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Tasimelteon (Hetlioz™)

Number 5.01.552

Effective Date June 9, 2014

Revision Date(s) N/A

Replaces N/A

This policy is managed by the Pharmacy benefit.

Policy

Tasimelteon (Hetlioz™) may be considered medically necessary for treatment of non-24-hour sleep-wake disorder when ALL of the following conditions have been met:

  • Diagnosis of non-24-hour sleep-wake disorder by a sleep specialist, AND
  • Failure of an adequate trial of at least 3 months of ramelteon (Rozerem), AND
  • Documented evidence of objective response, after 6 months and annually thereafter.

Documentation of the diagnosis including appropriate sleep studies must be submitted with the request.

All other uses of Tasimelteon (Hetlioz™) are considered investigational.

Related Policies

5.01.605

Medical Necessity Criteria for Pharmacy Edits

Description

Non-24 hour sleep-wake disorder (also known as “non-24” or “free-running disorder”) is a severe, chronic, circadian sleep rhythm disorder (CSRD) characterized by the inability to entrain (synchronize) the master body clock to the 24-hour day. Patients with non-24 have prolonged periods of misalignment of circadian rhythms, including the timing of melatonin and cortisol secretion and the sleep-wake cycle, which are associated with significant impairments in social and occupational functioning, or marked subjective distress.

Most cases of non-24 occur in blind patients with no perception of light. As a result of light information failing to reach the suprachiasmatic nucleus (SCN) to synchronize the clock to the 24-hour light-dark cycle, the SCN reverts to an endogenous non-24-hour period. As a result, physiologic processes and behavior that are controlled by the circadian system (eg, the timing of melatonin and cortisol production, the core body temperature rhythm, metabolic processes, the sleep-wake cycle, and alertness and performance patterns) becomes desynchronized from the 24-hour day, which has consequences for daily functioning. Most blind individuals can perceive enough light to prevent non-24. Entrainment is a measure of synchronization of an individual’s intrinsic master clock (τ) to the 24-hour day. Most patients with non-24 have intrinsic clocks (τ) longer than 24.0 hours.

Epidemiology and Risk Factors

Most patients with non-24 are totally blind and without light perception. The estimated prevalence of non-24 in the totally blind is approximately 80,000 to 100,000 individuals in the U.S.

Clinical Presentation

Symptoms of non-24 include nighttime sleeplessness and daytime fatigue and sleepiness. Persons with non-24 may have comorbidities of depression or other mood disorders. Patients with non-24 may not experience the same degree of symptom severity.

Diagnosis

The International Classification of Sleep Disorders criteria for non-24 (780.55-2) include:

  • Primary complaint of either difficulty initiating sleep or difficulty in awakening.
  • Progressive delays of sleep onset and offset with the inability to maintain stable entrainment to a 24-hour sleep–wake pattern.
  • Presence of the sleep pattern for at least 6 weeks.
  • Evidence of a progressive sequential delay of the sleep period by polysomnography performed over several consecutive days on a fixed 24-hour bedtime and wake-time schedule, continuous 24-hour temperature monitoring over at least 5 days that shows a progressive delay of the temperature nadir, and the patient does not meet criteria for any other sleep disorder causing inability to initiate sleep or excessive sleepiness.

The American Academy for Sleep Medicine CSRD practice parameters recommend (based on consensus) sleep logs to determine sleep patterns and also recommend measurement of circadian phase markers (including the urinary biomarker 6-sulfatoxy-melatonin or aMT6s) to determine the circadian phase (τ) and confirm the diagnosis. Entrainment is a measure of synchronization of an individual’s intrinsic master clock (τ) to the 24-hour day. Entrainment can be measured by 2 distinct circadian rhythms: melatonin, (or aMT6s in urine), and cortisol. For aMT6s measurement, urine is collected every 4 hours (every 8 hours overnight) over a 48-hour period and the acrophase, or peak timing of analyte secretion, determined. Quartile-nighttime Total Sleep Time (LQ-nTST), Upper Quartile-daytime Total Sleep Duration (UQ-dTSD), Midpoint of Sleep Time (MoST), and Clinician Global Impression- Change (CGI-C) assessments. Q-nTST and UQ-dTSD correlate with the most symptomatic phases of circadian cycle (maximum misalignment), reflecting the 25% most symptomatic days of nighttime sleeplessness or daytime sleepiness, respectively. The CGI-C is a 7-point clinician-performed evaluation of global functioning ranging from 1 (very much improved) to 7 (very much worse). Each assessment on the scale is scored as a 1 or 0 depending on whether the prespecified threshold was achieved or not (Table 1). The score for each assessment is summarized with a range of 0 to 4.

Therapeutic Alternatives

There are no other FDA-approved treatments for non-24 in blind individuals without light perception; however, two other pharmacologic treatment options are available:

  • Another oral melatonin receptor agonist, ramelteon (Rozerem™, Takeda) was approved in 2005 for the treatment of insomnia characterized by difficulty with sleep onset in adult patients ≥18 years of age. There are no published trials or studies of ramelteon for non-24, nor are there any ongoing or completed trials listed at ClinicalTrials.gov, but the similarity in pharmacology suggests that ramelteon would be an effective and much lower cost option.
  • Melatonin, which is regulated as a dietary supplement in the U.S., has been used in the treatment of non-24 and is listed as a guideline-level recommendation in the 2007 American Academy of Sleep Medicine guidelines for the evaluation and treatment of CSRDs. This recommendation was based on several small studies. A 2004 review article cites several issues with using melatonin in the treatment of insomnia and CSRDs, including pharmacokinetic issues such as its short half-life and large first-pass metabolism, as well as nonspecific effect on melatonin subreceptors. However, they generally note the lack of large-scale clinical trials, partially owing to the fact that melatonin cannot be patented. Melatonin is approved as a drug in the EU and in Australia.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This policy does not apply to Medicare Advantage.

Benefit Application

N/A

Rationale

The Sponsor submitted to the FDA two randomized, placebo-controlled, double-masked, Phase III trials in support of the new drug application, SET (cited as “Study 1” in PI) and RESET (cited as “Study 2” in PI). SET was a multicenter, randomized, double-masked, placebo-controlled, parallel study designed to evaluate the efficacy and safety of tasimelteon 20 mg versus placebo in 84 totally blind patients with non-24. SET included a screening phase, a double-blind phase, and an open-label extension phase.

Patient inclusion criteria included:In the Sponsor analysis of the intention-to-treat population of SET, 20% of patients in the tasimelteon group entrained by aMT6s measurement at 1 month compared with 2.6% in the placebo group (p=0.017). There was also a statistically significant difference the step down primary end point of entrainment plus a greater than 3-point change in the N24CRS. The Sponsor analysis of RESET showed a higher rate of non-entrainment in patients who had previously been entrained in on tasimelteon and switched to placebo (80%) than in patients entrained on tasimelteon and maintained on the drug (10%, p=0.003).

In the FDA analysis of SET (cited as Study 1 in the package insert), patients in the tasimelteon group had, at baseline, an average 195 minutes of nighttime sleep and 137 minutes of daytime nap time on the 25% of most 10 symptomatic nights and days, respectively. Treatment with tasimelteon resulted in a significant improvement, compared with placebo, for both of these end points in both SET and RESET. A responder analysis of patients with both ≥45 minutes increase in nighttime sleep and ≥45 minutes decrease in daytime nap time was conducted in SET (Study 1): 29% (n=12) of patients treated with tasimelteon, compared with 12% (n=5) of patients treated with placebo met the responder criteria. There is no evidence to assess real world comparative effectiveness. No head-to-head studies vs. ramelteon or melatonin were performed.

Tasimelteon was generally well tolerated in SET and RESET. Adverse effects that occurred in at least 5% of patients in the tasimelteon group and at a two-fold higher rate than placebo were headache (17% vs. 7%), increased alanine aminotransferase (10% vs. 5%), nightmare/abnormal dreams (10% vs. 0%), upper respiratory tract infection (7% vs. 0%), and urinary tract infection (7% vs. 2%). There were no withdrawal symptoms, next day residual effect, or increase in suicidality observed in patients receiving tasimelteon.

References

  1. Vanda Pharmaceuticals. Tasimelteon. Advisory Committee Briefing Materials, November 14, 2013. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/p eripheralandcentralnervoussystemdrugsadvisorycommittee/ucm374388.pdf. Last accessed February 2014.
  2. U.S. Food and Drug AdministrationDivision of Neurology Products Center for Drug Evaluation and Research. FDA Slide Presentation. Tasimelteon. FDA Presentations for the November 14, 2013 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM376700.pdf. Last accessed February 2014.
  3. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. Briefing Materials. Tasimelteon (melatonin agonist). For the treatment of Non-24 hour sleepwake disorder in blind individuals without light perception. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/p%20eripheralandcentralnervoussystemdrugsadvisorycommittee/ucm374385.pdf.. Last accessed February 2014.
  4. Vanda Pharmaceuticals. Vanda Pharmaceuticals Slide Presentation. Tasimelteon. Presentations for the November 14, 2013 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM376701.pdf. Last accessed February 2014.
  5. Vanda Pharmaceuticals, Inc. Hetlioz (tasimelteon) capsules, for oral use, January 2014. Available at: http://www.hetlioz.com/Content/HetliozPI.pdf. Last accessed February 2014.
  6. Vanda Pharmaceuticals. A Multicenter, Randomized, Double-Mask, Placebo-Controlled, Parallel Study to Investigate the Efficacy and Safety of 20 mg Tasimelteon Versus Placebo in Totally Blind Subjects With N24HSWD Followed by an OLE Phase (SET). November 2012. Available at: http://clinicaltrials.gov/ct2/show/NCT01163032?term=tasimelteon&rank=3. Last accessed February 2014.
  7. Vanda Pharmaceuticals. A Randomized Withdrawal Study to Demonstrate the Maintenance of Effect of 20 mg Tasimelteon in the Treatment of N24HSWD (RESET). December 2012. Available at: http://clinicaltrials.gov/ct2/show/NCT01430754?term=tasimelteon&rank=12.
  8. Martinez D, Lenz Mdo C. Circadian rhythm sleep disorders. Indian J Med Res. Feb 2010;131:141-149. PMID 20308739
  9. Sack RL, Lewy AJ. Circadian rhythm sleep disorders: lessons from the blind. Sleep Med Rev. Jun 2001;5(3):189-206. PMID 1253098
  10. Hardeland R. Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders. Curr Opin Investig Drugs. Jul 2009;10(7):691-701. PMID 19579175
  11. Eisenstein M. Chronobiology: stepping out of time. Nature. May 23 2013;497(7450):S10- 12. PMID 23698500
  12. Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. Nov 2007;30(11):1445-1459. PMID 18041479
  13. Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. Nov 2004;5(6):523-532. PMID 15511698
  14. Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol. Jan 2000;164(1):R1-6. PMID 10607943
  15. Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med. Oct 12 2000;343(15):1070-1077. PMID 11027741
  16. Hack LM, Lockley SW, Arendt J, Skene DJ. The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. J Biol Rhythms. Oct 2003;18(5):420-429. PMID 14582858
  17. Lewy AJ, Hasler BP, Emens JS, Sack RL. Pretreatment circadian period in free-running blind people may predict the phase angle of entrainment to melatonin. Neurosci Lett. Nov 9 2001;313(3):158-160. PMID 11682151
  18. Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires ML, Sack RL. Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin. Brain Res. Nov 9 2001;918(1-2):96-100. PMID 11684046
  19. Rajaratnam SM, Polymeropoulos MH, Fisher DM, et al. Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet. Feb 7 2009;373(9662):482-491. PMID 19054552

Coding

Codes

Number

Description

 

 

This policy is managed by the pharmacy benefit.

Appendix

N/A

History

Date

Reason

06/09/14

New policy, add to Prescription Drug section. Tasimelteon (Hetlioz™) may be considered medically necessary for treatment of non-24-hour sleep-wake disorder when criteria are met and documentation of the diagnosis including appropriate sleep studies must be submitted with the request. All other uses are considered investigational. Approved by P&T Committee on May 22, 2014.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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