Givosiran

Indications

Givosiran is used for: Acute Hepatic Porphyria

Adult Dose

Acute Hepatic Porphyria Indicated for acute hepatic porphyria (AHP) 2.5 mg/kg SC qMonth; dose based on actual body weight Hepatic impairment Mild (bilirubin ?1× ULN and AST >1 x ULN, or bilirubin >1-1.5 x ULN): No clinically meaningful differences in pharmacokinetics or pharmacodynamics Moderate-to-severe: Unknown

Child Dose

Renal Dose

Renal impairment Mild, moderate, or severe (eGFR 15 to <89 mL/min/1.73m2): No clinically meaningful differences in pharmacokinetics or pharmacodynamics End-stage renal disease: Unknown

Administration

SC Preparation Ensure that medical support is available to appropriately manage anaphylactic reactions when administering Inspect visually for particulate matter and discoloration before administration Givosiran is a sterile, preservative-free, clear, colorless-to-yellow ready-to-use solution Does not require additional reconstitution or dilution prior to administration SC Administration Intended for SC administration by a healthcare professional only Calculate weight-based dose Withdraw volume of solution from vial using ?21-gauge needle Divide doses requiring volumes >1.5 mL equally into multiple syringes After withdrawing solution, replace the ?21-gauge or larger needle with either a 25- or 27-gauge needle with 1/2” or 5/8” needle length Avoid having solution on the needle tip until the needle is in the SC space Administer SC into abdomen, back or side of upper arms, or thighs; rotate injection sites Do not inject into scar tissue or areas that are reddened, inflamed, or swollen If injecting into abdomen, avoid 5-cm diameter circle around the navel If >1 injection needed for a single dose, the injection sites should be at least 2 cm apart from previous injection locations Discard unused portion of the drug

Contra Indications

Severe hypersensitivity, including anaphylaxis

Precautions

Anaphylaxis observed; ensure medical support is available to appropriately manage anaphylactic reactions when administering; monitor for signs and symptoms of anaphylaxis Transaminase elevations (ALT) of ≥3x ULN observed in the placebo-controlled trial; primarily occurred 3-5 months after initiating treatment; monitor Increased serum creatinine levels and decreased eGFR reported; monitor renal function as clinically indicated Injection-site reactions reported; symptoms included erythema, pain, pruritus, rash, discoloration, or swelling

Pregnancy-Lactation

Pregnancy Data are not available regarding use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Animal studies Administration to pregnant rabbits during organogenesis resulted in adverse developmental outcomes at doses that produced maternal toxicity Clinical considerations Porphyria attacks during pregnancy, often triggered by hormonal changes, occur in 24-95% of patients with AHP, with maternal mortality ranging from 2-42% Pregnancy in patients with AHP is associated with higher rates of spontaneous abortion, hypertension, and low-birth-weight infants Lactation Data are not available regarding use in breastfeeding women

Interactions

In vitro studies indicate that givosiran does not directly inhibit or induce CYP enzymes; however, because of its pharmacological effects on the hepatic heme biosynthesis pathway, givosiran has the potential to reduce the activity of CYP enzymes in the liver Sensitive CYP1A2 or CYP2D6 substrates Sensitive CYP1A2 substrates: Coadministration increased caffeine (sensitive CYP1A2 substrate) AUC by 3.1-fold and Cmax by 1.3-fold Sensitive CYP2D6 substrates: Coadministration increased dextromethorphan (sensitive CYP2D6 substrate) AUC by 2.4-fold and Cmax by 2-fold Avoid use with CYP1A2 or CYP2D6 substrates, for which minimal concentration changes may lead to serious or life-threatening toxicities If concomitant use is unavoidable, decrease CYP1A2 or CYP2D6 substrate dosage in accordance with its prescribing information

Adverse Effects

Side effects of Givosiran : >10% Nausea (27%) Injection-site reactions (25%) Rash (17%) Increased serum creatinine (15%) Elevated transaminases (13%) 1-10% Fatigue (10%) <1% Anaphylaxis

Mechanism of Action

Double-stranded small-interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) 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 (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP