Ganaxolone (Ztalmy®) is an oral suspension administered three times daily with food.

• Dosage Form: Oral suspension, typically 50 mg/mL.
• Administration:
  • With Food: It is crucial to administer ganaxolone with food to maximize its absorption and optimize efficacy.
  • Preparation: Shake the bottle thoroughly for at least 1 minute before each use. After shaking, wait for 1 minute to allow any foam to settle before measuring the dose.
  • Measuring Dose: Always use the oral syringe(s) provided by the pharmacist to measure the prescribed dose accurately. Do not use household teaspoons or tablespoons, as they are not accurate measuring devices. If the dose is less than 1 mL, an appropriately sized syringe will be provided.
• Dosing Schedule: Ganaxolone is typically administered three times a day (TID).
• Titration: Treatment usually begins with a low starting dose, which is then gradually increased (titrated) over several weeks, based on tolerability, until the target maintenance dose is reached. Dose increases should occur no more frequently than every 7 days, following the specific titration schedule outlined in the prescribing information.
• Discontinuation: Abrupt discontinuation of ganaxolone should be avoided, if possible, as it may increase the frequency of seizures or even lead to status epilepticus (a prolonged or recurrent seizure). When discontinuing therapy, the dose should be gradually decreased under medical supervision. Rapid discontinuation may be considered only if withdrawal is necessary due to a serious adverse event.
• Storage: Store the original bottle in an upright position at room temperature (15°C to 30°C or 59°F to 86°F). Keep the cap tightly closed. Once opened, the bottle must be used within 30 days, or by the “Discard After” date on the bottle, whichever comes first, and any remainder should be discarded.

Ganaxolone exerts its anticonvulsant effects by acting as a positive allosteric modulator of GABAA receptors.

• GABAA Receptors: Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain, and GABAA receptors are crucial for mediating its effects. When GABA binds to these receptors, it opens an ion channel that allows chloride ions to flow into the neuron, making the neuron less excitable and thus inhibiting nerve impulses.
• Modulation by Ganaxolone: Ganaxolone binds to specific sites on both synaptic and extrasynaptic GABAA receptors. By doing so, it enhances the effects of GABA, increasing the frequency and/or duration of chloride channel opening. This leads to increased inhibitory signaling in the brain.
• Anticonvulsant Effect: In conditions like CDD, there can be an imbalance leading to excessive neuronal excitability, which results in seizures. By boosting GABAergic inhibition, ganaxolone helps to:
  • Inhibit the abnormal electrical discharges that cause seizures.
  • Restore balance in disrupted neuronal activity in the central nervous system.
  • This dual action on both synaptic (phasic inhibition) and extrasynaptic (tonic inhibition) GABAA receptors is thought to contribute to its broad anticonvulsant properties and potential effectiveness in seizures resistant to other medications.

Like all medications, Ganaxolone can cause side effects. The most common side effects are typically related to its CNS depressant effects.

Very Common Side Effects (often dose-related and more frequent during initiation/titration):

• Somnolence (drowsiness) and Sedation: These are the most frequently reported side effects and can be significant. They tend to appear early in treatment. Patients should be cautioned about operating machinery or driving.
• Fatigue/Tiredness

Common Side Effects (incidence ≥5% and more frequent than placebo):

• Fever (pyrexia)
• Upper respiratory tract infection
• Salivary hypersecretion (increased drooling)
• Seasonal allergy
• Dizziness
• Trouble concentrating
• Trouble sleeping
• Irritability
• Changes in behavior
• Gait disturbance (difficulty walking)

Less Common Side Effects (but reported):

• Headache
• Nausea, vomiting, diarrhea
• Chills
• Cough, nasal congestion, sore throat
• Muscle aches and pains, joint pain
• Generalized feeling of discomfort or illness
• Suicidal thoughts or behavior (as with other antiepileptic drugs)

Serious Side Effects (rare but important):

• Severe Sedation: Can be profound, especially when combined with other CNS depressants.
• Worsening of Depression or Suicidal Thoughts/Behavior: As with other antiepileptic drugs, patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.
• Increased Seizure Frequency or Status Epilepticus: Risk if the drug is discontinued abruptly.

Patients should report any new, worsening, or severe side effects to their healthcare provider immediately.

Ganaxolone carries several important warnings and precautions that healthcare providers and patients should be aware of.

• Somnolence and Sedation: Gamaxolone can cause significant somnolence and sedation. These effects typically appear early in treatment and are generally dose-related. Concomitant use with other CNS depressants (e.g., alcohol, opioids, other sedatives) can potentiate these effects. Patients should be advised not to drive or operate hazardous machinery until they know how Gamaxolone affects them.
• Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including ganaxolone, increase the risk of suicidal thoughts or behavior. Patients taking ganaxolone should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Family members and caregivers should also be alerted to this risk and encouraged to seek immediate medical attention if such changes occur.
• Withdrawal of Antiepileptic Drugs (AEDs): As with most AEDs, ganaxolone should be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus. If rapid discontinuation is necessary due to a serious adverse event, it should still be done under close medical supervision.
• Drug Interactions (CYP3A4 Inducers): Coadministration with strong or moderate CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort) will decrease ganaxolone exposure, which can lower its efficacy. Avoid concomitant use whenever possible. If unavoidable, consider increasing the dosage of ganaxolone, but do not exceed the maximum daily dosage.
• Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh class C) require dosage adjustments as ganaxolone concentrations can be significantly increased. No dosage adjustment is necessary for mild or moderate hepatic impairment. Monitor patients with liver dysfunction for the occurrence of side effects.
• Renal Impairment: No specific dosage adjustment is required for patients with renal impairment.
• Pregnancy and Lactation:
  • Pregnancy: Limited human data are available. Animal studies have shown adverse effects on development. Ganaxolone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Lactation: Ganaxolone is present in human milk. The calculated relative infant dose is low, but the effects on a breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ganaxolone and any potential adverse effects on the breastfed infant.
• Abuse Potential: Ganaxolone is a Schedule V controlled substance (CV) under the Controlled Substances Act, indicating it has a low potential for abuse relative to drugs or other substances in Schedule IV. Patients should be monitored for signs of abuse or dependence.

Ganaxolone can interact with other medications, primarily those that affect the central nervous system (CNS) or are metabolized by certain liver enzymes.

• Central Nervous System (CNS) Depressants: Ganaxolone can cause somnolence and sedation. Concomitant use with other CNS depressants, including:
  • Alcohol
  • Opioids
  • Antidepressants (e.g., tricyclic antidepressants, some SSRIs)
  • Antihistamines (sedating)
  • Benzodiazepines (e.g., diazepam, clonazepam)
  • Sedatives/hypnotics
  • Muscle relaxants Can potentiate these effects, leading to increased drowsiness, dizziness, and impaired coordination. Careful monitoring is required, and dose adjustments of either ganaxolone or the concomitant CNS depressant may be necessary.
• CYP3A4 Inducers: Ganaxolone is metabolized primarily by CYP3A4 enzymes in the liver. Strong or moderate inducers of CYP3A4 (drugs that increase the activity of this enzyme) can significantly decrease ganaxolone plasma concentrations, potentially reducing its efficacy.
  • Examples of strong CYP3A4 inducers: Carbamazepine, phenytoin, rifampin, St. John’s Wort.
  • Examples of moderate CYP3A4 inducers: Efavirenz, modafinil.
  • Management: Concomitant use with strong or moderate CYP3A4 inducers should generally be avoided. If unavoidable, consider increasing the dosage of ganaxolone, but do not exceed the maximum recommended daily dose.
• CYP3A4 Inhibitors: Strong or moderate inhibitors of CYP3A4 (drugs that decrease the activity of this enzyme) could potentially increase ganaxolone plasma concentrations, increasing the risk of side effects.
  • Examples of strong CYP3A4 inhibitors: Ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice.
  • Management: Monitor for increased side effects. Dose adjustment of ganaxolone may be necessary.
• Antiepileptic Drugs (AEDs): Ganaxolone is often used as an adjunctive therapy with other AEDs. While generally compatible, clinicians should be aware of potential additive CNS depressant effects and monitor for changes in seizure control or side effects when adding or removing other AEDs.
• Ketogenic Diet: The prescribing information may advise against the use of ganaxolone with a ketogenic diet, as the effects are not well studied in this context.

Patients should always inform their healthcare provider and pharmacist about all prescription medications, over-the-the-counter drugs, herbal remedies, and supplements they are taking to avoid potential interactions.

The dosage of Ganaxolone (Ztalmy®) is individualized based on the patient’s body weight and tolerability. It is administered orally three times daily with food.

1. Recommended Titration Schedule (for CDKL5 Deficiency Disorder):

• For patients weighing ≤ 28 kg (approximately 61.7 lbs):
  • Days 1 to 7: 6 mg/kg orally three times a day (total 18 mg/kg/day)
  • Days 8 to 14: 11 mg/kg orally three times a day (total 33 mg/kg/day)
  • Days 15 to 21: 16 mg/kg orally three times a day (total 48 mg/kg/day)
  • Days 22 and ongoing: 21 mg/kg orally three times a day (total 63 mg/kg/day) – Maximum recommended dose.
• For patients weighing > 28 kg (approximately 61.7 lbs):
  • Days 1 to 7: 150 mg orally three times a day (total 450 mg/day)
  • Days 8 to 14: 300 mg orally three times a day (total 900 mg/day)
  • Days 15 to 21: 450 mg orally three times a day (total 1350 mg/day)
  • Days 22 and ongoing: 600 mg orally three times a day (total 1800 mg/day) – Maximum recommended dose.

1. Dosage Adjustments:

• Tolerability: The dosage should be increased based on tolerability, but no more frequently than every 7 days. Titration increments should not exceed those listed above.
• Hepatic Impairment:
  • Mild or Moderate (Child-Pugh A or B): No dosage adjustment is necessary.
  • Severe (Child-Pugh C): Dosage adjustments are required during both titration and maintenance phases due to increased drug concentrations. Specific reduced titration schedules are provided in the prescribing information for these patients.
• Renal Impairment: No dosage adjustment is required for patients with renal impairment.
• Discontinuation: When discontinuing therapy, the dose should be gradually decreased. Abrupt discontinuation should be avoided whenever possible to minimize the risk of increased seizure frequency and status epilepticus.

Ganaxolone (Ztalmy®) is a prescription-only medication (POM) and a Schedule V controlled substance (CV) in the United States. Its use requires strict medical oversight.

• Specialist Prescribing: It must be prescribed by a licensed medical professional, typically a neurologist or a specialist experienced in the diagnosis and management of CDKL5 deficiency disorder.
• Confirmed Diagnosis: A confirmed diagnosis of CDKL5 deficiency disorder (CDD), including documentation of a pathogenic or probably pathogenic mutation in the CDKL5 gene, is required to initiate therapy.
• Age Restriction: It is indicated for patients 2 years of age and older. It is not known if it is safe and effective in children under 2 years of age.
• Prior Authorization/Medical Necessity: Due to its specialized indication and cost, Ganaxolone often requires prior authorization from insurance providers. This typically involves submitting detailed clinical documentation to demonstrate medical necessity, including confirmation of diagnosis and history of other treatments.
• Patient Monitoring: Patients require ongoing monitoring for both efficacy (reduction in seizure frequency) and safety (e.g., somnolence, behavioral changes, suicidal ideation, liver function in severe hepatic impairment).
• Controlled Substance: As a Schedule V controlled substance, Ganaxolone is subject to specific regulations regarding prescribing, dispensing, and storage to prevent abuse and diversion. The prescription must include specific information required for controlled substances.

Patient and Caregiver Education: Extensive education is provided to patients and caregivers regarding proper administration (with food, shaking, accurate measurement), potential side effects, warning signs (e.g., increased somnolence, suicidal thoughts), and the importance of adherence and not abruptly discontinuing the medication.

1. What is ganaxolone?
   Ganaxolone is a synthetic neurosteroid medication used to treat certain seizure disorders.

2. How does ganaxolone work?
   It modulates GABAAA​ receptors to enhance inhibitory neurotransmission.

3. What conditions is ganaxolone approved to treat?
   It is approved for treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDKL5 deficiency) in some regions; other indications may vary.

4. What forms does ganaxolone come in?
   It is available as an oral suspension and in some formulations as capsules (availability varies by market).

5. What is the usual dosing frequency?
   Dosing is typically multiple times per day; follow prescriber instructions.

6. Can ganaxolone be used in children?
   Yes — it has pediatric approvals for certain seizure disorders (specific age ranges depend on the indication and region).

7. What are common side effects of ganaxolone?
   Common side effects include somnolence, dizziness, fatigue, and coordination problems.

8. Are there serious risks with ganaxolone?
   Potential risks include respiratory depression when combined with CNS depressants and possible liver enzyme changes; serious adverse events are possible but vary by patient.

9. Can ganaxolone interact with other medications?
   Yes — especially other central nervous system depressants and drugs affecting its metabolism.

10. Is ganaxolone safe during pregnancy?
    The safety in pregnancy is not well established; use only if clearly needed and after discussion with a provider.

11. Can ganaxolone cause dependence or withdrawal?
    It is not classified as a controlled substance; dependence risk appears low, but abrupt discontinuation should be discussed with a clinician.

12. How long before ganaxolone starts working?
    Time to effect varies; some patients may notice seizure frequency changes within days to weeks.

13. Does ganaxolone require blood level monitoring?
    Routine blood level monitoring is not typically required; monitoring may be guided by clinical response and labs as indicated.

14. How should ganaxolone be stored?
    Store at room temperature away from light; follow label instructions for the specific formulation.

15. Can ganaxolone impair driving or operating machinery?
    Yes — it may cause somnolence and dizziness; avoid driving until you know how it affects you.

16. What should I do if I miss a dose of ganaxolone?
    Take the missed dose as soon as you remember unless it’s near the next dose; do not double doses. Follow prescriber guidance.

17. Can ganaxolone be used with hormonal contraceptives?
    No major direct contraindication, but discuss all medications with your provider due to possible interactions.

18. Is ganaxolone covered by insurance?
    Coverage varies by insurer and indication; prior authorization may be required.

19. How is ganaxolone supplied?
    Supplied as prescription-only formulations in labeled containers; specifics depend on region and manufacturer.

20. Who should not take ganaxolone?
    Those with known hypersensitivity to ganaxolone or formulation excipients, and patients where risks outweigh benefits per prescriber assessment.