GIVLAARI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GIVLAARI (GIVLAARI).
GIVLAARI (givosiran) is an aminolevulinate synthase 1 (ALAS1)-directed small interfering RNA (siRNA) that reduces ALAS1 mRNA expression in hepatocytes, thereby decreasing circulating aminolevulinic acid (ALA) and porphobilinogen (PBG) levels.
| Metabolism | Metabolized via exonuclease-mediated hydrolysis to oligonucleotides of shorter length; not metabolized by CYP450 enzymes. |
| Excretion | Givlaari (givosiran) is eliminated primarily via the liver, with minimal renal excretion. Approximately 30% of the dose is excreted in feces unchanged, and less than 10% is excreted in urine. The remainder is metabolized hepatically. |
| Half-life | The terminal elimination half-life (t1/2) is approximately 6 days (range 4–8 days) in patients with acute hepatic porphyria. This long half-life supports monthly subcutaneous dosing. |
| Protein binding | Givosiran is moderately bound to plasma proteins, approximately 90% bound, primarily to albumin. |
| Volume of Distribution | The volume of distribution (Vd) is approximately 0.4 L/kg, indicating distribution primarily in the plasma and extracellular fluid. This reflects the limited tissue distribution of the GalNAc-conjugated siRNA. |
| Bioavailability | Subcutaneous administration: Bioavailability is approximately 80%, with peak plasma concentrations occurring 3–4 hours post-dose. |
| Onset of Action | Subcutaneous administration: Reduction in urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels is observed within 2–4 weeks. Clinical reduction in porphyria attacks is seen after 1–2 months of treatment. |
| Duration of Action | The therapeutic effect on lowering ALA and PBG levels persists for the entire monthly dosing interval. The duration of clinical benefit (reduced attack rate) is maintained with continued monthly dosing. |
2.5 mg/kg intravenously over 15 minutes once every 4 weeks.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. Not studied in GFR <30 mL/min; use caution. |
| Liver impairment | No dose adjustment for Child-Pugh A or B. Not studied in Child-Pugh C; use caution. |
| Pediatric use | Safety and efficacy not established in pediatric patients under 18 years. |
| Geriatric use | No specific dose adjustment; clinical studies included limited patients ≥65 years, no overall differences observed. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for GIVLAARI (GIVLAARI).
| Breastfeeding | There are no data on the presence of givosiran in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, advise patients that breastfeeding is not recommended during treatment with GIVLAARI and for at least 6 months after the last dose. M/P ratio is unknown. |
| Teratogenic Risk | GIVLAARI (givosiran) is an aminolevulinate synthase 1-directed small interfering RNA indicated for acute hepatic porphyria. Based on animal studies, there is evidence of embryofetal toxicity including increased post-implantation loss, reduced fetal body weight, and skeletal variations at doses below the human exposure. There are no adequate and well-controlled studies in pregnant women. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No data on trimester-specific risks. |
■ FDA Black Box Warning
None
| Serious Effects |
["History of hypersensitivity to givosiran or any component of the formulation"]
| Precautions | ["Severe infusion-related reactions including anaphylaxis","Elevations in serum transaminases and creatinine","Risk of acute porphyria attacks if treatment is delayed or missed"] |
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| Fetal Monitoring | Monitor pregnant women exposed to GIVLAARI for fetal growth and development with serial ultrasound assessments. Consider monitoring for maternal hepatic function and porphyrin levels as clinically indicated. |
| Fertility Effects | Based on animal studies, GIVLAARI may impair fertility in females. In rats, decreased fertility index and increased pre-implantation loss were observed at doses that resulted in maternal toxicity. No effect on male fertility was observed in animal studies. |