Drug Interactions between buspirone and nefazodone

ADJUST DOSE: Coadministration with nefazodone may significantly increase the plasma concentrations and pharmacologic effects of buspirone. The mechanism is nefazodone inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of buspirone. In healthy volunteers, administration of buspirone (2.5 or 5 mg twice a day) in combination with nefazodone (250 mg twice a day) increased steady-state buspirone peak plasma concentration (Cmax) by up to 20-fold and systemic exposure (AUC) by up to 50-fold. Plasma concentrations of the pharmacologically active metabolite of buspirone decreased by approximately 50%. Subjects receiving the higher dosage of buspirone with nefazodone experienced lightheadedness, asthenia, dizziness, and somnolence, although these adverse events also occurred with either drug alone. Buspirone did not have significant effects on the pharmacokinetics of nefazodone. At the 5 mg twice a day dosage, the AUC of nefazodone increased by 23% and that of its metabolites hydroxynefazodone and meta-chlorophenylpiperazine increased by 17% and 9%, respectively. The Cmax of nefazodone and hydroxynefazodone increased by approximately 10% each.

MONITOR CLOSELY: Concomitant use of nefazodone and buspirone 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. The mechanism involves an additive or synergistic serotonergic effect due to inhibition of serotonin reuptake by nefazodone and activation of serotonin 5-HT1A receptors by buspirone. Serotonin syndrome has been reported with both nefazodone and buspirone in combination with other serotonergic agents.

MANAGEMENT: A lower initial dosage of buspirone (e.g., 2.5 mg/day) is recommended when used in combination with nefazodone. Patients should be closely monitored for the development of serotonin syndrome, which 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, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea. The onset of symptoms is usually rapid--often within a day but sometimes longer--following initiation or addition of a drug, a dosage change, or overdose. If serotonin syndrome develops or is suspected during the course of therapy, both agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine, olanzapine, methysergide). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.