Stalevo (Carbidopa / Levodopa / Entacapone) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Caution should be exercised when the following drugs are administered concomitantly with Stalevo.

Anti-hypertensive agents:    Symptomatic postural hypotension has occurred when carbidopa-levodopa was added to the treatment of patients receiving antihypertensive drugs. Therefore, when therapy with Stalevo is started, dosage adjustment of the antihypertensive drug may be required.

MAO inhibitors:    For patients receiving nonselective MAO inhibitors, see CONTRAINDICATIONS. Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone.

Tricyclic antidepressants:    There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa.

Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid:    Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa.

Phenytoin and papaverine:    The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with carbidopa-levodopa should be carefully observed for loss of therapeutic response.

Iron salts:    Iron salts may reduce the bioavailability of levodopa, carbidopa and entacapone. The clinical relevance is unclear.

Metoclopramide:    Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.

Drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase (probenecid, cholestyramine, erythromycin, rifampicin, ampicillin and chloramphenicol):    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).

Pyridoxine:    Stalevo can be given to patients receiving supplemental pyridoxine. Oral coadministration of 10-25 mg of pyridoxine hydrochloride (vitamin B6) with levodopa may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine; therefore, Stalevo can be given to patients receiving supplemental pyridoxine.

Effect of levodopa and carbidopa in Stalevo on the metabolism of other drugs:    Inhibition or induction effect of levodopa and carbidopa has not been investigated.

Effect of entacapone in Stalevo on the metabolism of other drugs:    Entacapone is unlikely to inhibit the metabolism of other drugs that are metabolized by major P450s including CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. 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 to over 1000 µM; an oral 200 mg dose achieves a highest level of approximately 5 µM in people); these enzymes would therefore not be expected to be inhibited in clinical use. However, no information is available regarding the induction effect from entacapone.

OVERDOSAGE

Management of acute overdosage with Stalevo® (carbidopa, levodopa and entacapone) is the same as management of acute overdosage with levodopa and entacapone. Pyridoxine is not effective in reversing the actions of Stalevo.

Hospitalization is advised, and general supportive mea-sures should be employed, along with immediate gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of entacapone in particular, by decreasing its absorption/reabsorption from the GI tract. Intravenous fluids should be administered judiciously and an adequate airway maintained.

The adequacy of the respiratory, circulatory and renal systems should be carefully monitored and appropriate supportive measures employed. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs, increasing the risk of drug interactions (especially catechol-structured drugs) should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Hemodialysis or hemoperfusion is unlikely to reduce entacapone levels due to its high binding to plasma proteins.

There are very few cases of overdosage with levodopa reported in the published literature. Based on the limited available information, the acute symptoms of levodopa/dopa decarboxylase inhibitor overdosage can be expected to arise from dopaminergic overstimulation. Doses of a few grams may result in CNS disturbances, with an increasing likelihood of cardiovascular disturbance (e.g., hypotension, tachycardia) and more severe psychiatric problems at higher doses. An isolated report of rhabdomyolysis and another of transient renal insufficiency suggest that levodopa overdosage may give rise to systemic complications, secondary to dopaminergic overstimulation.

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 entacapone may theoretically produce a 100% inhibition of the COMT enzyme in people, thereby preventing the O-methylation 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 carbidopa-levodopa 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 entacapone have been administered as 200 mg 10 times daily with carbidopa-levodopa or benserazide-levodopa 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.

CONTRAINDICATIONS

Stalevo® (carbidopa, levodopa and entacapone) tablets are contraindicated in patients who have demonstrated hypersensitivity to any component (carbidopa, levodopa, or en-tacapone) of the drug or its excipients.

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 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. As with carbidopa-levodopa, nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with Stalevo. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo. Stalevo may be administered concomitantly with the manufacturer's recommended dose of MAO inhibitors with selectivity for MAO type B (e.g., selegiline HCl). (See PRECAUTIONS, Drug Interactions.)

Stalevo is contraindicated in patients with narrow-angle glaucoma.

Because levodopa may activate malignant melanoma, Stalevo should not be used in patients with suspicious, undiagnosed skin lesions or a history of melanoma.