tasimelteon (Rx)

>10%

Headache (17%)

1-10%

Increased ALT (10%)

Nightmares/abnormal dreams (10%)

Upper respiratory infections (7%)

Urinary tract infections (7%)

Contraindications

None

Cautions

Somnolence; can impair performance of activities requiring complete mental alertness

Tasimelteon is a CYP1A2 substrate; avoid coadministration with strong CYP1A2 inhibitors because of a potentially large increase in tasimelteon exposure and greater risk of adverse reactions

Smoking causes induction of CYP1A2 levels; tasimelteon exposure in smokers was lower (~40%) than in nonsmokers and therefore the efficacy may be reduced

Tasimelteon is a CYP3A4 substrate: avoid coadministration with CYP3A4 inducers because of a potentially large decrease in tasimelteon exposure with reduced efficacy

Risk of adverse reactions may be greater in elderly (>65 years) patients than younger patients because exposure to tasimelteon is increased by approximately 2-fold

In clinical trials, coadministration with alcohol showed a trend toward additive sedation

Pregnancy Category: C

Lactation: Unknown if distributed in human breast milk

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

Take on empty stomach without food

Limit activity to preparing for going to bed following administration