AHFS Class:

• GABA-mediated Anticonvulsants 28:12.28

Generic Name(s):

• Ganaxolone

Ganaxolone, a neuroactive steroid gamma-aminobutyric acid A (GABA_A) receptor positive modulator, is an anticonvulsant.1,3,7,8

Seizures Associated with Cyclin-dependent Kinase-like 5 Deficiency

Ganaxolone is used for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older.1

Efficacy of ganaxolone for the treatment of seizures associated with CDD was established in a multicenter, randomized, double-blind, placebo-controlled trial in 101 patients 2 to 21 years of age (Study 1; NCT03572933).1,3 Enrolled patients had molecular confirmation of a pathogenic or probably pathogenic CDKL5 gene mutation and inadequately controlled seizures including a minimum of 16 major motor seizures per 28 days during the 2 months prior to screening.1,3 Major motor seizures included bilateral tonic, generalized tonic-clonic, bilateral clonic, atonic, and focal to bilateral tonic-clonic seizures.1,3 Nearly all patients (96%) were taking between 1 to 4 concomitant antiepileptic drugs, most commonly valproate (42%), levetiracetam (32%), clobazam (29%), or vigabatrin (24%).1 The median age of patients was 6 years (range: 3 to 11); 79% were female.3 After a 6-week baseline period, patients were randomized to adjunctive ganaxolone or placebo.1,3 Ganaxolone or placebo was given as an oral solution and titrated for 4 weeks up to a maximum dosage of 21 mg/kg 3 times daily in patients weighing ≤28 kg or 600 mg 3 times daily in patients weighing >28 kg.1,3 Maintenance dosing was continued for 13 weeks, at which point patients were allowed to enter the open-label phase of the trial.3

The primary efficacy endpoint was the percentage change in the 28-day frequency of major motor seizures from the 6-week baseline period during the 17-week double-blind treatment phase.1,3 At baseline, median 28-day seizure frequency was 54 in the ganaxolone group and 49 in the placebo group.1,3 3 Major motor seizure frequency decreased by a median of 31% in the ganaxolone group and 7% in the placebo group during treatment.1,3 Similar results were observed during the 4-week titration period and continued throughout the 13-week maintenance period.3 Reduction of major motor seizure frequency of at least 50% occurred in approximately 24% of patients receiving ganaxolone and 10% of patients receiving placebo.3

Clinical Perspective

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare, X-linked epileptic encephalopathy.3,4 The condition is caused by mutations in the CDKL5 gene and is characterized by early-onset, refractory seizures that develop shortly after birth as well as severe neurodevelopmental impairment.3,4 Patients with CDD often have multiple seizures daily and can have differing seizure types over time.3 There are currently no available treatment guidelines for CDD; seizures associated with the disorder are commonly refractory to anticonvulsant drugs.3,4 Ganaxolone is the first treatment labeled for seizures associated with CDD.3,4

General

Patient Monitoring

• Monitor all patients currently receiving or beginning therapy with any anticonvulsant for the emergence or worsening of suicidal thoughts or behavior or depression.1
• Monitor for the development of somnolence and sedation.1

Other General Considerations

• Titrate slowly based on tolerability.1 Do not increase dose more frequently than every 7 days or in increments exceeding manufacturer dosage recommendations.1
• Avoid abrupt discontinuation; taper medication slowly to minimize the risk of increased seizure frequency and status epilepticus.1 Rapid discontinuation may be considered if withdrawal is needed due to a serious adverse event.1

Administration

Ganaxolone is administered orally 3 times daily as an oral suspension; the drug must be taken with food.1 Shake the bottle thoroughly for at least 1 minute, then wait 1 minute before measuring and administering the dose.1 An oral syringe must be used for measuring and administering the drug.1

Store ganaxolone upright in the original bottle at 20 to 25°C; excursions permitted from 15 to 30°C.1 Close the cap tightly after each use.1 Use within 30 days of first opening the bottle; discard any remaining drug.1

Dosage

Ganaxolone is available as a 50 mg/mL oral suspension.1

Pediatric Patients

Seizures Associated with Cyclin-dependent Kinase-like 5 Deficiency

For the treatment of seizures associated with CDD, the dosage of ganaxolone is based on weight and is titrated based on tolerability.1 The dosage may be increased no more frequently than every 7 days.1 Do not exceed recommended titration increments.1

For children ≥2 years of age weighing ≤28 kg:

• Days 1-7: 6 mg/kg 3 times daily1
• Days 8-14: 11 mg/kg 3 times daily1
• Days 15-21: 16 mg/kg 3 times daily1
• Days 22 to ongoing: 21 mg/kg 3 times daily (maximum recommended dose)1

For children ≥2 years of age weighing >28 kg:

• Days 1-7: 150 mg (3 mL) 3 times daily1
• Days 8-14: 300 mg (6 mL) 3 times daily1
• Days 15-21: 450 mg (9 mL) 3 times daily1
• Days 22 to ongoing: 600 mg (12 mL) 3 times daily (maximum recommeded dose)1

Adults

Seizures Associated with Cyclin-dependent Kinase-like 5 Deficiency

For the treatment of seizures associated with CDD, the dosage of ganaxolone is based on weight and is titrated based on tolerability.1 The dosage may be increased no more frequently than every 7 days.1 Do not exceed recommended titration increments.1

Patients weighing >28 kg:

• Days 1-7: 150 mg (3 mL) 3 times daily1
• Days 8-14: 300 mg (6 mL) 3 times daily1
• Days 15-21: 450 mg (9 mL) 3 times daily1
• Days 22 to ongoing: 600 mg (12 mL) 3 times daily (maximum recommended dose)1

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 The manufacturer recommends titration and maintenance dosage adjustments for patients with severe hepatic impairment (Child-Pugh class C); refer to Tables 1 and 2.1 Dosage should be increased based on tolerability no more frequently than every 7 days and titration increments should not exceed those seen in Tables 1 and 2.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Geriatric Use

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• None.1

Warnings/Precautions

Neurologic Effects

Ganaxolone can cause somnolence and sedation.1 In Study 1, the incidence of somnolence and sedation was 44% in patients receiving ganaxolone compared with 24% in patients receiving placebo.1 Somnolence and sedation appeared early during treatment and were generally dose-related.1

Other CNS depressants (e.g., opioids, antidepressants, alcohol) may potentiate somnolence and sedation in patients receiving ganaxolone.1 Monitor patients for somnolence and sedation and advise patients not to drive or operate machinery until the effects of the drug are known.1

Suicidality Risk

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of 199 studies using various anticonvulsants (but not ganaxolone) compared with placebo.1 The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,6 This increased suicidality risk was observed as early as 1 week after beginning therapy and persisted for the duration of treatment assessed.1 6 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,6

Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy; closely monitor all patients currently receiving or beginning therapy with any anticonvulsant for the emergence or worsening of suicidal thoughts or behavior or depression.1

Clinicians who prescribe ganaxolone or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness.1 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness being treated.1

Discontinuance of Therapy

As with most anticonvulsant agents, there is a potential for increased seizure frequency and status epilepticus when ganaxolone is discontinued abruptly.1 Taper medication slowly to minimize risk.1 Rapid discontinuation may be considered if withdrawal is needed due to a serious adverse event.1

Abuse Potential and Dependence

Ganaxolone is subject to control as a schedule V (C-V) drug.1 In an abuse-potential study, positive subjective measures of drug liking and euphoria were similar for ganaxolone doses of 400 mg or 800 mg and placebo.1 These effects were reported more frequently with ganaxolone 2000 mg compared with placebo.1 Positive subjective measures were reported less frequently with ganaxolone than lorazepam, a schedule IV drug.1

Physical dependence and withdrawal syndrome were not evaluated.1 Ganaxolone should be withdrawn gradually according to the dosage recommendations unless symptoms warrant immediate discontinuation.1

Specific Populations

Pregnancy

There are no adequate data in humans to determine if there is any risk associated with the use of ganaxolone during pregnancy.1 In animal studies, adverse effects on development (i.e., fetal malformations, neurobehavioral and growth impairment) were observed in mice or rats during organogenesis (mice) or throughout gestation and lactation (rats) at maternal exposures lower than those occurring at the maximum recommended human dose.1 Widespread neurodegeneration in the cortex, thalamus, and hippocampus was observed in rats exposed to ganaxolone on postnatal day 7.1 A no-effect dose was not identified.1 Brain development in rats on postnatal day 7 corresponds to a period of brain development in humans that begins during the third trimester of pregnancy and continues for the first several months to years after birth.1

Women who are pregnant while receiving ganaxolone should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].1

Lactation

Ganaxolone is excreted in human milk.1 Following a single oral dose of ganaxolone 300 mg, exposures in human milk were approximately 4 times higher than those in maternal plasma.1 The calculated maximum relative infant dose of ganaxolone is approximately 0.157 mg/kg per day based on an average milk intake of 150 mL/kg per day, which is <1% of the maternal dose, and approximately 0.24% of the labeled pediatric dose of 63 mg/kg per day.1 It is not known whether ganaxolone affects milk production or the breast-fed infant.1

Consider the benefits of breast-feeding along with the importance of ganaxolone to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy for the treatment of seizures associated with CDD in pediatric patients 2 years of age and older were established in the principle efficacy study (Study 1).1

Safety and efficacy in pediatric patients <2 years of age have not been established.1 Oral administration of ganaxolone to juvenile rats from postnatal day 7 through postnatal day 91 resulted in deaths associated with sedation as well as developmental toxicity at clinically relevant doses.1 Neurobehavioral (locomotor activity, auditory startle response, learning and memory) and reproductive function were not affected.1 Widespread neurodegeneration in multiple brain regions was observed in rats exposed to ganaxolone on postnatal day 7; effects on neurobehavioral function were not assessed.1

Geriatric Use

Safety and efficacy of ganaxolone have not been established in patients 65 years of age and older.1 CDD is largely a disease of pediatric and young adult patients.1

Hepatic Impairment

Administration of ganaxolone in patients with severe hepatic impairment (Child-Pugh class C) results in an increase in ganaxolone plasma concentrations.1 Dosage adjustments are required for these patients.1 Patients with mild or moderate hepatic impairment (Child-Pugh class A or B) do not require dosage adjustments.1

Renal Impairment

Mild, moderate, or severe renal impairment (creatinine clearance <90 mL/minute) is not expected to have a clinically important effect on the pharmacokinetics of ganaxolone.1 Following a single dose of ganaxolone 300 mg, systemic exposure decreased 8% and maximum plasma concentration decreased 11% in patients with severe renal impairment (creatinine clearance 15-30 mL/minute) compared with those with normal renal function.1

Common Adverse Effects

Common adverse reactions occurring at an incidence ≥5% for ganaxolone and at least twice the rate of placebo are somnolence, pyrexia, salivary hypersecretion, and seasonal allergy.1

Ganaxolone is metabolized by cytochrome P-450 (CYP) isoenzymes 3A4/5, 2B6, 2C19, and 2D6.1

In vitro, ganaxolone is 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.1

Ganaxolone 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.1 Ganaxolone is not a substrate of BCRP, P-gp, OCT1, OCT2, OATP1B1, or OATP1B3 at clinically relevant concentrations.1

Drugs Affected or Metabolized by Hepatic Microsomal Enzymes

Coadministration of ganaxolone with CYP inducers, such as strong or moderate CYP3A4 inducers, will decrease ganaxolone exposure, which can decrease efficacy of the anticonvulsant.1 Avoid concomitant use of ganaxolone with strong or moderate CYP3A4 inducers.1 If concomitant use is unavoidable, consider an increase in the dosage of ganaxolone; however, do not exceed the maximum daily dosage.1

In patients on a stable ganaxolone dosage who are initiating or increasing dosages of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, phenobarbital, and primidone), the dosage of ganaxolone may need to be increased; however, do not exceed the maximum daily dosage.1

Rifampin, a strong CYP2C19 and CYP3A4 inducer and moderate CYP2B6 inducer, decreased ganaxolone Cmax and AUC by 57% and 68%, respectively.1

CNS Depressants and Alcohol

Concomitant use of ganaxolone with CNS depressants, including alcohol, may increase the risk of somnolence and sedation.1

Pharmacology

Description

Ganaxolone, a neuroactive steroid gamma-aminobutyric acid A (GABA_A) receptor positive modulator, is an anticonvulsant.1,3,7,8 Ganaxolone is a synthetic analog of allopregnanolone, an endogenous metabolite of progesterone and neurosteroid with GABAergic inhibitor effects that interacts with GABA_A receptors and increases CNS inhibition.7,8 Ganaxolone exhibits similar neurosteroid modulating effects.7,8 While the exact mechanism of action in the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder is unknown, ganaxolone is thought to block seizure propagation via positive allosteric modulation of GABA_A receptors to normalize over-excited neurons.1,7,8

Pharmacokinetics

Peak ganaxolone plasma concentrations occur 2 to 3 hours following oral administration.1 Administration with a high-fat meal increases ganaxolone maximum plasma concentration and systemic exposure 3- and 2-fold, respectively, compared with administration under fasted conditions.1 Ganaxolone should be administered with food.1 Ganaxolone is approximately 99% protein-bound in serum.1 It is metabolized by CYP3A4/5, CYP2B6, CYP2C19, and CYP2D6.1 Following administration of radiolabeled ganaxolone, approximately 55% of the total radioactive dose was recovered in feces (2% unchanged drug) and 18% in urine (unchanged drug undetected).1 The apparent terminal half-life of ganaxolone is 34 hours.1 Pharmacokinetics of the drug are not affected by age, sex, or race after accounting for body weight.1

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).1
• 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.1 Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers.1
• Advise patients not to discontinue use of ganaxolone without consulting with their healthcare provider.1 Ganaxolone should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.1
• Advise patients who are prescribed ganaxolone to use the adapter and oral dosing syringes provided by their pharmacist.1
• Instruct patients to take ganaxolone with food.1
• Instruct patients to shake ganaxolone thoroughly for at least 1 minute and then wait for 1 minute before measuring and administering each dose.1
• Instruct patients to discard any unused ganaxolone oral suspension after 30 days of first opening the bottle.1
• Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during ganaxolone therapy.1 Encourage women who are taking ganaxolone to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.1 This registry is collecting information about the safety of antiepileptic drugs during pregnancy.1
• Advise patients that ganaxolone can be abused or lead to dependence.1
• 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.1
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1
• Inform patients of other important precautionary information.1

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.

Only references cited for selected revisions after 1984 are available electronically.

1. Marinus Pharmaceuticals, Inc. ZTALMY® (ganaxolone) ORAL prescribing information. 2023 Jun [Web]

3. Knight EMP, Amin S, Bahi-Buisson N, et al. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial. Lancet Neurol. May 2022;21(5):417-427.

4. National Organization for Rare Disorders (NORD). CDKL5 Deficiency Disorder. From NORD website. Last updated 2022 Mar 29. Accessed 2023 May 18 [Web]

5. Olson HE, Demarest ST, Pestana-Knight EM, et al. Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review. Pediatr Neurol. Aug 2019;97:18-25.

6. US Food and Drug Administration. Statistical Review and Evaluation: Antiepileptic Drugs and Suicidality. Rockville, MD; 2008 May 23. From the FDA website [Web]

7. Yawno T, Miller SL, Bennet L, et al. Ganaxolone: A New Treatment for Neonatal Seizures. Front Cell Neurosci. 2017;11:246.

8. De SK. Ganaxolone: First FDA-Approved Medicine for the Treatment of Seizures Associated with Cyclin-dependent Kinase-like 5 Deficiency Disorder. Curr Med Chem. Mar 20 2023;doi:10.2174/0929867330666230320123952

9. Marinus Pharmaceuticals, Inc. Ztalmy® Prescribing Resources. From Marinus Pharmaceuticals Inc for US Healthcare Professionals website. Accessed 2023 Jun 5. [Web]