givosiran (Rx)

>10%

Nausea (27%)

Injection-site reactions (25%)

Rash (17%)

Increased serum creatinine (15%)

Elevated transaminases (13%)

1-10%

Fatigue (10%)

<1%

Anaphylaxis

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

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.

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; AUC_0-24 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)

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