OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Tasimelteon – Hetlioz®

DRUG CLASS

Sedatives and Hypnotics

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Tasimelteon	609799-22-6	C15-H19-N-O2

ANNOTATED BIBLIOGRAPHY

References updated: 20 August 2020

• Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 731-4.

  (Expert review of hepatotoxicity published in 1999; melatonin, ramelteon and tasimelteon are not discussed).
• Larrey D, Ripault MP. Anxiolytic agents. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 455-6.

  (Review of hepatotoxicity of hypnotics and sedatives discusses benzodiazepines, buspirone and valerian, all of which have been linked to rare cases of liver injury; melatonin, ramelteon and tasimelteon are not discussed).
• Mihic SJ, Mayfield J, Harris RA. Hypnotics and sedatives. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 339-53.

  (Textbook of pharmacology and therapeutics).
• Penev PD, Zee PC. Melatonin: a clinical perspective. Ann Neurol. 1997;42:545–53. [PubMed: 9382465]

  (Discussion of physiological functions of melatonin and potential clinical uses).
• Seabra ML, Bignotto M, Pinto LR Jr, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29:193–200. [PubMed: 11068941]

  (Controlled trial of melatonin [10 mg daily] vs placebo for 28 days in 40 volunteers found no changes or abnormalities of serum bilirubin, ALT, AST or Alk P during the 4 weeks of treatment).
• Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ. 2006;332:385–93. [PMC free article: PMC1370968] [PubMed: 16473858]

  (Systematic review of literature on efficacy and safety of melatonin for sleep disorders; in 9 randomized controlled trials there was no overall evidence of benefit; in 10 studies evaluating safety there was no evidence of adverse effects occurring more often than with placebo, with use limited to 3 months).
• Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep. 2009;32:351–60. [PMC free article: PMC2647789] [PubMed: 19294955]

  (Controlled trial of 6 month course of ramelteon vs. placebo in 451 adults with primary chronic insomnia; adverse effects were similar between the two groups; no mention of ALT levels).
• Rajaratnam SM, Polymeropoulos MH, Fisher DM, Roth T, Scott C, Birznieks G, Klerman EB. Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet. 2009;373(9662):482–91. [PubMed: 19054552]

  (Controlled trial of 3 doses of tasimelteon vs placebo in 411 patients with transient insomnia found improvements in time to sleep latency and total sleep time, while the “frequency and severity of adverse events were similar across treatment groups”).
• Morris CJ, Aeschbach D, Scheer FA. Circadian system, sleep and endocrinology. Mol Cell Endocrinol. 2012;349:91–104. [PMC free article: PMC3242827] [PubMed: 21939733]

  (Review of the biologic basis of circadian rhythm including the role of melatonin).
• Johnsa JD, Neville MW. Tasimelteon: a melatonin receptor agonist for non-24-hour sleep-wake disorder. Ann Pharmacother. 2014;48:1636–41. [PubMed: 25204464]

  (Systematic review of published literature on use of tasimelteon mentions that the most common adverse event was headache [<10%] and that “fewer [1% to 10%] patients experienced: increased alanine transaminase…”).
• Tasimelteon (Hetlioz) for non-24-hour sleep-wake disorder. Med Lett Drugs Ther. 2014;56(1441):34–5. [PubMed: 24759294]

  (Concise review of the efficacy, safety and cost of tasimelteon shortly after its approval for use in the US mentions that the most common adverse events are headache [17%], elevated aminotransferase levels [10%], and nightmares or unusual dreams [10%]).
• Leger D, Quera-Salva MA, Vecchierini MF, Ogrizek P, Perry CA, Dressman MA. Safety profile of tasimelteon, a melatonin MT1 and MT2 receptor agonist: pooled safety analyses from six clinical studies. Expert Opin Drug Saf. 2015;14:1673–85. [PubMed: 26393492]

  (In a combined analysis of 2 open label and 4 controlled trials of tasimelteon with a total of 259 patient years of exposure, common adverse events included headache [15%], ALT elevations [6.5%] and abnormal dreams [5.5%], but none led to premature discontinuation; 15 ALT elevations above 3 times ULN [2 were above 5 but none were above 10 times ULN], none were associated with jaundice or symptoms, and all except one were a single elevated value, the exception being a patient with pre-existing mild elevations).
• Lockley SW, Dressman MA, Licamele L, Xiao C, Fisher DM, Flynn-Evans EE, Hull JT, et al. Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials. Lancet. 2015;386(10005):1754–64. [PubMed: 26466871]

  (Among 84 totally blind individuals treated with tasimelteon or placebo 1 hour before bedtime for 26 weeks, clinical responses occurred in 24% vs none and adverse events included headache [17% vs 7%], elevated liver enzymes [10% vs 5%] and abnormal dreams [10% vs none], but there were no deaths and no serious adverse events that were considered related to tasimelteon).
• Advice for travelers. Med Lett Drugs Ther. 2019;61(1582):153–60. [PubMed: 31599872]

  (Advice for travelers mentions drugs for jet lag including zolpidem, melatonin, ramelteon and tasimelteon, but does not discuss adverse side effects).
• Polymeropoulos CM, Mohrman MA, Keefe MS, Brzezynski JL, Wang J, Prokosch LS, Polymeropoulos VM, et al. Efficacy of tasimelteon (HETLIOZ®) in the treatment of jet lag disorder evaluated in an 8-h phase advance model; a multicenter, randomized, double-blind, placebo-controlled trial. Front Neurol. 2020;11:611. [PMC free article: PMC7381312] [PubMed: 32754110]

  (Among 320 healthy travelers treated with tasimelteon or placebo in a single dose before an 8 hour phase activated bedtime, sleep time increased by an average of 60 minutes and decreased next-day sleepness; the only adverse event reported being headache [5% vs 2.5%]).