Ganaxolone

1 INDICATIONS AND USAGE ZTALMY is indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older. ZTALMY is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older. ( 1 )

12.1 Mechanism of Action The precise mechanism by which ganaxolone exerts its therapeutic effects in the treatment of seizures associated with CDD is unknown, but its anticonvulsant effects are thought to result from positive allosteric modulation of the gamma-aminobutyric acid type A (GABA A ) receptor in the CNS.

2 DOSAGE AND ADMINISTRATION Administer ZTALMY orally three times daily with food. ( 2.1 ) Titrate ZTALMY gradually according to the recommended schedules. See full prescribing information. ( 2.1 ) Dosage for patients weighing 28 kg or less ( 2.1 ): the starting dosage is 2 mg/kg three times daily (6 mg/kg/day) the maximum dosage is 21 mg/kg three times daily (63 mg/kg/day). Dosage for patients weighing over 28 kg ( 2.1 ): the starting dosage is 50 mg three times daily (150 mg daily) the maximum dosage is 600 mg three times daily (1800 mg daily). Patients with severe hepatic impairment: see full prescribing information for dosage recommendation. ( 2.3 ) 2.1 Dosage Information ZTALMY is administered by mouth three times daily and must be taken with food [see Clinical Pharmacology (12.3) ] . The recommended titration schedule and maintenance dosage are based on body weight for patients weighing 28 kg or less. Dosage recommendations for patients weighing 28 kg or less are included in Table 1, and dosage recommendations for patients weighing more than 28 kg are included in Table 2. Dosage should be increased based on tolerability no more frequently than every 7 days. Titration increments should not exceed those shown in Table 1 and Table 2. Table 1 ZTALMY Recommended Titration Schedule for Patients Weighing 28 kg or Less Dosage Total Daily Dose Day 2 mg/kg three times daily 6 mg/kg/day 1 to 7 4 mg/kg three times daily 12 mg/kg/day 8 to 14 8 mg/kg three times daily 24 mg/kg/day 15 to 21 14 mg/kg three times daily 42 mg/kg/day 22 to 28 21 mg/kg three times daily 63 mg/kg/day 29 and thereafter Table 2 ZTALMY Recommended Titration Schedule for Patients Weighing More Than 28 kg Dosage Total Daily Dose Day 50 mg three times daily 150 mg 1 to 7 100 mg three times daily 300 mg 8 to 14 200 mg three times daily 600 mg 15 to 21 400 mg three times daily 1,200 mg 22 to 28 600 mg three times daily 1,800 mg 29 and thereafter 2.2 Administration Instructions See the Instructions for Use for complete instructions on how to properly prepare and administer ZTALMY. Shake the bottle thoroughly for at least 1 minute and then wait for 1 minute before measuring and administering each dose. Measure and administer the prescribed dose using the oral syringe(s) provided by your pharmacist. A household teaspoon or tablespoon is not an adequate measuring device and should not be used. ZTALMY must be administered with food [see Clinical Pharmacology (12.3) ] . Discard any unused ZTALMY oral suspension after 30 days of first opening the bottle [see How Supplied/Storage and Handling (16.2) ] . 2.3 Dosage in Patients with Severe Hepatic Impairment ZTALMY is administered by mouth three times daily and must be taken with food [see Clinical Pharmacology (12.3) ] . The recommended titration schedule and maintenance dosage are based on body weight for patients weighing 28 kg or less. Dosage recommendations for patients with severe hepatic impairment and weighing 28 kg or less are included in Table 3, and dosage recommendations for patients with severe hepatic impairment (Child-Pugh class C) weighing more than 28 kg are included in Table 4. Dosage should be increased based on tolerability no more frequently than every 7 days. Titration increments should not exceed those shown in Table 3 and Table 4. No dosage adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Table 3 ZTALMY Recommended Titration Schedule for Patients with Severe Hepatic Impairment and Weighing 28 kg or Less Dosage Total Daily Dose Approximate daily dose. Days 0.66 mg/kg three times daily 2 mg/kg/day 1 to 7 1.33 mg/kg three times daily 4 mg/kg/day 8 to 14 2.66 mg/kg three times daily 8 mg/kg/day 15 to 21 4.66 mg/kg three times daily 14 mg/kg/day 22 to 28 7 mg/kg three times daily 21 mg/kg/day 29 and thereafter Table 4 ZTALMY Recommended Titration Schedule for Patients with Severe Hepatic Impairment and Weighing More Than 28 kg Dosage Tota

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

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 tria

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE There is limited clinical trial experience regarding overdose with ZTALMY. Unintentional overdose has been reported in 1 pediatric patient. This patient received ten times the prescribed dose. The patient was hospitalized for evaluation, including an electrocardiogram (ECG) and blood tests, and recovered. Patients who overdose should be closely monitored and receive standard supportive care. No specific information is available regarding treatment of overdose. In the event of overdose, a certified poison control center should be contacted for updated information on the management of overdose with ZTALMY.