tasimelteon (Rx)

>10%

Headache (17%)

1-10%

Increased ALT (10%)

Nightmares/abnormal dreams (10%)

Upper respiratory infections (7%)

Urinary tract infections (7%)

Postmarketing Reports

Nighttime Sleep Disturbances in Smith-Magenis Syndrome (SMS)

Contraindications

None

Cautions

After administration, advise patients to limit activity to prepare for going to bed

May potentially impair performance of activities requiring complete mental alertness

Drug interaction overview

• Tasimelteon is a CYP3A4 and CYP1A2 substrate

• Smokers

  • Smoking is a moderate CYP1A2 inducer
  • Tasimelteon exposure decreased by ~40% in smokers compared with nonsmokers

• Strong CYP1A2 Inhibitors

  • Avoid coadministration
  • Fluvoxamine or other strong CYP1A2 inhibitors may potentially increase tasimelteon exposure and increase risk of adverse reactions

• Strong CYP3A4 inducers

  • Avoid coadministration
  • Rifampin or other CYP3A4 inducers may potentially decrease tasimelteon exposure and reduced efficacy

• Beta-adrenergic receptor antagonists

  • Beta-adrenergic receptor antagonists have been shown to reduce production of melatonin via specific inhibition of beta-1 adrenergic receptors
  • Nighttime administration of beta-adrenergic receptor antagonists may reduce tasimelteon efficacy

Pregnancy

Available postmarketing case reports use in pregnant females are not sufficient to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes

Animal data

• In pregnant rats, no embryofetal developmental toxicity was observed at exposures of 50 mg/kg/day, or up to 24x higher than the human exposure at the maximum recommended human dose

Lactation

No data available on drug presence or its metabolites in human or animal milk, effects on breastfed infants, effects on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Melatonin receptor agonist with high affinity for MT1 and MT2 receptors in the suprachiasmatic nucleus of the brain; MT1 and MT2 are thought to synchronize the body's melatonin and cortisol circadian rhythms with the day-night cycle in patients with non-24-hour disorder

Absorption

Peak plasma concentration: 0.5-3 hr (fasting)

When administered with a high-fat meal, peak plasma concentration was 44% lower than when given in a fasted state, and the median peak concentration was delayed by approximately 1.75 hr

Oral bioavailability: 38.3%

Distribution

Protein bound: 96%

Vd: 59-126 L

Metabolism

Extensively metabolized primarily by oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid

CYP1A2 and CYP3A4 are the major isozymes involved

Phenolic glucuronidation is the major phase II metabolic route

Major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon

Elimination

Half-life: 1.3 hr; 1.3-3.7 hr (metabolites)

Excretion: 80% urine (<1% as parent compound); 4% feces

Oral Administration

All formulations

• Administer without food
• If unable to take dose at approximately the same time on a given night, skip that dose and take next dose as scheduled

Capsules

• Swallow capsules whole

Oral suspension

• Shake well for at least 30 seconds before administration
• Remove seal and insert press-in bottle adapter (included in packaging) until tightly sealed
• Turn upside down and withdraw prescribed dose with oral syringe

Storage

Capsules

• Store at room temperature, 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)
• Protect from exposure to light and moisture

Oral suspension

• Unopened bottle: Refrigerate at 5ºC (41ºF), excursions permitted to 2-8ºC (36-46ºF)

Opened bottle

• Refrigerate at 5ºC (41ºF), excursions permitted to 2-8ºC (36-46ºF)
• After opening, discard after 5 weeks (for 48-mL bottle) and after 8 weeks (for 158-mL bottle)