Givosiran
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omid Afkhami-Ardakani
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Overview
Givosiran is a Small interfering RNA (siRNA) agent that is FDA approved for the treatment of acute hepatic porphyria (AHP) in adults.. Common adverse reactions include nausea, injection site reactions, fatigue, and elevated liver enzymes..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
2.5 mg/kg administered once monthly via subcutaneous injection. Dosage is based on actual body weight.
Use without dilution. Administer by a healthcare professional. Injection sites should be rotated, and areas with skin reactions should be avoided.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Givosiran in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Givosiran in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Givosiran FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Givosiran in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Givosiran in pediatric patients.
Contraindications
There is limited information regarding Givosiran Contraindications in the drug label.
Warnings
Hepatic Toxicity:
Increases in liver transaminases (ALT, AST) have been observed.
Monitor liver function tests prior to initiation and periodically during treatment.
Consider interrupting or discontinuing therapy if clinically significant elevations occur.
Renal Toxicity:
Cases of serum creatinine elevations and reduced estimated glomerular filtration rate (eGFR) have been reported.
Monitor renal function before and during treatment, especially in patients with pre-existing renal impairment.
Anaphylactic Reaction:
A case of anaphylaxis requiring hospitalization was reported.
Monitor patients for signs and symptoms of hypersensitivity; discontinue Givosiran if anaphylaxis occurs.
Injection Site Reactions:
Commonly reported and may include erythema, pain, or swelling.
Rotate injection sites and avoid areas of active skin disease or injury.
Elevations in Homocysteine:
Givosiran is associated with increased plasma homocysteine levels.
The clinical implications are unknown; monitor if clinically indicated.
Adverse Reactions
Clinical Trials Experience
Gastrointestinal Disorders:
Nausea (27%)
Vomiting
Diarrhea
General Disorders and Administration Site Conditions:
Injection site reactions (including erythema, pain, pruritus, swelling)
Nervous System Disorders:
Fatigue (23%)
Headache
Hepatobiliary Disorders:
Elevated liver enzymes (ALT, AST)
Renal Disorders:
Increased serum creatinine
Decreased estimated GFR
Skin and Subcutaneous Tissue Disorders:
Rash
Pruritus
Postmarketing Experience
There is limited information regarding Givosiran Postmarketing Experience in the drug label.
Drug Interactions
Effect of Givosiran on Cytochrome P450 (CYP) Enzymes:
Givosiran reduces the expression of ALAS1 in the liver, which may decrease levels of heme, a cofactor for multiple CYP enzymes.
As a result, reduced activity of CYP1A2, CYP2D6, and CYP3A4 has been observed in clinical studies.
This may lead to increased exposure to drugs metabolized by these enzymes.
Caution with Narrow Therapeutic Index Drugs:
Use caution when co-administering Givosiran with medications metabolized by CYP1A2, CYP2D6, and CYP3A4 that have a narrow therapeutic index (e.g., theophylline, warfarin, certain antiarrhythmics).
Consider dose adjustments and close monitoring of such medications.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Givosiran in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Givosiran in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Givosiran during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Givosiran in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Givosiran in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Givosiran in geriatric settings.
Gender
There is no FDA guidance on the use of Givosiran with respect to specific gender populations.
Race
There is no FDA guidance on the use of Givosiran with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Givosiran in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Givosiran in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Givosiran in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Givosiran in patients who are immunocompromised.
Administration and Monitoring
Administration
Dosage: Administer 2.5 mg/kg via subcutaneous injection once monthly, based on actual body weight.
Route: Subcutaneous injection only – not for intravenous or intramuscular use.
Preparation:
Givosiran is supplied as a ready-to-use solution in a single-dose vial.
Do not shake or dilute.
Inspect visually for particulate matter or discoloration prior to administration.
Allow the vial to reach room temperature before injecting.
Injection Site:
Inject into the abdomen, upper arms, or thighs.
Rotate injection sites; avoid areas of active skin disease or injury.
Monitoring
Liver Function Tests (LFTs):
Monitor ALT, AST, and total bilirubin before starting treatment and periodically during therapy due to risk of hepatic toxicity.
Renal Function:
Monitor serum creatinine and eGFR at baseline and periodically, especially in patients with pre-existing renal impairment.
Homocysteine Levels:
Givosiran is associated with increased plasma homocysteine; monitor levels if clinically indicated.
Signs of Hypersensitivity:
Observe for signs of anaphylaxis or severe allergic reactions, especially after the first dose.
IV Compatibility
Not applicable. It is administered only via subcutaneous injection.
Overdosage
There is limited information regarding Givosiran overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Givosiran Pharmacology in the drug label.
Mechanism of Action
Givosiran is a small interfering RNA (siRNA) therapeutic that targets 5-aminolevulinic acid synthase 1 (ALAS1) mRNA in hepatocytes. By degrading ALAS1 mRNA through RNA interference, givosiran reduces the elevated levels of liver ALAS1 mRNA. This leads to decreased production of neurotoxic intermediates, aminolevulinic acid (ALA) and porphobilinogen (PBG), which are associated with the attacks and other disease manifestations of acute hepatic porphyria (AHP).
Structure
There is limited information regarding Givosiran Structure in the drug label.
Pharmacodynamics
Upon subcutaneous administration, givosiran leads to a rapid and dose-dependent reduction in urinary levels of ALA and PBG, aligning them toward the upper limit of normal. This reduction is achieved through the inhibition of ALAS1, thereby preventing the accumulation of toxic heme intermediates responsible for the neurovisceral symptoms characteristic of AHP.
Pharmacokinetics
Absorption: Givosiran is rapidly absorbed following subcutaneous injection, with peak plasma concentrations reached within 0.5 to 5 hours.
Distribution: The drug predominantly distributes to the liver through asialoglycoprotein receptor–mediated uptake, with a hepatic half-life of approximately 1 week.
Metabolism: Givosiran is metabolized by nucleases into an active metabolite, AS(N-1)3' givosiran, which is equipotent to the parent compound. It is not metabolized by cytochrome P450 enzymes.
Elimination: Renal and fecal excretion are minor pathways, with approximately 10% and 16% of the dose recovered intact in rats and monkeys, respectively.
Nonclinical Toxicology
There is limited information regarding Givosiran Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Givosiran Clinical Studies in the drug label.
How Supplied
Supplied as a ready-to-use, sterile, preservative-free solution in a single-dose vial.
Strength: 189 mg/mL in a 1 mL vial (total 189 mg per vial).
Storage
Refrigerate at 2°C to 8°C (36°F to 46°F).
Store in the original carton to protect from light.
Do not freeze.
Do not shake.
Once removed from refrigeration, the vial may be kept at room temperature (up to 30°C / 86°F) for no more than 14 days, but must be used or discarded afterward.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Administration and Frequency: Inform patients that Givosiran is given as a subcutaneous injection once monthly by a healthcare professional.
Expected Benefits: Explain that the medication is used to reduce the frequency of acute attacks associated with acute hepatic porphyria (AHP).
Monitoring: Patients should be aware that regular blood tests will be conducted to monitor liver function, renal function, and potentially homocysteine levels.
Adverse Reactions: Educate patients about possible side effects such as:
Injection site reactions (e.g., pain, redness, swelling)
Nausea
Fatigue
Liver enzyme elevations
Hypersensitivity: Advise patients to seek immediate medical attention if they experience symptoms of an allergic reaction, such as swelling, difficulty breathing, or rash.
Pregnancy and Contraception: Inform females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose. Pregnancy testing may be required before starting therapy.
Precautions with Alcohol
Alcohol-Givosiran interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Givlaari® Manufactured and marketed by Alnylam Pharmaceuticals, Inc.
Look-Alike Drug Names
There is limited information regarding Givosiran Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.