Mechanism of effect
Givosiran causes degradation of aminolevulinate synthase 1 (ALAS1) messenger RNA (mRNA) in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid and porphobilinogen, factors associated with attacks and other disease manifestations of acute hepatic porphyria.
Distribution: Vd: 10.4 L.
Protein binding: 90% (concentration dependent; decreases with increasing concentrations).
Metabolism: Metabolized by nucleases to oligonucleotides of shorter lengths; AS(N-1)3’ is the active metabolite and is equipotent to givosiran.
Half-life elimination: 6 hours.
Time to peak: Givosiran: 3 hours (range: 0.5 to 8 hours); AS(N-1)3’ givosiran: 7 hours (range: 1.5 to 12 hours).
Excretion: Urine (5% to 14% as unchanged drug; 4% to 13% as AS[N-1]3’givosiran
Acute hepatic porphyria:
Treatment of adults with acute hepatic porphyria.
Acute hepatic porphyria: SubQ: 2.5 mg/kg once monthly. Note: Dosing is based on actual body weight.
Missed dose: Administer as soon as possible; then resume dosing at monthly intervals
Severe hypersensitivity (eg, anaphylaxis) to givosiran or any component of the formulation.
Dermatologic: Skin rash (17%)
Gastrointestinal: Nausea (27%)
Hepatic: Increased serum alanine aminotransferase (≥3 x ULN: 15%), increased serum transaminases (13%)
Local: Injection site reaction (25%)
Renal: Renal function abnormality (15%), decreased estimated GFR (eGFR) (≤15%), increased serum creatinine (≤15%)
1% to 10%: Central nervous system: Fatigue (10%)
<1%: Anaphylaxis, antibody development, hypersensitivity reaction
• Anaphylaxis: Anaphylaxis has occurred; ensure the availability of proper medical support to appropriately manage anaphylactic reactions during administration. Monitor for signs and symptoms; discontinue and administer appropriate medical treatment if anaphylaxis occurs.
• Hepatic toxicity: Transaminase elevations (ALT) of ≥3 times the ULN have occurred, primarily between 3 to 5 months following initiation of therapy. Monitor liver function at baseline, every month during the first 6 months of therapy, and as clinically indicated. Interrupt or discontinue use if severe or clinically significant transaminase elevations occur during therapy.
• Injection-site reactions: Injection-site reactions have been reported, including erythema, pain, pruritus, rash, discoloration, and swelling around the injection site; monitor and treat appropriately.
• Renal toxicity: Increases in serum creatinine and decreases in eGFR have been reported; monitor renal function during therapy as clinically indicated.
Points of recommendation
SubQ: For SubQ administration by a health care professional only. Ensure the availability of proper medical support to appropriately manage anaphylactic reactions during administration. Use a 25-gauge or 27-gauge needle with 1/2-inch or 5/8-inch needle length for administration; avoid givosiran solution on the needle tip until the needle is in the SubQ space. Administer into the abdomen (avoid the 5-cm diameter around the navel), thighs, or the back or side of upper arms. Rotate injection sites; do not inject into scar tissue or inflamed, reddened, or swollen areas. If more than one injection is needed for a single dose, space injection sites ≥2 cm apart. Discard unused portion.
Breast feeding warning
It is not known if givosiran is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.