Ztalmy

Description for Ztalmy

ZTALMY (ganaxolone) oral suspension contains ganaxolone, a neuroactive steroid gammaaminobutyric acid A (GABAA) receptor positive modulator. Ganaxolone (1-[(3R, 5S, 8R, 9S, 10S, 13S, 14S, 17S)-3-hydroxy-3, 10, 13-trimethyl-1, 2, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16, 17- tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone) is a methyl-substituted (at the 3ß position) analog of the endogenous neurosteroid allopregnanolone, a derivative of progesterone. Its empirical formula is C₂₂H₃₆O₂, and the molecular weight is 332.53 g/mol. The chemical structure is:

Ganaxolone is a white to off-white crystalline powder that only exists in one crystal form and has low aqueous solubility.

ZTALMY is an oral suspension of ganaxolone. Each mL of oral suspension contains 50 mg of ganaxolone. Inactive ingredients include artificial cherry flavor, citric acid, hypromellose, methylparaben, polyvinyl alcohol, propylparaben, purified water, simethicone emulsion, sodium benzoate, sodium citrate, sodium lauryl sulfate, and sucralose.

ADVERSE REACTIONS

The following important adverse reactions are described elsewhere in the labeling:

• Somnolence and Sedation [see Warnings and Precautions (1)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (2)]
• Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (3)]

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*	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
* somnolence includes the terms lethargy and hypersomnia

Drug Interactions for Ztalmy

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)].

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)].

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)].

DRUG ABUSE AND DEPENDENCE

Controlled Substance

ZTALMY contains ganaxolone, a Schedule V controlled substance (CV).

Abuse

Ganaxolone has potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. In a human abuse potential study, 400, 800, and 2000 mg oral doses of ZTALMY were compared to a 6 mg oral dose of lorazepam and placebo. On positive subjective measures of "drug liking”, “overall drug liking”, “high”, “good drug effects”, and “take drug again”, the 400 and 800 mg doses of ZTALMY produced mean scores that were within or just outside of the acceptable placebo range and were not statistically significantly different than placebo. The 2000 mg dose of ZTALMY produced responses on these positive subjective measures that were slightly greater than the acceptable placebo range and were statistically significantly greater than placebo. Scores on these positive subjective measures for all three doses of ZTALMY were statistically significantly lower than those produced by lorazepam.

Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. During clinical studies with ZTALMY, it was not possible to assess physical dependence because abrupt discontinuation of an antiepileptic medication in patients with epilepsy presents a serious safety concern. It is recommended that ZTALMY be tapered according to the dosage recommendations, unless symptoms warrant immediate discontinuation [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].

Warnings for Ztalmy

Included as part of the PRECAUTIONS section.

Precautions for Ztalmy

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.

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.

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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenicity studies have been conducted with ganaxolone.

Mutagenesis

Ganaxolone was negative for genotoxicity in in vitro (Ames and mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays. The major circulating human metabolite, oxy-dehydro- ganaxolone, was negative for mutagenicity in the in vitro Ames assay but positive for clastogenicity in an in vitro mammalian chromosomal aberration test in human peripheral blood lymphocytes.

Impairment of Fertility

Oral administration of ganaxolone (0, 10, 20 or 40 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females during early gestation resulted in alterations in estrous cyclicity at the high dose. There were no effects on spermatogenesis, reproductive performance and fertility, or early embryonic development. The highest dose tested (40 mg/kg/day) was associated with plasma exposures (AUC) less than that in adult humans at the maximum recommended human dose of 1800 mg.

OVERDOSES

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.

Contraindications for Ztalmy

No information provided.

Clinical Pharmacology for Ztalmy

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.

Pharmacodynamics

Cardiac Electrophysiology

At therapeutic exposures, ZTALMY does not prolong the QTc interval. QT effects of ZTALMY at high clinical exposure scenarios have not been evaluated.

Pharmacokinetics

Absorption

Following oral administration of ZTALMY, ganaxolone is absorbed with a time to maximum plasma concentration (Tmax) of 2 to 3 hours. 

Effect of Food

When ZTALMY was administered with a high-fat meal, the Cmax and AUC increased by 3- and 2-fold, respectively, when compared to administration under fasted conditions. ZTALMY was administered with food in the clinical efficacy study, Study 1 [see Dosage and Administration (2.1)]. The efficacy of ZTALMY when administered in the fasted state is unknown. 

Distribution

Ganaxolone is 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, CYP2D6, UGT1A3, UGT1A6, UGT1A9, UGT2B7, and UGT2B15.

Excretion

Following a single oral dose of 300 mg [14C]-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 AUC0-INF of ganaxolone decreased 8% and Cmax 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 was studied following a single oral dose of ZTALMY 300 mg. In subjects with mild hepatic impairment (Child-Pugh class A), Cmax and AUClast increased by 38% and 8%, respectively, compared to subjects with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B), Cmax and AUClast increased by 45% and 50%, respectively, compared to subjects with normal hepatic function. In subjects with severe hepatic impairment (Child-Pugh class C), Cmax and AUClast increased by 148% and 269%, respectively, compared to subjects with normal hepatic function [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies CYP3A4 Inducers

Coadministration of ZTALMY with rifampin, a strong inducer of CYP2C19 and CYP3A4, and a

moderate inducer of CYP2B6, decreased Cmax and AUC of ganaxolone by 57% and 68%, respectively, in healthy subjects [see Drug Interactions (7.2)]. 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 AUC of ganaxolone by 17% in healthy subjects (Cmax was unchanged). 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.

In Vitro Studies CYP450 Enzymes

Ganaxolone does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 at clinically relevant concentrations. Ganaxolone does not induce CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

UGT Enzymes

Ganaxolone is a substrate for UGT1A3, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. Ganaxolone does not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.

Transporter Systems

Ganaxolone is not a substrate of BCRP, P-gp, OCT1, OCT2, OATP1B1, or OATP1B3 at clinically relevant concentrations. Ganaxolone does not inhibit BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or BSEP at clinically relevant concentrations.

Patient Information for Ztalmy

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Somnolence and Sedation

Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that ZTALMY does not affect them adversely (e.g., impair judgment, thinking, or motor skills) [see Warnings and Precautions (5.1)].

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and their families that antiepileptic drugs, including ZTALMY, may increase the risk of suicidal thoughts and behavior and advise them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.2)].

Withdrawal of Antiepileptic Drugs (AEDs)

Advise patients 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 (2.4) 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)].

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