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

Available postmarketing case reports in pregnant women 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 24 times higher than human exposure at the maximum recommended human dose (MRHD)

Lactation

There are no data on presence of drug or its metabolites in human or animal milk, effects on breastfed infant, or on milk production; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug or from underlying maternal condition

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