ZTALMY

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 )

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 Total Daily Dose Approximate daily dose. Days 17 mg three times daily 50 mg 1 to 7 33 mg three times daily 100 mg 8 to 14 67 mg three times daily 200 mg 15 to 21 133 mg three times daily 400 mg 22 to 28 200 mg three times daily 600 mg 29 and thereafter 2.4 Discontinuation of ZTALMY Decrease the dose of ZTALMY gradually when discontinuing treatment. As with all antiepileptic drugs, abrupt discontinuation should be avoided, when possible, to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.3) ] .

4 CONTRAINDICATIONS None. None. ( 4 )

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.

7 DRUG INTERACTIONS UGT inhibitors may increase ganaxolone exposures; consider reduction of a stable ZTALMY dosage when initiating a UGT inhibitor. ( 7.1 ) Cytochrome P450 inducers will decrease ganaxolone exposure. It is recommended to avoid concomitant use with strong or moderate CYP3A4 inducers; if unavoidable, consider a dosage increase of ZTALMY, but do not exceed the maximum recommended dosage. ( 7.2 ) 7.1 Effect of UGT Inhibitors on ZTALMY Concomitant use of ZTALMY and UGT inhibitors (e.g., valproic acid) may increase the exposure of ganaxolone, which may increase the risk of ZTALMY associated adverse reactions in patients who have titrated to a stable ZTALMY dosage. Consider a reduction of ZTALMY maintenance dosage when initiating a UGT inhibitor [see Clinical Pharmacology (12.3) ]. 7.2 Effect of Strong or Moderate Cytochrome P450 Inducers on ZTALMY Coadministration of ZTALMY with CYP450 inducers, such as strong or moderate CYP3A4 inducers, will decrease ganaxolone exposure, which can lower the efficacy of ZTALMY [see Clinical Pharmacology (12.3) ] . It is recommended to avoid concomitant use of strong or moderate CYP3A4 inducers with ZTALMY. When concomitant use of strong or moderate CYP3A4 inducers is unavoidable, consider an increase in the dosage of ZTALMY; however, do not exceed the maximum daily dosage of ZTALMY [see Dosage and Administration (2.1) ] . In patients on a stable ZTALMY dosage who are initiating or increasing the dosages of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, phenobarbital, and primidone), the ZTALMY dosage may need to be increased; however, do not exceed the maximum daily dosage of ZTALMY [see Dosage and Administration (2.1) ] . 7.3 Concomitant Use of ZTALMY with CNS Depressants and Alcohol Concomitant use of ZTALMY with CNS depressants, including alcohol, may increase the risk of somnolence and sedation [see Warnings and Precautions (5.1) ] .

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

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as ZTALMY, during pregnancy. Encourage women who are taking ZTALMY during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary There are no available data on ZTALMY use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal studies, adverse effects on development were observed in mice (fetal malformations) and rats (neurobehavioral and growth impairment) following exposure during organogenesis (mouse) or throughout gestation and lactation (rat) at maternal exposures lower than that in human adults at the maximum recommended human dose (MRHD) of 1800 mg. In addition, neuronal death was observed in rats exposed to ganaxolone during a period of brain development that begins during the third trimester of pregnancy in humans and continues during the first few years after birth. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risks of major birth defects and miscarriage for the indicated populations are unknown. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including ZTALMY, due to the risk of status epilepticus or severe seizures, which may be life-threatening [see Warnings and Precautions (5.3) ]. Data Animal Data In an embryofetal development study in mice, oral administration of ganaxolone (0, 50, 175, or 300 mg/kg/day) throughout the period of organogenesis resulted in increased incidences of fetal malformations (external and/or visceral) at all doses in the absence of maternal toxicity. Maternal plasma drug exposures (AUC) at the low-effect dose (50 mg/kg/day) for embryofetal developmental toxicity in the mouse were approximately 10-fold lower than that in humans at the MRHD. In a combined embryofetal development and pre- and postnatal development study in rats, ganaxolone (0, 10, 20, or 40 mg/kg/day) was administered orally to females throughout gestation and lactation. There were no effects on embryofetal growth, survival, or morphology; however, adverse effects on offspring growth (delayed reflex development, decreased body weight gain) were observed during the postnatal period (prior to and after weaning) at the high dose, and neurobehavioral impairment (decreased locomotor activity) was observed in the offspring at the two highest doses. The no-effect dose (10 mg/kg/day) for pre- and postnatal developmental toxicity in rats was associated with maternal drug exposures less than that in humans at the MRHD. Oral administration of ganaxolone (0, 20, 45, or 90 mg/kg/day) to rats on postnatal day (PND) 7 resulted in widespread apoptotic neurodegeneration in the brain (cortex, thalamus, and hippocampus) at all doses; a no-effect dose was not identified. Brain development on PND 7 in rat corresponds to that beginning in humans during the third trimester of pregnancy and continuing for the first several months to years after birth [see Use in Specific Populations (8.4) ] .