Entacapone

Drug Interactions In vitro studies of human CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A only at very high concentrations (IC50 from 200 microM to over 1,000 microM; an oral 200 mg dose achieves a highest level of approximately 5 microM in people); these enzymes would therefore not be expected to be inhibited in clinical use. 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% [CI90 11% to 26%] and the international normalized ratio (INR) values increased on average by 13% [CI90 6% to 19%].

Nevertheless, cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postapproval use of entacapone. Therefore, monitoring of INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Protein Binding Entacapone is highly protein bound (98%). In vitro studies have shown no binding displacement between entacapone and other highly bound drugs, such as warfarin, salicylic acid, phenylbutazone and diazepam. Drugs Metabolized by Catechol-O-Methyltransferase (COMT) See WARNINGS. Hormone Levels Levodopa is known to depress prolactin secretion and increase growth hormone levels.

Treatment with entacapone coadministered with levodopa and dopa decarboxylase inhibitor does not change these effects. Effect of Entacapone on the Metabolism of Other Drugs See WARNINGS regarding concomitant use of entacapone 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 and dopa decarboxylase inhibitor (n=29). More than 600 patients with Parkinson’s disease in clinical studies have used selegiline in combination with entacapone and levodopa and 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 and dopa-decarboxylase inhibitor.

Pregnancy). Entacapone is excreted into maternal milk in rats. Because of the possibility that entacapone may be excreted into human maternal milk, advise patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant. Tell patients and family members to notify their healthcare practitioner if they notice that the patient develops unusual urges or behaviors. Laboratory Tests Entacapone is a chelator of iron. The impact of entacapone on the body’s iron stores is unknown; however, a tendency towards decreasing serum iron concentrations was noted in clinical studies.

In a controlled clinical study, serum ferritin levels (as marker of iron deficiency and subclinical anemia) were not changed with entacapone compared to placebo after one year of treatment and there was no difference in rates of anemia or decreased hemoglobin levels. Special Populations Patients with hepatic impairment should be treated with caution (see INDICATIONS, DOSAGE AND ADMINISTRATION).