Tasimelteon (tasimelteon)

The recommended adult dosage of tasimelteon for the treatment of non-24-hour sleep-wake disorder is 20 mg once daily taken before bedtime, at the same time every night.

Because of individual differences in circadian rhythms, tasimelteon's therapeutic effect in patients with non-24-hour sleep-wake disorder may not occur for weeks or months.

If a dose of tasimelteon is missed, the dose should be skipped; the next dose should be taken at the regularly scheduled time. (See Advice to Patients.)

Tasimelteon is administered orally before bedtime, without food, at the same time every night. The capsules should be swallowed whole. Administration of tasimelteon with food may result in lower drug concentrations and reduced efficacy. (See Description.)

After taking tasimelteon, patients should limit their activities to preparing for going to bed. (See Somnolence under Cautions: Warnings/Precautions and also see Advice to Patients.)

Tasimelteon is extensively metabolized, principally by cytochrome P-450 (CYP) isoenzymes 1A2 and 3A4. Other than CYP1A2- and CYP3A4-mediated drug interactions, in vitro and in vivo studies suggest that tasimelteon is unlikely to be involved in clinically important pharmacokinetic drug interactions.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selected Cyp1a2 Substrates/Viloxazine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Viloxazine is a strong inhibitor of CYP1A2 and may increase the total exposure of sensitive CYP1A2 substrates.(1) The FDA defines strong inhibition as an increase in drug area-under-curve (AUC) greater than 5-fold.(2)

CLINICAL EFFECTS: Concurrent use of viloxazine with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increase the risk of adverse reactions associated with the CYP1A2 substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drugs linked to this monograph have a narrow therapeutic window or are sensitive to CYP1A2 inhibition. Coadministration of viloxazine with sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic window is contraindicated.(1)

DISCUSSION: Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may increase the risk of adverse reactions associated with these CYP1A2 substrates. In a study, viloxazine increased the AUC of caffeine by almost 6-fold.(1) CYP1A2 substrates linked to this monograph include: agomelatine, alosetron, aminophylline, duloxetine, ramelteon, tasimelteon, and theophylline.(2,3)

Tasimelteon/Strong Cyp1a2 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of tasimelteon.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP1A2 may result in elevated levels of and toxicity from tasimelteon.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP1A2 inhibitors and tasimelteon.(1)

DISCUSSION: Fluvoxamine (50 mg daily for 6 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of tasimelteon by 2-fold and 7-fold, respectively.(1) Strong inhibitors of CYP1A2 include angelica root (angelica dahurica radix), ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2,3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Ramelteon; Suvorexant; Tasimelteon/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of ramelteon, suvorexant or tasimelteon.(1-3)

CLINICAL EFFECTS: Concurrent use with strong inducers of CYP3A4 may result in substantially lower systemic concentrations and decreased efficacy of ramelteon, suvorexant or tasimelteon.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Ramelteon: The manufacturer notes that ramelteon efficacy may be reduced when used in combination with a strong CYP3A4 inducer.(1) Suvorexant: If possible, use alternatives to strong CYP3A4 inducers in patients who require suvorexant therapy. Patients requiring concurrent therapy may need larger doses of suvorexant; however, the maximum daily dose of 20 mg should not be exceeded.(2) Tasimelteon: The manufacturer of tasimelteon recommends avoiding concurrent use with strong CYP3A4 inducers due to the potentially large decrease in tasimelteon exposure and reduced efficacy.(3)

DISCUSSION: Rifampin (600 mg daily for 11 days) decreased both maximum concentration (Cmax) and total exposure (area-under-curve or AUC) to ramelteon by 80%.(1) In an interaction study, rifampin substantially decreased levels of suvorexant. Suvorexant AUC and Cmax decreased by approximately 90% and 70%, respectively.(2) Rifampin (600 mg daily for 11 days) decreased exposure to tasimelteon by 90%.(3) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's wort.(4-5)

There are no moderate interactions for this drug.

The manufacturer states there are no known contraindications to the use of tasimelteon.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• No disease contraindications

Adverse effects reported in more than 5% of patients with non-24-hour sleep-wake disorder receiving tasimelteon and with an incidence at least twice that reported with placebo in the SET study include headache, increased ALT concentrations, nightmares or abnormal dreams, upper respiratory tract infection, and urinary tract infection.

More Frequent

• Increased alanine transaminase

More Frequent

• Dream disorder
• Drowsy
• Headache disorder
• Nightmares
• Upper respiratory infection
• Urinary tract infection

No enhanced messaging available.

Safety and effectiveness of tasimelteon have not been established in pediatric patients.

Category C. (See Users Guide.)

It is not known whether tasimelteon is distributed into human milk. Because many drugs are distributed into human milk, caution should be exercised when tasimelteon is administered in nursing women.

In a single-dose pharmacokinetic study, individuals greater than 65 years of age had an approximately twofold increase in drug exposure compared with younger adults. Therefore, the risk of adverse effects with tasimelteon may be greater in geriatric patients than younger patients. However, dosage adjustment is not necessary in geriatric patients.