This policy is managed by the Pharmacy benefit.
Documentation of the diagnosis including appropriate sleep studies must be submitted with the request.
All other uses of Tasimelteon (Hetlioz™) are considered investigational.
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.
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.
The International Classification of Sleep Disorders criteria for non-24 (780.55-2) include:
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.
There are no other FDA-approved treatments for non-24 in blind individuals without light perception; however, two other pharmacologic treatment options are available:
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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.
This policy is managed by the pharmacy benefit.
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).