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Uses

Parkinsonian Syndrome

Entacapone is used as an adjunct to levodopa-carbidopa in the symptomatic treatment of idiopathic parkinsonian syndrome in patients who experience manifestations of end-of-dose ''wearing-off.'' Efficacy of entacapone as an adjunct to levodopa for the management of parkinsonian syndrome 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). 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. 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. In the third study, slight but insignificant improvements in ''on'' time were observed in the subgroup of patients with ''off'' phenomena. When manifestations of parkinsonian syndrome 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. No substantial improvement was observed using subscale I (mentation). 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. No substantial changes occurred in levodopa dosage or global percent improved in patients enrolled in the third study. Although patients in the third study were not required to have been experiencing motor fluctuations, the drug has not been evaluated systematically in patients who do not experience such fluctuations.

For additional information on the management of parkinsonian syndrome,

Dosage and Administration

General

Entacapone is administered orally without regard to meals.

The recommended dosage is 200 mg administered with each levodopa-carbidopa dose up to a maximum of 8 times daily (1.6 g daily). Clinical experience with dosages exceeding 1.6 g daily is limited. Entacapone should be administered only in conjunction with levodopa-carbidopa.

To optimize patient response, reductions in the daily levodopa dosage or frequency of administration may be necessary. 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 dosage; the average reduction in daily levodopa dosage was about 25%.

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).

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. Tablets containing the fixed combination of levodopa, carbidopa, and entacapone should not be divided, and only one tablet should be administered per dosing interval. 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. 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.

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. 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). 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.

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. 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. 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. 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. 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. However, a reduction in the dosage of levodopa-carbidopa or entacapone may be necessary. 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.

Special Populations

Entacapone should be administered with caution in patients with biliary obstruction because biliary excretion is the principal route of elimination of the drug. Based on limited data, pharmacokinetics may be altered in patients with hepatic failure, and the drug should be used with caution in such patients. The effects of liver disease on the pharmacokinetics of entacapone following long-term therapy in conjunction with levodopa and carbidopa have not been evaluated to date.

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

Cautions

Contraindications

Known hypersensitivity to entacapone or any ingredient in the formulation.

Warnings/Precautions

Warnings

Monoamine Oxidase Inhibitors

Because monoamine oxidase (MAO) and catechol-O-methyltransferase (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. Therefore, patients ordinarily should not be treated concomitantly with entacapone and a nonselective MAO inhibitor. However, entacapone can be used concomitantly with a selective MAO-B inhibitor (e.g., selegiline).

Drugs Metabolized by COMT

Concomitant use of entacapone and drugs known to be metabolized by COMT (e.g., bitolterol [no longer commercially available in the US], dobutamine, dopamine, epinephrine, isoetharine, isoproterenol, methyldopa, norepinephrine) may result in increased heart rate, arrhythmias, and excessive changes in blood pressure regardless of the route of administration (including inhalation). The manufacturer of entacapone includes apomorphine in this list of drugs. However, data from in vivo studies indicate that apomorphine is not metabolized by COMT.

Potential Risk of Prostate Cancer

In 2010, the US Food and Drug Administration (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. The STRIDE-PD study, which was conducted over 4 years in more than 700 patients requiring initiation of levodopa therapy for early parkinsonian syndrome, was designed to evaluate the time to onset of dyskinesias in patients initiating such therapy with levodopa, carbidopa, and entacapone compared with those initiating therapy with levodopa-carbidopa. A higher incidence of prostate cancer was observed among patients receiving levodopa, carbidopa, and entacapone compared with those receiving levodopa-carbidopa (3.7 versus 0.9%, respectively). Patients received the combined regimen of levodopa, carbidopa, and entacapone for an average of 664 days (range: 148-949 days) prior to the diagnosis of prostate cancer. While previous controlled studies evaluating entacapone as an adjunct to levodopa-carbidopa in patients with parkinsonian syndrome have not found an increased risk of prostate cancer, most of these trials were of shorter duration (e.g., less than 1 year) than the STRIDE-PD trial. At this time, FDA has not concluded that combined therapy with levodopa, carbidopa, and entacapone is associated with an increased risk of prostate cancer and is continuing to review available data related to this safety concern. Patients currently receiving entacapone as an adjunct to levodopa-carbidopa (either separately or as a fixed-combination preparation) should continue to take the drugs as prescribed unless otherwise instructed by a clinician. Since most men receiving such therapy are in an age group associated with increased risk of prostate cancer, FDA states that such patients should continue to be monitored for the development of prostate cancer according to current prostate cancer screening guidelines.

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. However, in clinical studies, the incidence of orthostatic hypotension or syncope was similar in patients receiving entacapone or placebo.

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. 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). 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. 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. 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.

GI Effects

Diarrhea was reported in 10% of patients receiving entacapone in clinical studies, and about 2% of patients required discontinuance of the drug because of diarrhea. Diarrhea generally was of mild to moderate intensity, but severe diarrhea, which required hospitalization, may occur rarely. 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 entacapone therapy. Diarrhea generally resolved following discontinuance of the drug.

Hallucinations

Hallucinations were reported in about 4% of patients receiving entacapone or placebo in clinical studies and resulted in hospitalization in 1 or 0.3% of patients, respectively.

Dyskinesia

Entacapone may potentiate the adverse dopaminergic effects of levodopa and may cause or exacerbate dyskinesias. 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. Discontinuance of therapy because of dyskinesia was required in 2 or 1% of patients receiving entacapone or placebo, respectively.

Rhabdomyolysis

Severe rhabdomyolysis has been reported rarely in patients receiving entacapone. Because of the complex nature of these adverse events, the role of the drug, if any, remains to be determined.

Nervous System and Muscular Effects

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. 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. No such manifestations were reported following the abrupt withdrawal or dosage reduction of entacapone during clinical studies of the drug.(See Warnings/Precautions: General Precautions, in 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). 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. 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).

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.

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. Although tapering the dosage of entacapone has not been systematically evaluated, the manufacturer recommends the slow withdrawal of the drug if the decision to discontinue treatment is made. 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.

Melanoma

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

Intense Urges

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). Although a causal relationship has not been established, these urges stopped in some cases when dosage was reduced or the drug was discontinued. Clinicians should ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving entacapone and should advise them of the importance of reporting such urges. If a patient develops such urges while receiving entacapone, consideration should be given to reducing the dosage or discontinuing the drug.

Specific Populations

Pregnancy

Category C.

Lactation

Entacapone is distributed into milk in rats; caution if used in nursing women.

Pediatric Use

Not indicated.

Geriatric Use

No substantial differences in safety or pharmacokinetics relative to younger adults.

Hepatic Impairment

Use with caution.

Biliary Obstruction

Use with caution.

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. Adverse effects resulting in discontinuance include psychiatric reasons, diarrhea, dyskinesia/hyperkinesia, nausea, abdominal pain, and aggravation of parkinsonian syndrome.

Drug Interactions

Levodopa

Pharmacokinetic interaction (increased plasma concentration of levodopa, improved therapeutic and adverse effect profile of levodopa).(See Warnings/Precautions: Major Toxicities, in Cautions.)

Drugs Metabolized by Catechol-O-methyltransferase

Potential pharmacokinetic interaction with drugs metabolized by catechol-O-methyltransferase (COMT) (e.g., dopamine, epinephrine, isoproterenol).(See Warnings/Precautions: Warnings, in Cautions.)

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.

Monoamine Oxidase Inhibitors

Potential pharmacologic interaction (inhibits catecholamine metabolism) with nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine).(See Warnings: Monoamine Oxidase Inhibitors, in Cautions: Warnings/Precautions.) Pharmacologic interaction unlikely with selective MAO-B inhibitors (e.g., selegiline).

Drugs Interfering with Biliary Excretion, Glucuronidation, and Intestinal β-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]).

Protein-bound Drugs

Pharmacokinetic interaction unlikely. In vitro studies of entacapone have shown no binding displacement with drugs such as diazepam, phenylbutazone, salicylic acid, or warfarin.

Imipramine

Pharmacologic interaction unlikely.

CNS Depressants

Potential pharmacologic interaction (additive sedative effects).