Tasimelteon

TASIMELTEON- tasimelteon capsule, gelatin coated
Teva Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

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

• Tasimelteon capsules are indicated for the treatment of Non-24 in adults.

2 DOSAGE AND ADMINISTRATION

2.2 Recommended Dosage for Tasimelteon Capsules for Non-24

Adults

The recommended dosage of tasimelteon capsules in adults is 20 mg one hour before bedtime, at the same time every night.

Because of individual differences in circadian rhythms, drug effect may not occur for weeks or months.

2.4 Important Administration Information

Administer tasimelteon capsules without food [see Clinical Pharmacology (12.3)].

If a patient is unable to take tasimelteon capsules at approximately the same time on a given night, they should skip that dose and take the next dose as scheduled.

3 DOSAGE FORMS AND STRENGTHS

Capsules: Each size 1 hard gelatin capsule with light blue opaque cap and body imprinted with A44 on cap in black ink contains white to off-white color granular powder.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Somnolence

After taking tasimelteon capsules, patients should limit their activity to preparing for going to bed. Tasimelteon can potentially impair the performance of activities requiring complete mental alertness.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

More than 2080 subjects have been treated with at least one dose of tasimelteon, of which more than 380 have been treated for > 26 weeks and more than 170 have been treated for > 1 year.

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

A 26-week, parallel-arm placebo-controlled study (Study 1) evaluated tasimelteon (n=42) compared to placebo (n=42) in patients with Non-24. A randomized-withdrawal, placebo-controlled study of 8 weeks duration (Study 2) also evaluated tasimelteon (n=10), compared to placebo (n=10), in patients with Non-24.

In placebo-controlled studies, 6% of patients exposed to tasimelteon discontinued treatment due to an adverse event, compared with 4% of patients who received placebo.

Table 2 shows the incidence of adverse reactions from Study 1.

Table 2: Adverse Reactions in Study 1

	Tasimelteon N=42	Placebo N=42
Headache	17%	7%
Alanine aminotransferase increased	10%	5%
Nightmare/abnormal dreams	10%	0%
Upper respiratory tract infection	7%	0%
Urinary tract infection	7%	2%
*Adverse reactions with an incidence >5% and at least twice as high on tasimelteon than on placebo are displayed.

7 DRUG INTERACTIONS

7.1 Strong CYP1A2 Inhibitors (e.g., fluvoxamine)

Avoid use of tasimelteon in combination with fluvoxamine or other strong CYP1A2 inhibitors because of a potentially large increase in tasimelteon exposure and greater risk of adverse reactions [see Clinical Pharmacology (12.3)].

7.2 Strong CYP3A4 Inducers (e.g., rifampin)

Avoid use of tasimelteon in combination with rifampin or other CYP3A4 inducers because of a potentially large decrease in tasimelteon exposure with reduced efficacy [see Clinical Pharmacology (12.3)].

7.3 Beta-Adrenergic Receptor Antagonists (e.g., acebutolol, metoprolol)

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available postmarketing case reports with tasimelteon use in pregnant women are not sufficient to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In pregnant rats, no embryofetal developmental toxicity was observed at exposures of 50 mg/kg/day, or up to 24 times higher than the human exposure at the maximum recommended human dose (MRHD) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In pregnant rats administered tasimelteon at oral doses of 5 mg/kg/day, 50 mg/kg/day, or 500 mg/kg/day during the period of organogenesis, there were no effects on embryofetal development. The highest dose tested is approximately 240 times the MRHD of 20 mg/day, based on mg/m² body surface area.

In pregnant rabbits administered tasimelteon at oral doses of 5 mg/kg/day, 30 mg/kg/day, or 200 mg/kg/day during the period of organogenesis, embryolethality and embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. The highest dose is approximately 200 times the MRHD.

Oral administration of tasimelteon at 50 mg/kg/day, 150 mg/kg/day, or 450 mg/kg/day to rats throughout organogenesis resulted in persistent reductions in body weight, delayed sexual maturation, and physical development, and neurobehavioral impairment in offspring at the highest dose tested which is approximately 220 times the MRHD based on mg/m² body surface area. Reduced body weight in offspring was also observed at the mid-dose. The no effect dose (NOEL), (50 mg/kg/day) is approximately 25 times the MRHD based on mg/m² body surface area.

8.2 Lactation

Risk Summary

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