Givosiran (Monograph)

Brand name: Givlaari
Drug class: Other Miscellaneous Therapeutic Agents
Chemical name: RNA, (Cm-sp-Am-sp-Gm-Am-Am-Am-(2′-deoxy-2′-fluoro)G-Am-(2′-deoxy-2′-fluoro)G-Um-(2′-deoxy-2′-fluoro)G-Um-(2′-deoxy-2′-fluoro)C-Um-(2′-deoxy-2′-fluoro)C-Am-Um-Cm-Um-Um-Am), 3′-[[(2S,4R)-1-[29-[[2-(acetylamino)-2-deoxy-β-d-galactopyranosyl]oxy]-14,14-bis[[3-[[3-[[5-[[2-(acetylamino)-2-deoxy-β-d-galactopyranosyl]oxy]-1-oxopentyl]amino]propyl]amino]-3-oxopropoxy]methyl]-1,12,19,25-tetraoxo-16-oxa-13,20,24-triazanonacos-1-yl]-4-hydroxy-2-pyrrolidinyl]methyl hydrogen phosphate], complex with RNA (Um-sp-(2′-deoxy-2′-fluoro)A-sp-(2′-deoxy-2′-fluoro)A-(2′-deoxy-2′-fluoro)G-Am-(2′-deoxy-2′-fluoro)U-Gm-(2′-deoxy-2′-fluoro)A-Gm-(2′-deoxy-2′-fluoro)A-Cm-(2′-deoxy-2′-fluoro)A-Cm-(2′-deoxy-2′-fluoro)U-Cm-(2′-deoxy-2′-fluoro)U-Um-(2′-deoxy-2′-fluoro)U-Cm-(2′-deoxy-2′-fluoro)U-Gm-sp-Gm-sp-Um) (1:1)
Molecular formula: C₅₂₄H₆₉₄F₁₆N₁₇₃O₃₁₆P₄₃S₆
CAS number: 1639325-43-1

Medically reviewed by Drugs.com on Jan 3, 2023. Written by ASHP.

Introduction

Givosiran sodium is an RNA interference agent that causes degradation of aminolevulinate synthase 1 (ALAS1) messenger RNA (mRNA) in hepatocytes, thereby reducing neurotoxic aminolevulinic acid and porphobilinogen accumulation in patients with acute hepatic porphyria (AHP).

Uses for Givosiran

Givosiran sodium has the following uses:

Givosiran sodium is an aminolevulinate synthase 1-directed small interfering RNA indicated for the treatment of adults with acute hepatic porphyria (AHP).

Givosiran Dosage and Administration

General

Givosiran sodium is available in the following dosage form(s) and strength(s):

Injection: 189 mg/mL in a single-dose vial.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

The recommended dose of givosiran sodium is 2.5 mg/kg once monthly by subcutaneous injection.

Cautions for Givosiran

Contraindications

Severe hypersensitivity to givosiran.

Warnings/Precautions

Anaphylactic Reaction

Anaphylaxis has occurred with givosiran sodium treatment (<1% of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering givosiran sodium. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of givosiran sodium and institute appropriate medical treatment.

Hepatic Toxicity

Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients treated with givosiran sodium in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.

Measure liver function tests prior to initiating treatment with givosiran sodium, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with givosiran sodium for severe or clinically significant transaminase elevations.

Renal Toxicity

Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with givosiran sodium. In the placebo-controlled study, 15% of the patients in the givosiran sodium arm experienced a renally related adverse reaction. The median increase in creatinine at month 3 was 0.07 mg/dL. Monitor renal function during treatment with givosiran sodium as clinically indicated.

Injection Site Reactions

Injection site reactions were reported in 25% of patients receiving givosiran sodium in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. Among 12 patients with reactions, the highest severity of the reaction was mild among 11 (92%) patients and moderate in one (8%) patient. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with administration of a subsequent dose.

Specific Populations

Pregnancy

Risk Summary: In animal reproduction studies, subcutaneous administration of givosiran to pregnant rabbits during the period of organogenesis resulted in adverse developmental outcomes at doses that produced maternal toxicity.

There are no available data with givosiran sodium use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Consider the benefits and risks of givosiran sodium for the mother and potential adverse effects to the fetus when prescribing givosiran sodium for a pregnant woman.

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations: Porphyria attacks during pregnancy, often triggered by hormonal changes, occur in 24% to 95% of AHP patients, with maternal mortality ranging from 2% to 42%. Pregnancy in AHP patients is associated with higher rates of spontaneous abortion, hypertension, and low birth weight infants.

Animal Data: In an embryo-fetal development study in pregnant rabbits, givosiran was administered subcutaneously at doses of 0.5, 1.5, and 5 mg/kg/day during organogenesis (gestational days 7–19) or 20 mg/kg as a single administration on gestation day 7. Administration of givosiran was maternally toxic based on decreased body weight gain at all dose levels tested and resulted in increased postimplantation loss starting at 1.5 mg/kg/day. An increased incidence of skeletal variations of the sternebrae was observed at 20 mg/kg. The 1.5 mg/kg/day dose in rabbits is 5 times the maximum recommended human dose (MRHD) of 2.5 mg/kg/month normalized to 0.089 mg/kg/day, based on body surface area. In a combined fertility and embryo-fetal development study in female rats, givosiran was administered subcutaneously at doses of 0.5 to 5 mg/kg/day during organogenesis (gestational days 6–17). The 5 mg/kg/day dose (9 times the normalized MRHD based on body surface area) was associated with a skeletal variation (incomplete ossification of pubes) and produced maternal toxicity.

In a pre- and postnatal development study, givosiran administered subcutaneously to pregnant rats on gestation days 7, 13, and 19 and postnatal days 6, 12, and 18 at doses up to 30 mg/kg did not produce maternal toxicity or developmental effects in the offspring.

Lactation

Risk Summary: There are no data on the presence of givosiran sodium in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for givosiran sodium and any potential adverse effects on the breastfed child from givosiran sodium or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of givosiran sodium did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Common Adverse Effects

The most common adverse reactions (≥20% of patients) included nausea and injection site reactions.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Sensitive CYP1A2 and CYP2D6 Substrates: Avoid concomitant use with CYP1A2 and CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities.

Actions

Mechanism of Action

Givosiran is a double-stranded small interfering RNA that 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 (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of acute hepatic porphyria (AHP).

Advice to Patients

Anaphylactic Reaction: Inform patients about the risk and possible symptoms of severe hypersensitivity reactions that could occur.

Hepatic Toxicity: Inform patients that transaminase elevations may occur and that laboratory testing will be conducted in the first 6 months of treatment and as clinically indicated thereafter.

Renal Toxicity: Inform patients that increases in serum creatinine and decreases in eGFR have been reported and that laboratory testing will be conducted as clinically indicated.

Injection Site Reactions: Inform patients of the signs and symptoms of injection site reactions (examples include redness, pain, itching, rash, discoloration, and localized swelling).

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.