Givlaari
(givosiran)Dosage & Administration
The recommended dose of GIVLAARI is 2.5 mg/kg once monthly by subcutaneous injection.
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Givlaari Prescribing Information
GIVLAARI is indicated for the treatment of adults with acute hepatic porphyria (AHP).
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.
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.
Injection: 189 mg/mL clear, colorless-to-yellow solution in a single-dose vial
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 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 GIVLAARI 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 GIVLAARI and any potential adverse effects on the breastfed child from GIVLAARI or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of GIVLAARI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].
Anaphylactic Reaction
Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials) [see Adverse Reactions (6.1)]. Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI 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 GIVLAARI in the placebo-controlled trial [see Adverse Reactions (6.1)]. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.
Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. For resumption of dosing after interruption, see Dosage and Administration (2.1).
Renal Toxicity
Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI [see Adverse Reactions (6.1)]. In the placebo-controlled study, 15% of the patients in the GIVLAARI 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 GIVLAARI as clinically indicated.
Injection Site Reactions
Injection site reactions have been reported in 25% of patients receiving GIVLAARI 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 a subsequent dose administration [see Adverse Reactions (6.1)].
Blood Homocysteine Increased
Increases in blood homocysteine levels have occurred in patients receiving GIVLAARI [see Adverse Reactions (6.1)]. 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. The clinical relevance of the elevations in blood homocysteine during treatment with GIVLAARI is unknown. Measure blood homocysteine levels prior to initiating treatment and monitor for changes during treatment with GIVLAARI. In patients with elevated blood homocysteine levels, assess folate, vitamins B12 and B6. Consider treatment with a supplement containing vitamin B6 (as monotherapy or a multivitamin preparation).
Pancreatitis
Cases of acute pancreatitis, some severe, have been reported in GIVLAARI-treated patients.
Consider acute pancreatitis as a potential diagnosis in GIVLAARI-treated patients with signs/symptoms of acute pancreatitis including acute upper abdominal pain, clinically significant elevation of pancreatic enzymes, and/or imaging findings of acute pancreatitis, to ensure appropriate management. Consider interruption and/or discontinuation of GIVLAARI treatment for severe cases.