Ganaxolone (Monograph)

Brand name: Ztalmy
Drug class: Anticonvulsants, Miscellaneous

Medically reviewed by Drugs.com on Aug 28, 2023. Written by ASHP.

Introduction

Anticonvulsant; a neuroactive steroid gamma-aminobutyric acid A (GABA_A) receptor positive modulator.

Uses for Ganaxolone

Seizures Associated with Cyclin-dependent Kinase-like 5 Deficiency

Treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients ≥2 years of age.

Ganaxolone Dosage and Administration

General

Patient Monitoring

• Monitor for suicidal thoughts or behavior.

• Monitor for the development of somnolence and sedation.

Other General Considerations

• Titrate slowly based on tolerability. Do not increase dose more frequently than every 7 days or in increments exceeding manufacturer dosage recommendations.

• Avoid abrupt discontinuation; taper medication slowly to minimize the risk of increased seizure frequency and status epilepticus. Rapid discontinuation may be considered if withdrawal is needed due to a serious adverse event.

Administration

Administer orally 3 times daily with food.

Available as a 50-mg/mL oral suspension.

Shake thoroughly for at least 1 minute before use. Wait 1 minute before measuring and administering dose to allow foam to settle. Use an oral syringe for administration.

Dosage

Pediatric Patients

Seizures Associated with Cyclin-dependent Kinase-like 5 Deficiency

Children ≥2 years of age weighing ≤28 kg:

Oral

• Days 1–7: 6 mg/kg 3 times daily

• Days 8–14: 11 mg/kg 3 times daily

• Days 15–21: 16 mg/kg 3 times daily

• Days 22 to ongoing: 21 mg/kg 3 times daily (maximum recommended dose)

Children ≥2 years of age weighing >28 kg:

Oral

• Days 1–7: 150 mg (3 mL) 3 times daily

• Days 8–14: 300 mg (6 mL) 3 times daily

• Days 15–21: 450 mg (9 mL) 3 times daily

• Days 22 to ongoing: 600 mg (12 mL) 3 times daily (maximum recommended dose)

Adults

Seizures Associated with Cyclin-dependent Kinase-like 5 Deficiency

Patients weighing >28 kg:

Oral

• Days 1–7: 150 mg (3 mL) 3 times daily

• Days 8–14: 300 mg (6 mL) 3 times daily

• Days 15–21: 450 mg (9 mL) 3 times daily

• Days 22 to ongoing: 600 mg (12 mL) 3 times daily (maximum recommended dose)

Special Populations

Hepatic Impairment

No dosage adjustment necessary for mild or moderate hepatic impairment (Child-Pugh class A or B). Manufacturer recommends dosage adjustments for severe hepatic impairment (Child-Pugh class C); refer to Tables 1 and 2.

Renal Impairment

No dosage adjustment required.

Geriatric Use

No specific dosage recommendations at this time.

Cautions for Ganaxolone

Contraindications

None.

Warnings/Precautions

Neurologic Effects

Somnolence and sedation reported. Usually dose-related. Often appear early during treatment.

Concurrent use with other CNS depressants may potentiate neurologic effects. Monitor patients for somnolence and sedation. Advise patients not to drive or operate machinery until the effects of the drug are known.

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed as early as 1 week after beginning therapy and persisted for the duration of treatment assessed. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Closely monitor all patients currently receiving or beginning therapy with any anticonvulsant for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.

Balance risk of suicidality with risk of untreated illness. Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality. If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.

Discontinuance of Therapy

Abrupt withdrawal of anticonvulsants may increase seizure frequency and risk of status epilepticus. Gradually withdraw therapy. Consider prompt withdrawal if discontinuance is necessary because of serious adverse effects.

Abuse Potential and Dependence

Ganaxolone is subject to control as a schedule V (C-V) drug. Positive subjective measures of drug-liking and euphoria reported.

Physical dependence and withdrawal syndrome were not evaluated. Taper ganaxolone gradually per dosage recommendations unless symptoms warrant immediate discontinuation.

Specific Populations

Pregnancy

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].

No adequate data in humans; in animal studies, developmental toxicity (i.e., fetal malformations, neurodegeneration, neurobehavioral and growth impairment) observed at clinically relevant doses.

Lactation

Distributed into human milk; effects on milk production or on breast-fed infant unknown. Exposures in human milk are approximately 4 times higher than those in maternal plasma; estimated daily infant dose <1% of the maternal dose and approximately 0.24% of the labeled pediatric dose.

Pediatric Use

Safety and efficacy for treatment of seizures associated with CDD in pediatric patients ≥2 years of age established in principal efficacy study.

Safety and efficacy in pediatric patients <2 years of age not established. Animal data suggest possible toxicity at clinically relevant dosages.

Geriatric Use

Safety and efficacy not established in patients ≥65 years of age. CDD is largely a disease of pediatric and young adult patients.

Hepatic Impairment

Administration in severe hepatic impairment (Child-Pugh class C) results in increase in ganaxolone concentrations; dosage adjustments required for these patients. No dosage adjustments required for patients with mild or moderate hepatic impairment (Child-Pugh class A or B).

Renal Impairment

Mild, moderate, or severe renal impairment (Cr_Cl <90 mL/minute) not expected to have clinically important effect on pharmacokinetics.

Common Adverse Effects

Common adverse reactions (≥5%): somnolence, pyrexia, salivary hypersecretion, seasonal allergy.

Drug Interactions

Metabolized by CYP isoenzymes 3A4/5, 2B6, 2C19, and 2D6.

Not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 or an inducer of CYP1A2, CYP2B6, or CYP3A4/5 at clinically relevant concentrations.

Does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein (MATE) 1, MATE2-K, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transporter protein (OATP) 1B1, OATP1B3, or bile salt export pump (BSEP) at clinically relevant concentrations. Not a substrate of BCRP, P-gp, OCT1, OCT2, OATP1B1, or OATP1B3 at clinically relevant concentrations.

Drugs Affecting Hepatic Microsomal Enzymes

Strong or moderate CYP inducers: Coadministration can decrease ganaxolone plasma concentrations and result in decreased efficacy. Avoid concomitant use. If coadministration is necessary, consider increasing ganaxolone dosage. Do not exceed the maximum daily dosage.

CYP3A4 inhibitors: Clinically important changes in ganaxolone exposure not expected when coadministered with strong, moderate, or weak CYP3A4 inhibitors.

Specific Drugs and Foods

Ganaxolone Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma concentrations 2-3 hours.

Food

Peak plasma concentrations and overall exposure increased by 3- and 2-fold, respectively, when administered with high-fat meal compared with fasted conditions. Efficacy not evaluated when administered in the fasted state.

Special Populations

Systemic exposure and peak plasma concentrations decreased by 8% and 11%, respectively, in patients with severe renal impairment (Cr_Cl 15–30 mL/minute) compared to those with normal renal function.

Distribution

Extent

Distributed into human milk. Calculated relative infant dose approximately 0.157 mg/kg per day based on average milk intake of 150 mL/kg per day. Equivalent to <1% of the maternal dose and approximately 0.24% of the labeled pediatric dose.

Plasma Protein Binding

Approximately 99%.

Elimination

Metabolism

Metabolized by CYP3A4/5, CYP2B6, CYP2C19, and CYP2D6.

Elimination Route

Approximately 55% of a radioactive dose was recovered in feces (2% unchanged drug) and 18% in urine (unchanged drug not detected).

Half-life

34 hours.

Stability

Storage

Oral

Suspension

Store in original bottle in upright position at 20–25°C (excursions permitted from 15–30°C). Keep cap tightly closed. Use within 30 days of first opening bottle.

Actions

Exact mechanism of anticonvulsant action in CDD unknown.

Synthetic analog of allopregnanolone, an endogenous GABAergic inhibitor.

Exhibits neurosteroid modulating effects; thought to block seizure propagation via positive allosteric modulation of GABAA receptors to normalize over-excited neurons.

Advice to Patients

• Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that ganaxolone does not affect them adversely (e.g., impair judgment, thinking, or motor skills).

• Counsel patients, their caregivers, and their families that antiepileptic drugs, including ganaxolone, 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.

• Advise patients not to discontinue use of ganaxolone without consulting with their healthcare provider. Ganaxolone should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.

• Advise patients who are prescribed ganaxolone to use the adapter and oral dosing syringes provided by their pharmacist.

• Instruct patients to take ganaxolone with food.

• Instruct patients to shake ganaxolone thoroughly for at least 1 minute and then wait for 1 minute before measuring and administering each dose.

• Instruct patients to discard any unused ganaxolone oral suspension after 30 days of first opening the bottle.

• Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during ganaxolone therapy. Encourage women who are taking ganaxolone 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.

• Advise patients that ganaxolone can be abused or lead to dependence.

• Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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