ZTALMY
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZTALMY (ZTALMY).
Ganaxolone is a positive allosteric modulator of GABAA receptors, acting at extrasynaptic and synaptic receptors to enhance chloride ion conductance and inhibit neuronal excitability.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19. |
| Excretion | Primarily hepatic metabolism via glucuronidation and oxidation; <1% excreted unchanged in urine. Fecal elimination accounts for approximately 90% of the administered dose, with <5% in urine. |
| Half-life | Terminal elimination half-life is approximately 30 hours (range 20-40 hours) in adults, supporting once-daily dosing. Steady-state is achieved within 5-7 days. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Approximately 0.5 L/kg (range 0.4-0.6 L/kg), indicating distribution primarily into extracellular fluid and limited tissue binding. |
| Bioavailability | Oral bioavailability is approximately 40-50% due to first-pass metabolism; administration with food increases bioavailability by approximately 20%. |
| Onset of Action | Oral administration: Clinical effect (seizure reduction) observed within 1-2 weeks of initiating therapy, with maximal effect by 4-6 weeks. |
| Duration of Action | Duration is approximately 24 hours due to once-daily dosing regimen; sustained seizure control with consistent trough concentrations above therapeutic threshold. |
Initial: 5 mg orally once daily for 7 days; titrate by 5 mg/day every 7 days to a maintenance dose of 30 mg once daily. Maximum: 30 mg daily.
| Dosage form | SUSPENSION |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min). Not recommended in severe renal impairment (eGFR <30 mL/min) or end-stage renal disease. |
| Liver impairment | Child-Pugh Class A: No dose adjustment. Child-Pugh Class B: Reduce starting dose to 2.5 mg daily; titrate slowly. Child-Pugh Class C: Not recommended. |
| Pediatric use | Not approved for patients under 18 years of age. |
| Geriatric use | No specific dose adjustment recommended, but consider renal function (eGFR ≥30 mL/min required). Monitor for dizziness and falls. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ZTALMY (ZTALMY).
| Breastfeeding | It is unknown whether ganaxolone is excreted in human milk. In animal studies, ganaxolone was detected in milk. The M/P ratio has not been established in humans. Due to the potential for adverse effects on the nursing infant, breastfeeding is not recommended during ZTALMY treatment. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for ZTALMY and any potential adverse effects on the breastfed child from the drug or underlying maternal condition. |
| Teratogenic Risk | ZTALMY (ganaxolone) is a neuroactive steroid that acts as a positive allosteric modulator of GABA-A receptors. In animal studies, ganaxolone has been associated with teratogenic effects, including skeletal and visceral malformations in rats and rabbits at clinically relevant doses. There are no adequate and well-controlled studies in pregnant women. Given its mechanism of action and animal data, ZTALMY carries a risk of fetal harm, particularly during the first trimester (organogenesis). Second and third trimester exposure may affect fetal growth and neurodevelopment due to potential disruption of GABAergic signaling. ZTALMY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Known hypersensitivity to ganaxolone or any component of the formulation."]
| Precautions | ["Somnolence and sedation","Suicidal behavior and ideation","Withdrawal-precipitated seizure (including status epilepticus) upon abrupt discontinuation","Hepatic injury (elevated transaminases) - monitoring recommended"] |
Loading safety data…
| Fetal Monitoring | If ZTALMY is used during pregnancy, monitor maternal seizure control and hepatic function. Perform fetal ultrasound at appropriate intervals to assess fetal growth and anatomy. Consider monitoring for signs of fetal distress or maternal toxicity. Due to the GABAergic effects, monitor for neonatal withdrawal symptoms (e.g., irritability, hypotonia, respiratory depression) post-delivery. |
| Fertility Effects | Animal studies have shown that ganaxolone may impair fertility in females, including prolonged estrus cycles and reduced pregnancy rates at clinically relevant doses. The effect on male fertility is unknown. In clinical studies, no specific fertility data have been reported. Women of childbearing potential should use effective contraception during treatment. |