ZTALMY

5 WARNINGS AND PRECAUTIONS Somnolence and Sedation: Monitor for somnolence and sedation and advise patients not to drive or operate machinery until they have gained sufficient experience with ZTALMY. Concomitant use with other CNS depressants or alcohol could potentiate adverse effects. ( 5.1 ) Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts. ( 5.2 ) Withdrawal of Antiepileptic Drugs: ZTALMY should be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus. ( 5.3 ) 5.1 Somnolence and Sedation ZTALMY can cause somnolence and sedation. In Study 1 [see Clinical Studies (14) ] , the incidence of somnolence and sedation was 44% in patients treated with ZTALMY, compared with 24% in patients receiving placebo. Somnolence and sedation appeared early during treatment and were generally dose-related [see Adverse Reactions (6.1) ] . Other central nervous system (CNS) depressants, including opioids, antidepressants, and alcohol, could potentiate somnolence and sedation in patients receiving ZTALMY [see Clinical Pharmacology (12.3) ] . Prescribers should monitor patients for somnolence and sedation, and advise patients not to drive or operate machinery until they have gained sufficient experience on ZTALMY to gauge whether it adversely affects their ability to drive or operate machinery. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including ZTALMY, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs, that did not include ZTALMY, showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed. Table 5 shows absolute and relative risk by indication for all evaluated AEDs. Table 5 Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing ZTALMY, or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.3 Withdrawal of Antiepileptic Drugs As with most AEDs, ZTALMY should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration (2.4) ] . If withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

<table width="85%"><caption>Table 5 Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis</caption><col width="12%" align="left" valign="top"/><col width="22%" align="center" valign="top"/><col width="22%" align="center" valign="top"/><col width="22%" align="center" valign="top"/><col width="22%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="bottom">Indication</th><th styleCode="Rrule" valign="bottom">Placebo Patients with Events per 1000 Patients</th><th styleCode="Rrule" valign="bottom">Drug Patients with Events per 1000 Patients</th><th styleCode="Rrule" valign="bottom">Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients</th><th styleCode="Rrule" valign="bottom">Risk Difference: Additional Drug Patients with Events per 1000 Patients</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epilepsy</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">3.5</td><td styleCode="Rrule">2.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Psychiatric</td><td styleCode="Rrule">5.7</td><td styleCode="Rrule">8.5</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">2.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Other</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">0.9</td></tr><tr><td styleCode="Lrule Rrule">Total</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">4.3</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.9</td></tr></tbody></table>

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Somnolence and Sedation [see Warnings and Precautions (5.1) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.2) ] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence of at least 5% for ZTALMY and at least twice the rate of placebo) are somnolence, pyrexia, salivary hypersecretion, and seasonal allergy. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Immedica at 1-844-627-4687 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. In controlled and uncontrolled trials in patients with seizures associated with CDD, 102 patients were treated with ZTALMY, including 83 patients treated for more than 6 months, and 50 patients treated for more than 1 year. In Study 1, 50 patients received ZTALMY [see Clinical Studies (14) ] . The duration of treatment in this trial was up to 17 weeks. Approximately 78% of these patients were female, 92% were White, and the mean age was 6.8 years (range 2 to 19 years). All patients receiving ZTALMY, except 1, were taking other AEDs. Adverse reactions in these patients are presented below. The most common adverse reactions (an incidence of at least 5% and at least twice the rate of placebo) were somnolence, pyrexia, salivary hypersecretion, and seasonal allergy (Table 6). The adverse reactions leading to treatment discontinuation in ZTALMY-treated patients were somnolence and seizure (1 patient) and seizure (1 patient). Twenty-two percent of ZTALMY-treated patients had dosing interrupted or reduced because of any adverse reaction, compared to 16% of placebo-treated patients. The most frequent adverse reactions leading to a dose interruption or reduction in ZTALMY-treated patients were somnolence (10%) and sedation (2%). Table 6 presents the adverse reactions that occurred in ZTALMY-treated patients with seizures associated with CDD at a rate of at least 3% and at a rate greater than in placebo-treated patients during the double-blind phase. Table 6 Adverse Reactions that Occurred in ZTALMY-Treated Patients with Seizures Associated with CDD at a Rate of At Least 3% and Greater Than in Placebo (Study 1) Adverse Reactions ZTALMY (N=50) Placebo (N=51) % % Somnolence somnolence includes the terms lethargy and hypersomnia adverse reactions that occurred with a 21-day titration; somnolence and sedation are expected to be reduced with the recommended 28-day titration [see Dosage and Administration (2.1, 2.3)] 38 20 Pyrexia 18 8 Upper respiratory tract infection 10 6 Sedation 6 4 Salivary Hypersecretion 6 2 Seasonal allergy 6 0 Bronchitis 4 0 Influenza 4 2 Gait disturbance 4 2 Nasal congestion 4 2

<table width="75%"><caption>Table 6 Adverse Reactions that Occurred in ZTALMY-Treated Patients with Seizures Associated with CDD at a Rate of At Least 3% and Greater Than in Placebo (Study 1)</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="middle">Adverse Reactions</th><th styleCode="Rrule">ZTALMY (N=50) </th><th styleCode="Rrule">Placebo (N=51) </th></tr><tr><th styleCode="Lrule Rrule" valign="middle"/><th styleCode="Rrule">%</th><th styleCode="Rrule">%</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Somnolence <footnote ID="K1555">somnolence includes the terms lethargy and hypersomnia</footnote><footnote ID="t62">adverse reactions that occurred with a 21-day titration; somnolence and sedation are expected to be reduced with the recommended 28-day titration [see Dosage and Administration (2.1, 2.3)] </footnote></td><td styleCode="Rrule">38</td><td styleCode="Rrule">20</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">18</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">10</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sedation <footnoteRef IDREF="t62"/></td><td styleCode="Rrule">6</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Salivary Hypersecretion</td><td styleCode="Rrule">6</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Seasonal allergy</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bronchitis</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Influenza</td><td styleCode="Rrule">4</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gait disturbance</td><td styleCode="Rrule">4</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule">Nasal congestion</td><td styleCode="Rrule">4</td><td styleCode="Rrule">2</td></tr></tbody></table>