Givosiran Sodium (Monograph)

Drug class: Other Miscellaneous Therapeutic Agents

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Aminolevulinate synthase 1-directed small interfering RNA.

Uses for Givosiran Sodium

Acute Hepatic Porphyria

Treatment of adults with acute hepatic porphyria; designated an orphan drug by FDA for this use.

American Gastroenterological Association recommends use of givosiran to reduce attacks in patients with acute hepatic porphyria who have recurrent acute attacks (4 or more per year).

Givosiran Sodium Dosage and Administration

General

Pretreatment Screening

Measure liver function tests prior to initiating treatment.
Measure blood homocysteine levels prior to initiating treatment.

Patient Monitoring

Monitor for signs and symptoms of anaphylaxis.
Monitor renal function during treatment as clinically indicated.
Measure liver function tests monthly during the first 6 months of treatment and as clinically indicated thereafter.
Measure blood homocysteine levels and monitor for changes during treatment. If elevated blood homocysteine levels, assess folate, vitamin B12, and vitamin B6. Consider treatment with a supplement containing vitamin B6 (as monotherapy or in a multivitamin preparation).

Administration

Administer by sub-Q injection by a healthcare professional; ensure that appropriate medical support is available to manage anaphylactic reactions during administration.

Sub-Q Injection

Ready-to-use solution; does not require reconstitution or dilution.

Inspect for particulate matter and discoloration prior to administration; should be a clear, colorless-to-yellow solution.

Required volume for administration determined based on weight-based dosage.

Withdraw indicated volume using a 21-gauge (or larger) needle and discard any unused portion. Dosages requiring volumes ≥1.5 mL should be divided equally into multiple syringes. Replace the 21-gauge (or larger) needle with either a 25- or 27-gauge needle with 1/2- or 5/8-inch needle length. Avoid having givosiran on needle tip until needle is in the subcutaneous space.

Administer in the abdomen, back or side of the upper arms, or thighs. Avoid administration within 5 cm of the navel. If more than one injection is needed, sites should be at least 2 cm apart. Rotate injection sites. Do not administer into scar tissue or reddened, inflamed, or swollen areas.

If a dose is missed, administer next dose as soon as possible. Subsequent dosages should resume at monthly intervals.

Dosage

Adults

Acute Hepatic Porphyria

Sub-Q

2.5 mg/kg based on actual body weight once monthly.

Dosage Modification for Toxicity

In patients with severe or clinically significant aminotransferase elevations who have dose interruption and subsequent improvement, reduce dosage to 1.25 mg/kg once monthly. In patients who resume dosing at 1.25 mg/kg once monthly without recurrence of severe or clinically significant aminotransferase elevations, the dosage may be increased to 2.5 mg/kg once monthly.

Special Populations

Hepatic Impairment

No specific population dosage recommendations.

Renal Impairment

No specific population dosage recommendations.

Geriatric Patients

No specific population dosage recommendations.

Cautions for Givosiran Sodium

Contraindications

Known severe hypersensitivity to givosiran.

Warnings/Precautions

Anaphylactic Reactions

Anaphylaxis reported.

Monitor for signs and symptoms of anaphylaxis. Ensure medical support is available to manage anaphylactic reactions.

If anaphylaxis occurs, immediately discontinue givosiran and institute appropriate medical treatment.

Hepatic Toxicity

ALT of at least 3 times the upper limit of normal (ULN) reported. Such elevations primarily occurred between 3 to 5 months following initiation.

Measure liver function tests prior to initiating treatment, every month during the first 6 months of treatment, and as clinically indicated thereafter.

Interrupt or discontinue treatment for severe or clinically significant aminotransferase elevations.

Renal Toxicity

Increases in serum creatinine levels and decreases in eGFR reported. The median increase in creatinine at month 3 was 0.07 mg/dL.

Monitor renal function during treatment as clinically indicated.

Injection Site Reactions

Injection site reactions (e.g., erythema, pain, pruritus, rash, discoloration, swelling around injection site) reported.

Increased Blood Homocysteine

Increases in blood homocysteine levels have occurred. Clinical relevance is unknown.

Measure blood homocysteine levels prior to initiating treatment and monitor for changes during treatment with givosiran.

In patients with elevated blood homocysteine levels, assess folate, vitamin B12, and vitamin B6. Consider treatment with a supplement containing vitamin B6 (as monotherapy or in a multivitamin preparation).

Immunogenicity

As with all oligonucleotides, there is a potential for immunogenicity.

In clinical trials, one patient developed treatment-emergent anti-drug antibodies. No clinically significant differences in the clinical efficacy, safety, pharmacokinetic, or pharmacodynamic profiles observed.

Specific Populations

Pregnancy

No available data in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Porphyria attacks during pregnancy, often triggered by hormonal changes, occur in 24 to 95% of patients with acute hepatic porphyria, with maternal mortality ranging from 2 to 42%.

Pregnancy in patients with acute hepatic porphyria is associated with higher rates of spontaneous abortion, hypertension, and low birth weight infants.

Consider benefits and risks of givosiran for the mother and potential adverse effects to the fetus when prescribing givosiran to a pregnant woman.

Lactation

No data on the presence of givosiran in human milk, effects on the breastfed child, or effects on milk production.

Consider developmental and health benefits of breastfeeding along with the mother's clinical need for givosiran and any potential adverse effects on the breastfed child from the drug or underlying maternal condition.

Geriatric Use

Clinical studies of givosiran did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.

Hepatic Impairment

No clinically meaningful differences in givosiran pharmacokinetics or pharmacodynamics in mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, or bilirubin >1 x ULN to 1.5 x ULN).

Effect of moderate to severe hepatic impairment on givosiran pharmacokinetics is unknown.

Renal Impairment

No clinically meaningful differences in givosiran pharmacokinetics or pharmacodynamics in mild, moderate, or severe renal impairment (eGFR ≥15 to <89 mL/min/1.73 m²).

Effect of end-stage renal disease (eGFR <15 mL/min/1.73 m²) on givosiran pharmacokinetics is unknown.

Common Adverse Effects

Most common adverse events (≥20%): nausea and injection site reactions.

Drug Interactions

Not a substrate of and does not directly inhibit or induce CYP enzymes; however, due to pharmacological effects on the hepatic heme biosynthesis pathway, has the potential to reduce the activity of CYP enzymes.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Givosiran increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates.

Avoid concomitant use with CYP1A2 and CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.

Specific Drugs

Drug	Interaction	Comments
Caffeine and caffeine-containing products	Increased caffeine concentration and AUC	If concomitant use unavoidable, decrease dosage of caffeine
Dextromethorphan	Increased dextromethorphan concentration and AUC	Monitor for adverse effects
Losartan	Increased losartan AUC, no effect on concentration	Not considered clinically relevant
Midazolam	Increased midazolam concentration and AUC	Not considered clinically relevant
Omeprazole	Increased omeprazole concentration and AUC	Not considered clinically relevant

Givosiran Sodium Pharmacokinetics

Absorption

Peak plasma concentrations achieved 3 (range: 0.5-8) hours after sub-Q administration

No accumulation observed following multiple dosing.

Distribution

Extent

Distributes primarily to the liver.

Plasma Protein Binding

90%

Elimination

Metabolism

Metabolized by nucleases to oligonucleotides of shorter lengths; not a substrate of CYP isoenzymes.

Elimination Route

Excreted in the urine as the parent drug (5-14%) and active metabolite (4-13%).

Half-life

6 hours.

Stability

Storage

Sub-Q Injection

Store at 2-25°C in the original container until ready for use.

Actions

Double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) messenger RNA (mRNA) in hepatocytes through RNA interference, reducing elevated levels of liver ALAS1 mRNA.
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.

Advice to Patients

Advise patients on the risk and possible symptoms of severe hypersensitivity reactions that could occur.
Advise patients about the risk of hepatotoxicity and that aminotransferase elevations may occur. Advise patients that laboratory testing will be conducted prior to, during the first 6 months of treatment, and as clinically indicated thereafter.
Advise patients about the risk of renal toxicity and that increases in serum creatinine and decreases in eGFR have been reported. Advise patients that laboratory testing will be conducted as clinically indicated.
Advise patients of the signs and symptoms of injection site reactions (e.g., redness, pain, itching, rash, discoloration, and localized swelling).
Advise patients that increases in blood homocysteine levels may occur and that laboratory testing will be conducted prior to and during treatment. Advise patients that vitamin supplementation may be considered.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise women to inform their clinician if they are or plan to become pregnant or plan to breastfeed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.