NEREUS

5 WARNINGS AND PRECAUTIONS Effects on the Ability to Drive or Operate Machinery: May impair mental and/or physical abilities required for driving a motor vehicle or operating heavy machinery. Concomitant use of other drugs that cause central nervous system depression and strong CYP3A4 inhibitors may increase this effect. If concomitant use is unavoidable, warn patients against driving and other activities requiring complete mental alertness. ( 5.1 , 7.1 ) 5.1 Effects on the Ability to Drive or Operate Machinery In placebo-controlled clinical trials, somnolence (6%, 12%) and fatigue (6%, 8%) were adverse reactions reported in subjects who took a single dose of 85 mg or 170 mg NEREUS, respectively [see Adverse Reactions (6.1) ] . NEREUS may impair the mental and/or physical abilities required for driving a motor vehicle or operating heavy machinery. Concomitant use of other drugs that cause central nervous system depression and strong CYP3A4 inhibitors may increase this effect [see Drug Interactions (7.1) ] . If concomitant use is unavoidable, warn patients against driving and other activities requiring complete mental alertness.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5%) are: somnolence, headache, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals Inc. at 1-844-GO-VANDA (1-844-468-2632) 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 practice. The safety of a single 85 mg or 170 mg dose of NEREUS was evaluated in adult subjects with a history of motion sickness in two randomized, double-blind, placebo-controlled trials, Study 1 and Study 2 [see Clinical Studies (14) ] . Additional safety data for the 170 mg dose of NEREUS were obtained from a randomized, double-blind, placebo-controlled trial, Study 3 (NCT03772340). Adverse reactions reported in at least 5% of subjects treated with a single NEREUS 85 mg or 170 mg dose and at a higher frequency than subjects who received placebo, are shown in Table 1 . Table 1: Adverse Reactions a in Adult Subjects with a History of Motion Sickness in Single-Dose, Placebo-Controlled Studies Among Subjects Receiving NEREUS a Reported in at least 5% of subjects and at a higher frequency than placebo. b NEREUS was administered as a single 85 mg dose approximately 60 minutes prior to a boat trip and without food. c NEREUS was administered as a single 170 mg dose approximately 60 minutes prior to a boat trip and without food. Studies 1 and 2 Studies 1, 2, and 3 Adverse Reaction NEREUS 85 mg b N=227 n (%) Placebo N=228 n (%) NEREUS 170 mg c N=289 n (%) Placebo N=291 n (%) Somnolence 14 (6) 9 (4) 36 (12) 17 (6) Headache 16 (7) 12 (5) 28 (10) 17 (6) Fatigue 14 (6) 6 (3) 24 (8) 6 (2) In a 12-month randomized, open-label study, 382 subjects with a history of motion sickness were instructed to administer NEREUS 85 mg (N=199) or 170 mg (N=183) as a single dose 60 minutes before a travel event of at least 60 minutes in duration expected to induce symptoms of motion sickness. Subjects were allowed to take up to 90 doses during the study. The median exposure was 18 doses and the majority of subjects (69%) did not take more than 30 doses. Most subjects (95%) did not take more than 8 doses in any 30-day period. Adverse reactions were consistent with those observed in Study 1, Study 2, and Study 3.

<table ID="table1" width="700" styleCode="Noautorules"><caption>Table 1: Adverse Reactions^a in Adult Subjects with a History of Motion Sickness in Single-Dose, Placebo-Controlled Studies Among Subjects Receiving NEREUS</caption><col width="20%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph>^aReported in at least 5% of subjects and at a higher frequency than placebo.</paragraph><paragraph>^bNEREUS was administered as a single 85 mg dose approximately 60 minutes prior to a boat trip and without food.</paragraph><paragraph>^cNEREUS was administered as a single 170 mg dose approximately 60 minutes prior to a boat trip and without food.</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Toprule Botrule Lrule Rrule"/><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Studies 1 and 2</content></td><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Studies 1, 2, and 3</content></td></tr><tr><td styleCode="Toprule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">NEREUS 85 mg^b N=227 n (%)</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Placebo N=228 n (%)</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">NEREUS 170 mg^c N=289 n (%) </content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Placebo N=291 n (%) </content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Somnolence</td><td styleCode="Toprule Botrule Lrule Rrule">14 (6)</td><td styleCode="Toprule Botrule Lrule Rrule">9 (4)</td><td styleCode="Toprule Botrule Lrule Rrule">36 (12)</td><td styleCode="Toprule Botrule Lrule Rrule">17 (6)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Headache</td><td styleCode="Toprule Botrule Lrule Rrule">16 (7)</td><td styleCode="Toprule Botrule Lrule Rrule">12 (5)</td><td styleCode="Toprule Botrule Lrule Rrule">28 (10)</td><td styleCode="Toprule Botrule Lrule Rrule">17 (6)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule">Fatigue</td><td styleCode="Toprule Botrule Lrule Rrule">14 (6)</td><td styleCode="Toprule Botrule Lrule Rrule">6 (3)</td><td styleCode="Toprule Botrule Lrule Rrule">24 (8)</td><td styleCode="Toprule Botrule Lrule Rrule">6 (2)</td></tr></tbody></table>