Entacapone Tablets

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

In october, the fda approved entacapone, the second reversible catechol-O-methyltransferase (COMT) inhibitor for the treatment of Parkinson’s disease. Inhibition of the COMT enzyme reduces the peripheral metabolism of levodopa, allowing more levodopa to reach the brain. When a COMT inhibitor is used in conjunction with levodopa/carbidopa, the result is more sustained plasma levels of levodopa for a longer time.

The first approved COMT inhibitor, tocalpone (Tasmar) has been associated with acute, severe liver failure (estimated rate of 1 per 20,000), leading to withdrawal of the drug from the market in many countries.

Tocalpone remains on the market in this country, but the FDA has recommended liver function monitoring every two weeks for patients on the drug. Unlike tocalpone, entacapone has not been associated with liver disease and the FDA is not requiring monitoring of liver function tests when patients are treated with this new medication.

Entacapone is manufactured by Orion Pharma in Finland and marketed as Comtan by Novartis Pharmaceuticals.

Indications

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."

Dosage

The recommended dose of entacapone is 200 mg taken concomitantly with each dose of levodopa/carbidopa (immediate or controlled release formulations) up to a maximum of eight times daily (1600 mg). The drug may be taken without regard to meals. Entacapone is supplied as 200 mg tablets.

Potential Advantages

In contrast to tolcapone, monitoring of liver enzymes is not required. Although acute, severe (fulminant) liver failure has been reported with tolcapone, hepatotoxicity has not been reported with use of entacapone. The incidence of elevation in liver enzymes is similar between entacapone and placebo.1

Potential Disadvantages

Dopaminergic side effects including dyskinesia, nausea, dizziness, hallucinations, vomiting, and insomnia are the most common adverse effects.

The most common nondopaminergic side effects compared to placebo are diarrhea (20% vs 7%), constipation (14% vs 5%), and urine discoloration (up to 37% vs 0-1.2%).1 Entacapone turns the urine to dark yellow or even orange-red depending on the dose.2 On a milligram basis, entacapone is less potent than tolcapone in increasing the bioavailability of levodopa.3

Comments

Levodopa, combined with dopa decarboxylase inhibitor (carbidopa), is a mainstay in the pharmacologic management of Parkinson’s disease. But since this drug combination is taken orally, it is still subject to peripheral metabolism of levodopa by catechol-O-methyltransferase (COMT), which is found in the gut and liver. The addition of a COMT inhibitor increases the bioavailability of levodopa by 30-60% and increases levodopa concentration in the central nervous system as assessed by positron emission tomography studies.1,2 Clinical efficacy has been demonstrated in three 24-week multicenter, randomized, double-blind, placebo-controlled trials conducted in Finland, Norway, Sweden, Denmark, United States, Canada, Germany, and Austria involving 678 patients with wearing-off-type motor fluctuations.4,5 Treatment with entacapone resulted in an increase in mean "on" time of 0.6-1.4 hours, a decrease in "off" time of 0.6-1.3 hours, and an increase from baseline the percent of awake time "on" 3.0-8.7%. There were also significant (P < 0.05) improvements in the United Parkinson Disease Rating Scale (UPDRS) total scores, subscores for part II (activity of daily living), and part III (motor disability).2,4,5 There was generally no improvement in subscore I (mentation, behavior, and mood). Levodopa/carbidopa dosing generally needs to be decreased when starting entacapone by an average of 25%. More than 58% of patients with daily doses equal to or greater than 800 mg require dose reduction.5 Data were obtained from daily patient 18- or 24-hour diaries. Analyses were based on intent-to-treat using last observation carried forward method. Limited data suggest that the treatment effect may be greater in patients with less than 55% "on-time."6 Entacapone is $1.68 per tablet with a daily cost of up to $13.44.

Clinical Implications

Parkinson’s disease is a progressive neurodegenerative disorder that affects about 1.5 million Americans. Levodopa is an effective treatment for Parkinson’s disease, although there is debate when therapy should be initiated. Long-term levodopa therapy combined with disease progression results in changes in the dopaminergic pharmacodynamics leading to the "wearing-off" phenomenon. The addition of a COMT inhibitor, such as entacapone as an adjunct to levodopa/carbidopa, provides another strategy in managing patients with the "wearing-off" phenomenon.

References

1. Holm KJ, et al. Drugs 1999;58(1):159-177.

2. Rinne UK, et al. Adv Neurol 1999;80:491-494.

3. Luer MS. Pharmacotherapy 1999;19(11 Pt 2): 169S-179S.

4. Rinne UK, et al. Neurology 1998;51(5):1309-1314.

5. Comtan Product Information. Novartis Pharmaceuticals. October 1999.

6. McDermott M, et al. Ann Neurol 1998;44(2):292.