Dosing & Uses
Dosage Forms & Strengths
injection, SC solution
- 189mg/mL (single-dose vial)
Acute Hepatic Porphyria
Indicated for acute hepatic porphyria (AHP)
2.5 mg/kg SC qMonth; dose based on actual body weight
Dosage Modifications
Transaminase elevations
- Interrupt or discontinue for severe or clinically significant transaminase elevations
- Severe or clinically significant transaminase elevations: Reduce dose to 1.25 mg/kg qMonth in patients who have dose interruption and subsequent transaminase improvement
- In patients who resume dosing at 1.25 mg/kg qMonth without recurrence of severe or clinically significant transaminase elevations, may increase dose to 2.5 mg/kg qMonth
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
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
Dosing Considerations
Measure liver function tests before initiating treatment, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter
Safety and efficacy not established
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
>10%
Nausea (27%)
Injection-site reactions (25%)
Rash (17%)
Increased serum creatinine (15%)
Elevated transaminases (13%)
1-10%
Fatigue (10%)
<1%
Anaphylaxis
Warnings
Contraindications
Severe hypersensitivity, including anaphylaxis
Cautions
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
Drug interaction overview
- 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
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
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
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
Absorption
Peak plasma time: 3 hr (parent drug); 7 hr (metabolite)
Peak plasma concentration: 321 ng/mL (parent drug); 123 ng/mL (metabolite)
AUC: 4130 ng⋅hr/mL (parent drug); 1930 ng⋅hr/mL (metabolite)
Distribution
Vd: 10.4 L
Protein bound: 90% (parent drug)
Organ distribution: Parent drug and metabolite primarily distributed to liver
Metabolism
Metabolized by nucleases to oligonucleotides of shorter lengths
Not a substrate of CYP enzymes
Active metabolite: AS(N-1)3' givosiran is equipotent to givosiran in plasma; AUC0-24 represents 45% of givosiran AUC at the recommended dosage
Elimination
Half-life: 6 hr (parent drug or metabolite)
Clearance: 35.1 L/hr (18%; parent drug); 64.7 L/hr (33%; metabolite)
Excretion: Urine 5-14% (parent drug); 4-13% (metabolite)
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
Missed dose
- Administer as soon as possible after a missed dose
- Resume dosing at monthly intervals following administration of the missed dose
Storage
Store refrigerated or at controlled room temperature of 2-25°C (36-77°F)
Store in original container until ready for use
Images
Patient Handout
Formulary
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