Drug Interactions between fluoxetine / olanzapine 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.

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

MONITOR: Lorcaserin is a serotonergic drug. Potentially life-threatening neuroleptic malignant syndrome (NMS)-like reactions have been reported during use of serotonergic drugs and antipsychotics or other dopamine antagonists. The safety of lorcaserin when coadministered with antidopaminergic agents has not been systematically evaluated and has not been established.

MONITOR: Lorcaserin can cause elevations in prolactin, which may be additive to the hyperprolactinemic effects of dopamine antagonists. In clinical trials of at least one year duration, elevations of prolactin greater than the upper limit of normal, two times the upper limit of normal, and five times the upper limit of normal occurred in 6.7%, 1.7%, and 0.1% of lorcaserin-treated patients, compared to 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively. One patient treated with lorcaserin developed a prolactinoma. Although elevated serum prolactin levels have been associated with reports of amenorrhea, galactorrhea, gynecomastia and impotence, the clinical significance of hyperprolactinemia is unknown for most patients. Long-standing hyperprolactinemia may lead to low levels of estrogen and increased risk of osteoporosis. In rodents, an increase in mammary neoplasms has been found after chronic administration of prolactin-stimulating neuroleptic drugs. However, clinical and epidemiologic studies conducted to date have not established a causal relationship.

MONITOR: Coadministration with lorcaserin may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 2D6, including many neuroleptic agents and phenothiazines. 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 when lorcaserin is prescribed in combination with antipsychotics or other antidopaminergic agents (e.g., droperidol, domperidone, metoclopramide, phenothiazines, tetrabenazine). Clinicians, caregivers, and family members should be apprised of the risk of neuroleptic malignant syndrome and be alert to potential signs and symptoms such as mental status changes (e.g., mutism, catatonia, stupor, coma, agitation, confusion, hallucinations, delusions), autonomic instability, restlessness, rigidity, ataxia, myoclonus, hyperreflexia, tremors, diaphoresis, elevated creatine phosphokinase levels, and hyperpyrexia. If NMS is suspected, treatment with these agents should be discontinued immediately and emergency medical attention sought. Prolactin levels should be measured when there are signs and symptoms of prolactin excess such as galactorrhea or gynecomastia. Consideration should be given to discontinuation of prolactin-stimulating drugs including lorcaserin.