GIVLAARI Solution for injection (2019)

Βιβλιογραφική αναφορά

Συγγραφείς

Alnylam Pharmaceuticals, Inc.

Λέξεις κλειδιά

71336-1001

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1. Indications and Usage

GIVLAARI is indicated for the treatment of adults with acute hepatic porphyria (AHP).

2. Dosage and Administration

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 ...

3. Dosage Forms and Strengths

Injection: 189 mg/mL clear, colorless-to-yellow solution in a single-dose vial.

4. Contraindications

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

5. 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 ...

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 ...

6.1. Clinical Trials 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 ...

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 ...

7. Drug Interactions

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)] ...

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 ...

8.2. 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 ...

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.

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 ...

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 ...

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 ...

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 ...

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with givosiran. Givosiran was not genotoxic in the in vitro bacterial reverse mutation (Ames) assays, an in vitro chromosomal aberration assay in cultured ...

14. Clinical Studies

The efficacy of GIVLAARI in patients with acute hepatic porphyria was evaluated in the ENVISION trial (NCT03338816), a randomized, double-blind, placebo-controlled, multinational study. ENVISION enrolled ...

16.1 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.

16.2 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).

17. Patient Counseling Information

Advise patients of the potential risks of GIVLAARI treatment: Anaphylactic Reaction: Inform patients about the risk and possible symptoms of severe hypersensitivity reactions that could occur ...