Effective Date

Date of Origin 

7/1/2023

Hetlioz®

(tasimelteon)*

Capsules

Treatment of Non-24-Hour Sleep-Wake Disorder (Non-24 SWD) in adults

Treatment of nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) in patients 16 years of age and older

1

Hetlioz LQ™

(tasimelteon)

Oral suspension

Treatment of nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) in pediatric patients 3 to 15 years of age

1

Non-24 Hour Sleep-Wake Disorder

Non-24 hour sleep-wake disorder (N24) is a circadian rhythm sleep disorder that is due to the failure of the biological clock to synchronize to a 24-hour day.(2) Numerous biological processes require an endogenous, entrainable oscillation with a period of about 24 hours, also known as the circadian rhythm. Retinal rods, cones, and ganglion cells that express the photopigment melanopsin play a key role in circadian photoentrainment. Light that reaches the photoreceptors activates the suprachiasmatic nuclei (SCN), which contains the master biological clock, activating a regulatory feedback loop that inhibits melatonin synthesis. In totally blind patients, the circadian process can become desynchronized due to the absence of light input into the master biological clock.(5)  

Patients with N24 typically find their sleep time gradually delaying by minutes to hours every day, rather than sleeping at roughly the same time every day. Cycles of body temperature and hormone rhythms also follow a non-24 hour rhythm. If Non-24 is not detected and addressed, and the person attempts to stay on a 24-hour schedule, the symptoms of chronic sleep deprivation will accumulate, such as excessive daytime sleepiness, fatigue, depression, difficulty concentrating, and memory problems. Non-24 can be severely disabling as it causes extreme difficulty for the individual attempting to maintain social and career obligations.(2) The condition primarily occurs in blind individuals, and at least 50% of the totally blind (i.e., those with no light perception) are thought to suffer from the disorder.(3)   

The American Academy of Sleep Medicine guidelines on treatment of circadian rhythm disorders (AASM, 2015) recommends clinicians use strategically timed administration of melatonin for treatment of Non-24-Hour Sleep-Wake Disorder in blind adults (vs. no treatment).  The suggestion carried a “Weak” recommendation, as there were only 3 studies that met the task force’s inclusion criteria for analysis, and the level of evidence from these small trials was low.  The task force states that no serious adverse reactions to melatonin have been described to date and therefore benefits of use appear to outweigh any potential harm.(3)

Efficacy(1)

The effectiveness of Hetlioz in the treatment of Non-24-Hour Sleep-Wake Disorder(Non-24) was established in two randomized double-masked, placebo-controlled, multicenter, parallel-group studies (Studies 1 and 2) in totally blind patients with Non-24. In study 1, 84 patients with Non-24 (median age 54 years) were randomized to receive Hetlioz 20 mg or placebo, one hour prior to bedtime, at the same time every night for up to 6 months. Study 2 was a randomized withdrawal trial in 20 patients with Non-24 (median age 55 years) that was designed to evaluate the maintenance of efficacy of Hetlioz after 12 weeks. Patients were treated for approximately 12 weeks with Hetlioz 20 mg one hour prior to bedtime, at the same time every night.

Efficacy endpoints for nighttime total sleep time and daytime nap duration were based on the 25% of nights with the least nighttime sleep, and the 25% of days with the most daytime nap time. Treatment with Hetlioz resulted in a significant improvement, compared with placebo, for both of these endpoints in Study 1 and Study 2.

Smith-Magenis Syndrome (SMS)

Smith-Magenis Syndrome (SMS) is genetic condition resulting in developmental delays, cognitive impairment, behavioral abnormalities, sleep disturbances, distinctive physical features, and childhood abdominal obesity. SMS is a result of a deletion of the retinoic acid induced 1 (RAI1) gene in chromosome 17p11.2. Most cases are the result of de novo deletions, but rare occurrences of inherited cases have occurred.(7)

The diagnosis of SMS is established via a combination of clinical features and genetic testing. Clinical features suspect of SMS include the following:(6)

• Subtly distinctive facial appearance that becomes more evident with age
• Mild to moderate infantile hypotonia with feeding difficulties and failure to thrive
• Some level of developmental delay and/or intellectual disability, including early speech delays with or without associated hearing loss
• Distinct neurobehavioral phenotype that includes stereotypic and maladaptive behaviors
• Sleep disturbance
• Short stature (prepubertal)
• Childhood obesity
• Minor skeletal anomalies, including brachydactyly
• Signs of peripheral neuropathy
• Ophthalmologic abnormalities
• Otolaryngologic abnormalities

The presence of either a heterozygous deletion at chromosome 17p11.2 that includes RAI1 or a heterozygous intragenic RAI1 pathogenic variant are definitive of a SMS diagnosis.(6)

Sleep disturbances are a major clinical characteristic of SMS. The sleep disturbances are believed to be attributed to a primary disturbance of the circadian clock, with RAI1 functioning as a positive regulator of the Circadian Locomotor Output Cycles Kaput (CLOCK) gene transcription. The dysregulation of CLOCK results in dysregulation of other circadian clock components. Patients with SMS also have elevated levels of daytime melatonin resulting in daytime sleepiness. The sleep disturbances manifest as fragmented sleep cycles with a reduction in total sleep time. Patients may complain of frequent nighttime awakenings, parasomnias, and excessive daytime sleepiness.(7)

Sleep disturbances contribute to behavioral problems typical to SMS, and normalizing sleep habits, improved both behavior and quality of life for patients and families. There is currently no pharmaceutical standard of care, but melatonin has been used in case reports with some response.(6,7) Hetlioz (tasimelteon) is first FDA-approved treatment of nighttime sleep disturbance in SMS.(6)

Efficacy(1)

The effectiveness of Hetlioz in the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) was established in a 9-week, double-blind, placebo-controlled crossover study in adults and pediatric patients with SMS (Study 3; NCT 02231008). Patients 16 years of age and older received Hetlioz 20 mg capsules, and pediatric patients 3 years to 15 years of age received a weight-based dose of oral suspension. The efficacy comparisons for nighttime sleep quality and total sleep time were based on the 50% of nights with the worst sleep quality and the 50% of nights with the least nighttime sleep in each 4-week period. In accordance with the cross-over design, the efficacy comparisons were within patient. Compared to placebo, treatment with Hetlioz resulted in a statistically significant improvement in the 50% worst nights’ sleep quality.

Safety(1)

Hetlioz and Hetlioz LQ have no FDA labeled contraindications for use. 

1

Hetlioz prescribing information. Vanda Pharmaceuticals Inc. December 2022.

2

Non-24-Hour Sleep-Wake Disorder.  National Organization for Rare Disorders (NORD).  Accessed January 2023.  https://rarediseases.org/rare-diseases/non-24-hour-sleep-wake-disorder/

3

Auger RR, Burgess HJ, Emens JS, et. al.  Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders:  Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD).  An Update for 2015. http://jcsm.aasm.org/ViewAbstract.aspx?pid=30219

4

Lockley SW, Dressman MA, et al.  Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicenter, randomized, double-masked, placebo-controlled phase 3 trials.  The Lancet, October 31, 2015, 386:10005 1754-1764. Reference no longer used. 

5

Quera Salva Maria Antonia, Hartley Sarah, Léger Damien, Dauvilliers Yves A. (2017) Non-24-Hour Sleep–Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management. Frontiers in Neurology, 8(686), pages 1-7. Doi: 10.3389/fneur.2017.00686.

6

Smith ACM, Boyd KE, Elsea SH, et. al. Smith-Magenis Syndrome. GeneReviews. October, 2022; https://www.ncbi.nlm.nih.gov/books/NBK1310/

7

Shayota, B. J., & Elsea, S. H. (2019). Behavior and sleep disturbance in Smith-Magenis syndrome. Current opinion in psychiatry, 32(2), 73–78. https://doi.org/10.1097/YCO.0000000000000474

Hetlioz

tasimelteon capsule

20 MG

M ; N ; O ; Y

O ; Y

Hetlioz lq

tasimelteon oral susp

4 MG/ML

M ; N ; O ; Y

N

Hetlioz

Tasimelteon Capsule 20 MG

20 MG

30

CAPS

30

Days

Hetlioz lq

Tasimelteon Oral Susp

4 MG/ML

158

MLS

30

Days

Hetlioz

tasimelteon capsule

20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Hetlioz lq

tasimelteon oral susp

4 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Hetlioz

Tasimelteon Capsule 20 MG

20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Hetlioz lq

Tasimelteon Oral Susp

4 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met: 

1. ONE of the following: 
   1. BOTH of the following:
      1. The patient has a diagnosis of Non-24-hour sleep-wake disorder AND
      2. The patient is totally blind (i.e., no light perception) OR
   2. BOTH of the following:
      1. The patient has a diagnosis of Smith-Magenis Syndrome (SMS) confirmed by the presence of ONE of the following genetic mutations:
         1. A heterozygous deletion of 17p11.2 OR
         2. A heterozygous pathogenic variant involving RAI1 AND
      2. The requested agent is being used to treat nighttime sleep disturbances associated with SMS OR
   3. The patient has another FDA approved indication for the requested agent and route of administration AND
2. If the patient has an FDA approved indication, ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., sleep specialist, neurologist, psychiatrist) or has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met: 

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process AND
2. The patient has had clinical benefit with the requested agent AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., sleep specialist, neurologist, psychiatrist) or has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Evaluation

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) is greater than the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit OR
3. ALL of the following:
   1. The requested quantity (dose) is greater than the program quantity limit AND
   2. The requested quantity (dose) is greater than the maximum FDA labeled dose for the requested indication AND
   3. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Length of Approval: 12 months