Comtan Information
Comtan () Description
Comtan () (entacapone) is available as tablets containing 200-mg entacapone.
Entacapone is an inhibitor of catechol--methyltransferase (COMT), used in the treatment of Parkinson's Disease as an adjunct to levodopa/carbidopa therapy. It is a nitrocatechol-structured compound with a relative molecular mass of 305.29. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is CHNO and its structural formula is:
The inactive ingredients of the Comtan () tablet are microcrystalline cellulose, mannitol, croscarmellose sodium, hydrogenated vegetable oil, hydroxypropyl methylcellulose, polysorbate 80, glycerol 85%, sucrose, magnesium stearate, yellow iron oxide, red oxide, and titanium dioxide.
Comtan () Clinical Pharmacology
Entacapone is a selective and reversible inhibitor of catechol--methyltransferase (COMT).
In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells, and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.
The mechanism of action of entacapone is believed to be through its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's Disease. The higher levodopa levels also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa.
In animals, while entacapone enters the CNS to a minimal extent, it has been shown to inhibit central COMT activity. In humans, entacapone inhibits the COMT enzyme in peripheral tissues. The effects of entacapone on central COMT activity in humans have not been studied.
The effectiveness of Comtan () (entacapone) as an adjunct to levodopa in the treatment of Parkinson's Disease was established in three 24-week multicenter, randomized, double-blind placebo-controlled trials in patients with Parkinson's Disease. In two of these trials, the patients' disease was "fluctuating", i.e., was characterized by documented periods of "On" (periods of relatively good functioning) and "Off" (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of the trials, patients were stabilized on levodopa for 2 - 4 weeks. Comtan () has not been systematically evaluated in patients who do not experience fluctuations.
In the first two studies to be described, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of levodopa/carbidopa (up to 10 times daily, but averaging 4-6 doses per day). The formal double-blind portion of both trials was 6 months long. Patients recorded the time spent in the "On" and "Off" states in home diaries periodically throughout the duration of the trial. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the "On" state during an 18-hour diary recorded day (6 AM to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the "On" state.
In addition to the primary outcome measure, the amount of time spent in the "Off" state was evaluated, and patients were also evaluated by subparts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V & VI); an investigator's and patient's global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson's Disease; and the change in daily levodopa/carbidopa dose.
In one of the studies, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Nordic study), all of whom received concomitant levodopa plus dopa-decarboxylase inhibitor (either levodopa/carbidopa or levodopa/benserazide). In the second trial, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant levodopa/carbidopa.
The following tables display the results of these two trials:
Effects on "On" time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline.
Comtan () Indications
Comtan () (entacapone) is indicated as an adjunct to levodopa/carbidopa to treat patients with idiopathic Parkinson's Disease who experience the signs and symptoms of end-of-dose "wearing-off" (see).
Comtan () 's effectiveness has not been systematically evaluated in patients with idiopathic Parkinson's Disease who do not experience end-of-dose "wearing-off".
Comtan () Contraindications
Comtan () (entacapone) tablets are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
Comtan () Warnings
Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of Comtan () (entacapone) and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with Comtan () and a non-selective MAO inhibitor.
Entacapone can be taken concomitantly with a selective MAO-B inhibitor (e.g., selegiline).
Comtan () Precautions
Dopaminergic therapy in Parkinson's Disease patients has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and, therefore, might be expected to increase the occurrence of orthostatic hypotension. In Comtan () (entacapone) clinical trials, however, no differences from placebo were seen for measured orthostasis or symptoms of orthostasis. Orthostatic hypotension was documented at least once in 2.7% and 3.0% of the patients treated with 200 mg Comtan () and placebo, respectively. A total of 4.3% and 4.0% of the patients treated with 200 mg Comtan () and placebo, respectively, reported orthostatic symptoms at some time during their treatment and also had at least one episode of orthostatic hypotension documented (however, the episode of orthostatic symptoms itself was not accompanied by vital sign measurements). Neither baseline treatment with dopamine agonists or selegiline, nor the presence of orthostasis at baseline, increased the risk of orthostatic hypotension in patients treated with Comtan () compared to patients on placebo.
In the large controlled trials, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in both treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement).
In clinical trials, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg Comtan () and placebo, respectively. In patients treated with Comtan () , diarrhea was generally mild to moderate in severity (8.6%) but was regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of Comtan () . Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 - 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.
Post-marketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases 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, diarrhea and other colitis-related symptoms resolved or significantly improved when Comtan () treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of Comtan () but recurred after retreatment with Comtan () .
If prolonged diarrhea is suspected to be related to Comtan () , 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.
Patients should be instructed to take Comtan () only as prescribed.
Patients should be informed that hallucinations can occur.
Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sweating. Hypotension may occur more frequently during initial therapy. Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially at the initiation of treatment with Comtan () .
Patients should be advised that they should neither drive a car nor operate other complex machinery until they have gained sufficient experience on Comtan () to gauge whether or not it affects their mental and/or motor performance adversely. Because of the possible additive sedative effects, caution should be used when patients are taking other CNS depressants in combination with Comtan () .
Patients should be informed that nausea may occur, especially at the initiation of treatment with Comtan () .
Patients should be informed that diarrhea may occur with Comtan () and it may have a delayed onset. Sometimes prolonged diarrhea may be caused by colitis (inflammation of the large intestine). Patients with diarrhea should drink fluids to maintain adequate hydration and monitor for weight loss. If diarrhea associated with Comtan () is prolonged, discontinuing the drug is expected to lead to resolution, if diarrhea continues after stopping entacapone, further diagnostic investigations may be needed.
Patients should be advised of the possibility of an increase in dyskinesia.
Patients should be advised that treatment with entacapone may cause a change in the color of their urine (a brownish orange discoloration) that is not clinically relevant. In controlled trials, 10% of patients treated with Comtan () reported urine discoloration compared to 0% of placebo patients.
Although Comtan () has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in the rabbit. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see).
Entacapone is excreted into maternal milk in rats. Because of the possibility that entacapone may be excreted into human maternal milk, patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson's disease, including Comtan () . Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Comtan () . Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Comtan () . Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Comtan () .
Seeregarding concomitant use of Comtan () and non-selective MAO inhibitors.
No interaction was noted with the MAO-B inhibitor selegiline in two multiple-dose interaction studies when entacapone was coadministered with a levodopa/dopa decarboxylase inhibitor (n=29). More than 600 Parkinson's Disease patients in clinical trials have used selegiline in combination with entacapone and levodopa/dopa decarboxylase inhibitor.
As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin and chloramphenicol).
No interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone without coadministered levodopa/dopa-decarboxylase inhibitor.
In animal studies, entacapone was excreted into maternal rat milk.
It is not known whether entacapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when entacapone is administered to a nursing woman.
Comtan () Adverse Reactions
During the pre-marketing development of entacapone, 1450 patients with Parkinson's Disease were treated with entacapone. Included were patients with fluctuating symptoms, as well as those with stable responses to levodopa therapy. All patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects.
The most commonly observed adverse events (>5%) in the double-blind, placebo-controlled trials (N=1003) associated with the use of Comtan () (entacapone) and not seen at an equivalent frequency among the placebo-treated patients were: dyskinesia/hyperkinesia, nausea, urine discoloration, diarrhea, and abdominal pain.
Approximately 14% of the 603 patients given entacapone in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared to 9% of the 400 patients who received placebo. The most frequent causes of discontinuation in decreasing order are: psychiatric reasons (2% vs. 1%), diarrhea (2% vs. 0%), dyskinesia/hyperkinesia (2% vs. 1%), nausea (2% vs. 1%), abdominal pain (1% vs. 0%), and aggravation of Parkinson's Disease symptoms (1% vs. 1%).
Comtan () Drug Abuse And Dependence
Comtan () (entacapone) is not a controlled substance. Animal studies to evaluate the drug abuse and potential dependence have not been conducted. Although clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence, systematic studies in humans designed to evaluate these effects have not been performed.
Comtan () Overdosage
There have been no reported cases of either accidental or intentional overdose with entacapone tablets. However, COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of Comtan () (entacapone) may theoretically produce a 100% inhibition of the COMT enzyme in people, thereby preventing the metabolism of endogenous and exogenous catechols.
The highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 µg/mL. The highest daily dose given to humans was 2400 mg, administered in one study as 400 mg six times daily with levodopa/carbidopa for 14 days in 15 Parkinson's Disease patients, and in another study as 800 mg t.i.d. for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 µg/mL (at 45 min., compared to 1.0 and 1.2 µg/mL with 200 mg entacapone at 45 min.). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2000 mg Comtan () have been administered as 200 mg 10 times daily with levodopa/carbidopa or levodopa/benserazide for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1600 mg is limited.
The range of lethal plasma concentrations of entacapone based on animal data was 80 - 130 µg/mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses.
Comtan () Dosage And Administration
The recommended dose of Comtan () (entacapone) is one 200 mg tablet administered concomitantly with each levodopa/carbidopa dose to a maximum of 8 times daily (200 mg × 8 = 1600 mg per day). Clinical experience with daily doses above 1600 mg is limited.
Comtan () should always be administered in association with levodopa/carbidopa. Entacapone has no antiparkinsonian effect of its own.
In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been ≥ 800 mg or if patients had moderate or severe dyskinesias before beginning treatment.
To optimize an individual patient's response, reductions in daily levodopa dose or extending the interval between doses may be necessary. In clinical trials, the average reduction in daily levodopa dose was about 25% in those patients requiring a levodopa dose reduction. (More than 58% of patients with levodopa doses above 800 mg daily required such a reduction.)
Comtan () can be combined with both the immediate and sustained-release formulations of levodopa/carbidopa.
Comtan () may be taken with or without food (see).
Comtan () How Supplied
Comtan () (entacapone) is supplied as 200-mg film-coated tablets for oral administration. The oval-shaped tablets are brownish-orange, unscored, and embossed "Comtan () " on one side. Tablets are provided in HDPE containers as follows:
Comtan ()
Comtan () Principal Display Panel - Mg Bottle Label
