Givosiran Sodium

FDA Drug Information • Also known as: Givlaari

Brand Names: Givlaari
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA (siRNA), covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes. The structural formulas of the givosiran drug substance in its sodium form, and the ligand (L96), are presented below. Abbreviations: Af = adenine 2'-F ribonucleoside; Cf = cytosine 2'-F ribonucleoside; Uf = uracil 2'-F ribonucleoside; Am = adenine 2'-OMe ribonucleoside; Cm = cytosine 2'-OMe ribonucleoside; Gf = guanine 2'-F ribonucleoside; Gm = guanine 2'-OMe ribonucleoside; Um = uracil 2'-OMe ribonucleoside; L96 = triantennary GalNAc (N-acetylgalactosamine) GIVLAARI is supplied as a sterile, preservative-free, 1-mL colorless-to-yellow solution for subcutaneous injection containing 189 mg givosiran in a single-dose, 2-mL Type 1 glass vial with a fluoropolymer-coated rubber stopper and a flip-off aluminum seal. GIVLAARI is available in cartons containing one single-dose vial each . GIVLAARI is formulated in Water for Injection. Sodium hydroxide and/or phosphoric acid may have been added for pH adjustment during product manufacturing. The molecular formula of givosiran sodium is C 524 H 651 F 16 N 173 Na 43 O 316 P 43 S 6 with a molecular weight of 17,245.56 Da. The molecular formula of givosiran (free acid) is C 524 H 694 F 16 N 173 O 316 P 43 S 6 with a molecular weight of 16,300.34 Da. Chemical Structure

What Is Givosiran Sodium Used For?

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

Dosage and Administration

2 DOSAGE AND ADMINISTRATION The recommended dose of GIVLAARI is 2.5 mg/kg once monthly by subcutaneous injection. ( 2.1 ) 2.1 Recommended Dosage The recommended dose of GIVLAARI is 2.5 mg/kg administered via subcutaneous injection once monthly. Dosing is based on actual body weight. Missed Dose Administer GIVLAARI as soon as possible after a missed dose. Resume dosing at monthly intervals following administration of the missed dose. Dose Modification for Adverse Reactions In patients with severe or clinically significant transaminase elevations, who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly [see Warnings and Precautions (5.2) ] . In patients who resume dosing at 1.25 mg/kg once monthly without recurrence of severe or clinically significant transaminase elevations, the dose may be increased to the recommended dose of 2.5 mg/kg once monthly. 2.2 Administration Instructions Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI [see Warnings and Precautions (5.1) ]. GIVLAARI is intended for subcutaneous use by a healthcare professional only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. GIVLAARI is a sterile, preservative-free, clear, colorless-to-yellow solution. It is supplied in a single-dose vial, as a ready-to-use solution that does not require additional reconstitution or dilution prior to administration. Use aseptic technique. Calculate the required volume of GIVLAARI based on the recommended weight-based dosage [see Dosage and Administration (2.1) ] . Withdraw the indicated injection volume of GIVLAARI using a 21-gauge or larger needle. Divide doses requiring volumes greater than 1.5 mL equally into multiple syringes. Replace the 21-gauge or larger needle with either a 25-gauge or 27-gauge needle with 1/2" or 5/8" needle length. Avoid having GIVLAARI on the needle tip until the needle is in the subcutaneous space. Administer injection into the abdomen, the back or side of the upper arms, or the thighs. Rotate injection sites. An injection should never be given into scar tissue or areas that are reddened, inflamed, or swollen. If injecting into the abdomen, avoid a 5 cm diameter circle around the navel. If more than one injection is needed for a single dose of GIVLAARI, the injection sites should be at least 2 cm apart from previous injection locations. Discard unused portion of the drug.

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Anaphylactic Reaction [see Warnings and Precautions (5.1) ] Transaminase Elevations [see Warnings and Precautions (5.2) ] Serum Creatinine Increase [see Warnings and Precautions (5.3) ] Injection Site Reactions [see Warnings and Precautions (5.4) ] Blood Homocysteine Increased [see Warnings and Precautions (5.5) ] Pancreatitis [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥20% of patients) included nausea and injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the pivotal placebo-controlled, double-blind study (ENVISION), 48 patients received 2.5 mg/kg GIVLAARI and 46 patients received placebo, administered once monthly via subcutaneous injection for up to 6 months. Patients received GIVLAARI for a median of 5.5 months (range 2.7-6.4 months). Of these, 47 patients received ≥5 months of treatment. The most frequently occurring (≥20% incidence) adverse reactions reported in patients treated with GIVLAARI were nausea (27%) and injection site reactions (25%). Permanent discontinuation occurred in one patient due to elevated transaminases. Table 1: Adverse Reactions that Occurred at Least 5% More Frequently in Patients Treated with GIVLAARI Compared to Patients Treated with Placebo Adverse Reaction GIVLAARI N=48 N (%) Placebo N=46 N (%) Nausea 13 (27) 5 (11) Injection site reactions 12 (25) 0 Rash Grouped term includes pruritus, eczema, erythema, rash, rash pruritic, urticaria 8 (17) 2 (4) Serum creatinine increase Grouped term includes blood creatinine increased, glomerular filtration rate decreased, chronic kidney disease (decreased eGFR) 7 (15) 2 (4) Transaminase elevations 6 (13) 1 (2) Fatigue 5 (10) 2 (4) Adverse reactions observed at a lower frequency occurring in placebo-controlled and open-label clinical studies included anaphylactic reaction (one patient, 0.9%) and hypersensitivity (one patient, 0.9%). In the ENVISION study, during the open label extension, adverse reactions of blood homocysteine increased were reported in 15 of 93 (16%) patients treated with GIVLAARI [see Warnings and Precautions (5.5) ]. 6.2 Immunogenicity As with all oligonucleotides, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In placebo-controlled and open-label clinical studies, 1 of 111 patients with AHP (0.9%) developed treatment-emergent anti-drug antibodies (ADA) during treatment with GIVLAARI. No clinically significant differences in the clinical efficacy, safety, pharmacokinetic, or pharmacodynamic profiles of GIVLAARI were observed in the patient who tested positive for anti-givosiran antibodies. 6.3 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure....

Drug Interactions

7 DRUG INTERACTIONS 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. ( 7.1 ) 7.1 Effect of GIVLAARI on Other Drugs Sensitive CYP1A2 and CYP2D6 Substrates Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates [see Clinical Pharmacology (12.3) ] , which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or 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.

Contraindications

4 CONTRAINDICATIONS GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis [see Warnings and Precautions (5.1) ]. Severe hypersensitivity to givosiran. ( 4 )

Pregnancy and Breastfeeding

8.1 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 (see Data ). There are no available data with GIVLAARI 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 GIVLAARI for the mother and potential adverse effects to the fetus when prescribing GIVLAARI to 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 Disease-associated maternal and/or embryo/fetal risk 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. Data 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...

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied GIVLAARI (givosiran) is a clear, colorless-to-yellow ready-to-use solution available in single-dose vials of 189 mg/mL in cartons containing one vial (NDC 71336-1001-1). 16.2 Storage and Handling Store at 2°C to 25°C (36°F to 77°F). Store GIVLAARI in its original container until ready for use.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.