Drug Interactions between armodafinil and aspirin / carisoprodol / 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: Coadministration with modafinil (the racemate) or armodafinil (the R-enantiomer) may increase the plasma concentrations of drugs that are primarily metabolized by the CYP450 2C19 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2C19 activity by modafinil and armodafinil. In pharmacokinetic studies, coadministration of a single 400 mg dose of armodafinil with omeprazole 40 mg increased systemic exposure to omeprazole by approximately 40%. A case report implicated modafinil in the development of clozapine toxicity characterized by dizziness, ataxia, and tachycardia. Clozapine serum levels increased from 761 ng/mL to 1400 ng/mL several weeks after initiation of modafinil therapy.

MANAGEMENT: Caution is advised if modafinil or armodafinil must be used concurrently with medications that undergo metabolism by CYP450 2C19, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever modafinil or armodafinil is added to or withdrawn from therapy.

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Coadministration with modafinil (the racemate) or armodafinil (the R-enantiomer) may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. Modafinil and armodafinil are modest inducers of CYP450 3A4, and pharmacokinetic studies suggest that their effects may be primarily intestinal rather than hepatic. Thus, clinically significant interactions would most likely be expected with drugs that have low oral bioavailability due to significant intestinal CYP450 3A4-mediated first-pass metabolism (e.g., buspirone, cyclosporine, lovastatin, midazolam, saquinavir, simvastatin, sirolimus, tacrolimus, triazolam, calcium channel blockers). However, the potential for interaction should be considered with any drug metabolized by CYP450 3A4, especially given the high degree of interpatient variability with respect to CYP450-mediated metabolism. Pharmacologic response to these drugs may be altered and should be monitored more closely whenever modafinil or armodafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.

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