Givosiran Sodium (Monograph)
Drug class: Other Miscellaneous Therapeutic Agents
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.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Parenteral |
Injection, for subcutanoeus use |
189 mg/mL |
Givlaari |
Alynlam Pharmaceuticals |
AHFS DI Essentials™. © Copyright 2025, Selected Revisions April 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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