Entacapone Interactions

Drug Interactions See PRECAUTIONS, Drug Interactions .

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% [Cl90 11% to 26%], and the INR values increased on average by 13% [Cl90 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.

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% [Cl90 11% to 26%], and the INR values increased on average by 13% [Cl90 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.

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 Tablets. Therefore, monitoring of INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin.

7 DRUG INTERACTIONS Drugs metabolized by COMT: use with caution ( 5.11 , 7.2 ) Anti-hypertensive agents: dose adjustment may be required ( 7.3 ) Tricyclic antidepressants: risk of hypertension and dyskinesia reported during concomitant use with carbidopa/levodopa ( 7.4 ) Dopamine D2 receptor antagonists, isoniazid, phenytoin, papaverine and iron salts: may reduce efficacy of carbidopa, levodopa and entacapone tablets ( 7.5 , 7.6 , 7.7 , 7.8 , 7.9 ) Drugs that interfere with biliary excretion, glucuronidation and intestinal beta-glucuronidase: dose adjustment of carbidopa, levodopa and entacapone tablets may be required ( 7.10 ) Drugs metabolized by CYP2C9 (e.g., coumadin): dose adjustment of carbidopa, levodopa and entacapone tablets may be required; monitor INR when initiating carbidopa, levodopa and entacapone tablets in patients on coumadin ( 7.11 ) 7.1 MAO Inhibitors Patients receiving nonselective MAO inhibitors and carbidopa, levodopa and entacapone may be at risk of increased adrenergic tone. Therefore, the use of carbidopa, levodopa and entacapone tablets is contraindicated in patients receiving nonselective MAO inhibitors [ see Contraindications (4) ]. 7.2 Drugs Metabolized by Catechol-O-Methyltransferase (COMT) Drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure [ see Warnings and Precautions (5.11) ]. 7.3 Antihypertensive Agents Symptomatic postural hypotension has occurred when carbidopa/levodopa was added to the treatment of patients receiving antihypertensive drugs. When starting therapy with carbidopa, levodopa and entacapone tablets, dosage adjustment of antihypertensive drug may be required. 7.4 Tricyclic Antidepressants There have been reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa/levodopa. 7.5 Dopamine D2 Receptor Antagonists Dopamine D2 receptor antagonists (e.g., metoclopramide, phenothiazines, butyrophenones, risperidone) may reduce the therapeutic effects of levodopa. 7.6 Isoniazid Isoniazid may reduce the therapeutic effects of levodopa, a dose increase may be necessary. 7.7 Phenytoin The beneficial effects of levodopa in Parkinson’s disease have been reported to be reversed by phenytoin. Patients taking phenytoin with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Carbidopa, levodopa and entacapone tablets dosage should be increased as clinically needed in patients receiving phenytoin. 7.8 Papaverine The beneficial effects of levodopa in Parkinson’s disease have been reported to be reversed by papaverine. Patients taking papaverine with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Carbidopa, levodopa and entacapone tablets dosage should be increased as clinically needed in patients receiving papaverine. 7.9 Iron Salts Iron salts or multi vitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa, carbidopa and entacapone and consequently reduce bioavailability of levodopa, carbidopa and entacapone. 7.10 Drugs Known to Interfere with Biliary Excretion, Glucuronidation, and Intestinal Beta-glucuronidase 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). 7.11 Drugs Metabolized via CYP2C9 (e.g., coumadin) The dosage of carbidopa, levodopa and entacapone tablets should be adjusted as clinically needed in patients using other drugs metabolized via CYP2C9. An interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values on average by 13%. Cases of increased INR in patients concomitantly using warfarin have been reported during the post-approval use of entacapone. Thus, monitoring of INR is recommended when carbidopa, levodopa and entacapone tablets treatment is initiated for patients receiving warfarin.

Drug Interactions See PRECAUTIONS, Drug Interactions .

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% [Cl90 11% to 26%], and the INR values increased on average by 13% [Cl90 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.