VA Class:CN500

AHFS Class:

• Catechol-O-Methyltransferase (COMT) Inhibitors 28:36.12

Generic Name(s):

• Entacapone

Chemical Name:

• ( E )-α-Cyano- N , N -diethyl-1,3,4-dihydroxy-5-nitrocinnamamide

Molecular Formula:

• C₁₄H₁₅N₃O₅

Entacapone is a selective and reversible inhibitor of catechol- O -methyltransferase (COMT); 1,2,3,7 concomitant administration of entacapone with levodopa and a decarboxylase inhibitor (e.g., carbidopa) results in increased and more sustained plasma levodopa concentrations compared with administration of levodopa and a decarboxylase inhibitor.1,3,4

Parkinsonian Syndrome

Entacapone is used as an adjunct to levodopa-carbidopa in the symptomatic treatment of parkinson disease in patients who experience manifestations of end-of-dose “wearing-off.”1,4

Levodopa is currently the most effective drug available for relieving the motor symptoms of parkinson disease and has traditionally been considered the drug of choice for this use.115,123,157 However, the effectiveness of levodopa decreases over time as the disease progresses, and most patients develop motor complications (e.g., end-of-dose failure, “on-off” phenomenon, dyskinesias) with long-term use.101,115,157 Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents such as a COMT inhibitor.101,115,116,123,157 The appropriate treatment approach should be individualized based on the patient's age, symptoms, degree of disability, and adverse effects of therapy.101,120,122,123,124,125 (For additional information on treatment options in parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.)

Efficacy of entacapone as an adjunct to levodopa for the management of parkinson disease has been established in 3 randomized, double-blind, placebo-controlled studies of up to 24 weeks' duration in patients receiving levodopa in combination with a decarboxylase inhibitor (i.e., benserazide, carbidopa).1,4,5,6 In 2 of these studies, participation was limited to patients who exhibited end-of-dose motor fluctuations in response to levodopa (i.e., fluctuating response with “off” phenomena); patients in the third study were not required to exhibit end-of-dose fluctuations for enrollment.1,4,5,6 In the first 2 studies, daily “on” time increased by 1-1.5 hours with entacapone therapy compared with minimal changes (0.1-0.4 hours) in patients receiving placebo.1,4,5,6 In the third study, slight but insignificant improvements in “on” time were observed in the subgroup of patients with “off” phenomena.1 When manifestations of parkinson disease were assessed using parts of the Unified Parkinson's Disease Rating Scale (UPDRS), substantial improvements were observed in the total score and in UPDRS subscales II (activities of daily living) and III (motor functioning) in all 3 studies.1,4,5,6 No substantial improvement was observed using subscale I (mentation).1,4,5,6 In the first 2 studies, the investigator's global assessment also improved, and the mean daily dosage of levodopa was decreased substantially in patients receiving entacapone.1,4,5,6 No substantial changes occurred in levodopa dosage or global percent improved in patients enrolled in the third study.1 Although patients in the third study were not required to have been experiencing motor fluctuations, the drug has not been evaluated systematically in patients with parkinson disease who do not experience such fluctuations.1

Entacapone is administered orally without regard to meals.1 Entacapone should be administered only in conjunction with levodopa-carbidopa.1

Entacapone can be administered with conventional tablets, orally disintegrating tablets, or extended-release preparations of levodopa-carbidopa or as a fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®).1,8

Dosage

The recommended dosage of entacapone is 200 mg administered with each levodopa-carbidopa dose up to a maximum of 8 times daily (1.6 g daily).1 Clinical experience with dosages exceeding 1.6 g daily is limited.1

To optimize patient response, reductions in the daily levodopa dosage or frequency of administration may be necessary.1 In clinical studies, most patients (58%) who were receiving 800 mg or more of levodopa daily or who had moderate or severe dyskinesias before initiating entacapone therapy required a reduction in levodopa dosa the average reduction in daily levodopa dosage was about 25%.1

Fixed Combination of Levodopa, Carbidopa, and Entacapone

The fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®) generally is used in patients receiving stable dosages of levodopa, carbidopa, and entacapone equivalent to those in the combination preparation, but also may be used in certain patients receiving stable dosages of levodopa and carbidopa equivalent to the dosages in the fixed-combination preparation when a decision has been made to add entacapone to the regimen.8 Tablets containing the fixed combination of levodopa, carbidopa, and entacapone should not be divided, and only one tablet should be administered per dosing interval.8 Because there is limited clinical experience with entacapone dosages exceeding 1.6 g daily, the maximum dosage of fixed-combination preparations containing levodopa 50-150 mg, carbidopa 12.5-37.5 mg, and entacapone 200 mg (Stalevo^® 50, 75, 100, 125, and 150) is 8 tablets daily.8 Because there is limited clinical experience with carbidopa dosages exceeding 300 mg daily, maximum dosage of the fixed-combination preparation containing levodopa 200 mg, carbidopa 50 mg, and entacapone 200 mg (Stalevo^® 200) is 6 tablets daily.8

For patients transferring from therapy with levodopa-carbidopa and entacapone (as separate preparations) to the fixed-combination preparation, recommendations are available for transferring patients currently receiving levodopa-carbidopa preparations containing a 1:4 ratio of carbidopa to levodopa.8 Patients receiving entacapone 200 mg with each dose of levodopa-carbidopa (e.g., conventional tablet preparation containing 100 mg of levodopa and 25 mg of carbidopa) can be switched to the corresponding strength of the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®).8 The manufacturer states that there is no experience to date in transferring patients currently receiving entacapone together with extended-release preparations of levodopa-carbidopa or levodopa-carbidopa preparations containing a 1:10 ratio of carbidopa to levodopa to the fixed-combination preparation.8

For patients initiating entacapone therapy, recommendations regarding use of the fixed-combination preparation should be individualized according to the current levodopa dosage and the presence of dyskinesias.8 For patients treated with levodopa-carbidopa conventional tablets who are receiving more than 600 mg of levodopa daily or who have a history of moderate or severe dyskinesias before initiation of entacapone therapy, dosage should first be adjusted by administering levodopa-carbidopa (1:4 ratio) and entacapone as separate preparations.8 If it is determined that optimum maintenance dosages of levodopa, carbidopa, and entacapone correspond to the doses in the commercial combination product, the fixed-combination preparation (Stalevo^®) may be used.8 For patients receiving levodopa dosages of 600 mg or less daily (conventional tablets, 1:4 ratio) and who do not have dyskinesias, an attempt can be made to initiate therapy with the fixed-combination preparation.8 The initial dosage of the fixed-combination preparation of levodopa, carbidopa, and entacapone should provide the same dosage of levodopa and carbidopa that the patient currently is taking.8 However, a reduction in the dosage of levodopa-carbidopa or entacapone may be necessary.8 Because dosage of levodopa, carbidopa, or entacapone cannot be adjusted individually using the fixed-combination preparation, administration of levodopa-carbidopa and entacapone as separate preparations may be necessary.8

Special Populations

Pharmacokinetics of entacapone were not affected by age or renal impairment,1,3 and dosage adjustment is not necessary for patients with renal impairment nor for geriatric patients.7 The manufacturer makes no special population (e.g., hepatic impairment) dosage recommendations at this time.1

Contraindications

Known hypersensitivity to entacapone or any ingredient in the formulation.1,8

Warnings/Precautions

Warnings

Concomitant Use with Monoamine Oxidase Inhibitors

Because monoamine oxidase (MAO) and COMT are the 2 major enzyme systems involved in the metabolism of catecholamines, the possibility exists that concomitant use of entacapone and a nonselective MAO inhibitor (e.g., phenelzine, tranylcypromine) could result in inhibition of the principal pathways involved in the metabolism of catecholamines.1 Therefore, patients ordinarily should not be treated concomitantly with entacapone and a nonselective MAO inhibitor.1 However, entacapone can be used concomitantly with a selective MAO-B inhibitor (e.g., selegiline).1

Falling Asleep During Activities of Daily Living

Falling asleep while engaged in activities of daily living, including operating a motor vehicle, has been reported in patients receiving entacapone and/or levodopa/carbidopa; in some cases, these events resulted in accidents.1 Some of the cases were reported as late as 1 year after initiation of treatment.1 Although many patients reported somnolence, some patients did not perceive warning signs, such as excessive drowsiness, and believed they were alert prior to sudden sleep onset.1 Falling asleep while engaged in activities of daily living reportedly always occurs in a setting of preexisting somnolence, although patients may not give such a history.1

Prior to initiating entacapone therapy, patients should be advised of the potential to develop drowsiness and specifically asked about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs, presence of sleep disorders).1 Patients should be continually reassessed for drowsiness or sleepiness during therapy, especially since some of these episodes occur well after starting treatment.1 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), entacapone generally should be discontinued.1 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.1 There is insufficient information to establish whether dosage reduction will eliminate this adverse event.1

Drugs Metabolized by COMT

Concomitant use of entacapone and drugs known to be metabolized by COMT (e.g., dobutamine, dopamine, epinephrine, isoproterenol, methyldopa, norepinephrine) may result in increased heart rate, arrhythmias, and excessive changes in blood pressure regardless of the route of administration (including inhalation).1 The manufacturer of entacapone includes apomorphine in this list of drugs.1,8 However, data from in vivo studies indicate that apomorphine is not metabolized by COMT.9,10

Potential Risk of Prostate Cancer

In 2010, FDA notified healthcare professionals and patients about the results of a long-term, randomized, controlled study (Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease [STRIDE-PD]) suggesting an increased risk of prostate cancer in patients receiving combined therapy with levodopa, carbidopa, and entacapone (administered as the fixed-combination preparation Stalevo^®) compared with those receiving a conventional levodopa-carbidopa formulation.11,13 The STRIDE-PD study was designed to evaluate the time to onset of dyskinesias in patients receiving the fixed combination of levodopa, carbidopa, and entacapone compared with those receiving levodopa-carbidopa only.11,13 An unexpected finding from the study was a higher incidence of prostate cancer among patients receiving levodopa, carbidopa, and entacapone compared with those receiving levodopa-carbidopa (3.7 versus 0.9%, respectively).11

Additional studies were subsequently conducted to further investigate this safety concern.15,16,17 One study was a retrospective cohort evaluation in 11,396 men with parkinson disease, of whom 1141 received entacapone.15 The study compared a cohort of patients treated with levodopa-carbidopa plus entacapone with a cohort of patients treated with levodopa-carbidopa without entacapone.15,16 Analysis of data after an average follow-up period of 4.7 years showed no evidence of an increased risk of prostate cancer incidence (hazard ratio 1.05) or prostate cancer mortality (hazard ratio 0.93) with the use of entacapone compared with no entacapone treatment.15,16 There was also no evidence that a longer cumulative treatment period was associated with an increased risk of prostate cancer.15 A total of 359 cases of prostate cancer and 89 prostate cancer deaths occurred during the observation period.15 Another retrospective cohort study using data from the Department of Veterans Affairs healthcare system compared a group of parkinson disease patients who received levodopa-carbidopa plus add-on entacapone therapy to a control group of patients who received levodopa-carbidopa plus add-on therapy with a dopamine agonist or MAO-B inhibitor.15,17 Prostate cancer occurred in 23 patients in the entacapone group after a mean follow-up of 3.1 years, and in 97 patients in the control group after a mean follow-up period of 4 years.15,17 There was no difference in the risk of prostate cancer between the cohorts for increased duration of entacapone use (adjusted hazard ratio 1.08).17

Although there were limitations to these observational studies, FDA has concluded that based on the overall findings, entacapone use is not associated with an increased risk of prostate cancer.15 FDA states that clinicians should follow current prostate cancer screening guidelines.15

Major Toxicities

Cardiovascular Effects

Entacapone enhances levodopa availability and therefore may be expected to increase the occurrence of orthostatic hypotension or syncope when administered with levodopa/carbidopa.1 However, in clinical studies, the incidence of orthostatic hypotension or syncope was similar in patients receiving entacapone or placebo.1,3,7

Findings from an FDA-conducted meta-analysis, which combined cardiovascular-related findings from 15 clinical trials, suggested an increased risk of cardiovascular events (i.e., myocardial infarction, stroke, cardiovascular death) with entacapone.12,14 In the meta-analysis, patients who received combined therapy with levodopa, carbidopa, and entacapone had a small but statistically significant increase in the risk of cardiovascular events compared with those who received levodopa-carbidopa, raising concerns about entacapone (the drug component lacking in the comparator regimen).12 However, the increased risk was driven largely by results of a single trial (STRIDE-PD), and subsequent analysis of the available data found no evidence to support such an association.12,14 Results of 2 additional analyses that were conducted using data from Medicare or a commercial insurance database showed no increased risk of cardiovascular events (myocardial infarction, stroke, death) with entacapone compared with other antiparkinsonian agents.14 Based on this information, FDA believes that the cardiovascular findings from the previous meta-analysis were due to chance and do not represent a true risk associated with entacapone.14

Hallucinations and Psychotic-like Behavior

Hallucinations have been reported in patients receiving entacapone and resulted in drug discontinuance or hospitalization in 0.8 or 1% of the patients, respectively, in clinical studies.1

New or worsening mental status and behavioral changes, which can be severe and include psychotic-like behavior, have been reported during postmarketing experience with entacapone.1 Such abnormal thinking and behavior may include paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.1 Other drugs used in the treatment of parkinson disease can produce similar effects on thinking and behavior.1

Because of the risk of exacerbating psychosis, entacapone should generally not be used in patients with a major psychotic disorder.1 In addition, concomitant use of entacapone with certain antipsychotic agents may exacerbate parkinsonian symptoms and result in decreased efficacy of entacapone.1

Diarrhea

Diarrhea was reported in 10% of patients receiving entacapone in clinical studies; in most cases, diarrhea was mild to moderate, but severe diarrhea requiring hospitalization has been reported rarely.1 Diarrhea generally occurs during the first 4-12 weeks of entacapone therapy, but may occur as early as the first week or as late as several months following initiation of therapy.1

Postmarketing experience suggests that the diarrhea reported in patients receiving entacapone may be related to drug-induced colitis, primarily lymphocytic colitis.1 In these cases, patients presented with moderate to severe watery (but nonbloody) diarrhea associated with dehydration, abdominal pain, weight loss, and hypokalemia.1 Resolution or substantial improvement occurred in the majority of patients when treatment with the drug was discontinued.1

In patients with prolonged diarrhea suspected to be related to entacapone, the drug should be discontinued and appropriate medical treatment considered; further diagnostic evaluation may be necessary if symptoms continue after discontinuing entacapone.1

Dyskinesia

Entacapone may potentiate the adverse dopaminergic effects of levodopa and may cause or exacerbate dyskinesias.1,3,4 In clinical studies, dyskinesia was reported in 25% of patients receiving entacapone compared with 15% of those receiving placebo.1 Although decreasing the dosage of levodopa may ameliorate the dyskinesias, many patients in placebo-controlled studies continued to experience frequent dyskinesias despite a reduction in levodopa dosage.1

Rhabdomyolysis

Severe rhabdomyolysis has been reported in patients receiving entacapone.1,4,7 Manifestations included fever, altered consciousness, myalgia, and increased concentrations of creatine phosphokinase (CPK) and myoglobin.1 Because of the complex nature of these adverse events, the role of the drug, if any, remains to be determined.1,4,7

Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (NMS; elevated temperature, muscular rigidity, altered consciousness, elevated CPK) has been reported in association with abrupt withdrawal or dosage lowering of other dopaminergic agents.1 Similar episodes have been reported in association with entacapone, although limited information is available on dosage adjustments in these patients and a causal relationship to the drug has not been established.1,4,7 No such manifestations were reported following the abrupt withdrawal or dosage reduction of entacapone during clinical studies of the drug.1 (See Withdrawal of Therapy under Cautions.)

Respiratory Effects

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and thickening of the pleura have been reported in a few patients treated with ergot-derivative dopamine receptor agonists (e.g., bromocriptine, pergolide).1 Although these adverse effects presumably are related to the ergoline structure of these compounds, the possibility exists that nonergot-derived drugs that increase dopaminergic activity such as entacapone may induce similar pulmonary changes.1 Pulmonary fibrosis occurred in 4 patients receiving entacapone in clinical studies for 7-17 months; these patients also were receiving an ergot-derivative dopamine-receptor agonist (i.e., bromocriptine, pergolide).1

General Precautions

Whenever the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®) is used, the precautions and contraindications associated with all the drugs in the preparation must be considered.8

Withdrawal of Therapy

If entacapone therapy is discontinued, the patient should be closely monitored and adjustments made, if necessary, in the dosage of dopaminergic therapy.1 Although tapering the dosage of entacapone has not been systematically evaluated, the manufacturer recommends slow withdrawal of the drug if the decision to discontinue treatment is made.1 If a patient experiences hyperpyrexia or severe rigidity following discontinuance of entacapone, the possibility that the patient is experiencing a symptom complex resembling the neuroleptic malignant syndrome should be considered in the differential diagnosis.1

Melanoma

Data from epidemiologic studies indicate that patients with Parkinson disease have a twofold to approximately sixfold greater risk of developing melanoma than the general population.1,8 It is unclear whether this increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat the disease).1,8 Because of these findings, patients and clinicians should monitor for melanoma on a frequent and regular basis.1,8 The manufacturer recommends that dermatologic examinations be performed periodically by qualified clinicians (e.g., dermatologists).1,8

Impulse Control/Compulsive Behaviors

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges have been reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including entacapone).1,8 These urges stopped in some cases when dosage was reduced or the drug was discontinued.1,8

Clinicians should ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving entacapone.1,8 (See Advice to Patients.) If a patient develops such urges while receiving entacapone, consideration should be given to reducing the dosage or discontinuing the drug.1,8

Specific Populations

Pregnancy

In animal reproduction studies in which entacapone was administered to pregnant rats and rabbits during the period of organogenesis, no evidence of teratogenicity was observed; however, there was an increased frequency of abortions, resorptions, decreased fetal weights, and fetal variations.1 When the drug was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies was observed; exposure to the drug during later stages of gestation and throughout lactation produced no evidence of developmental impairment in the offspring.1

Entacapone has not been studied in pregnant women; therefore, the drug should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.1

Lactation

Entacapone is distributed into milk in rats; caution is advised if the drug is used in nursing women.1

Pediatric Use

Safety and effectiveness of entacapone have not been established in pediatric patients.1

Geriatric Use

No substantial differences in safety or pharmacokinetics of entacapone have been observed relative to younger adults.1,3,7

Hepatic Impairment

Peak plasma concentrations and systemic exposure of entacapone may be increased in patients with hepatic impairment; caution is advised if the drug is used in such patients.1

Biliary excretion is the major route of elimination for entacapone; the drug should be used with caution in patients with biliary obstruction.1

Common Adverse Effects

Adverse effects occurring in 1% or more of patients receiving entacapone and more frequently than placebo include dyskinesia, nausea, hyperkinesia, diarrhea, urine discoloration, hypokinesia, dizziness, abdominal pain, constipation, fatigue, vomiting, back pain, dry mouth, dyspnea, increased sweating, anxiety, somnolence, dyspepsia, flatulence, purpura, asthenia, taste perversion, agitation, gastritis, GI disorder, and bacterial infection.1

Drugs Metabolized by Catechol- O -methyltransferase

Potential pharmacokinetic interaction with drugs metabolized by COMT (e.g., dopamine, epinephrine, isoproterenol).1 (See Concomitant Use with Drugs Metabolized by COMT under Cautions.)

Drugs Affecting Hepatic Microsomal Enzymes

In vitro studies indicate that entacapone inhibits cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A only at very high concentrations; therefore, drug interactions mediated by these CYP isoenzymes are not likely during clinical use.1

Drugs Interfering with Biliary Excretion, Glucuronidation, and Intestinal -Glucuronidase

Potential pharmacokinetic interaction (decreased entacapone excretion) with drugs interfering with biliary excretion, glucuronidation, and intestinal β-glucuronidase (e.g., cholestyramine, probenecid, some anti-infectives [e.g., ampicillin, chloramphenicol, erythromycin, rifampin]).1,7 Such drugs should be used concomitantly with caution in patients receiving entacapone.1

Antipsychotic Agents

Concomitant use of entacapone with certain antipsychotic agents may exacerbate parkinsonian symptoms and result in decreased efficacy of entacapone.1

CNS Depressants

Potential pharmacologic interaction (additive sedative effects).1

Imipramine

Pharmacologic interaction is unlikely.1

Levodopa

Pharmacokinetic interaction (increased plasma concentration of levodopa, improved therapeutic and adverse effect profile of levodopa).1 (See Major Toxicities under Cautions.)

Monoamine Oxidase Inhibitors

Potential pharmacologic interaction (inhibits catecholamine metabolism) with nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine).1 (See Concomitant Use with Monoamine Oxidase Inhibitors under Cautions.) Pharmacologic interaction unlikely with selective MAO-B inhibitors (e.g., selegiline).1

Protein-bound Drugs

Pharmacokinetic interaction is unlikely.1 In vitro studies of entacapone have shown no binding displacement between entacapone and other highly protein-bound drugs such as diazepam, phenylbutazone, salicylic acid, or warfarin.1

Warfarin

Substantial changes in INR have been reported in patients receiving entacapone and warfarin concomitantly in the postmarketing setting.1 The manufacturer recommends that the INR be monitored when entacapone is initiated or when the dosage is increased in patients receiving warfarin.1

Description

Entacapone is a selective and reversible inhibitor of COMT that is structurally and pharmacologically related to tolcapone.1,2,3,7 The drugs are nitrocatechols and are chemically and pharmacologically unrelated to other currently available antiparkinsonian agents (e.g., levodopa, carbidopa, dopamine-receptor agonists, selective MAO-B inhibitors).2,7 However, unlike tolcapone, entacapone has not been associated with hepatotoxicity (e.g., drug-induced hepatitis, fatal liver failure).1,3,4,7 In humans, entacapone inhibits the COMT enzyme in peripheral tissues.1,3,4 The effects of the drug on central COMT activity in humans have not been studied.1 For information on COMT, see Pharmacology in Tolcapone 28:36.12.

Concomitant administration of entacapone with levodopa and a decarboxylase inhibitor (e.g., carbidopa) results in increased and more sustained plasma levodopa concentrations compared with administration of levodopa and a decarboxylase inhibitor.1,3,4 Sustained levodopa concentrations presumably result in more consistent dopaminergic stimulation, resulting in greater reduction in the manifestations of parkinson disease.1 Entacapone lacks antiparkinsonian activity when administered alone.1

Entacapone is almost completely metabolized prior to excretion with only 0.2% of a dose excreted unchanged in urine.1 The main metabolic pathway is isomerization followed by glucuronidation to an inactive conjugate.1 Biliary excretion apparently is the principal route of elimination of the drug and its metabolites.1,3,4

Advice to Patients

Importance of not discontinuing entacapone abruptly and of taking only as prescribed.1

Advise patients of the potential for sedating effects, including somnolence and the possibility of falling asleep while engaged in activities of daily living.1 Patients should avoid driving, operating machinery, or engaging in other potentially dangerous activities until effects on the individual are known.1 Importance of advising patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving) occur at any time during therapy, they should not drive or participate in potentially dangerous activities until they have contacted their clinician.1

Advise patients to use caution when taking other CNS depressants concomitantly.1

Advise patients that entacapone may cause a change in the color of their urine (a brownish orange discoloration); not clinically important.1

Advise patients that hallucinations and other psychotic-like behaviors can occur.1

Importance of informing patients of the risk of exacerbation of dyskinesia.1

Advise patients that nausea can occur, especially during initiation of therapy.1

Advise patients that diarrhea may occur and may have a delayed onset; in some cases, diarrhea may be caused by colitis.1 If diarrhea occurs, advise patients to drink fluids and maintain adequate hydration and monitor for weight loss.1 Resolution is expected when the drug is discontinued; however, further diagnostic evaluation may be required.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving entacapone and of advising them of the importance of reporting such urges.1,8

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Advise patients not to rise rapidly after prolonged sitting or lying down, especially during the first few weeks of entacapone therapy.1

Importance of informing patients of other important precautionary information.1,8 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Novartis Pharmaceuticals Corporation. Comtan^® (entacapone) tablets prescribing information. East Hanover, NJ; 2018 Jun.

2. LeWitt PA. New drugs for the treatment of Parkinson's disease. Pharmacotherapy . 2000; 20:26S-32S. [PubMed 10641989]

3. Holm KJ, Spencer CM. Entacapone: a review of its use in Parkinson's disease. Drugs . 1999; 58:159-77. [PubMed 10439935]

4. Anon. Entacapone for Parkinson's disease. Med Lett Drugs Ther . 2000; 42:7-8. [PubMed 10696231]

5. Rinne UK, Larsen JP, Siden A et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology . 1998; 51:1309-14. [PubMed 9818851]

6. Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients. Ann Neurol . 1997; 42:747-55. [PubMed 9392574]

7. Novartis, East Hanover, NJ: Personal communication.

8. Novartis. Stalevo^® 50, Stalevo^® 75, Stalevo^® 100, Stalevo^® 125, Stalevo^® 150, Stalevo^® 200 (carbidopa, levodopa, and entacapone) tablets prescribing information. East Hanover, NJ; 2009 Mar.

9. US WorldMeds. Apokyn^® (apomorphine hydrochloride) injection prescribing information. Louisville, KY; 2019 Dec.

10. van der Geest R, van Laar T, Kruger PP et al. Pharmacokinetics, enantiomer interconversion, and metabolism of R -apomorphine in patients with idiopathic Parkinson's disease. Clin Neuropharmacol . 1998; 21:159-68. [PubMed 9617507]

11. Food and Drug Administration. FDA drug safety communication: ongoing safety review of Stalevo (entacapone/carbidopa/levodopa) and possible development of prostate cancer. Rockville, MD; 2010 Mar 31. From FDA website ([Web]).

12. Food and Drug Administration. FDA drug safety communication: ongoing safety review of Stalevo and possible increased cardiovascular risk. Rockville, MD; 2010 Aug 20. From FDA website ([Web]).

13. Stocchi F, Rascol O, Kieburtz K et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol . 2010; 68:18-27. [PubMed 20582993]

14. Food and Drug Administration. FDA drug safety communication: FDA review found no increased cardiovascular risks with Parkinson's disease drug entacapone. Rockville, MD; 2015 Oct 26. From FDA website ([Web]). [Web]

15. Food and Drug Administration. FDA drug safety communication: FDA review finds no increased risk of prostate cancer with Parkinson's disease medications containing entacapone (Comtan, Stalevo). Rockville, MD; 2019 Aug 13. From FDA website ([Web]). [Web]

16. Korhonen P, Kuoppamäki M, Prami T et al. Entacapone and prostate cancer risk in patients with Parkinson's disease. Mov Disord . 2015; 30:724-8. [PubMed 25639262]

17. Major JM, Dong D, Cunningham F et al. Entacapone and prostate cancer in Parkinson's disease patients: A large Veterans Affairs healthcare system study. Parkinsonism Relat Disord . 2018; 53:46-52. [PubMed 29759929]

101. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology . 2001; 56:S1-S88.

115. Lewitt PA. Levodopa for the treatment of Parkinson's disease. N Engl J Med . 2008; 359:2468-76. [PubMed 19052127]

116. PD Med Collaborative Group, Gray R, Ives N et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet . 2014; 384:1196-205. [PubMed 24928805]

120. Fahn S, Oakes D, Shoulson I et al. Levodopa and the progression of Parkinson's disease. N Engl J Med . 2004; 351:2498-508. [PubMed 15590952]

122. Bressman S, Saunders-Pullman R. When to Start Levodopa Therapy for Parkinson's Disease. N Engl J Med . 2019; 380:389-390. [PubMed 30673551]

123. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA . 2014 Apr 23-30; 311:1670-83. [PubMed 24756517]

124. Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) . 2013; 19:1189-212. [PubMed 24092286]

125. Patel T, Chang F, Parkinson Society Canada. Parkinson's disease guidelines for pharmacists. Can Pharm J (Ott) . 2014; 147:161-70. [PubMed 24847369]

157. . Drugs for Parkinson's disease. Med Lett Drugs Ther . 2017; 59:187-194. [PubMed 29136401]