Drug Interactions between Etrafon Forte and Stalevo 100

GENERALLY AVOID: Agents with central antidopaminergic activity such as phenothiazines, neuroleptics, and certain antiemetics may antagonize the pharmacologic effects of dopaminergic drugs, and vice versa. In addition, the central nervous system depressant and hypotensive effects of these agents may be additively or synergistically increased when taken together.

MANAGEMENT: Concomitant use of dopaminergic drugs with antidopaminergic agents should generally be avoided. If coadministration is necessary, patients should be alerted to the possibility of excessive drowsiness and monitored for potentially diminished therapeutic response to both treatments. Patients treated for Parkinson's disease should generally avoid antidopaminergic agents, particularly phenothiazines and older neuroleptic agents, since these agents may cause extrapyramidal reactions and exacerbate the symptoms of Parkinson's disease. Likewise, patients with a major psychotic disorder should ordinarily not be treated with dopaminergic drugs because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone.

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GENERALLY AVOID: Agents with central antidopaminergic activity such as phenothiazines, neuroleptics, and certain antiemetics may antagonize the pharmacologic effects of dopaminergic drugs, and vice versa. In addition, the central nervous system depressant and hypotensive effects of these agents may be additively or synergistically increased when taken together.

MANAGEMENT: Concomitant use of dopaminergic drugs with antidopaminergic agents should generally be avoided. If coadministration is necessary, patients should be alerted to the possibility of excessive drowsiness and monitored for potentially diminished therapeutic response to both treatments. Patients treated for Parkinson's disease should generally avoid antidopaminergic agents, particularly phenothiazines and older neuroleptic agents, since these agents may cause extrapyramidal reactions and exacerbate the symptoms of Parkinson's disease. Likewise, patients with a major psychotic disorder should ordinarily not be treated with dopaminergic drugs because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone.

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MONITOR: Coadministration of levodopa with tricyclic antidepressants may increase the risk of hypertension and dyskinesia. The mechanism of this interaction is not understood. There have been rare case reports of this interaction; however, causality was not established.

MANAGEMENT: Until more information is available, it may be prudent to monitor patients for hypertension and dyskinesia if levodopa is coadministered with tricyclic antidepressants. Patients may be advised to report changes in blood pressure and new or worsened involuntary movement.

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MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: When catechol-O-methyltransferase (COMT) inhibitors are administered together with levodopa/carbidopa, they may increase the relative bioavailability (AUC) of levodopa. This is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). Adverse effects such as dyskinesia, somnolence, and orthostatic hypotension may be potentiated. In the presence of the decarboxylase inhibitor carbidopa, COMT is the major metabolizing enzyme for levodopa. In clinical trials of COMT inhibitors administered concomitantly with levodopa, patients required a dosage reduction in levodopa if their daily dose of levodopa was greater than 600 mg with tolcapone or 800 mg with entacapone, or if they had moderate or severe dyskinesia before beginning COMT inhibitor treatment. In patients receiving once daily opicapone at bedtime with levodopa/carbidopa administered every three or four hours, levodopa peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 43% to 44% and 62% to 94%, respectively, compared to administration of levodopa/carbidopa alone.

MANAGEMENT: Although COMT inhibitors are intended for use with levodopa/carbidopa, clinicians should be aware that dose reduction of levodopa may be necessary during coadministration. This is especially true if the patient is experiencing dyskinesia induced by levodopa. Use with caution in patients with severe dyskinesia or dystonia. Likewise, when discontinuing a COMT inhibitor, monitor patients and consider adjustment of other dopaminergic therapies as needed. In addition, some authorities advise that opicapone should be administered as a once-daily dose at least one hour before or after combinations containing levodopa so as to avoid any interaction with the absorption of levodopa (AU, UK).

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