Drug Interactions between Limbitrol DS and phenytoin

MONITOR: Tricyclic antidepressants may increase serum phenytoin levels. In vitro studies suggest the mechanism may involve inhibition of CYP450 2C19-catalyzed phenytoin p-hydroxylation by tricyclic antidepressants, especially imipramine and amitriptyline. Phenytoin may induce the hepatic metabolism of desipramine resulting in decreased plasma concentrations. In addition, tricyclic antidepressants may lower the seizure threshold.

MANAGEMENT: Clinical monitoring of patient response, tolerance, and serum phenytoin concentrations is recommended. Patients should be advised to notify their doctor if they experience loss of seizure control or symptoms of phenytoin toxicity (drowsiness, visual disturbances, change in mental status, nausea, or ataxia). Phenytoin dosage may need to be adjusted.

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MONITOR: Coadministration with some benzodiazepines may alter the serum concentrations of phenytoin. Both increases and decreases have been cited by case reports and pharmacokinetic studies, while a few reported no changes. The exact mechanism of interaction is unknown, and it is uncertain whether other hydantoins are also affected. Phenytoin toxicity has been reported in patients treated with various benzodiazepines, including clobazam, chlordiazepoxide, clonazepam, and diazepam. Conversely, phenytoin may reduce the plasma concentrations of some benzodiazepines by inducing their metabolism via hepatic microsomal enzymes. In one study, pretreatment with phenytoin (4.3 mg/kg/day for 19 days) increased the clearance of clonazepam (0.03 mg/kg single oral dose) by 46% to 58% and decreased its half-life by 31% in eight healthy volunteers. In another study, mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of midazolam (15 mg oral dose) in six epileptic patients treated concomitantly with phenytoin or carbamazepine were 7.4% and 5.7%, respectively, of those observed in seven control subjects who were not receiving enzyme inducers. The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects.

MANAGEMENT: Pharmacologic response and serum hydantoin levels should be monitored more closely whenever a benzodiazepine is added to or withdrawn from therapy, and the hydantoin dosage adjusted as necessary. Patients should be advised to contact their physician if they experience symptoms of hydantoin toxicity such as nausea, vomiting, tremors, ataxia, lethargy, slurred speech, visual disturbances, or changes in mental status. The potential for diminished or inadequate benzodiazepine effects should be considered during concomitant use with phenytoin.

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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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