epine, 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) ] . 7.2 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) ] .

ohol, 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 3 shows absolute and relative risk by indication for all evaluated aeds. table 3 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 (2.3) ] . if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

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 dosage days 6 mg/kg three times daily 18 mg/kg/day 1 to 7 11 mg/kg three times daily 33 mg/kg/day 8 to 14 16 mg/kg three times daily 48 mg/kg/day 15 to 21 21 mg/kg three times daily 63 mg/kg/day 22 to ongoing table 2 ztalmy recommended titration schedule for patients weighing more than 28 kg dosage ml per dose total daily dosage days 150 mg three times daily 3 450 mg 1 to 7 300 mg three times daily 6 900 mg 8 to 14 450 mg three times daily 9 1350 mg 15 to 21 600 mg three times daily 12 1800 mg 22 to ongoing 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 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) ] .

iated 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 4). 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 4 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 4 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 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

epine, 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) ] . 7.2 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) ] .

0 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. 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, 10, 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) ] . 8.2 lactation risk summary ganaxolone is excreted in human milk. following a single oral dose of ganaxolone (300 mg), ganaxolone exposures (auc (0-24 h) ) in human milk were approximately 4 times higher than those in maternal plasma, resulting in an estimated daily dose in the infant of less than 1% of the maternal dose (see data ) . the effects of ganaxolone on milk production and the breastfed infant are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ztalmy, and any potential adverse effects on the breastfed child from ztalmy, or from the underlying maternal condition. data a study was conducted in 5 healthy adult lactating women treated with a 300 mg oral dose of ganaxolone. ganaxolone exposures in breast milk were approximately 4 times those in maternal plasma. the calculated maximum relative infant dose for ganaxolone is approximately 0.157 mg/kg/day based on an average milk intake of 150 ml/kg/day, which is less than 1% of the maternal dose, and approximately 0.24% the labeled pediatric dose of 63 mg/kg/day. 8.4 pediatric use the safety and effectiveness of ztalmy for the treatment of seizures associated with cdd have been established in pediatric patients 2 years of age and older. the use of ztalmy for the treatment of seizures associated with cdd in patients 2 years of age and older is supported by a randomized, double-blind, placebo-controlled trial that included 99 pediatric patients 2 to less than 18 years of age [see clinical studies (14) ] . safety and effectiveness of ztalmy in pediatric patients below 2 years of age have not been established. juvenile animal data oral administration of ganaxolone (0, 20, 45, 90/150/250/500 mg/kg/day) to juvenile rats from postnatal day (pnd) 7 through pnd 91 resulted in deaths associated with sedation and decreased male reproductive organ weights at the mid and high doses, and delayed female sexual maturation and decreased brain weights at all doses. there were no adverse effects on neurobehavioral (locomotor activity, auditory startle response, learning and memory) or reproductive function. a no-effect dose was not established. the lowest dose producing developmental toxicity in juvenile rats (20 mg/kg/day) was associated with plasma drug exposures (auc) less than that in pediatric patients at the maximum recommended human dose (mrhd) of 1800 mg. oral administration of ganaxolone (0, 10, 45, or 90 mg/kg/day) to rats on postnatal day (pnd) 7 resulted in widespread neuronal death in multiple brain regions, including cortex, thalamus, and hippocampus, at all doses. the pattern and extent of neuronal death was similar to that produced by intraperitoneal injection of the positive control, the nmda receptor antagonist mk-801 (1 mg/kg). the hippocampus, in particular, is recognized to have an important role in learning and memory. effects of ganaxolone and mk-801 on neurobehavioral function were not assessed in this study. 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. at the lowest-effect dose for neuronal death, plasma drug exposure in the neonatal rat was less than that in pediatric patients at the mrhd. 8.5 geriatric use cdd is largely a disease of pediatric and young adult patients. clinical studies of ztalmy did not include patients 65 years of age and older. 8.6 hepatic impairment the influence of hepatic impairment on the pharmacokinetics of ztalmy has not been evaluated. since ganaxolone undergoes clearance via the hepatic route, hepatic impairment can increase ganaxolone exposure. monitor patients with impaired hepatic function for the incidence of adverse reactions [see warnings and precautions (5) and adverse reactions (6) ] . patients with impaired hepatic function may require a reduced dosage of ztalmy.

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. 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, 10, 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) ] .

earning and memory) or reproductive function. a no-effect dose was not established. the lowest dose producing developmental toxicity in juvenile rats (20 mg/kg/day) was associated with plasma drug exposures (auc) less than that in pediatric patients at the maximum recommended human dose (mrhd) of 1800 mg. oral administration of ganaxolone (0, 10, 45, or 90 mg/kg/day) to rats on postnatal day (pnd) 7 resulted in widespread neuronal death in multiple brain regions, including cortex, thalamus, and hippocampus, at all doses. the pattern and extent of neuronal death was similar to that produced by intraperitoneal injection of the positive control, the nmda receptor antagonist mk-801 (1 mg/kg). the hippocampus, in particular, is recognized to have an important role in learning and memory. effects of ganaxolone and mk-801 on neurobehavioral function were not assessed in this study. 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. at the lowest-effect dose for neuronal death, plasma drug exposure in the neonatal rat was less than that in pediatric patients at the mrhd.

s approximately 99% protein-bound in serum. elimination the terminal half-life for ganaxolone is 34 hours. metabolism ganaxolone is metabolized by cyp3a4/5, cyp2b6, cyp2c19, and cyp2d6. excretion following a single oral dose of 300 mg [ 14 c]-ganaxolone to healthy male subjects, 55% of the total radioactivity was recovered in feces (2% as unchanged ganaxolone) and 18% of the total radioactivity dose was recovered in urine (undetected as unchanged ganaxolone). specific populations age, sex, and race are not expected to have a clinically-relevant effect on ganaxolone pharmacokinetics, after accounting for body weight. pediatric patients after accounting for body weight, the observed pharmacokinetic exposures in patients in study 1 [see clinical studies (14) ] were comparable across the age groups 2 to less than 6 years of age (n=45), 6 to less than 12 years of age (n=28), and 12 to less than 18 years of age (n=16). patients with renal impairment following oral administration of a single 300 mg dose of ztalmy in subjects with severe renal impairment (creatine clearance between 15 and 30 ml/min as estimated by cockcroft-gault formula), the auc 0-inf of ganaxolone decreased 8% and c max decreased 11% as compared to that in subjects with normal renal function (creatinine clearance ≥ 90 ml/min as estimated by cockcroft-gault formula). the changes in ganaxolone exposures when administered in patients with impaired renal function (creatinine clearance <90 ml/min) are not expected to be clinically significant. patients with hepatic impairment the influence of hepatic impairment on the pharmacokinetics of ganaxolone has not been studied. since ganaxolone undergoes clearance via the hepatic route, hepatic impairment is likely to increase ganaxolone exposures [see use in specific populations (8.6) ] . drug interaction studies in vitro studies enzymes ganaxolone is not an inhibitor of cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, or cyp3a4/5 at clinically relevant concentrations. ganaxolone is not an inducer of cyp1a2, cyp2b6, or cyp3a4/5 at clinically relevant concentrations. transporters ganaxolone does not inhibit bcrp, p-gp, mate1, mate2-k, oat1, oat3, oct1, oct2, oatp1b1, oatp1b3, or bsep at clinically relevant concentrations. ganaxolone is not a substrate of bcrp, p-gp, oct1, oct2, oatp1b1, or oatp1b3 at clinically relevant concentrations. in vivo studies cyp3a4 inducers coadministration of ztalmy with rifampin, a strong inducer of cyp2c19 and cyp3a4, and a moderate inducer of cyp2b6, decreased the ganaxolone c max and auc by 57% and 68%, respectively, in healthy subjects [see drug interactions (7.1) ] . no dedicated drug-interaction studies were conducted with moderate or weak cyp3a4 inducers. cyp3a4 inhibitors coadministration of ztalmy with itraconazole, a strong cyp3a4 inhibitor, increased the ganaxolone auc by 17% in healthy subjects (the c max was unchanged). the changes in ganaxolone exposures when coadministered with strong, moderate, or weak cyp3a4 inhibitors are not expected to be clinically significant. cyp3a4 substrates coadministration of ganaxolone at steady state (400 mg twice daily; 0.44 times the maximum recommended dosage) with midazolam, a sensitive cyp3a4 substrate, did not result in clinically relevant changes in exposures of the substrate in healthy subjects.

as unchanged ganaxolone). specific populations age, sex, and race are not expected to have a clinically-relevant effect on ganaxolone pharmacokinetics, after accounting for body weight. pediatric patients after accounting for body weight, the observed pharmacokinetic exposures in patients in study 1 [see clinical studies (14) ] were comparable across the age groups 2 to less than 6 years of age (n=45), 6 to less than 12 years of age (n=28), and 12 to less than 18 years of age (n=16). patients with renal impairment following oral administration of a single 300 mg dose of ztalmy in subjects with severe renal impairment (creatine clearance between 15 and 30 ml/min as estimated by cockcroft-gault formula), the auc 0-inf of ganaxolone decreased 8% and c max decreased 11% as compared to that in subjects with normal renal function (creatinine clearance ≥ 90 ml/min as estimated by cockcroft-gault formula). the changes in ganaxolone exposures when administered in patients with impaired renal function (creatinine clearance <90 ml/min) are not expected to be clinically significant. patients with hepatic impairment the influence of hepatic impairment on the pharmacokinetics of ganaxolone has not been studied. since ganaxolone undergoes clearance via the hepatic route, hepatic impairment is likely to increase ganaxolone exposures [see use in specific populations (8.6) ] . drug interaction studies in vitro studies enzymes ganaxolone is not an inhibitor of cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, or cyp3a4/5 at clinically relevant concentrations. ganaxolone is not an inducer of cyp1a2, cyp2b6, or cyp3a4/5 at clinically relevant concentrations. transporters ganaxolone does not inhibit bcrp, p-gp, mate1, mate2-k, oat1, oat3, oct1, oct2, oatp1b1, oatp1b3, or bsep at clinically relevant concentrations. ganaxolone is not a substrate of bcrp, p-gp, oct1, oct2, oatp1b1, or oatp1b3 at clinically relevant concentrations. in vivo studies cyp3a4 inducers coadministration of ztalmy with rifampin, a strong inducer of cyp2c19 and cyp3a4, and a moderate inducer of cyp2b6, decreased the ganaxolone c max and auc by 57% and 68%, respectively, in healthy subjects [see drug interactions (7.1) ] . no dedicated drug-interaction studies were conducted with moderate or weak cyp3a4 inducers. cyp3a4 inhibitors coadministration of ztalmy with itraconazole, a strong cyp3a4 inhibitor, increased the ganaxolone auc by 17% in healthy subjects (the c max was unchanged). the changes in ganaxolone exposures when coadministered with strong, moderate, or weak cyp3a4 inhibitors are not expected to be clinically significant. cyp3a4 substrates coadministration of ganaxolone at steady state (400 mg twice daily; 0.44 times the maximum recommended dosage) with midazolam, a sensitive cyp3a4 substrate, did not result in clinically relevant changes in exposures of the substrate in healthy subjects.

ess than that in adult humans at the maximum recommended human dose of 1800 mg.

ans at the maximum recommended human dose of 1800 mg.

ts in the ztalmy arm weighing more than 28 kg received a maintenance dosage of 600 mg three times daily [see dosage and administration (2.1) ]. ninety-six percent of patients were taking between 1 to 4 concomitant aeds. the most frequently used concomitant aeds (in at least 20% of patients) were valproate (42%), levetiracetam (32%), clobazam (29%), and vigabatrin (24%). the primary efficacy endpoint was the percentage change in the 28-day frequency of major motor seizures (defined similarly as in the 2-month period prior to screening) from a 6-week prospective baseline phase during the 17-week double-blind phase. patients treated with ztalmy had a significantly greater reduction in the 28-day frequency of major motor seizures compared to patients receiving placebo (see table 5 ). table 5 change in frequency of major motor seizures per 28 days in patients with cdd (study 1) frequency of major motor seizures (per 28 days) placebo (n=51) ztalmy (n=49) prospective baseline phase median seizure frequency 49 54 median percent change from baseline during treatment -7 -31 p-value compared to placebo obtained from a wilcoxon rank-sum test 0.0036 figure 1 displays the percentage of patients by category of reduction from baseline in the 28-day frequency of major motor seizures during the 17-week double-blind phase. figure 1 proportion of patients by category of seizure response for ztalmy and placebo in patients with cdd (study 1) figure 1

atients not to discontinue use of ztalmy without consulting with their healthcare provider. ztalmy should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see dosage and administration (2.3) and warnings and precautions (5.3) ] . administration information advise patients who are prescribed ztalmy to use the adapter and oral dosing syringes provided by their pharmacist [see dosage and administration (2.2) and instructions for use ] . instruct patients to take ztalmy with food [see dosage and administration (2.1) ] . instruct patients to shake ztalmy thoroughly for at least 1 minute and then wait for 1 minute before measuring and administering each dose [see dosage and administration (2.2) and instructions for use ] . instruct patients to discard any unused ztalmy oral suspension after 30 days of first opening the bottle [see dosage and administration (2.2) and how supplied/storage and handling (16.2) ] . pregnancy registry advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during ztalmy therapy. encourage women who are taking ztalmy to enroll in the north american antiepileptic drug (naaed) pregnancy registry if they become pregnant. this registry is collecting information about the safety of antiepileptic drugs during pregnancy [see use in specific populations (8.1) ] . potential for abuse advise patients that ztalmy can be abused or lead to dependence [see drug abuse and dependence (9) ] .