unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.lonapegsomatropinMonitor Closely (1)lonapegsomatropin will decrease the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. Caution with sensitive CYP substrateslopinavirMonitor Closely (1)lopinavir will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.lorlatinibMonitor Closely (1)lorlatinib will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.methoxsalenMonitor Closely (1)methoxsalen will increase the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Avoid coadministration; potentially large increase in tasimelteon exposure and greater risk of adverse reactions with strong CYP1A2 inhibitorsmetoclopramide intranasalSerious - Use Alternative (1)tasimelteon, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.mexiletineMonitor Closely (1)mexiletine will increase the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Avoid coadministration; potentially large increase in tasimelteon exposure and greater risk of adverse reactions with strong CYP1A2 inhibitorsmidazolam intranasalMonitor Closely (1)midazolam intranasal, tasimelteon. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.mifepristoneMonitor Closely (1)mifepristone will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.mitotaneMonitor Closely (1)mitotane will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersnefazodoneMonitor Closely (1)nefazodone will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.nelfinavirMonitor Closely (1)nelfinavir will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.nevirapineMonitor Closely (1)nevirapine will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersnicardipineMonitor Closely (1)nicardipine will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.ofloxacinMonitor Closely (1)ofloxacin will increase the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Avoid coadministration; potentially large increase in tasimelteon exposure and greater risk of adverse reactions with strong CYP1A2 inhibitorsoliceridineMonitor Closely (1)oliceridine, tasimelteon. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.olopatadine intranasalSerious - Use Alternative (1)tasimelteon and olopatadine intranasal both increase sedation. Avoid or Use Alternate Drug. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment. oxcarbazepineMonitor Closely (1)oxcarbazepine will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersoxycodoneSerious - Use Alternative (1)tasimelteon and oxycodone both increase sedation. Avoid or Use Alternate Drug. Additive CNS depression may lead to hypotension, profound sedation, respiratory depression, or comapentobarbitalMonitor Closely (1)pentobarbital will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersphenobarbitalMonitor Closely (1)phenobarbital will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersphenytoinMonitor Closely (1)phenytoin will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersposaconazoleMonitor Closely (1)posaconazole will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.pregabalinMonitor Closely (1)pregabalin, tasimelteon. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.primaquineMonitor Closely (1)primaquine will increase the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Avoid coadministration; potentially large increase in tasimelteon exposure and greater risk of adverse reactions with strong CYP1A2 inhibitorsprimidoneMonitor Closely (1)primidone will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersquinidineMonitor Closely (1)quinidine will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.remimazolamMonitor Closely (1)remimazolam, tasimelteon. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.ribociclibMinor (1)ribociclib will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.rifabutinMonitor Closely (1)rifabutin will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersrifampinMonitor Closely (1)rifampin will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersrifapentineMonitor Closely (1)rifapentine will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducersritlecitinibMonitor Closely (1)ritlecitinib will increase the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Ritlecitinib inhibits CYP1A2 substrates; coadministration increases AUC and peak plasma concentration sensitive substrates, which may increase risk of adverse reactions. Additional monitoring and dosage adjustment may be needed in accordance with product labeling of CYP1A2 substrates. ritonavirMonitor Closely (1)ritonavir will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.rucaparibMonitor Closely (1)rucaparib will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.saquinavirMonitor Closely (1)saquinavir will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.secobarbitalSerious - Use Alternative (1)secobarbital will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.selinexorSerious - Use Alternative (1)selinexor, tasimelteon. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.somapacitanMonitor Closely (1)somapacitan will decrease the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. Caution with sensitive CYP substratessomatrogonMonitor Closely (1)somatrogon will decrease the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. Caution with sensitive CYP substratessomatropinMonitor Closely (1)somatropin will decrease the level or effect of tasimelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. Caution with sensitive CYP substratesstiripentolMonitor Closely (3)stiripentol, tasimelteon. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence. stiripentol, tasimelteon. affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP1A2 inhibitor and inducer. Monitor CYP1A2 substrates coadministered with stiripentol for increased or decreased effects. CYP1A2 substrates may require dosage adjustment. stiripentol, tasimelteon. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.sufentanil SLSerious - Use Alternative (1)sufentanil SL, tasimelteon. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration may result in hypotension, profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.tazemetostatMonitor Closely (1)tazemetostat will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tecovirimatMonitor Closely (1)tecovirimat will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.tipranavirMonitor Closely (1)tipranavir will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tucatinibSerious - Use Alternative (1)tucatinib will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.valerianSerious - Use Alternative (1)valerian and tasimelteon both increase sedation. Avoid or Use Alternate Drug.voriconazoleMonitor Closely (1)voriconazole will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid. >10% Headache (17%) 1-10% Increased ALT (10%) Nightmares/abnormal dreams (10%) Upper respiratory infections (7%) Urinary tract infections (7%) Postmarketing Reports Nighttime Sleep Disturbances in Smith-Magenis Syndrome (SMS) Contraindications None Cautions After administration, advise patients to limit activity to prepare for going to bed May potentially impair performance of activities requiring complete mental alertness Drug interaction overview Tasimelteon is a CYP3A4 and CYP1A2 substrate Smokers Smoking is a moderate CYP1A2 inducer Tasimelteon exposure decreased by ~40% in smokers compared with nonsmokers Strong CYP1A2 Inhibitors Avoid coadministration Fluvoxamine or other strong CYP1A2 inhibitors may potentially increase tasimelteon exposure and increase risk of adverse reactions Strong CYP3A4 inducers Avoid coadministration Rifampin or other CYP3A4 inducers may potentially decrease tasimelteon exposure and reduced efficacy Beta-adrenergic receptor antagonists Beta-adrenergic receptor antagonists have been shown to reduce production of melatonin via specific inhibition of beta-1 adrenergic receptors Nighttime administration of beta-adrenergic receptor antagonists may reduce tasimelteon efficacy Pregnancy Available postmarketing case reports use in pregnant females are not sufficient to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes Animal data In pregnant rats, no embryofetal developmental toxicity was observed at exposures of 50 mg/kg/day, or up to 24x higher than the human exposure at the maximum recommended human dose Lactation No data available on drug presence or its metabolites in human or animal milk, effects on breastfed infants, effects on milk productionPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Melatonin receptor agonist with high affinity for MT1 and MT2 receptors in the suprachiasmatic nucleus of the brain; MT1 and MT2 are thought to synchronize the body's melatonin and cortisol circadian rhythms with the day-night cycle in patients with non-24-hour disorder Absorption Peak plasma concentration: 0.5-3 hr (fasting) When administered with a high-fat meal, peak plasma concentration was 44% lower than when given in a fasted state, and the median peak concentration was delayed by approximately 1.75 hr Oral bioavailability: 38.3% Distribution Protein bound: 96% Vd: 59-126 L Metabolism Extensively metabolized primarily by oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid CYP1A2 and CYP3A4 are the major isozymes involved Phenolic glucuronidation is the major phase II metabolic route Major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon Elimination Half-life: 1.3 hr; 1.3-3.7 hr (metabolites) Excretion: 80% urine (<1%