8/22. Ganaxolone- (ZYTALMY)- (Mar 2022)- to treat seizures in cyclic-dependent kinase like deficiency
Drug Interaction:
DRUG INTERACTIONS(Summary)-
• 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.
DRUG INTERACTIONS-(details)
1. 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
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
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 .
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
Indication:
BRIEF SUMMARY-
GANAXOLONE- (Mar 2022)
Indn- To treat Seizures in Cyclic -dependent Kinase - like s deficiency disorder
Dosage- Oral suspension 50 mg/mL Administer ZTALMY orally three times daily with food.
Titrate gradually according to the recommended schedules.
Dosage for patients weighing 28 kg or less : the starting dosage is 6 mg/kg three times daily (18 mg/kg/day)
the maximum dosage is 21 mg/kg three times daily (63 mg/kg/daily)
ADR- Most common adverse reactions and at least twice the rate of placebo) are somnolence, pyrexia, salivary hypersecretion, and seasonal allergy.
CI- None.
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 the drug. Concomitant use with other CNS depressants or alcohol could potentiate adverse effects.
Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts.
Pat Inform
Somnolence and Sedation- Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that the drug does not affect them adversely.
Suicidal Thinking and Behavior- Counsel patients, their caregivers, and their families that antiepileptic drugs, including , may increase the risk of suicidal thoughts and behavior and advise them to be alert for the emergence or worsening of symptoms of depression,
==================================================================
U.S. FDA APPROVED DRUGS SURING 2022
Serial No 8
Name of the Drug- ZTALMY
Active Ingredient - Ganaxolone
Pharmacological Classification- To treat Seizures in Cyclic -dependent Kinase - like s deficiency disorder
Date of Approval- 3/18/22
HIGHLIGHTS OF PRESCRIBING INFORMATION-
These highlights do not include all the information needed to use ZTALMY® safely and effectively. See full prescribing information for ZTALMY. ZTALMY® (ganaxolone) oral suspension, CXX [pending controlled substance scheduling]
Initial U.S. Approval: [pending controlled substance scheduling]
INDICATIONS AND USAGE-
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.
Adverse Reaction:
ADVERSE REACTIONS-
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.
Contra-Indications:
CONTRAINDICATIONS- None.
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.
.•Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts.
•Withdrawal of Antiepileptic Drugs: ZTALMY should be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus.
ADVERSE REACTIONS-
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)
Dosages/ Overdosage Etc:
DOSAGE AND ADMINISTRATION-
• Administer ZTALMY orally three times daily with food.
• Titrate ZTALMY gradually according to the recommended schedules. See full prescribing information.
• Dosage for patients weighing 28 kg or less : o the starting dosage is 6 mg/kg three times daily (18 mg/kg/day)
o the maximum dosage is 21 mg/kg three times daily (63 mg/kg/daily)
• Dosage for patients weighing over 28 kg): o the starting dosage is 150 mg three times daily (450 mg daily)
o the maximum dosage is 600 mg three times daily (1800 mg daily).
DOSAGE FORMS AND STRENGTHS- - Oral suspension 50 mg/mL
Patient Information:
PATIENT COUNSELING INFORMATION
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)
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.
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
Administration information - Advise patients who are prescribed ZTALMY to use the adaptor and oral dosing syringes provided by their pharmacist..
Instruct patients to take ZTALMY with food ].
Instruct patients to shake ZTALMY thoroughly for at least 1 minute and then wait for 1 minute before measuring and administering each dose.
Instruct patients to discard any unused ZTALMY oral solution after 30 days of first opening the bottle,
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..
Potential for Abuse- Advise patients that ZTALMY can be abused or lead to dependence.
.
Marketed by:
Marinus Pharmaceuticals, Inc.
5 Radnor Corporate Center
100 Matsonford Road,
Suite 500 (5th Floor)
Radnor, PA 19807 USA
© 2022 Marinus Pharmaceuticals, Inc. All rights reserved.
14
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
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 (GABAA) receptor in the CNS.
2. Pharmacodynamics-
There are no relevant data on the pharmacodynamic effects of ganaxolone.
3. 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,
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, and CYP2D6.
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 ganoxolone).
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 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
The influence of renal impairment on the pharmacokinetics of ganaxolone has not been studied; however, renal excretion is a minor pathway in the elimination of ganaxolone.
Therefore, renal impairment is unlikely to result in clinically significant increases in ganaxolone exposures.
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 .
Drug Interaction Studies-
In Vitro Studies-
Enzymes-
Ganaxolone is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 at clinically relev ant 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 ofBCRP, 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 Cmax and AUC by 57% and 68%, respectively, in healthy subjects 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 Cmax 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.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
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..
Risk Summary- There are no available data on ZTALMY use in pregnant women to inform a drug-associated risk of adverse developmental outcomes.
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.
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
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.
3.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
Safety and effectiveness of ZTALMY in pediatric patients below 2 years of age have not been established.
4. 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.
5.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.
DRUG ABUSE AND DEPENDENCE
1. Controlled Substance
ZTALMY contains ganaxolone. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration.)
2. 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 effec
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.
3. 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
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.
