Drug Interactions between Nuedexta and tedizolid

GENERALLY AVOID: Coadministration with potent CYP450 2D6 inhibitors (e.g., quinidine, terbinafine) may significantly increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Studies in humans have shown an increase in systemic exposure of dextromethorphan of up to 43-fold when given concurrently with quinidine. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. However, this interaction has also been used clinically, with dextromethorphan in combination with quinidine indicated by some authorities for the treatment of pseudobulbar affect. Data evaluating the impact of this interaction in patients who are poor metabolizers of CYP450 2D6 are limited; most studies include extensive metabolizers of this isoenzyme. It is expected that poor metabolizers would have elevated dextromethorphan levels without concurrent quinidine

MANAGEMENT: The combination of dextromethorphan with potent CYP450 2D6 inhibitors should be generally avoided. Some manufacturers consider the concomitant use of dextromethorphan and selective serotonin reuptake inhibitors contraindicated. If use is considered necessary, the patient should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.

MONITOR: The concurrent use of tedizolid with agents that have serotonergic activity including serotonin reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan may elevate the risk of developing serotonin syndrome. The proposed mechanism is tedizolid-mediated non-selective and reversible inhibition of monoamine oxidase (MAO), with more potent inhibition of MAO-A than linezolid in vitro. In a retrospective cohort study from January 2015 to July 2023 of 479 adult patients receiving tedizolid, 62% (297/479) received concomitant serotonergic agents, but suspected serotonin syndrome requiring tedizolid discontinuation was found to be rare, occurring in only 0.4% (2/479) of cases. Symptoms of serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, unstable blood pressure, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: Caution and closer monitoring for serotonin syndrome are recommended during concomitant treatment with tedizolid and serotonergic agents, especially during dose escalations, and patients should be instructed to notify their healthcare provider if they experience symptoms of serotonin syndrome. Due to variability and occasionally prolonged half-lives of these coadministered agents, consulting individual product labeling for specific guidance is advised. If serotonin syndrome is suspected, discontinuation of therapy or dose reductions should be considered depending on the severity of the symptoms, and supportive care should be provided. Moderately ill patients may benefit from serotonin antagonists like cyproheptadine or chlorpromazine. Severe cases require consultation with a toxicologist and may need sedation, neuromuscular paralysis, intubation, and mechanical ventilation.