Drug Interactions between cimetidine and Fiortal with Codeine

GENERALLY AVOID: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may result in profound sedation, respiratory depression, coma, and death. The risk of hypotension may also be increased with some CNS depressants (e.g., alcohol, benzodiazepines, phenothiazines).

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Cough medications containing opioids (e.g., codeine, hydrocodone) should not be prescribed to patients using benzodiazepines or other CNS depressants including alcohol. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

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MONITOR: Drugs that are inhibitors of CYP450 2D6 may interfere with the analgesic effect of codeine. The mechanism is decreased in vivo conversion of codeine to morphine, a metabolic reaction mediated by CYP450 2D6. If an inhibitor is started after a stable dose of codeine is achieved, reduced analgesia and possible opioid withdrawal may result. Conversely, ceasing CYP450 2D6 inhibitor therapy may lead to increased morphine levels, increasing the risk of opioid-related adverse effects.

MANAGEMENT: The possibility of reduced or inadequate pain relief should be considered in patients receiving codeine with drugs that inhibit CYP450 2D6. An increase in the codeine dosage or a different analgesic agent may be necessary in patients requiring therapy with CYP450 2D6 inhibitors. If concurrent therapy is used and the CYP450 2D6 inhibitor is stopped, the dose of codeine may need to be reduced and the patient should be monitored for signs and symptoms of respiratory depression or sedation. In addition, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may interfere with the analgesic effects of codeine for at least 28 days after administration of rolapitant. The manufacturer's prescribing information should be consulted for further information.

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Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

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One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

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Barbiturates may slightly reduce the bioavailability of cimetidine. Phenobarbital is the only barbiturate specifically implicated in this interaction. However, other barbiturates may behave in a similar fashion.

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