Drug Interactions between aspirin / carisoprodol / codeine and mitotane

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.

MONITOR: Coadministration of codeine with potent or moderate CYP450 3A4 inducers may result in lower codeine plasma concentrations, higher levels of the inactive metabolite norcodeine, and less metabolism via CYP450 2D6, resulting in lower morphine levels. This interaction may lead to reduced codeine efficacy and potentially initiate the onset of withdrawal symptoms in patients who are physically dependent. In addition, patients may be at an increased risk of CNS and/or respiratory-depressant effects from increased levels of codeine once concomitant therapy with the CYP450 3A4 inducer is ceased. This is particularly worrisome if the CYP450 3A4 inducer also possesses CNS- and/or respiratory-depressant effects. This interaction has also been reported with dihydrocodeine.

MANAGEMENT: The potential loss of efficacy of codeine or dihydrocodeine and onset of opioid withdrawal symptoms should be considered when used in combination with a potent or moderate CYP450 3A4 inducer. Alternative agents with no or minimal CYP450 3A4 induction potential are recommended whenever possible. Some manufacturers of products containing codeine advise against the concomitant use of codeine with CYP450 3A4 inducers. If concomitant use is considered necessary, caution and close clinical and laboratory monitoring are recommended. Dosage adjustments may also be required whenever a CYP450 3A4 inducer is added to or withdrawn from therapy. Following discontinuation of a CYP450 3A4 inducer, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression.

MONITOR: Coadministration with alcohol or other central nervous system (CNS) depressants may enhance the sedative effects of mitotane and increase the likelihood and/or severity of central nervous system (CNS) side effects. In clinical studies and post marketing reports, CNS side effects occurred in 40% of patients, primarily consisting of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%). Mitotane plasma concentrations exceeding 20 mcg/mL are associated with a greater incidence of severe neurologic toxicity. Clinical data are not available for the concomitant use of mitotane with other CNS depressants.

MANAGEMENT: Caution and clinical monitoring for increased CNS adverse effects is advised if mitotane is coadministered with alcohol, other CNS depressants, or agents that cause dizziness or vertigo. Patients should not drive, operate machinery, or engage in hazardous activities requiring mental alertness and motor coordination until they know how the medications affect them. In addition, more frequent monitoring of serum mitotane levels may be considered.