What medications are approved for treating circadian rhythm sleep-wake disorder?

Medications Approved for Circadian Rhythm Sleep-Wake Disorders

Tasimelteon is the only FDA-approved medication specifically indicated for circadian rhythm sleep-wake disorders, approved for Non-24-Hour Sleep-Wake Disorder (N24SWD) in adults at a dose of 20 mg taken one hour before bedtime. 1

FDA-Approved Pharmacotherapy

Tasimelteon (Hetlioz)

• FDA-approved indication: Treatment of Non-24-Hour Sleep-Wake Disorder in adults 1
• Dosing: 20 mg orally once daily, taken one hour before bedtime at the same time every night 1
• Administration: Must be taken without food; if a dose is missed, skip it and resume the next scheduled dose 1
• Onset of effect: Drug effect may not occur for weeks to months due to individual differences in circadian rhythms 1
• Adverse effects: Most common include headache (17%), elevated alanine aminotransferase (10%), nightmares/abnormal dreams (10%), upper respiratory tract infection (7%), and urinary tract infection (7%) 1
• Contraindications: None listed 1
• Drug interactions: Avoid concurrent use with strong CYP1A2 inhibitors (e.g., fluvoxamine) due to increased exposure risk, and avoid strong CYP3A4 inducers (e.g., rifampin) due to reduced efficacy 1

Off-Label Pharmacotherapy with Guideline Support

Melatonin (Not FDA-Approved but Guideline-Recommended)

Important caveat: Melatonin is regulated as a dietary supplement in the United States, not as an FDA-approved medication, raising concerns about purity and reliability of stated doses. 2, 3, 4

Delayed Sleep-Wake Phase Disorder (DSWPD)

• Adults with or without depression: Strategically timed melatonin is suggested as treatment (WEAK FOR recommendation, LOW quality evidence) 2
• Children/adolescents without comorbidities: Strategically timed melatonin is suggested (WEAK FOR recommendation, MODERATE quality evidence) 2
• Children/adolescents with psychiatric comorbidities: Strategically timed melatonin is suggested (WEAK FOR recommendation, LOW quality evidence) 2
• Dosing for children: 0.15 mg/kg for those without comorbidities (approximately 1.6-4.4 mg), or 3-5 mg for those with psychiatric comorbidities (3 mg if <40 kg, 5 mg if >40 kg) 4
• Timing: Administer 1.5-2 hours before habitual bedtime 4

Non-24-Hour Sleep-Wake Disorder (N24SWD)

• Blind adults: Strategically timed melatonin is suggested (WEAK FOR recommendation, LOW quality evidence) 2
• This represents the off-label use of melatonin for the same condition tasimelteon is FDA-approved to treat 3

Irregular Sleep-Wake Rhythm Disorder (ISWRD)

• Children/adolescents with neurologic disorders: Strategically timed melatonin is suggested (WEAK FOR recommendation, MODERATE quality evidence) 2
• Elderly with dementia: Melatonin should be AVOIDED (WEAK AGAINST recommendation, LOW quality evidence) due to lack of benefit and potential harm including detrimental effects on mood and daytime functioning 2, 4

General Melatonin Dosing Principles

• Starting dose for adults: 3 mg immediate-release melatonin 3, 4
• Dose titration: Increase in 3 mg increments only if needed after 1-2 weeks, up to maximum of 15 mg 4
• Duration limitations: Long-term use beyond 3-4 months for chronic insomnia is not recommended due to insufficient safety data, though longer use may be appropriate for specific circadian rhythm disorders requiring ongoing chronobiotic therapy 3, 4
• Product selection: Choose United States Pharmacopeial Convention Verified formulations when possible for more reliable dosing and purity 4

Medications to AVOID

Sleep-Promoting Medications (Hypnotics/Sedatives)

• Elderly with ISWRD and dementia: The American Academy of Sleep Medicine recommends STRONGLY AGAINST the use of sleep-promoting medications (STRONG AGAINST recommendation) due to increased risks of falls and other adverse outcomes 2
• General principle: Hypnotics and sedatives do not address the underlying circadian misalignment and may worsen outcomes 5

Combination Therapy Caution

• Light therapy combined with melatonin in elderly with dementia and ISWRD: Should be AVOIDED (WEAK AGAINST recommendation, VERY LOW quality evidence) 2

Clinical Algorithm for Medication Selection

1. Confirm CRSWD diagnosis using sleep diaries/logs and actigraphy for at least 7-14 days depending on disorder type 2

2. Identify specific CRSWD subtype:

   • N24SWD in adults: Tasimelteon 20 mg is FDA-approved first-line option 1; melatonin is guideline-supported alternative for blind adults 2
   • DSWPD (all ages): Melatonin is guideline-supported (no FDA-approved medication exists) 2
   • ISWRD in children with neurologic disorders: Melatonin is guideline-supported 2
   • ISWRD in elderly with dementia: Avoid melatonin and sleep-promoting medications 2

3. Initiate melatonin therapy (when appropriate):

   • Start with 3 mg (adults) or weight-based dosing (children) 3, 4
   • Time administration 1.5-2 hours before desired bedtime 4
   • Assess response after 1-2 weeks using sleep diaries 4
   • Titrate by 3 mg increments if ineffective, up to 15 mg maximum 4

4. Monitor for adverse effects:

   • Common: headache, daytime sleepiness, dizziness, nausea 4
   • Serious: None documented, but use caution with warfarin and in epilepsy 4
   • Reassess need every 3-6 months for long-term use 4

Critical Pitfalls to Avoid

• Misdiagnosis as primary insomnia: CRSWDs are frequently misdiagnosed and inappropriately treated with hypnotics rather than chronotherapy 5
• Incorrect melatonin timing: Melatonin must be timed according to phase response curves; afternoon/evening dosing advances rhythms, morning dosing delays them 2
• Using melatonin in elderly with dementia: This population shows no benefit and potential harm 2, 4
• Expecting immediate results: Circadian medications may take weeks to months to show effect 1
• Ignoring product quality: Melatonin supplement quality varies significantly; verified formulations are essential 4