AHFS Class:

• Melatonin Receptor Agonists 28:24.48

Generic Name(s):

• Tasimelteon

Tasimelteon is a melatonin receptor agonist and circadian rhythm regulator.1,3,5,15

Non-24-Hour Sleep-Wake Disorder

Tasimelteon is used for the treatment of non-24-hour sleep-wake disorder in adults.1 Tasimelteon has been designated an orphan drug by the FDA for this use.13

Non-24-hour sleep-wake disorder (non-24), also known as free-running or nonentrained rhythm disorder, is a chronic circadian rhythm sleep-wake disorder in which an individual's endogenous circadian rhythm is not synchronized, or entrained, to the 24-hour environment.6,7,8,9 Although non-24-hour sleep-wake disorder can occur in both sighted and blind individuals, it occurs most often in blind individuals who have decreased or no light perception, with an estimated prevalence of 50% or more in blind individuals.2,6,7,9 Circadian rhythm is controlled by the suprachiasmatic nucleus (SCN) in the hypothalamus, which regulates melatonin secretion by the pineal gland.6,9,10,11 The endogenous circadian cycle in humans is, on average, slightly longer than 24 hours and requires entrainment, or synchronization, to the 24-hour day by environmental cues (e.g., light and dark).6,8,9 In sighted individuals, light signals from retinal photoreceptors in the eye are conveyed directly to the SCN and play an important role in melatonin release and circadian entrainment.6,9,10 In addition to promoting sleep, melatonin plays a role in circadian entrainment of the SCN.9,10,11 In blind individuals without light perception, circadian rhythm is not entrained by light cues and continuously drifts out of phase with the 24-hour clock.6,7,8,9,10 Non-24-hour sleep-wake disorder affects many physiologic functions, but the most common signs and symptoms include periods of nighttime insomnia and/or excessive daytime sleepiness that alternate with asymptomatic periods, difficulty concentrating and performing everyday functions, and social isolation.2,6,7,8,9,10

Efficacy and safety of tasimelteon in the treatment of non-24-hour sleep-wake disorder have been established in 2 multicenter, randomized, double-blind, placebo-controlled studies of up to 6 months' duration in a total of 104 totally blind patients with the disorder.1,2,3,4 Because symptoms of insomnia and daytime sleepiness are dependent on circadian phase misalignment and occur cyclically in patients with non-24-hour sleep-wake disorder, efficacy end points in both studies were the change in total nighttime sleep duration for the 25% of nights with the least nighttime sleep (lower quartile of nighttime total sleep time [LQ-nTST]) and the change in daytime nap duration for the 25% of days with the most daytime nap time (upper quartile of daytime total sleep duration [UQ-dTSD]).1,2 The duration and timing of nighttime sleep and daytime naps were reported by patients twice daily using an electronic interactive voice recording system.1,2,3,4

In the Safety and Efficacy of Tasimelteon (SET) study, 84 patients with non-24-hour sleep-wake disorder (median age: 54 years) were randomized to receive either tasimelteon 20 mg or placebo one hour prior to bedtime, at the same time every night, for up to 6 months.1,2,3 For the LQ-nTST, tasimelteon increased nighttime sleep time by 50 minutes compared with 22 minutes with placebo.1,2,3 For the UQ-dTSD, tasimelteon reduced daytime nap duration by 49 minutes compared with a 22-minute reduction with placebo.1,2,3 Clinical response (i.e., at least 45 minutes increase in nighttime sleep and at least 45 minutes decrease in daytime nap time) was achieved in 29% of patients treated with tasimelteon and 12% of patients receiving placebo.1,2

The Randomized-withdrawal Study of the Efficacy and Safety of Tasimelteon to treat non-24 (RESET) was a withdrawal trial primarily designed to evaluate the maintenance efficacy of tasimelteon after 12 weeks.1,2,4 In this study, 20 totally blind patients with non-24-hour sleep-wake disorder (median age: 55 years) were treated with tasimelteon 20 mg one hour prior to bedtime, at the same time every night, for approximately 12 weeks, and then randomized to either continue tasimelteon or be switched to placebo for 8 weeks.1,2,4 Like the SET study, the RESET study demonstrated the efficacy and safety of tasimelteon in the treatment of non-24-hour sleep-wake disorder, with significant improvements observed in the study end points (i.e., increased nighttime sleep time and decreased daytime nap duration).1,2,4 For the LQ-nTST, nighttime sleep time was 74 minutes less in patients switched from tasimelteon to placebo compared with 7 minutes less in patients who continued to receive tasimelteon therapy.1,2 For the UQ-dTSD, daytime nap duration decreased by 9 minutes in patients continuing tasimelteon compared with an increase of 50 minutes with placebo.1,2 These results demonstrated that chronic therapy with tasimelteon is necessary for continued efficacy in patients with non-24-hour sleep-wake disorder.2,4

Because of individual differences in circadian rhythms, the manufacturer states that the therapeutic effect of tasimelteon may not occur for weeks or months.1

Tasimelteon is only labeled for the treatment of non-24-hour sleep-wake disorder in the US.1,15 Ramelteon, which also is a melatonin receptor agonist, is labeled for the treatment of insomnia in the US.15 Melatonin (which is available as a dietary supplement and promoted as a sleep aid in the US) has been used in blind patients to entrain circadian rhythms in patients with non-24-hour sleep-wake disorder;5,8 however, efficacy and safety of melatonin have not been systematically evaluated in randomized controlled trials and an optimal dosage has not been established.2,6,8

General

Restricted Distribution

Tasimelteon can only be obtained through a specialty pharmacy.14 Patients and clinicians may contact the manufacturer (Vanda) by telephone at 844-438-5469 or consult the Hetlioz^® website for specific availability information ([Web]).14

Administration

Tasimelteon is administered orally before bedtime, without food, at the same time every night.1 The capsules should be swallowed whole.1 Administration of tasimelteon with food may result in lower drug concentrations and reduced efficacy.1 (See Description.)

After taking tasimelteon, patients should limit their activities to preparing for going to bed.1 (See Somnolence under Cautions: Warnings/Precautions and also see Advice to Patients.)

Dosage

The recommended adult dosage of tasimelteon for the treatment of non-24-hour sleep-wake disorder is 20 mg once daily taken before bedtime, at the same time every night.1

Because of individual differences in circadian rhythms, tasimelteon's therapeutic effect in patients with non-24-hour sleep-wake disorder may not occur for weeks or months.1

If a dose of tasimelteon is missed, the dose should be skipped; the next dose should be taken at the regularly scheduled time.1 (See Advice to Patients.)

Special Populations

Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment.1 Tasimelteon has not been studied in patients with severe hepatic impairment (Child-Pugh class C), and is not recommended for use in such patients.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in patients with renal impairment.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in geriatric patients;5 however, such patients may be more likely to experience adverse effects.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

The manufacturer states there are no known contraindications to the use of tasimelteon.1

Warnings/Precautions

Somnolence

Tasimelteon may impair the performance of activities requiring complete mental alertness.1 After taking tasimelteon, patients should therefore limit their activities to preparing for going to bed.1

Abuse Potential and Dependence

In animal behavioral studies, tasimelteon did not produce any abuse-related signals.1 Rats did not self-administer tasimelteon, suggesting that the drug does not possess rewarding properties.1 In addition, no signs or symptoms indicative of abuse potential were observed in clinical studies with the drug.1

Discontinuance of tasimelteon following chronic administration did not produce withdrawal signs.1 The drug does not appear to produce physical dependence.1

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Lactation

It is not known whether tasimelteon is distributed into human milk.1 Because many drugs are distributed into human milk, caution should be exercised when tasimelteon is administered in nursing women.1

Pediatric Use

Safety and effectiveness of tasimelteon have not been established in pediatric patients.1

Geriatric Use

In a single-dose pharmacokinetic study, individuals greater than 65 years of age had an approximately twofold increase in drug exposure compared with younger adults.1,2,5 Therefore, the risk of adverse effects with tasimelteon may be greater in geriatric patients than younger patients.1 However, dosage adjustment is not necessary in geriatric patients.1,5

Hepatic Impairment

In a single-dose pharmacokinetic study, tasimelteon exposure was increased less than twofold in individuals with moderate hepatic impairment; therefore, no dosage adjustment is necessary in patients with mild or moderate hepatic impairment.1 Tasimelteon has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and is not recommended for use in such patients.1

Renal Impairment

Results of a single-dose pharmacokinetic study showed no apparent relationship between oral clearance of tasimelteon and renal function.1 Therefore, dosage adjustment is not necessary in patients with renal impairment.1

Tasimelteon and the majority of its principal metabolites are cleared by hemodialysis.1

Common Adverse Effects

Adverse effects reported in more than 5% of patients with non-24-hour sleep-wake disorder receiving tasimelteon and with an incidence at least twice that reported with placebo in the SET study include headache,1 increased ALT concentrations,1 nightmares or abnormal dreams,1 upper respiratory tract infection,1 and urinary tract infection.1

Tasimelteon is extensively metabolized, principally by cytochrome P-450 (CYP) isoenzymes 1A2 and 3A4.1 Other than CYP1A2- and CYP3A4-mediated drug interactions, in vitro and in vivo studies suggest that tasimelteon is unlikely to be involved in clinically important pharmacokinetic drug interactions.1

Drugs Affecting Hepatic Microsomal Enzymes

Fluvoxamine and Other Potent CYP1A2 Inhibitors

Because of the potential for a large increase in tasimelteon exposure and a greater risk of adverse effects, concomitant use of tasimelteon and potent CYP1A2 inhibitors (e.g., fluvoxamine) should be avoided.1

The area under the concentration-time curve (AUC) and peak plasma concentrations of tasimelteon increased by sevenfold and twofold, respectively, when administered concurrently with fluvoxamine (50 mg daily).1,2,5

Ketoconazole and Other CYP3A4 Inhibitors

Concomitant administration of ketoconazole (400 mg daily for 5 days), a potent CYP3A4 inhibitor, increased the AUC and peak plasma concentrations of tasimelteon by 53 and 33%, respectively, in one study.1,5 The manufacturer states that dosage adjustment is not necessary when tasimelteon is administered with CYP3A4 inhibitors.5

Rifampin and Other CYP3A4 Inducers

Because of the potential for a large decrease in tasimelteon exposure and reduced efficacy, concomitant use of tasimelteon and CYP3A4 inducers (e.g., rifampin) should be avoided.1

Concomitant administration of tasimelteon and rifampin (600 mg daily for 11 days; a potent CYP3A4 inducer and moderate CYP2C19 inducer) decreased tasimelteon exposure by approximately 90% in one study.1,5

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4

No clinically important changes in midazolam (a CYP3A4 substrate) or 1-hydroxymethylmidazolam (its active metabolite) exposure occurred with daily administration of tasimelteon 20 mg for 14 days, suggesting that tasimelteon does not induce CYP3A4 at the usual recommended dosage.1,5

Substrates of CYP2C8

No clinically important changes in rosiglitazone (a CYP2C8 substrate) exposure occurred with concurrent daily administration of tasimelteon 20 mg for 16 days, suggesting that tasimelteon does not induce CYP2C8 at the usual recommended dosage.1,5

Beta-Adrenergic Blocking Agents

β-Adrenergic blocking agents (e.g., atenolol, metoprolol, propranolol) can markedly reduce endogenous melatonin secretion and cause insomnia and other sleep disturbances.10,12,17 The manufacturer cautions that the efficacy of tasimelteon may be reduced in patients with concomitant administration of β-adrenergic blocking agents.1

Alcohol

Concurrent administration of a single dose of tasimelteon and alcohol indicated a trend for a possible additive effect on some psychomotor tests.1 Administration of tasimelteon with alcohol also increased tasimelteon exposure by 10-25%.5

Smoking

Cigarette smoking moderately induces CYP1A2.1 Tasimelteon exposure was approximately 40% lower in smokers compared with nonsmokers.1 Therefore, the efficacy of the drug may be reduced in smokers.1

Description

Tasimelteon, a melatonin receptor agonist, is a circadian rhythm regulator.1,3,5,15 The precise mechanism of action by which tasimelteon exerts its therapeutic effect in non-24-hour sleep-wake disorder is not fully understood, but is thought to be related to the drug's ability to entrain or synchronize pathologic circadian rhythms to the 24-hour clock through its actions in the suprachiasmatic nucleus (SCN) of the hypothalamus.1,2 Tasimelteon is an agonist at melatonin MT₁ and MT₂ receptors, which are thought to be involved in the control of circadian rhythms.1,2,11 The drug demonstrates greater affinity for MT₂ receptors than MT₁ receptors.1,2

Following oral administration in the fasting state, peak tasimelteon concentrations are achieved in approximately 0.5-3 hours.1 Administration of tasimelteon with a high-fat meal decreases peak plasma concentrations by 44% and delays time to peak plasma concentrations by approximately 1.75 hours.1 (See Dosage and Administration: Administration.) Tasimelteon is approximately 90% bound to plasma proteins at therapeutic concentrations.1 The drug is extensively metabolized principally by oxidation at multiple sites and oxidative dealkylation, resulting in opening of the dihydrofuran ring followed by further oxidation to yield a carboxylic acid.1 Tasimelteon is metabolized principally by cytochrome P450 (CYP) isoenzymes 1A2 and 3A4.1 Glucuronide conjugation is the main phase II metabolic pathway.1 Following oral administration of radiolabeled tasimelteon, 80% of the dose is recovered in urine and approximately 4% in feces; less than 1% of the dose is excreted in urine as the parent drug.1 The mean elimination half-life of tasimelteon is approximately 1.3 hours.1 The principal active metabolites of the drug are 13-fold or less potent at melatonin receptors than the parent drug1 and have a mean elimination half-life ranging from 1.3-3.7 hours.1

Advice to Patients

Importance of instructing patients to take tasimelteon before bedtime, at the same time every night.1 Importance of advising patients to swallow tasimelteon capsules whole and to take the drug without food for better absorption.1

Importance of advising patients to skip the tasimelteon dose if they cannot take the drug at approximately the same time on any given night.1

Risk of somnolence.1 Importance of advising patients to limit their activities to preparing for going to bed after taking tasimelteon since the drug can potentially impair performance of activities requiring complete mental alertness, such as driving or operating machinery.1

Importance of informing patients that tasimelteon's therapeutic effect may not occur for weeks or months because of individual differences in circadian rhythms.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,16

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., fluvoxamine, rifampin) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,16

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Vanda Pharmaceuticals, Inc. Hetlioz® (tasimelteon) capsules prescribing information. Washington, DC; 2014 Jan.

2. Vanda Pharmaceuticals, Inc. Submission of clinical and economic data supporting formulary consideration of Hetlioz® (tasimelteon) capsules 20 mg. Washington, DC; 2014 Mar 7.

3. Lockley SW, Dressman MA, Xiao C, et al. Tasimelteon treatment entrains the circadian clock and demonstrates a clinically meaningful benefit in totally blind individuals with non-24-hour circadian rhythms. Poster presented at the Endocrine Society's 95th annual meeting; 2013 Jun 15-18; San Francisco, CA.

4. Lockley SW, Dressman MA, Xiao C, et al. RESET study demonstrates that tasimelteon maintains entrainment of melatonin and cortisol in totally blind individuals with non-24-hour circadian rhythms. Poster presented at the Endocrine Society's 95th annual meeting; 2013 Jun 15-18; San Francisco, CA.

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205677: Clinical pharmacology and biopharmaceutics review(s). From FDA website. Accessed 2014 Apr 24. [Web]

6. Lockley SW, Arendt J, Skene DJ. Visual impairment and circadian rhythm disorders. Dialogues Clin Neurosci . 2007; 9:301-14. [PubMed 17969867][PubMedCentral]

7. American Psychiatric Association. DSM-5: diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:361-422.

8. Sack RL, Brandes RW, Kendall AR et al. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med . 2000; 343:1070-7. [PubMed 11027741]

9. Zee PC, Attarian H, Videnovic A. Circadian rhythm abnormalities. Continuum (Minneap Minn) . 2013; 19:132-47. [PubMed 23385698][PubMedCentral]

10. Brown GM. Light, melatonin and the sleep-wake cycle. J Psychiatry Neurosci . 1994; 19:345-53. [PubMed 7803368][PubMedCentral]

11. Dubocovich ML. Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Med . 2007; 8 Suppl 3:34-42. [PubMed 18032103]

12. Stoschitzky K, Sakotnik A, Lercher P et al. Influence of beta-blockers on melatonin release. Eur J Clin Pharmacol . 1999; 55:111-5. [PubMed 10335905]

13. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2014 Apr 23. [Web]

14. Vanda Pharmaceuticals, Inc. HetliozSolutions^® prescription and service request form. Washington, DC. Accessed 2014 Apr 29. [Web]

15. Anon. Tasimelteon (Hetlioz) for non-24-hour sleep-wake disorder. Med Lett Drugs Ther . 2014; 56:34-5. [PubMed 24759294]

16. Vanda Pharmaceuticals, Inc. Here's important safety information for Hetlioz^® (tasimelteon). Washington, DC. Accessed 2014 Aug 25. [Web]

17. Novartis. Lopressor^® (metoprolol tartrate) tablets and injection prescribing information. East Hanover, NJ; 2013 Mar.