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.

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.

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.

5.2 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).

5.3 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.

5.4 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)].

5.5 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).

5.6 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.

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.

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.

Gastrointestinal Disorders: Acute pancreatitis

7.1 Effect of GIVLAARI on Other Drugs

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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.

12.1 Mechanism of Action

Givosiran is a double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP.

12.2 Pharmacodynamics

The pharmacodynamic effects of GIVLAARI were evaluated in chronic high excreters treated with 0.035 to 2.5 mg/kg single dose and AHP patients treated with 2.5 to 5 mg/kg once monthly and 2.5 to 5 mg/kg once quarterly dose via subcutaneous injection. Dose-dependent reduction in urinary ALAS1 mRNA, ALA and PBG levels was observed over the 0.035 to 5 mg/kg dose range (0.14 to 2-fold the approved recommended dosage). Median reductions from baseline in urinary ALA and PBG of 83.7% and 75.1%, respectively, were observed 14 days after the first dose of GIVLAARI 2.5 mg/kg once monthly in AHP patients. Maximal reductions in ALA and PBG levels were achieved around Month 3, with median reductions from baseline of 93.8% for ALA and 94.5% for PBG, and were sustained thereafter with repeated once monthly dosing.

12.3 Pharmacokinetics

The pharmacokinetics of givosiran and its active metabolite [AS(N-1)3′ givosiran] were evaluated following single and multiple dosing in chronic high excreter subjects and AHP patients as summarized in Table 2.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a carcinogenicity study in Sprague Dawley rats administered 25, 50, or 100 mg/kg givosiran by subcutaneous injection every 28 days for up to 89 weeks (males) or 85 weeks (females), givosiran doses in rats were 2, 3, and 6 times, respectively, the MRHD based on body surface area. A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.

In a carcinogenicity study in male and female Tg.rasH2 mice administered givosiran by subcutaneous injection every 28 days for 26 weeks, up to 1500 mg/kg, givosiran was not carcinogenic.

Givosiran was not genotoxic in the in vitro bacterial reverse mutation (Ames) assays, an in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes or the in vivo micronucleus assay in rats.

In fertility and early embryonic development studies, givosiran administered subcutaneously once weekly at doses up to 30 mg/kg in male and female rats prior to and during mating, and continuing in females throughout organogenesis, resulted in no adverse effects on fertility or reproductive function in male or female animals.

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.