Hetlioz

5 WARNINGS AND PRECAUTIONS May cause somnolence: After taking HETLIOZ, patients should limit their activity to preparing for going to bed, because HETLIOZ can impair the performance of activities requiring complete mental alertness ( 5.1 ) 5.1 Somnolence After taking HETLIOZ, patients should limit their activity to preparing for going to bed. HETLIOZ can potentially impair the performance of activities requiring complete mental alertness.

6 ADVERSE REACTIONS The most common adverse reactions (incidence >5% and at least twice as high on HETLIOZ than on placebo) were headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infection ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals Inc. at 1-844-438-5469 or www.hetlioz.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 HETLIOZ, 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 HETLIOZ (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 HETLIOZ (n=10), compared to placebo (n=10), in patients with Non-24. In placebo-controlled studies, 6% of patients exposed to HETLIOZ 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. *Adverse reactions with an incidence > 5% and at least twice as high on HETLIOZ than on placebo are displayed. Table 2: Adverse Reactions in Study 1 HETLIOZ 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 % Nighttime Sleep Disturbances in Smith-Magenis Syndrome (SMS) A 9-week, double-blind, randomized, placebo-controlled, two-period crossover study evaluated HETLIOZ (capsules and oral suspension; n=25) compared to placebo (n=26) in the treatment of nighttime sleep disturbances in patients with Smith-Magenis Syndrome. Pediatric patients (n=11, age 3 to 15 years) received HETLIOZ LQ oral suspension, and patients ≥16 years of age (n=14) received HETLIOZ capsules. Adverse reactions were similar in patients treated for Non-24 and patients with Smith-Magenis syndrome treated for nighttime sleep disturbances. Adverse reactions were also similar in pediatric patients (3 years to 15 years) who received HETLIOZ LQ oral suspension, and patients ≥16 years of age who received HETLIOZ capsules.

<table ID="table2" styleCode="Noautorules" width="575"><col width="48%" align="left"/><col width="26%" align="center"/><col width="26%" align="center"/><tfoot><tr valign="top"><td colspan="3" align="left"><paragraph styleCode="footnote">*Adverse reactions with an incidence &gt; 5% and at least twice as high on HETLIOZ than on placebo are displayed.</paragraph></td></tr></tfoot><tbody><tr valign="top"><td colspan="3" align="left"><content styleCode="bold">Table 2: Adverse Reactions in Study 1</content></td></tr><tr valign="middle"><td styleCode="Toprule Botrule Lrule Rrule"/><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">HETLIOZ N=42</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Placebo N=42</content></td></tr><tr valign="middle"><td styleCode="Botrule Lrule Rrule">Headache</td><td styleCode="Botrule Lrule Rrule">17 %</td><td styleCode="Botrule Lrule Rrule">7 %</td></tr><tr valign="middle"><td styleCode="Botrule Lrule Rrule">Alanine aminotransferase increased</td><td styleCode="Botrule Lrule Rrule">10 %</td><td styleCode="Botrule Lrule Rrule">5 %</td></tr><tr valign="middle"><td styleCode="Botrule Lrule Rrule">Nightmare/abnormal dreams</td><td styleCode="Botrule Lrule Rrule">10 %</td><td styleCode="Botrule Lrule Rrule">0 %</td></tr><tr valign="middle"><td styleCode="Botrule Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Botrule Lrule Rrule">7 %</td><td styleCode="Botrule Lrule Rrule">0 %</td></tr><tr valign="middle"><td styleCode="Botrule Lrule Rrule">Urinary tract infection</td><td styleCode="Botrule Lrule Rrule">7 %</td><td styleCode="Botrule Lrule Rrule">2 %</td></tr></tbody></table>