ZULRESSO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZULRESSO (ZULRESSO).
Allopregnanolone is a positive allosteric modulator of GABAA receptors, enhancing phasic and tonic inhibition via binding to delta-subunit-containing receptors.
| Metabolism | Primarily metabolized via glucuronidation (UGT2B7, UGT1A4, and UGT1A1) and minor sulfation; not CYP-mediated. |
| Excretion | Primarily via renal excretion as unchanged drug (approximately 90% of dose) and minor fecal elimination (approximately 5%); no active metabolites identified. |
| Half-life | Terminal elimination half-life is approximately 18 hours (range 15-23 hours) following intravenous administration; clinically, this supports once-daily dosing. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily to alpha-1-acid glycoprotein and albumin. |
| Volume of Distribution | Mean volume of distribution is approximately 0.1 L/kg, indicating minimal distribution into tissues; consistent with high protein binding and polar nature. |
| Bioavailability | Not applicable for oral administration; only available as intravenous infusion, hence 100% bioavailability by IV route. |
| Onset of Action | Intravenous: Rapid reduction in depressive symptoms observed within 24 hours (first assessment) after a single 60-minute infusion. |
| Duration of Action | Sustained antidepressant effect lasting approximately 2 weeks after a single infusion, as observed in clinical trials. |
| Molecular Weight | 314.38 |
Initial: 30 mcg/min IV infusion for 0-4 hours, then increase by 30 mcg/min every 4 hours if tolerated, maximum 120 mcg/min; typical duration up to 60 hours.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment; not studied in severe renal impairment (eGFR <30 mL/min/1.73m2) or ESRD. |
| Liver impairment | Child-Pugh Class A or B: No dose adjustment recommended. Child-Pugh Class C: Not studied; use not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no recommended dosage. |
| Geriatric use | No specific dose adjustment required; consider lower initial infusion rate due to potential for increased sensitivity and reduced hepatic metabolism. |
| 1st trimester | Limited data; animal studies show fetal harm; use only if benefit justifies risk. |
| 2nd trimester | Limited data; potential risks include preterm labor and low birth weight; use only if benefit justifies risk. |
| 3rd trimester | Associated with preterm labor and neonatal withdrawal; avoid use near term unless no alternative. |
Clinical note
Comprehensive clinical and safety monograph for ZULRESSO (ZULRESSO).
| Placental transfer | Crosses placenta; detected in cord blood and amniotic fluid. |
| Breastfeeding | Excreted into breast milk; monitor infant for sedation, poor feeding, and respiratory depression. Consider benefits vs risks. |
| Lactation Rating |
■ FDA Black Box Warning
No FDA boxed warnings.
| Serious Effects |
Hypersensitivity to brexanolone or any componentEnd-stage renal diseaseConcurrent use with strong CYP2C9 inhibitors (e.g., fluconazole)
| Precautions | Risk of excessive sedation or loss of consciousness during infusion, May cause suicidal thoughts or behavior, Dizziness, somnolence, headache, Monitor for hypoxia and excessive sedation during infusion |
| Food/Dietary | No specific food interactions reported. Grapefruit may increase brexanolone levels via CYP3A4 inhibition; avoid grapefruit and grapefruit juice during infusion and for several days after. No other dietary restrictions. |
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| L4 |
| Teratogenic Risk | First trimester: No adequate and well-controlled studies in pregnant women. Based on animal studies, may cause fetal harm. Risk cannot be ruled out. Second and third trimesters: No increased risk of major malformations reported; however, neonatal withdrawal (e.g., irritability, hypertonia, feeding difficulties) may occur with chronic use in late pregnancy. |
| Fetal Monitoring | Monitor maternal blood pressure, pulse, and respiratory rate during infusion. Assess for excessive sedation and respiratory depression. Fetal monitoring is not routinely required but consider if clinically indicated. |
| Fertility Effects | No specific human studies on fertility. Animal studies showed no significant effects on fertility. |
| Clinical Pearls |
| ZULRESSO (brexanolone) is a GABA-A receptor positive allosteric modulator for postpartum depression (PPD). Administer as a continuous IV infusion over 60 hours (total dose 90 mcg/kg). Must be in a healthcare setting with monitoring for excessive sedation and sudden loss of consciousness. Abrupt discontinuation can cause withdrawal symptoms; taper not required. Contraindicated with strong CYP2C9 inhibitors (e.g., fluconazole) as they increase brexanolone exposure. Use with caution in hepatic impairment as metabolism is CYP2C9/3A4. |
| Patient Advice | You will receive this medication as a continuous IV drip over 2.5 days in a hospital or clinic setting; you cannot go home during treatment. · Common side effects include sleepiness, dizziness, dry mouth, flushing, and loss of consciousness (syncope). You will be monitored closely. · Do not drive, operate machinery, or make important decisions until the drug is out of your system. · Tell your healthcare provider if you breastfeed—effects on infant are not fully known. · Inform your doctor about all medications you take, especially antifungals or blood thinners. · You may feel a sudden sense of well-being, but if you experience signs of mania or suicidal thoughts, seek help immediately. |