Ztalmy
(ganaxolone)Dosage & Administration
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Ztalmy Prescribing Information
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.
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.
| 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 |
| 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 |
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)].
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.
| Dosage | Total Daily Dosage | Days |
|---|---|---|
| 2 mg/kg three times daily | 6 mg/kg/day | 1 to 7 |
| 3.66 mg/kg three times daily | 11 mg/kg/day | 8 to 14 |
| 5.33 mg/kg three times daily | 16 mg/kg/day | 15 to 21 |
| 7 mg/kg three times daily | 21 mg/kg/day | 22 to ongoing |
| Dosage | mL per Dose | Total daily dosage | Days |
|---|---|---|---|
| 50 mg three times daily | 1 | 150 mg | 1 to 7 |
| 100 mg three times daily | 2 | 300 mg | 8 to 14 |
| 150 mg three times daily | 3 | 450 mg | 15 to 21 |
| 200 mg three times daily | 4 | 600 mg | 22 to ongoing |
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)].
Oral suspension: 50 mg/mL ganaxolone. Each bottle contains 110 mL of white to off-white cherry flavored suspension.
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.
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)].
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.
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.
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.
Hepatic Impairment
Administration of ZTALMY in patients with severe hepatic impairment (Child-Pugh class C) results in elevated ganaxolone plasma concentrations [see Clinical Pharmacology (12.3)]. Therefore, dosage adjustment in these patients during titration and maintenance is required [see Dosage and Administration (2.3)].
No dosage adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.
None.
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.
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.
| 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.
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.