopa alone or carbidopa; levodopa formulations include back pain, shoulder pain, muscle cramps, and leg pain.
During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, dyspnea was reported in 3% of patients in the entacapone treatment group and 1% of patients in the placebo treatment group. Adverse respiratory effects reported during treatment with levodopa alone or carbidopa; levodopa formulations include dyspnea, upper respiratory infection, pharyngeal pain, and cough.
Adverse ophthalmic effects reported during treatment with levodopa alone or carbidopa; levodopa formulations include diplopia, blurred vision, blepharospasm, and dilated pupils (mydriasis). Similar effects are possible during treatment with carbidopa; levodopa; entacapone.
During placebo-controlled trials assessing entacapone as add-on therapy to carbidopa; levodopa or its equivalent, the following psychiatric effects occurred more frequently in the entacapone treatment group than the placebo treatment group: anxiety (2% vs 1%) and agitation (1% vs 0%). Levodopa-induced psychiatric effects tend to be progressive and frequently a compromise must be reached between psychiatric effects and control of Parkinson symptoms. Psychiatric reactions including anxiety (2%) and agitation (1%) were among the most common causes of discontinuation of carbidopa; levodopa; entacapone therapy. Hallucinations developed in approximately 4% of patients treated with either entacapone or placebo in addition to levodopa therapy. The discontinuation rate due to hallucinations was 0.8% of patients in the entacapone group versus no patients in the placebo group. Hallucinations led to hospitalization in 1% of entacapone-treated patients versus 0.3% of placebo-treated patients. Adverse Psychiatric effects reported during treatment with levodopa alone or carbidopa; levodopa formulations include psychosis (delusions, hallucinations, paranoia), confusion, agitation, depression, suicidal ideation, anxiety, nervousness, disorientation, and euphoria.
Levodopa is a pyridoxine antagonist and may lead to vitamin B6 deficiency. Supplementation with vitamin B6 may be beneficial in preventing depletion and reducing adverse reactions.
The administration of carbidopa; levodopa; entacapone is contraindicated in any patient who has demonstrated a hypersensitivity to carbidopa, levodopa, entacapone, or any inactive ingredients in the formulation.
Dyskinesia (involuntary movements) may occur or be exacerbated at lower dosages and sooner with levodopa; carbidopa; entacapone than with preparations containing only carbidopa and levodopa. The occurrence of dyskinesias may require dosage reduction. In clinical trials, the treatment difference incidence of dyskinesia was 10% and for carbidopa-levodopa plus 200 mg entacapone. Decreasing the dose of levodopa may ameliorate this side effect; however many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa, and approximately 1% may discontinue entacapone due to this reason. Cases of severe rhabdomyolysis have also been reported with entacapone in combination with carbidopa and levodopa. Severe prolonged motor activity including dyskinesia may possibly account for rhabdomyolysis. Most of the cases were manifested by myalgia and increased values of creatine phosphokinase (CPK) and myoglobin. Some of the reactions also included fever and/or alteration of consciousness. It is also possible that rhabdomyolysis may be a result of the syndrome described when the drug product is abruptly withdrawn.
Avoid abrupt discontinuation of carbidopa; levodopa; entacapone therapy. Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been associated with dose reductions and withdrawal of carbidopa, levodopa and entacapone or other medications with dopaminergic properties, and may be life-threatening. However, in some cases, hyperpyrexia and confusion were reported after initiation of treatment with entacapone. Hyperpyrexia and confusion are uncommon but they may be life-threatening with a variety of features, including hyperthermia/fever/hyperpyrexia, muscle rigidity, involuntary movements, altered consciousness/mental status changes, delirium, autonomic dysfunction, tachycardia, tachypnea, sweating, hypo- or hypertension, and abnormal laboratory findings (e.g., creatine phosphokinase (CPK) elevation, leukocytosis, myoglobinuria, and increased serum myoglobin). The early diagnosis of this condition is important for the appropriate management of these patients, which includes intensive medical monitoring and management. If a patient needs to discontinue or reduce their daily dose of this product, the dose should be decreased slowly, with supervision from a health care provider. Specific methods for tapering entacapone have not been systematically evaluated. If a patient requires general anesthesia for surgery, carbidopa; levodopa; entacapone may be continued as long as the patient is permitted to take fluids and medication by mouth. Cases of neuroleptic malignant syndrome have been reported post-surgery so close monitoring is warranted; reinstitute carbidopa; levodopa; entacapone therapy as soon as possible after the procedure. In addition, some patients receiving levodopa have experienced postoperative bleeding episodes, so hematological studies are recommended for all patients who undergo surgery while receiving this drug. Patients should inform their surgeon and anesthesiologist of the use of entacapone prior to surgery, as COMT inhibitors may interact with some medications used in surgical procedures.
The administration of non-selective monoamine oxidase inhibitor therapy (MAOI therapy) is contraindicated with carbidopa; levodopa; entacapone. Concomitant use of non-selective MAOIs with carbidopa-levodopa combinations can result in hypertensive crisis. Nonselective MAO inhibitors must be discontinued at least 2 weeks prior to initiating therapy with levodopa; carbidopa entacapone. Selective MAO-B inhibitors and other standard drugs for Parkinson's disease may be used concomitantly with carbidopa; levodopa; entacapone; however, dosage adjustments of therapies may be required. Drugs known to be metabolized by COMT should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as interactions may result in increased heart rate, arrhythmia, and/or increased blood pressure.
Caution should be exercised when prescribing carbidopa; levodopa; entacapone to Parkinson's patients who are more prone to hypotension or orthostatic hypotension. Syncope and/or orthostatic hypotension have been reported with drugs that increase dopaminergic tone, including levodopa; carbidopa; entacapone. Reports of syncope were generally more frequent in patients in both treatment groups who had had a prior episode of documented hypotension. The FDA has reviewed extensive data for the cardiovascular safety of entacapone when used with levodopa; carbidopa, and there was no increased risk of heart attacks, stroke, or other cardiovascular events associated with the use of entacapone for the treatment of Parkinson's disease.
Patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during carbidopa; levodopa and/or entacapone treatment. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies or suicidal ideation. Patients with past or current psychosis should be treated with caution. Dopaminergic therapy in patients with Parkinson's disease has been associated with hallucinations and may lead to drug withdrawal or patient hospitalization in rare instances.
Carbidopa; levodopa; entacapone has the potential to cause drowsiness or somnolence. There have been postmarketing reports of patients who have experienced sudden sleep onset when taking dopaminergic agents. In some cases, excessive drowsiness has resulted in automobile accidents or other harmful events in the course of daily living. Patients should be advised of this effect and be instructed to use extreme caution when driving or operating machinery or performing other tasks that require alertness while receiving carbidopa; levodopa; entacapone. Reassessment for drowsiness or oversedation is necessary throughout therapy. Sleep disorders (e.g., narcolepsy, sleep apnea), coadministration with other CNS depressants, or interacting medications may increase the risk of suddenly falling asleep while on this medication. Patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Advise patients to speak with their health care prescriber before ethanol ingestion, taking sedating medications, or before taking other CNS depressant medications because of the possible additive effects in combination with carbidopa; levodopa; entacapone. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), this drug should ordinarily be discontinued. If a decision is made to continue treatment, patients should be advised to avoid driving or other potentially dangerous activities. There is insufficient data to establish if dose reduction will eliminate sudden episodes of falling asleep.
Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable impulse control symptoms, such as urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, or other intense urges. Advise patients that they may experience impulsive and/or compulsive behaviors while taking 1 or more of the medications used for the treatment of Parkinson's disease. Ask patients about the development of new or increased gambling urges, sexual urges, urges for uncontrolled spending, or other intense urges while being treated with carbidopa; levodopa; entacapone. Advise patients to inform their physician or health care provider if they experience new or increased symptoms of this type while taking this medication. Consider dose reduction or discontinuation if a patient develops these symptoms during treatment.
Carbidopa; levodopa; entacapone should be administered cautiously to patients with biliary obstruction, jaundice, or hepatic disease since biliary excretion appears to be the major route of excretion of entacapone and hepatic impairment increased entacapone exposure significantly. All patients studied had biopsy-proven liver cirrhosis caused by alcohol; According to Child-Pugh grading, 7 of these patients had mild hepatic impairment and 3 patients had moderate hepatic impairment. As with any therapy containing levodopa, periodic evaluation of hepatic function is recommended during extended therapy, as elevated hepatic enzymes may occur during treatment.
Carbidopa; levodopa; entacapone is contraindicated for use in patients with closed-angle glaucoma. Levodopa therapy can cause mydriasis which can increase intraocular pressure. Patients with other types of glaucoma may be treated cautiously with carbidopa; levodopa; entacapone if intraocular pressure is controlled and monitored.
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot-derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse reactions may be related to the ergoline structure of these compounds, a possible causal role of non-ergot drugs (e.g., entacapone, levodopa), which increase dopaminergic activity, has also been considered. The expected incidence of fibrotic complications is so low that even if entacapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that it would have been detected in a cohort of the size exposed to the drug during clinical trials prior to marketing. Four cases of pulmonary fibrosis have been reported during clinical development of entacapone; 3 of these patients were also treated with pergolide and 1 with bromocriptine. The duration of treatment with entacapone ranged from 7 months to 17 months.
Gastrointestinal (GI) symptoms may require evaluation and adjustment in therapy by the prescriber. Inform patients that carbidopa; levodopa; entacapone may cause nausea/vomiting more frequently during initial therapy and some patients may require dose adjustment. Entacapone therapy commonly (10%) causes diarrhea. Typically, diarrhea presents within 4 to 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment. Diarrhea may be associated with weight loss, dehydration, and hypokalemia, and in rare cases, has required hospitalization. Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In cases of colitis, the diarrhea has usually been moderate to severe, watery and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, the symptoms resolved or significantly improved when entacapone was discontinued. In some patients with biopsy-confirmed colitis, diarrhea had resolved or significantly improved , but recurred after retreatment with entacapone. If prolonged diarrhea is suspected to be related to treatment, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered. Use carbidopa; levodopa; entacapone with caution in patients with peptic ulcer disease. Levodopa therapy may increase the risk of upper GI bleeding in patients with a peptic ulcer disease history.
Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk is due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. Patients and providers are advised to monitor for melanoma frequently and on a regular basis when using carbidopa; levodopa; entacapone for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).
Use carbidopa; levodopa; entacapone with caution during the interpretation of certain urine tests in patients with diabetes mellitus. When a test tape is used for determination of ketonuria in patients taking carbidopa; levodopa; entacapone, a false-positive urinary ketone test may result. This reaction will not be altered by boiling the urine specimen. Additionally, false-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.
Rarely, falsely diagnosed pheochromocytoma has been reported in patients receiving levodopa due to a laboratory test interference. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on carbidopa; levodopa; entacapone therapy.
Carbidopa; levodopa; entacapone has not been studied in clinical trials in geriatric adults greater than 75 years of age. Reported clinical experience has not identified differences in responses between geriatric and younger adult patients, but caution is recommended since some older individuals may be more sensitive to the effects of the drugs.
There are no adequate or well-controlled studies regarding fetal developmental risks associated with carbidopa; levodopa; entacapone administration in pregnant women. Limited data suggest that carbidopa crosses human placenta in low concentrations. Levodopa crosses the placenta and reaches levels in the fetus comparable to maternal blood, although pregnancy outcomes have been primarily unremarkable. Two first trimester miscarriages were reported during the use of carbidopa; levodopa, and 1 infant exposed to levodopa in utero developed osteomalacia. One case of neonatal seizure occurred after use of bromocriptine plus carbidopa; levodopa; entacapone during pregnancy. Maternal complications reported in 3 pregnancies during use of carbidopa; levodopa included first trimester vaginal bleeding, third trimester nausea and vomiting, depression, and preeclampsia. Patients should be instructed to notify their physicians if they become pregnant or intend to become pregnant during therapy. In animal studies, administration of carbidopa; levodopa or entacapone was associated with fetal toxicities (e.g., visceral and skeletal malformations, decreased live births, fetal eye anomalies) at doses above the maximum recommended human dose (MRHD). The effects of carbidopa; levodopa; entacapone during labor and delivery are unknown.
The developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for carbidopa; levodopa; entacapone and any potential adverse effects on the breastfed child from the combination product or the mother's underlying condition. It is not known whether entacapone and carbidopa are excreted in human milk; however, they are excreted in rat milk. Levodopa has been detected in human milk. In a case report of a breast-feeding mother with Parkinson's disease receiving sustained-release (SR) carbidopa; levodopa 50/200 mg 4 times daily, peak levels of levodopa in milk occurred 3 hours after a dose and returned to baseline after 6 hours. After receiving the same dose of the immediate-release (IR) formulation, similar results were observed, with the exception of a higher milk to plasma ratio with the IR product (0.32 vs. 0.28). The infant ingested 0.127 mg and 0.181 mg of levodopa after maternal intake of the SR and IR products, respectively. It was estimated that the infant received an average of 0.3% of the maternal weight-adjusted dosage of the SR product and 0.5% of the maternal weight-adjusted dose of the IR product. Levodopa did not inhibit lactation. No adverse effects were observed in her infant, whose development was normal at 2 years of age. The authors suggest that nursing or pumping milk at times of lower levodopa breast milk levels may help minimize the amount of levodopa received by an infant. Because levodopa can inhibit prolactin secretion, interference with lactation is possible. If carbidopa; levodopa; entacapone must be administered during breast-feeding, the infant should be monitored for adverse effects such as dyskinesias, insomnia, sedation, nausea, and constipation.
The safety and efficacy of this carbidopa; levodopa; entacapone product have not been established in children and adolescents less than 18 years of age. This drug combination is not indicated in infants.
This monograph discusses the combination product Carbidopa; Levodopa; Entacapone. Clinicians may wish to consult the individual monographs for more information about each agent.
For the treatment of Parkinson's disease:
Oral dosage:
Adults: 12.5 to 50 mg carbidopa/50 to 200 mg levodopa/200 mg entacapone up to 8 times daily. Max: 1,600 mg/day entacapone. Convert persons currently treated with entacapone 200 mg with each dose of immediate-release carbidopa/levodopa to the equivalent dose of carbidopa/levodopa/entacapone. When converting persons with a history of moderate or severe dyskinesias or taking more than 600 mg/day of levodopa without entacapone, a levodopa dose reduction is likely to be needed when entacapone is added. Because dose adjustment of the individual carbidopa or levodopa component is not possible with fixed-dose products, initially titrate to a dose that is tolerated and meets individual therapeutic need using a separate carbidopa/levodopa tablet (1:4 ratio) plus an entacapone tablet. Once the individual dose of carbidopa/levodopa plus entacapone dose has been established using separate tablets, conversion to a corresponding single tablet of carbidopa/levodopa/entacapone may occur. When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa either by decreasing the strength of carbidopa/levodopa/entacapone at each administration or by decreasing the frequency of administration by extending the interval between doses. There is no experience in converting from extended-release carbidopa/levodopa or carbidopa/levodopa products that are not combined in a 1:4 ratio of carbidopa to levodopa. To discontinue carbidopa/levodopa/entacapone, reduce dose gradually; tapering of entacapone has not been systematically evaluated.
Maximum Dosage Limits:
-Adults
Do not exceed 1 tablet of carbidopa; levodopa; entacapone per dose. Daily limits: 300 mg/day PO carbidopa; 1,200 mg/day PO levodopa; 1,600 mg/day PO of entacapone. The maximum for tablets (50-, 75-, 100- or 150-mg of levodopa) is 8 tablets/day PO. The maximum for tablets with 200-mg of levodopa is 6 tablets/day PO.
-Geriatric
Do not exceed 1 tablet of carbidopa; levodopa; entacapone per dose. Daily limits: 300 mg/day PO carbidopa; 1,200 mg/day PO levodopa; 1,600 mg/day PO of entacapone. The maximum for tablets (50-, 75-, 100- or 150-mg of levodopa) is 8 tablets/day PO. The maximum for tablets with 200-mg of levodopa is 6 tablets/day PO.
-Adolescents
Safe and effective use has not been established.
-Children
Safe and effective use has not been established.
-Infants
Not indicated.
Patients with Hepatic Impairment Dosing
Patients with biliary obstruction or hepatic impairment should be treated with caution; carefully adjust dosage to clinical response. Specific dosage adjustment guidelines are not available.
Patients with Renal Impairment Dosing
No specific dosage adjustments are required.
*non-FDA-approved indication
Acebutolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Chlorpheniramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Diphenhydramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Acrivastine; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Alfentanil: (Major) COMT inhibitors may cause additive sedation or hypotension with alfentanil. Monitor patients receiving alfentanil with other CNS depressants for hypotension and prolonged respiratory depression and sedation. In such cases of combined treatment, a dose reduction of one or both agents may be necessary. (Major) Prior to general anesthesia, levodopa may be continued as long as the patient is permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the usual daily dosage may be reinstituted or titrated upward to the normal dosage as soon as the patient is able to take oral medications. The patient should be observed for symptoms resembling neuroleptic malignant syndrome, and the usual regimen should be administered as soon as the patient is able to take oral medication.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Alprazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Amantadine: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals.
Amiloride: (Moderate) Monitor blood pressure during concomitant levodopa and potassium-sparing diuretic use due to risk for additive hypotension; a potassium-sparing diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant levodopa and potassium-sparing diuretic use due to risk for additive hypotension; a potassium-sparing diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Amisulpride: (Major) Avoid using these drugs together. Amisulpride is a central dopamine antagonist and can antagonize the actions of dopamine agonists such as levodopa. Amisulpride is generally used perioperatively to prevent and treat postoperative nausea and vomiting. Prior to general anesthesia, levodopa may be continued as long as the patient is permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the usual daily dosage may be reinstituted or titrated upward to the normal dosage as soon as the patient is able to take oral medications.
Amitriptyline: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Amlodipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Amlodipine; Atorvastatin: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Amlodipine; Benazepril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Amlodipine; Celecoxib: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Amlodipine; Olmesartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Amlodipine; Valsartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Amobarbital: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Amoxapine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Amoxapine exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
Ampicillin: (Moderate) As entacapone is primarily excreted in the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidation, such as ampicillin, are given concurrently with entacapone.
Ampicillin; Sulbactam: (Moderate) As entacapone is primarily excreted in the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidation, such as ampicillin, are given concurrently with entacapone.
Angiotensin II receptor antagonists: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Angiotensin-converting enzyme inhibitors: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Aripiprazole: (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.
Articaine; Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Asenapine: (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.
Aspirin, ASA; Butalbital; Caffeine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Atenolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Atenolol; Chlorthalidone: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Atropine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including systemic atropine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Atropine; Difenoxin: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including systemic atropine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
atypical antipsychotic: (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.
Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including COMT inhibitors. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including COMT inhibitors. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Azilsartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Azilsartan; Chlorthalidone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Baclofen: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Barbiturates: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Belladonna; Opium: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Benazepril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of opioid agonists with COMT inhibitors, such as entacapone, may cause additive sedation and somnolence. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Benzodiazepines: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Benzphetamine: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions or discontinuation of benzphetamine is recommended if the two agents are used concurrently.
Benztropine: (Minor) Through its central antimuscarinic actions, antimuscarinics such as benztropine can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if benztropine is added.
Beta-blockers: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Betaxolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Bisoprolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Brentuximab vedotin: (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Peripheral neuropathy has been reported with the use of brentuximab vedotin. Brentuximab vedotin-induced peripheral neuropathy is cumulative.
Brexpiprazole: (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.
Brimonidine; Timolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Brompheniramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Brompheniramine; Phenylephrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Brompheniramine; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Bumetanide: (Moderate) Monitor blood pressure during concomitant levodopa and loop diuretic use due to risk for additive hypotension; a loop diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Bupivacaine; Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Buprenorphine: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist 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. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Buprenorphine; Naloxone: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist 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. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Bupropion: (Moderate) Use bupropion and levodopa with caution and monitor for CNS toxicity, including restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness, which may result from cumulative dopamine agonist effects.
Bupropion; Naltrexone: (Moderate) Use bupropion and levodopa with caution and monitor for CNS toxicity, including restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness, which may result from cumulative dopamine agonist effects.
Butalbital; Acetaminophen: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Butalbital; Acetaminophen; Caffeine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known. (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Butalbital; Aspirin; Caffeine; Codeine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known. (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Butorphanol: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist 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. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sodium oxybate, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Calcium-channel blockers: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Candesartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and entacapone. CNS depressants can potentiate the effects of cannabidiol.
Capsaicin; Metaxalone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Captopril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Carbinoxamine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Cariprazine: (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.
Carisoprodol: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Carteolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Carvedilol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Celecoxib; Tramadol: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and entacapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Central-acting adrenergic agents: (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Cetirizine: (Moderate) Caution is recommended during concurrent use of cetirizine or levocetirizine with COMT inhibitors because of the possibility for additive sedative effects. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Cetirizine; Pseudoephedrine: (Moderate) Caution is recommended during concurrent use of cetirizine or levocetirizine with COMT inhibitors because of the possibility for additive sedative effects. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlophedianol; Dexbrompheniramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chloramphenicol: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation, or intestinal beta-glucuronidation such as chloramphenicol. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Chlorcyclizine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlordiazepoxide: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlordiazepoxide; Amitriptyline: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Chlordiazepoxide; Clidinium: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorothiazide: (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Chlorpheniramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Dextromethorphan: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Phenylephrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpromazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Chlorthalidone: (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Chlorzoxazone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Cholestyramine: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation, or intestinal beta-glucuronidation such as cholestyramine. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Clemastine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Clevidipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Clobazam: (Moderate) An enhanced CNS depressant effect may occur when clobazam is combined with entacapone, a COMT inhibitor. Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. COMT inhibitors may cause drowsiness and have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Clomipramine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Clonazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Clonidine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including clonidine, due to the possibility of additive sedation and hypotension. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Clorazepate: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Clozapine: (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.
Cocaine: (Major) Concomitant use of cocaine with levodopa (including carbidopa; levodopa and carbidopa; levodopa; entacapone) can result in an increase in the risk of developing cardiac arrhythmias. Levodopa should be used cautiously in patients who are known users of cocaine. Conversely, electrocardiographic monitoring should be considered when using cocaine in patients receiving levodopa.
Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Codeine; Phenylephrine; Promethazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Codeine; Promethazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Cyclobenzaprine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Cyproheptadine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Dacarbazine, DTIC: (Moderate) Levodopa response may be decreased during chemotherapy with dacarbazine, DTIC. If dacarbazine is used in a patient stabilized on levodopa therapy, practitioners may wish to be alert for needed adjustments in the levodopa regimen to maintain patient status.
Dantrolene: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Darifenacin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
Desipramine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as entacapone, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
Dexbrompheniramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Dexbrompheniramine; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Dexchlorpheniramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Dexmedetomidine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including dexmedetomidine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Monitor patients closely for additive effects that may prolong recovery from dexmedetomidine administration.
Dexmethylphenidate: (Minor) Due to their pharmacologic actions, it is thought that increased dopaminergic effects may occur during coadministration of methylphenidate derivatives, inhibitors of dopamine reuptake, and COMT inhibitors. Be alert for any dopamine-related side effects such as nausea, reduced appetite, tremor, or changes in moods or behaviors.
Dextromethorphan; Bupropion: (Moderate) Use bupropion and levodopa with caution and monitor for CNS toxicity, including restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness, which may result from cumulative dopamine agonist effects.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Diazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Diazoxide: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Dicyclomine: (Minor) Anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
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.
Diltiazem: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Dimenhydrinate: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Diphenhydramine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Diphenhydramine; Ibuprofen: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Diphenhydramine; Naproxen: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Diphenhydramine; Phenylephrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Diphenoxylate; Atropine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including systemic atropine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Dobutamine: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase (COMT), such as dobutamine, should be administered cautiously to patients receiving COMT inhibitors. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Dopamine: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase (COMT), such as dopamine, should be administered cautiously to patients receiving COMT inhibitors. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Dorzolamide; Timolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Doxazosin: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Doxepin: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Doxylamine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Doxylamine; Pyridoxine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Dronabinol: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including dronabinol, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Droperidol: (Major) Droperidol, a butyrophenone derivative, is a dopamine D2 receptor antagonist and thus, may reduce the therapeutic effects of levodopa, which is an agonist at dopamine D2 receptors. Avoidance of droperidol use in a patient with Parkinson's disease may be advisable unless the benefit of droperidol outweighs the risk of CNS depressive effects and decreased therapeutic response to dopamine agonists. (Major) Use droperidol with caution in patients taking COMT inhibitors due to the possibility of additive sedation. Droperidol produces marked tranquilization and sedation; reduced dosages may be needed in debilitated patients, particularly when combined with other CNS depressants.
Droxidopa: (Major) Droxidopa is directly metabolized to norepinephrine by dopa-decarboxylase; therefore, coadministration with dopa-decarboxylase inhibitors (e.g., carbidopa) may prevent the conversion of droxidopa to norepinephrine outside of the central nervous system (CNS). Patients in the clinical trials with droxidopa received concomitant medications used to treat Parkinson's disease. Patients taking droxidopa with levodopa/dopa-decarboxylase inhibitor combinations (e.g., carbidopa; levodopa or carbidopa; levodopa; entacapone) had decreased clearance of droxidopa, an increase in exposure (AUC) to droxidopa of approximately 100%, and an increase in exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events. No dose adjustments are expected to be required. However, the manufacturer states that in some patients, it is possible that dose adjustments for droxidopa will be required.
Enalapril, Enalaprilat: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Ephedrine: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as ephedrine or ephedra, ma huang should be administered cautiously in patients receiving entacapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Ephedrine; Guaifenesin: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as ephedrine or ephedra, ma huang should be administered cautiously in patients receiving entacapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Eplerenone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Epoprostenol: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Eprosartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Erythromycin: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as erythromycin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Esketamine: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as entacapone, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as levodopa, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Esmolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Estazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Eszopiclone: (Major) A reduction in the dose of eszopiclone or concomitantly administered drugs with sedative properties (e.g., COMT inhibitors) should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment from eszopiclone may be increased during coadministration, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
Ethacrynic Acid: (Moderate) Monitor blood pressure during concomitant levodopa and loop diuretic use due to risk for additive hypotension; a loop diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Etomidate: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
Felodipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and entacapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Fenoldopam: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Fentanyl: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Ferric Maltol: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Flibanserin: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including flibanserin, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Fluphenazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Flurazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
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. (Major) Many levodopa products may be taken with or without food. Follow the directions of the product prescribed. However, foods with a high protein content may delay or impair the oral absorption of levodopa and may reduce efficacy. The Parkinson's Foundation states that most patients have no problem taking levodopa-containing products with meals, but some experience less benefit if they take such products with a stomach full of protein (including meats, cheeses and other dairy products). When this occurs, it is recommended to only take carbidopa/levodopa along with non-protein foods. For patients with more advanced PD, it is best to take levodopa-containing medications 30 to 60 minutes before eating a meal to limit food interference. If nausea occurs, the products may be taken with a small non-protein snack, such as fruit or a cracker, to help. (Major) Patients with Parkinson's disease should avoid foods high in fat around the time of taking carbidopa; levodopa. These foods may delay gastric emptying, which can decrease and delay the absorption of levodopa. (Major) Patients with Parkinson's disease should avoid foods high in fiber around the time of taking carbidopa; levodopa. These foods may delay gastric emptying, which can decrease and delay the absorption of levodopa.
Fosinopril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Fosphenytoin: (Moderate) Monitor for loss of efficacy in during concomitant use of levodopa and fosphenytoin. The beneficial effects of levodopa in Parkinson disease have been reported to be revered by phenytoin.
Furosemide: (Moderate) Monitor blood pressure during concomitant levodopa and loop diuretic use due to risk for additive hypotension; a loop diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and entacapone. Concomitant use of gabapentin with entacapone may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and levodopa. Concomitant use of gabapentin with levodopa may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
General anesthetics: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Glycopyrrolate; Formoterol: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Guanfacine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including guanfacine, due to the possibility of additive sedation or hypotension. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Haloperidol: (Major) Due to opposing effects on central dopaminergic activity, haloperidol and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to haloperidol. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. (Major) Due to opposing effects on central dopaminergic activity, haloperidol and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to haloperidol. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Heterocyclic antidepressants: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Hydralazine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Hydromorphone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Hydroxyzine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Hyoscyamine: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Iloperidone: (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.
Iloprost: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Imipramine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Indacaterol; Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Irbesartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Iron Salts: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Iron: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Isocarboxazid: (Contraindicated) At least 14 days should elapse between the discontinuation of isocarboxazid, which is a non-selective MAO inhibitor, and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the 2 major enzymes involved in the metabolism of catecholamines. The combination of a COMT inhibitor and isocarboxazid may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism, which may lead to hypertensive crisis or other adverse effects. (Contraindicated) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as isocarboxazid. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertensive crisis and other adverse cardiovascular effects can occur. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Isoflurane: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery. (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
Isoniazid, INH: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur. (Major) Patients should generally not receive COMT inhibitors in combination with agents that have some non-selective MAO inhibiting activity like isoniazid. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase and catechol-O-methyltransferase are the 2 major enzymes involved in the metabolism of catecholamines. It is possible that the combination of a COMT inhibitor and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Isoniazid, INH can cause peripheral neuropathy due to pyridoxine antagonism or increased excretion of pyridoxine. In addition, concomitant use of carbidopa; levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity, such as isoniazid, INH, can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents or combination products containing isoniazid (e.g., isoniazid, INH; pyrazinamide, PZA; rifampin or isoniazid, INH; rifampin) should be avoided if possible.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur. (Major) Patients should generally not receive COMT inhibitors in combination with agents that have some non-selective MAO inhibiting activity like isoniazid. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase and catechol-O-methyltransferase are the 2 major enzymes involved in the metabolism of catecholamines. It is possible that the combination of a COMT inhibitor and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Isoniazid, INH can cause peripheral neuropathy due to pyridoxine antagonism or increased excretion of pyridoxine. In addition, concomitant use of carbidopa; levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity, such as isoniazid, INH, can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents or combination products containing isoniazid (e.g., isoniazid, INH; pyrazinamide, PZA; rifampin or isoniazid, INH; rifampin) should be avoided if possible. (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as rifampin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Isoniazid, INH; Rifampin: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur. (Major) Patients should generally not receive COMT inhibitors in combination with agents that have some non-selective MAO inhibiting activity like isoniazid. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase and catechol-O-methyltransferase are the 2 major enzymes involved in the metabolism of catecholamines. It is possible that the combination of a COMT inhibitor and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Isoniazid, INH can cause peripheral neuropathy due to pyridoxine antagonism or increased excretion of pyridoxine. In addition, concomitant use of carbidopa; levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity, such as isoniazid, INH, can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents or combination products containing isoniazid (e.g., isoniazid, INH; pyrazinamide, PZA; rifampin or isoniazid, INH; rifampin) should be avoided if possible. (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as rifampin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Isoproterenol: (Major) Levodopa is the metabolic precursor to dopamine. Since a portion of administered levodopa is converted to dopamine peripherally, concomitant administration with isoproterenol should be used with caution as the risk of cardiovascular toxicity is increased. (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase, such as isoproterenol, should be administered cautiously in patients receiving COMT inhibitors. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Isradipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Ketamine: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
Labetalol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and entacapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and entacapone. Dosage adjustments of lemborexant and entacapone 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. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and levodopa. Dosage adjustments of lemborexant and levodopa 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. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Levamlodipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Levobunolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Levocetirizine: (Moderate) Caution is recommended during concurrent use of cetirizine or levocetirizine with COMT inhibitors because of the possibility for additive sedative effects. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Levorphanol: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Lidocaine; Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Linezolid: (Major) Avoid the concomitant use of COMT inhibitors in combination with linezoid, which has non-selective monoamine oxidase (MAO) inhibitor activity. Typically, at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of a COMT inhibitor to avoid potential interactions. Consider an alternative to linezolid if possible. Monoamine oxidase and catechol-O-methyltransferase (COMT) are the two major enzymes involved in the metabolism of catecholamines. It is theoretically possible that the coadministration of a COMT inhibitor with linezolid would result in inhibition of normal catecholamine metabolism and possible toxicity. (Major) Concomitant use of levodopa (including carbidopa; levodopa and carbidopa; levodopa; entacapone) and drugs with monoamine oxidase inhibitor (MAOI) activity, such as linezolid, can result in hypertensive crisis. Simultaneous use of these agents should be avoided if possible.
Lisinopril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Lofexidine: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and entacapone. Lofexidine can potentiate the effects of CNS depressants.
Loop diuretics: (Moderate) Monitor blood pressure during concomitant levodopa and loop diuretic use due to risk for additive hypotension; a loop diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Lorazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Losartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Loxapine: (Major) Due to opposing effects on central dopaminergic activity, loxapine and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider if an atypical antipsychotic is a potential alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. (Major) Due to opposing effects on central dopaminergic activity, loxapine and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Lumateperone: (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.
Lurasidone: (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.
Macimorelin: (Major) Avoid use of macimorelin with drugs that may transiently elevate growth hormone concentrations, such as levodopa. Healthcare providers are advised to discontinue levodopa therapy and observe a sufficient washout period before administering macimorelin. Use of these medications together may impact the accuracy of the macimorelin growth hormone test.
Maprotiline: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Maprotiline exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
Mecamylamine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Meclizine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Melatonin: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including melatonin, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Meperidine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Meprobamate: (Moderate) Additive CNS depressant effects are possible during coadministration of COMT inhibitors and meprobamate. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Metaxalone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Methadone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Methamphetamine: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of amphetamines are recommended if the two agents are used concurrently.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Methohexital: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Methscopolamine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Methyldopa: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase, such as methyldopa, should be administered cautiously in patients receiving COMT inhibitors. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure. Additive sedation and hypotension can occur. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Methylphenidate Derivatives: (Minor) Due to their pharmacologic actions, it is thought that increased dopaminergic effects may occur during coadministration of methylphenidate derivatives, inhibitors of dopamine reuptake, and COMT inhibitors. Be alert for any dopamine-related side effects such as nausea, reduced appetite, tremor, or changes in moods or behaviors.
Methylphenidate: (Minor) Due to their pharmacologic actions, it is thought that increased dopaminergic effects may occur during coadministration of methylphenidate derivatives, inhibitors of dopamine reuptake, and COMT inhibitors. Be alert for any dopamine-related side effects such as nausea, reduced appetite, tremor, or changes in moods or behaviors.
Metoclopramide: (Major) Metoclopramide is a central dopamine antagonist. Metoclopramide can antagonize the actions of dopamine agonists such as levodopa. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible. (Moderate) Coadministration of COMT inhibitors and metoclopramide should be avoided if possible. Metoclopramide may interfere with the effectiveness of COMT inhibitors. Metoclopramide has dopamine antagonist properties while COMT inhibitors increase the availability of catecholamine concentrations (e.g., dopamine) in the central nervous system.
Metolazone: (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Metoprolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Metyrosine: (Major) The extrapyramidal effects of metyrosine can antagonize the effects of levodopa. Dosage adjustments of either of these medications may be required.
Midazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Minoxidil: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Mirtazapine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Moexipril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Molindone: (Major) Due to opposing effects on central dopaminergic activity, molindone and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. (Major) Due to opposing effects on central dopaminergic activity, molindone and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Animal studies have not shown increased toxicity when molindone is given concurrently with representative members of the antiparkinson drugs class.
Morphine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Nabilone: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as levodopa, and CNS depressants. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Moderate) Concomitant use of nabilone with other CNS depressants like entacapone can potentiate the effects of nabilone on respiratory depression.
Nadolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Nalbuphine: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist 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. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Nebivolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Nebivolol; Valsartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Nefazodone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as nefazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Neostigmine; Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Nicardipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
NIFEdipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Nimodipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Nisoldipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Nitroprusside: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Norepinephrine: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase, such as norepinephrine, should be administered cautiously to patients receiving COMT inhibitors. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Nortriptyline: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Olanzapine: (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.
Olanzapine; Fluoxetine: (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.
Olanzapine; Samidorphan: (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.
Oliceridine: (Major) Concomitant use of oliceridine with entacapone may cause excessive sedation and somnolence. Limit the use of oliceridine with entacapone 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. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Major) Concomitant use of oliceridine with levodopa may cause excessive sedation and somnolence. Limit the use of oliceridine with levodopa 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. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Olmesartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Opiate Agonists-Antagonists: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist 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. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Orphenadrine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Oxazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Oxybutynin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
Oxycodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Oxymorphone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Paliperidone: (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.
Papaverine: (Major) The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by coadministration of papaverine; avoid concurrent use in these patients. Papaverine may block dopamine receptors in the striatum and result in loss of control of Parkinson's disease in patients who are taking levodopa.
Pentazocine; Naloxone: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist 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. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Pentobarbital: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
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 entacapone.
Perindopril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Perindopril; Amlodipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Perphenazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Perphenazine; Amitriptyline: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Phenelzine: (Contraindicated) At least 14 days should elapse between the discontinuation of phenelzine, which is a non-selective MAO inhibitor, and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the 2 major enzymes involved in the metabolism of catecholamines. The combination of a COMT inhibitor and phenelzine may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism, which may lead to hypertensive crisis or other adverse effects. (Contraindicated) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as phenelzine, due to increased risk of hypertensive crisis. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Phenobarbital: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known. (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including scopolamine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including systemic atropine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added. (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Phenothiazines: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Phenoxybenzamine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Phenytoin: (Moderate) Monitor for loss of efficacy in during concomitant use of levodopa and phenytoin. The beneficial effects of levodopa in Parkinson disease have been reported to be revered by phenytoin.
Pimozide: (Major) Due to opposing effects on central dopaminergic activity, pimozide and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic instead of pimozide if appropriate. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. (Major) Due to opposing effects on central dopaminergic activity, pimozide and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to pimozide. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Pindolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Polysaccharide-Iron Complex: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Potassium-sparing diuretics: (Moderate) Monitor blood pressure during concomitant levodopa and potassium-sparing diuretic use due to risk for additive hypotension; a potassium-sparing diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Pramipexole: (Moderate) Coadministration of COMT inhibitors and pramipexole may cause additive sedation. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Minor) Pramipexole increases the Cmax of levodopa and decreases Tmax from 2.5 to 0.5 hrs.
Prazosin: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and COMT inhibitors. Concomitant use of pregabalin with COMT inhibitors may cause additive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and levodopa. Concomitant use of pregabalin with levodopa may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Prilocaine; Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Primidone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Probenecid: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as probenecid. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Probenecid; Colchicine: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as probenecid. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Procarbazine: (Major) Concomitant use of levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity (e.g., procarbazine) can result in hypertensive crisis. Simultaneous use of these agents should be avoided if possible. (Major) Procarbazine has some non-selective MAO inhibiting activity. Typically, at least 14 days should elapse between the discontinuation of the non-selective MAOI and the use of a COMT inhibitor to avoid potential interactions. Patients should ordinarily not receive COMT-inhibitors in combination with agents with non-selective MAO inhibiting activity. MAO and COMT are the 2 major enzymes involved in the metabolism of catecholamines. It is theoretically possible that the combination of COMT-inhibitors and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism.
Prochlorperazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Promethazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Promethazine; Dextromethorphan: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Promethazine; Phenylephrine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Propantheline: (Moderate) Anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Propofol: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery. (Major) If administered before halogenated anesthetics, levodopa without concomitant use of a decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthetics are required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
Propranolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Protriptyline: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Pseudoephedrine; Triprolidine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Pyridoxine, Vitamin B6: (Moderate) Monitor for reduced levodopa efficacy during concomitant use of pyridoxine (vitamin B6). Pyridoxine, in doses as low as 10 mg/day, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine.
Quazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Quetiapine: (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.
Quinapril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Racepinephrine: (Major) Drugs known to be metabolized by catechol-O-methyltransferase (COMT), such as racepinephrine inhalations, should be administered cautiously in patients receiving COMT inhibitors like entacapone, tolcapone, or combinations containing these drugs such as carbidopa; levodopa; entacapone. If a patient is taking a COMT-inhibitor, then they should seek health care professional advice prior to the use of racepinephrine. Concomitant use may result in increased heart rate, possibly arrhythmias, and excessive changes in blood pressure. A single 400 mg dose of entacapone given with intravenous epinephrine has produced changes in heart rate and blood pressure. Ventricular tachycardia was noted in one healthy volunteer during an interaction study with epinephrine infusion and oral entacapone administration.
Ramelteon: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including ramelteon, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Ramipril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Rasagiline: (Moderate) There may be some increase in rasagiline blood levels in the presence of levodopa, the effect is modest and rasagiline dosing need not be modified in the presence of carbidopa; levodopa. Rasagiline and carbidopa; levodopa are frequently used together; however, there is the possibility of increased dyskinesia and postural hypotension when combined.
Remifentanil: (Major) COMT inhibitors may cause additive sedation or hypotension with remifentanil. Monitor patients receiving remifentanil with other CNS depressants for hypotension and prolonged respiratory depression and sedation. In such cases of combined treatment, a dose reduction of one or both agents may be necessary.
Remimazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Rifampin: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as rifampin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Risperidone: (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.
Rotigotine: (Moderate) In clinical studies, concurrent use of L-dopa/carbidopa with rotigotine had no effect on the pharmacokinetics of either agent. However, rotigotine may potentiate the dopaminergic side effects of levodopa via a pharmacodynamic interaction. Subsequent worsening of pre-existing dyskinesias may occur.
Sacubitril; Valsartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Safinamide: (Moderate) Safinamide and carbidopa; levodopa are indicated for use in combination; however, there is the possibility of new onset dyskinesias or exacerbation of pre-existing dyskinesias. Patients should be advised to contact their health care provider if they notice new or worsening dyskinesias while taking these medicines together.
Sapropterin: (Major) Coadministration of sapropterin and levodopa has been associated with seizures. Post-marketing safety surveillance showed 3 patients (all with underlying neurologic disorder) develop convulsions, exacerbation of convulsions, over-stimulation, or irritability while receiving concomitant levodopa and sapropterin.
Scopolamine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including scopolamine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Secobarbital: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Sedating H1-blockers: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Selegiline: (Moderate) Monitor blood pressure during concomitant use of levodopa and selegiline. Concomitant use of levodopa with selective MAO-B inhibitors may be associated with orthostatic hypotension.
Serdexmethylphenidate; Dexmethylphenidate: (Minor) Due to their pharmacologic actions, it is thought that increased dopaminergic effects may occur during coadministration of methylphenidate derivatives, inhibitors of dopamine reuptake, and COMT inhibitors. Be alert for any dopamine-related side effects such as nausea, reduced appetite, tremor, or changes in moods or behaviors.
Sevoflurane: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery. (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
Skeletal Muscle Relaxants: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Sodium Oxybate: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sodium oxybate, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Solifenacin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
Solriamfetol: (Moderate) Monitor for dopamine-mediated effects including nausea, vomiting, dizziness, tremor, and changes in moods or behaviors if solriamfetol, a central dopamine and norepinephrine reuptake inhibitor, is administered with other dopaminergic drugs, such as entacapone. Caution is recommended since this combination has not been evaluated. (Moderate) Monitor for dopamine-mediated effects including nausea, vomiting, dizziness, tremor, and changes in moods or behaviors if solriamfetol, a central dopamine and norepinephrine reuptake inhibitor, is administered with other dopaminergic drugs, such as levodopa. Caution is recommended since this combination has not been evaluated.
Sotalol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Spironolactone: (Moderate) Monitor blood pressure during concomitant levodopa and potassium-sparing diuretic use due to risk for additive hypotension; a potassium-sparing diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant levodopa and potassium-sparing diuretic use due to risk for additive hypotension; a potassium-sparing diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and entacapone. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Major) COMT inhibitors may cause additive sedation or hypotension with sufentanil. Monitor patients receiving sufentanil with other CNS depressants for hypotension and prolonged respiratory depression and sedation. In such cases of combined treatment, a dose reduction of one or both agents may be necessary.
Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
Tapentadol: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Tasimelteon: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tasimelteon, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Tedizolid: (Major) Concomitant use of levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity (e.g., tedizolid) can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents should be avoided if possible.
Telmisartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Telmisartan; Amlodipine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Temazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as entacapone, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how tetrabenazine affects them. (Moderate) Monitor for a decrease in levodopa efficacy during concomitant tetrabenazine use. Levodopa and tetrabenazine may antagonize each other's effects: levodopa is metabolized to dopamine while tetrabenazine depletes dopamine stores and acts as a dopamine receptor blocker. While concomitant use is generally not recommended for this reason, combination therapy may be beneficial in the management of some levodopa-related dyskinesias.
Thalidomide: (Major) The use of thalidomide and COMT inhibitors may cause an additive sedative effect and should be avoided if possible. If concurrent treatment is needed, prescribers should monitor patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Thiazide diuretics: (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Thioridazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Thiothixene: (Major) Due to opposing effects on central dopaminergic activity, thiothixene and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to thiothixene. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. (Major) Due to opposing effects on central dopaminergic activity, thiothixene and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to thiothixene. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Timolol: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Tizanidine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as tizanidine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Torsemide: (Moderate) Monitor blood pressure during concomitant levodopa and loop diuretic use due to risk for additive hypotension; a loop diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Tramadol: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Tramadol; Acetaminophen: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Trandolapril: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Trandolapril; Verapamil: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Tranylcypromine: (Contraindicated) At least 14 days should elapse between the discontinuation of tranylcypromine, which is a non-selective MAO inhibitor, and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the 2 major enzymes involved in the metabolism of catecholamines. The combination of a COMT inhibitor and tranylcypromine may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism, which may lead to hypertensive crisis or other adverse effects. (Contraindicated) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as tranylcypromine, due to the increased risk of hypertensive crisis. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Trazodone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as trazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Treprostinil: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Triamterene: (Moderate) Monitor blood pressure during concomitant levodopa and potassium-sparing diuretic use due to risk for additive hypotension; a potassium-sparing diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant levodopa and potassium-sparing diuretic use due to risk for additive hypotension; a potassium-sparing diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Triazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Tricyclic antidepressants: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Trifluoperazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Trihexyphenidyl: (Minor) The doses of trihexyphenidyl and levodopa may need to be adjusted when the drugs are given simultaneously. Trihexyphenidyl can potentiate the dopaminergic effects of levodopa.
Trimipramine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Triprolidine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Valerian, Valeriana officinalis: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valerian, due to the possibility of additive sedation.
Valproic Acid, Divalproex Sodium: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valproic acid, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Valsartan: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Vasodilators: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Verapamil: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Vitamin B Complex Supplements: (Moderate) Monitor for reduced levodopa efficacy during concomitant use of pyridoxine (vitamin B6). Pyridoxine, in doses as low as 10 mg/day, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine.
Warfarin: (Moderate) Monitoring of the INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postapproval use of entacapone. Entacapone has affinity for CYP2C9. In an interaction study in healthy volunteers, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% (Cl 90 11% to 26%), and the INR values increased on average by 13% (Cl 90 6% to 19%).
Zaleplon: (Major) Additive CNS depressant effects are possible during concurrent use of COMT inhibitors and zaleplon. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Ziprasidone: (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.
Zolpidem: (Major) COMT inhibitors such as entacapone and tolcapone should be given cautiously with other agents that cause CNS depression, including zolpidem, due to the possibility of additive sedation. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
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 combination of levodopa with carbidopa and entacapone are used together for the treatment of Parkinson's disease. Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease because it does not cross the blood-brain barrier. The administration of these drugs increases dopamine levels within the corpus striatum.
-Levodopa: Levodopa is the metabolic precursor of dopamine. Levodopa diffuses into the central nervous system where it is converted to dopamine. The resulting change in dopamine-acetylcholine balance is believed to improve nerve impulse control and to be the basis of the drug's antiparkinsonian activity.
-Carbidopa: Carbidopa is a noncompetitive decarboxylase inhibitor that, when administered with levodopa, inhibits the peripheral conversion of levodopa to dopamine, thereby increasing the CNS bioavailability of levodopa by roughly 75%. Carbidopa does not cross the blood-brain barrier. The addition of carbidopa allows lower doses of levodopa to be used and minimizes adverse reactions from levodopa such as nausea and vomiting. The carbidopa-levodopa combination also allows for a more rapid and even titration of levodopa dosage. With combination therapy, certain adverse effects (e.g., dyskinesias) will occur sooner and at lower levodopa dosages during therapy than with levodopa alone, as these adverse effects are centrally mediated.
-Entacapone: Entacapone is a reversible, selective inhibitor of peripheral catechol-O-methyltransferase (COMT). COMT acts to eliminate biologically active catechols and their metabolites. The effect of entacapone on central COMT activity in humans is not known, although in animals COMT is inhibited. COMT catalyzes the transfer of the methyl group of S-adenyl-L-methionine to the phenolic group of substrates that contain a catechol structure, including dopamine. COMT is distributed throughout various organs with the highest level of activity in the liver and kidney; activity is also present in neuronal glial cells. Inhibition of COMT by entacapone and inhibition of decarboxylase by carbidopa results in more sustained plasma concentrations of levodopa and markedly lower metabolite (3-O-methyldopa) concentrations. The levodopa metabolite has been associated with reduced efficacy, the 'wearing-off' phenomenon, and dyskinesia. As a result, more levodopa is available for diffusion into the CNS where it is converted to dopamine. Increased levodopa bioavailability and duration of action may lead to increased levodopa adverse effects, sometimes requiring a reduction in the levodopa dosage. In one study, the single dose administration of entacapone had no effect on cardiovascular autonomic regulation (blood pressure and pulse) in patients currently receiving carbidopa; levodopa.
The combination of carbidopa; levodopa; entacapone is administered orally. When entacapone is given with levodopa and carbidopa, the AUC of levodopa is increased by approximately 35% and the elimination half-life of levodopa is increased from 1.3 hours to 2.4 hours. Due to the short half-lives, no accumulation of the any of the 3 drugs occurs with repeat administration.
-Carbidopa; Levodopa: The plasma protein binding of carbidopa; levodopa; is negligible. The addition of carbidopa to levodopa therapy prolongs the half-life of levodopa from 50 minutes to 1.5 hours; the Tmax of levodopa is unaffected. Carbidopa and levodopa are both metabolized. Levodopa is extensively metabolized to metabolites. Two major pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT). Carbidopa is metabolized to 2 major metabolites that are excreted unchanged or as a glucuronide conjugate in the urine; 30% of carbidopa is excreted unchanged in the urine. The average elimination half-lives of carbidopa and levodopa are 1.6 to 2 hours (range: 0.7 to 4 hours) and 1.7 hours (range: 1.1 to 3.2 hours), respectively.
-Entacapone: Entacapone is 98% protein bound, primarily to serum albumin, with an average elimination half-life of one hour. Entacapone is extensively and almost completely metabolized in the liver to the active cis-isomer. Glucuronidation to inactive metabolites is the main metabolic pathway of the active cis-isomer. Entacapone and the cis-isomer metabolites are eliminated in the urine as glucuronide conjugates; only 0.2% of unchanged entacapone is found in the urine. Elimination pathways consist of 10% urinary excretion (70% as the active cis-isomer and 25% as the glucuronidated cis-isomer). Biliary excretion is a major elimination pathway (90%) of the parent and metabolites.The elimination half-life of entacapone was on average 0.8 hour to 1 hour (0.3 hour to 4.5 hours).
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: COMT, CYP2C9
Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT) and may influence the pharmacokinetics of drugs metabolized by COMT. Due to its affinity to CYP2C9 in vitro, entacapone may potentially interfere with medicinal products with metabolism dependent on this isoenzyme. Entacapone has been reported to increase the exposure of warfarin (a CYP2C9 substrate). In vitro studies have shown that entacapone can inhibit CYP1A2, CYP2A6, CYP2C6, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, but only at very high concentrations (IC50 more than 200 microM) that would not be seen with normal clinical use. A 200 mg entacapone dose in adults usually produces a concentration of 5 microM.
-Route-Specific Pharmacokinetics
Oral Route
Four carbidopa; levodopa; entacapone dosage strengths (12.5/50/200 mg, 25/100/200 mg, 37.5/150/200 mg, and 50/200/200 mg) have been shown to be bioequivalent to corresponding doses of immediate-release carbidopa; levodopa or entacapone. Inter- and intra-individual absorption of carbidopa; levodopa; entacapone can be highly variable, and may markedly affect peak plasma concentrations (Cmax). However, the mean plasma concentrations of carbidopa; levodopa and entacapone, whether administered separately as carbidopa; levodopa tablets and entacapone or as the single tablet formulation (carbidopa-levodopa-entacapone), are similar with corresponding doses.
-Carbidopa; Levodopa: The maximum concentrations of levodopa occur between 1.1 to 1.8 hours, while carbidopa is absorbed more slowly (Tmax roughly 2.5 to 3.4 hours). Because levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients after eating a high protein meal. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa. The manufacturer has not conducted food-effect studies with carbidopa-levodopa-entacapone, but similar results would be expected.
-Entacapone: The absorption of entacapone is rapid (Tmax roughly 0.8 to 1.2 hours).
-Special Populations
Hepatic Impairment
There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with hepatic impairment. Patients with biliary obstruction or hepatic impairment are at risk for accumulation of entacapone. Hepatic impairment had a significant effect on the pharmacokinetics of entacapone. A single 200-mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately 2-fold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment (n = 10) compared to normal subjects (n = 10). All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. Biliary excretion appears to be the major route of excretion of this drug.
Renal Impairment
There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment. Renal impairment does not appear to affect the pharmacokinetics of entacapone.
Geriatric
The AUC of levodopa and entacapone is significantly higher (roughly 15%) in elderly (60 to 75 years) vs. younger adults (45 to 60 years); however, Cmax was unaffected.
Gender Differences
The bioavailability of levodopa is significantly higher in females vs. males (on average, 40% higher for AUC and 30% for Cmax), primarily due to differences in body weight. Other published literature showed significant gender effect (higher levodopa concentrations in females) even after correction for body weight.
Store & manage your medication list
Medication pricing updates
Import medication from your pharmacy
Pill & refill reminders
Medication journal & mood log