Hetlioz

Unless your doctor tells you otherwise, continue your normal diet.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Common side effects of Hetlioz include the following:

• headaches
• unusual dreams
• nightmares
• upper airway infection
• urinary tract infection

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Before taking Hetlioz, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Hetlioz or to any of its ingredients
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Take Hetlioz exactly as prescribed.

• This medication comes as a capsule. It is taken once a day at night without food.
• Take Hetlioz before bedtime at the same time every night.
• Skip a dose that night if you cannot take Hetlioz at about the same time on a given night.

• Limit your activities and prepare for going to bed after taking Hetlioz. Hetlioz can potentially impair the performance of activities requiring complete mental alertness.
• Because of individual differences in sleep cycles, daily use for several weeks or months may be necessary before benefit from Hetlioz is observed.
• To swallow the capsule whole.
• Smoking can cause a reduction in how Hetlioz works.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended dose is 20 mg prior to bedtime, at same time every night.

Tasimelteon is a sedative, also called a hypnotic. It works by affecting certain substances in your body that help regulate your "sleep-wake cycle."

Tasimelteon is used to treat non-24-hour sleep-wake disorder.

Tasimelteon may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• pain or burning when you urinate.

Side effects may be more likely in older adults.

Common side effects may include:

• drowsiness;

• headache;

• strange dreams, nightmares; or

• cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Storage

Oral

25°C (may be exposed to 15–30°C).1 Protect from light and moisture.1

In the U.S.

• Hetlioz

Available Dosage Forms:

• Capsule

Therapeutic Class: Central Nervous System Agent

Pharmacologic Class: Melatonin Receptor Agonist

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Bad dreams.
• Cough.
• Sore throat.
• Runny nose.
• Stuffy nose.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Hetlioz is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24).

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Hetlioz in pregnant women. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically. Hetlioz should be used during pregnancy only if the potential benefit justifies the potential risks.

In pregnant rats administered tasimelteon at oral doses of 5, 50, 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 recommended human dose (RHD) of 20 mg/day, on a mg/m2 basis.

In pregnant rabbits administered tasimelteon at oral doses of 5, 30, 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 not associated with adverse effects (30 mg/kg/day) is approximately 30 times the RHD on a mg/m2 basis.

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

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Hetlioz is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

The 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 compared with younger patients.

Hepatic Impairment

Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. Hetlioz has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Hetlioz is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

Smokers

Smoking causes induction of CYP1A2 levels. The exposure of tasimelteon in smokers was lower than in non-smokers and therefore the efficacy of Hetlioz may be reduced in smokers [see Clinical pharmacology (12.3)].

The effectiveness of Hetlioz in the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) was established in two randomized double-masked, placebo-controlled, multicenter, parallel-group studies (Studies 1 and 2) in totally blind patients with Non-24.

In study 1, 84 patients with Non-24 (median age 54 years) were randomized to receive Hetlioz 20 mg or placebo, one hour prior to bedtime, at the same time every night for up to 6 months.

Study 2 was a randomized withdrawal trial in 20 patients with Non-24 (median age 55 years) that was designed to evaluate the maintenance of efficacy of Hetlioz after 12-weeks. Patients were treated for approximately 12 weeks with Hetlioz 20 mg one hour prior to bedtime, at the same time every night. Patients in whom the calculated time of peak melatonin level (melatonin acrophase) occurred at approximately the same time of day (in contrast to the expected daily delay) during the run-in phase were randomized to receive placebo or continue treatment with Hetlioz 20 mg for 8 weeks.

Study 1 and Study 2 evaluated the duration and timing of nighttime sleep and daytime naps via patient-recorded diaries. During Study 1, patient diaries were recorded for an average of 88 days during screening, and 133 days during randomization. During Study 2, patient diaries were recorded for an average of 57 days during the run-in phase, and 59 days during the randomized-withdrawal phase.

Because symptoms of nighttime sleep disruption and daytime sleepiness are cyclical in patients with Non-24, with severity varying according to the state of alignment of the individual patient’s circadian rhythm with the 24-hour day (least severe when fully aligned, most severe when 12 hours out of alignment), efficacy endpoints for nighttime total sleep time and daytime nap duration were based on the 25% of nights with the least nighttime sleep, and the 25% of days with the most daytime nap time. In Study 1, patients in the Hetlioz group had, at baseline, an average 195 minutes of nighttime sleep and 137 minutes of daytime nap time on the 25% of most symptomatic nights and days, respectively. Treatment with Hetlioz resulted in a significant improvement, compared with placebo, for both of these endpoints in Study 1 and Study 2 (see Table 2).

A responder analysis of patients with both ≥ 45 minutes increase in nighttime sleep and ≥ 45 minutes decrease in daytime nap time was conducted in Study 1: 29% (n=12) of patients treated with Hetlioz, compared with 12% (n=5) of patients treated with placebo met the responder criteria.

The efficacy of Hetlioz in treating Non-24 may be reduced in subjects with concomitant administration of beta adrenergic receptor antagonists.

Advise patients

• To take Hetlioz before bedtime at the same time every night.
   
• To skip the dose that night if they cannot take Hetlioz at approximately the same time on a given night.
   
• To limit their activities to preparing for going to bed after taking Hetlioz because Hetlioz can potentially impair the performance of activities requiring complete mental alertness.
   
• That because of individual differences in circadian rhythms, daily use for several weeks or months may be necessary before benefit from Hetlioz is observed.
   
• To swallow the capsule whole.

Distributed by:
Vanda Pharmaceuticals Inc.
Washington, D.C. 20037 USA
www.Hetlioz.com

Vanda and Hetlioz are registered trademarks of Vanda Pharmaceuticals Inc. in the United States and other countries.

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