XOLREMDI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for XOLREMDI (XOLREMDI).
Givosiran is a small interfering RNA (siRNA) that targets the 5-aminolevulinic acid synthase 1 (ALAS1) mRNA. By degrading ALAS1 mRNA, it reduces the hepatic production of the enzyme ALAS1, thereby decreasing the levels of neurotoxic heme precursors (aminolevulinic acid and porphobilinogen) that accumulate in acute hepatic porphyria.
| Metabolism | Givosiran is metabolized by nucleases to oligonucleotides of shorter lengths. It is not a substrate for cytochrome P450 enzymes. |
| Excretion | Primarily via renal excretion of unchanged drug (approximately 60-70%) and fecal/biliary elimination (30-40%) as metabolites. |
| Half-life | Terminal elimination half-life is approximately 20-24 hours in adults, allowing once-daily dosing; may be prolonged in renal impairment. |
| Protein binding | ~90% bound to serum albumin. |
| Volume of Distribution | Vd ≈ 1.5 L/kg, indicating extensive extravascular distribution. |
| Bioavailability | Oral: 60-70% (first-pass metabolism reduces absolute bioavailability). |
| Onset of Action | Oral: Therapeutic effect observed within 1-2 hours. |
| Duration of Action | Duration of action supports 24-hour dosing interval due to sustained plasma levels. |
0.3 mg/kg intravenously every 3 weeks for 4 doses; continue with 0.3 mg/kg intravenously every 4 weeks for maintenance.
| Dosage form | CAPSULE |
| 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 end-stage renal disease. |
| Liver impairment | No dose adjustment required for mild hepatic impairment (Child-Pugh A). Not studied in moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. |
| Pediatric use | Weight-based dosing: 0.3 mg/kg intravenously every 3 weeks for 4 doses, then 0.3 mg/kg intravenously every 4 weeks. Safety and efficacy not established in pediatric patients weighing <21 kg. |
| Geriatric use | No specific dose adjustment recommended; clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for XOLREMDI (XOLREMDI).
| Breastfeeding | No data on vamorolone in human milk. Corticosteroids are excreted in breast milk in low amounts. M/P ratio unknown. Use caution; consider benefit to mother versus potential for adverse effects (e.g., growth suppression) in nursing infant. |
| Teratogenic Risk | XOLREMDI (vamorolone) is a corticosteroid analog. No adequate human data on fetal risk. In animal studies, administration during organogenesis resulted in increased fetal malformations (cleft palate, skeletal variations) and reduced fetal weight at doses similar to human exposure. First trimester: potential for malformations based on corticosteroid class effects. Second/third trimester: chronic exposure may cause fetal growth restriction, adrenal suppression, and possible preterm birth. Avoid use in pregnancy unless benefit outweighs risk. |
■ FDA Black Box Warning
None
| Serious Effects |
None
| Precautions | ["Renal toxicity: Monitor renal function before and during therapy; dose reduction or discontinuation may be required.","Hepatotoxicity: Monitor liver function; elevations in transaminases and bilirubin have occurred.","Infusion-related reactions: Administer with premedication; monitor during infusion.","Immunogenicity: Development of anti-drug antibodies may occur; clinical significance unknown."] |
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| Fetal Monitoring | Monitor maternal blood glucose, blood pressure, and signs of infection. For fetus, consider growth ultrasounds if chronic in utero exposure. Newborns exposed in utero: monitor for adrenal suppression and hypoglycemia. |
| Fertility Effects | No human data. In animal studies, vamorolone did not impair fertility at clinically relevant doses. Corticosteroid class may alter menstrual cycle or reduce sperm count, but specific effects for vamorolone are unknown. |