Drug Interactions between cimetidine and Limbitrol

MONITOR: Cimetidine may increase the serum concentration of tricyclic antidepressants (TCAs) to toxic levels in some patients. The mechanism may be related to inhibition of CYP450 isoenzymes, including CYP450 2D6 and CYP450 3A4, that are responsible for the hepatic metabolism of TCAs.

MANAGEMENT: Close monitoring for clinical response and tolerance is recommended whenever cimetidine is added to or discontinued from a TCA regimen. Patients should be advised to notify their physician if they experience excessive TCA effects such as dry mouth, blurry vision, irregular or fast heartbeat, constipation, urinary retention, dizziness, or orthostatic hypotension. Lower doses of tricyclic antidepressants may be necessary. Ranitidine, famotidine, and nizatidine are not expected to interact and may be an alternative to cimetidine in this circumstance.

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MONITOR: Administration of cimetidine with benzodiazepines may increase systemic exposure to benzodiazepines. The mechanism may be related to inhibition of CYP450 3A4 hepatic metabolism by cimetidine, a moderate inhibitor of this isoenzyme. This interaction has been reported for alprazolam, diazepam, triazolam, midazolam and chlordiazepoxide, but may also occur with other benzodiazepines. In one pharmacokinetic study, two groups of healthy subjects (n=8) were administered cimetidine (1 g daily) for 2 weeks, with the addition of either alprazolam (0.5 mg three times a day) or triazolam (0.5 mg nightly) during the second week of cimetidine administration. Concomitant administration with cimetidine led to statistically significant alterations in some of the pharmacokinetic parameters of the benzodiazepines. Alprazolam systemic exposure, (AUC [0 to infinity]) and Cmax increased by 73% and 82%, respectively, and clearance (L/h) decreased by 42%. Triazolam systemic exposure (AUC [0 to infinity]) and Cmax increased by 120% and 51%, respectively, half-life increased by 68%, and clearance (L/h) decreased by 55%. This interaction appears to be minimal with lorazepam, oxazepam, and temazepam. Ranitidine may increase or decrease benzodiazepine plasma levels; however, the effects are not expected to be clinically significant. This interaction has not been noted with other H2 antagonists.

MANAGEMENT: The US manufacturers of alprazolam, estazolam and triazolam recommend consideration of a dose reduction when these medicines are co-administered with cimetidine. The authors of the abovementioned pharmacokinetic study suggest either a reduction to the alprazolam dose by one-third or an increase to the dosage interval to twice daily when used concomitantly with cimetidine. Use of H2 antagonists and benzodiazepines that are not reported to interact may also be considered. Patients should be advised 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: 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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