Drug Interaction Report

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 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.

GENERALLY AVOID: In a small, randomized, crossover study, the administration of quinidine with grapefruit juice (compared to water) to healthy volunteers significantly prolonged the time to reach peak plasma quinidine concentrations and decreased the plasma concentrations of its major metabolite, 3-hydroxyquinidine. These changes were associated pharmacodynamically with both a delay and a reduction in the maximal effect on QTc interval. The proposed mechanism is delay of gastric emptying as well as inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits.

MANAGEMENT: Given the drug's narrow therapeutic index, patients receiving quinidine therapy should avoid the consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Food does not appear to significantly affect the absorption and oral bioavailability of lurasidone. In twelve adult volunteers (6 men and 6 women), administration of a single 10 mg oral dose of lorcaserin following a high-fat (approximately 50% of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal resulted in less than 10% increases in lorcaserin peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration in the fasted state. The time to reach peak concentration (Tmax) was delayed by approximately 1 hour in the fed state. Lorcaserin may be administered with or without food.