Drug Interactions between Auvelity and linezolid

CONTRAINDICATED: Coadministration of linezolid with serotonergic agents may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Linezolid is a reversible, nonselective monoamine oxidase inhibitor (MAOI). As such, it can enhance serotonergic effects by inhibiting serotonin metabolism. Rare cases of serotonin syndrome have been reported in association with linezolid use, most often in combination with serotonin reuptake inhibitors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: Concomitant use of linezolid and serotonergic agents should be avoided unless no alternatives exist and close monitoring for the development of serotonin syndrome can be provided. In general, most serotonergic psychiatric drugs should be stopped 1 to 2 weeks (i.e., 4 to 5 half-lives) prior to treatment with an MAOI, while others such as fluoxetine may require discontinuation up to 5 weeks in advance due to its prolonged half-life. Treatment with serotonergic medications may be resumed 24 hours after the last dose of linezolid. In emergency situations that may necessitate urgent treatment with linezolid (e.g., vancomycin-resistant Enterococcus faecium (VRE) infections; nosocomial pneumonia and complicated skin and skin structure infections, including cases caused by methicillin-resistant Staphylococcus aureus), the availability of alternative interventions should be considered and the benefit of linezolid treatment should be weighed against the risk of serotonin toxicity. If the decision is made to administer linezolid to a patient receiving a serotonergic drug, the serotonergic drug must be immediately stopped, and the patient closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks if fluoxetine was taken; three weeks if vortioxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Patients and/or their caregivers should be advised to seek medical attention if potential symptoms of serotonin syndrome develop. The product labeling for the concomitant medication(s) should be consulted for more specific recommendations.

CONTRAINDICATED: Coadministration of dextromethorphan with linezolid may increase the risk of serotonin syndrome, a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Dextromethorphan is a weak serotonin reuptake inhibitor whose serotonergic activity may be enhanced by monoamine oxidase inhibitors (MAOIs). Serious and fatal reactions have been reported, primarily with the antidepressant MAOIs. The risk should be lower with linezolid, a relatively weak, reversible MAOI. When linezolid (600 mg orally every 12 hours for 6 days) and dextromethorphan (20 mg orally twice, 4 hours apart, on days 4 and 6 of linezolid administration) were given to 14 healthy volunteers, no changes in mental status (sedation, performance testing) or autonomic function (blood pressure, heart rate, body temperature) were observed relative to administration of either linezolid or dextromethorphan alone. The conversion of dextromethorphan to its primary metabolite was reduced by linezolid, as evidenced by an approximately 30% decrease in dextrorphan peak plasma concentration (Cmax) and systemic exposure (AUC) during coadministration, but clinical significance is unknown. The investigators concluded that linezolid may be prescribed with dextromethorphan without restrictions. There have been no published reports of serotonin syndrome with the concomitant use of dextromethorphan and linezolid, although known cases have been associated individually with each during coadministration with other serotonergic agents. The British labeling for linezolid describes a postmarketing report of a patient experiencing serotonin syndrome-like effects during concurrent use of dextromethorphan that resolved upon discontinuation of both drugs.

MANAGEMENT: Due to the risk of serotonin syndrome, concomitant use of dextromethorphan with MAOIs is considered contraindicated by manufacturers of dextromethorphan-containing products. If coadministration with linezolid is required, patients should be monitored for the development of serotonin syndrome. Symptoms may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

ADJUST DOSE: Coadministration with bupropion may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6 (e.g., selective serotonin reuptake inhibitors; tricyclic antidepressants; some beta blockers, antiarrhythmics, and antipsychotics). The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by bupropion. Approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent are extensive metabolizers of CYP450 2D6 and may be affected by this interaction. In a study of 15 male volunteers who were extensive metabolizers of CYP450 2D6, administration of a single 50 mg dose of desipramine following treatment with bupropion 150 mg twice daily increased the desipramine peak plasma concentration (Cmax), systemic exposure (AUC) and half-life by an average of 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. A case report describes a 4-fold increase in plasma levels of imipramine and its metabolite, desipramine, in a 64-year-old woman following the addition of bupropion 225 mg/day. Plasma levels of desipramine were increased twofold more than the imipramine levels, which is consistent with the fact that desipramine is primarily metabolized by CYP450 2D6 while imipramine is also metabolized by other CYP450 isoenzymes. In another report, an 83-year-old woman became unsteady, confused, and lethargic following the addition of bupropion SR 300 mg/day. Her nortriptyline level was found to have increased by 185%. A later rechallenge prompted recurrence of the interaction. Likewise, a 62-year-old woman with no history of seizures developed a generalized tonic-clonic seizure in association with toxic trimipramine plasma levels following the addition of bupropion 300 mg/day. No further seizures occurred following dosage reductions of both drugs.

MANAGEMENT: Caution is advised if bupropion must be used concomitantly with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Concomitant medications should be initiated at the lower end of the dose range. Clinical and laboratory monitoring may be appropriate for some drugs whenever bupropion is added to or withdrawn from therapy.