Drug Interactions between Endep and lorcaserin

MONITOR CLOSELY: Concomitant use of lorcaserin with agents that possess or enhance serotonergic activity such as selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), 5-HT1 receptor agonists (triptans), ergot alkaloids, phenylpiperidine opioids, bupropion, dextromethorphan, linezolid, lithium, St. John's wort, tramadol, and tryptophan 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. Although lorcaserin is primarily a serotonin 2C receptor agonist, the safety of concomitant use with other serotonergic agents has not been established. In lorcaserin clinical trials, patients receiving SSRIs, SNRIs, MAOIs, TCAs and bupropion were excluded, but use of triptans and dextromethorphan was permitted. According to the manufacturer, exposure to triptans and dextromethorphan occurred in 2% and 15%, respectively, of patients without diabetes and 1% and 12%, respectively, of patients with type 2 diabetes. Two patients treated with lorcaserin experienced a constellation of signs and symptoms consistent with serotonergic excess, including one patient on concomitant dextromethorphan who reported an event of serotonin syndrome. Some symptoms of possible serotonergic etiology that are included in the criteria for serotonin syndrome were reported by patients treated with lorcaserin and placebo during clinical trials of at least one year duration. In both groups, chills were the most frequent of these events (1.0% vs. 0.2), followed by tremor (0.3% vs 0.2%), confusional state (0.2% vs. less than 0.1%), disorientation (0.1% vs. 0.1%), and hyperhidrosis (0.1% vs. 0.2%). Because serotonin syndrome has a very low incidence, an association with lorcaserin cannot be ruled out.

MONITOR CLOSELY: Coadministration with lorcaserin may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 2D6, including many antidepressants (e.g., SSRIs, TCAs, trazodone), dextromethorphan, and tramadol. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by lorcaserin. In a study consisting of 21 CYP450 2D6 extensive metabolizers, administration of the probe substrate dextromethorphan in combination with lorcaserin 10 mg twice daily for 4 days increased dextromethorphan peak concentrations (Cmax) by approximately 76% and systemic exposure (AUC) by approximately 2-fold. A dosage adjustment may be necessary for CYP450 2D6 substrates following the initiation or discontinuation of lorcaserin.

MANAGEMENT: Caution is advised if lorcaserin must be used in combination with other agents that affect the serotonergic neurotransmitter system. Patients should be closely monitored for symptoms of the 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, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea. Particular caution is advised when initiating or increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life. For example, a 5-week washout period is typically recommended following use of fluoxetine and 2 weeks following use of MAOIs before administering another serotonergic agent. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic 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). 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.