LEQVIO

LEQVIO contains inclisiran sodium, a small interfering RNA (siRNA) directed to proprotein convertase subtilisin kexin type 9 (PCSK9) mRNA. Inclisiran contains a covalently linked ligand containing three N-acetylgalactosamine (GalNAc) residues to facilitate delivery to hepatocytes. With one exception, the 2'ribose moieties of the inclisiran sodium are present as 2'-F or 2'-OMe ribonucleotide. In addition, six of the terminal phosphodiester backbones are present as phosphorothioate linkages as indicated below. The molecular formula of inclisiran sodium is C 529 H 664 F 12 N 176 Na 43 O 316 P 43 S 6 and its molecular weight is 17,284.72 g/mol. It has the following structural formula: Abbreviations: Af = adenine 2'-F ribonucleotide; Cf = cytosine 2'-F ribonucleotide; Gf = guanine 2'-F ribonucleotide; Am = adenine 2'-OMe ribonucleotide; Cm = cytosine 2'-OMe ribonucleotide; Gm = guanine 2'-OMe ribonucleotide; Um = uracil 2'-OMe ribonucleotide; L96 = triantennary GalNAc (N-acetyl-galactosamine) LEQVIO is a sterile, preservative-free, clear, and colorless to pale yellow solution for subcutaneous use in a prefilled syringe. Each syringe contains 1.5 mL of solution containing the equivalent of 284 mg inclisiran (present as 300 mg inclisiran sodium salt). LEQVIO is formulated in Water for Injection and may also contain sodium hydroxide and/or phosphoric acid for pH adjustment to a target pH of 7.0. molecular formula of inclisiran sodium

LEQVIO ® is indicated as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). LEQVIO is a small interfering RNA (siRNA) directed to proprotein convertase subtilisin kexin type 9 (PCSK9) mRNA indicated as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). ( 1 )

The recommended dosage of LEQVIO is 284 mg administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months. ( 2.1 ) LEQVIO should be administered by a healthcare professional. ( 2.2 ) Inject LEQVIO subcutaneously into the abdomen, upper arm, or thigh. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of LEQVIO is 284 mg administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months. If a planned dose is missed by less than 3 months, administer LEQVIO and maintain dosing according to the patient’s original schedule. If a planned dose is missed by more than 3 months, restart with a new dosing schedule - administer LEQVIO initially, again at 3 months, and then every 6 months. Assess LDL-C when clinically indicated. The LDL-lowering effect of LEQVIO may be measured as early as 30 days after initiation and anytime thereafter without regard to timing of the dose. 2.2 Important Administration Instructions LEQVIO should be administered by a healthcare professional. Inject LEQVIO subcutaneously into the abdomen, upper arm, or thigh. Do not inject in areas of active skin disease or injury, such as sunburns, skin rashes, inflammation, or skin infections. Inspect LEQVIO visually before use. It should appear clear and colorless to pale yellow. Do not use if particulate matter or discoloration is seen. For more detailed instruction on administration of the prefilled syringe, see Instructions for Use.

LEQVIO is contraindicated in patients with a prior serious hypersensitivity reaction to inclisiran or any of the excipients in LEQVIO. Serious hypersensitivity reactions have included angioedema [see Adverse Reactions (6.2)] . Prior serious hypersensitivity to inclisiran or any of the excipients in LEQVIO.

Common adverse reactions in clinical trials (≥ 3%): injection site reaction, arthralgia, and bronchitis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 drug and may not reflect the rates observed in practice. The data in Table 1 are derived from 3 placebo-controlled trials that included 1,833 patients treated with LEQVIO, including 1,682 exposed for 18 months (median treatment duration of 77 weeks) [see Clinical Studies (14)] . The mean age of the population was 64 years, 32% of the population were women, 92% were White, 6% were Black or African American, 1% were Asian, and < 1% were other races; 6% identified as Hispanic or Latino ethnicity. At baseline, 12% of patients had a diagnosis of HeFH and 85% had clinical atherosclerotic cardiovascular disease (ASCVD). Adverse reactions reported in at least 3% of LEQVIO-treated patients, and more frequently than in placebo-treated patients, are shown in Table 1. Table 1: Adverse Reactions Occurring in Greater Than or Equal to 3% of LEQVIO-treated Patients and More Frequently than with Placebo (Studies 1, 2, and 3) Adverse Reactions Placebo (N = 1,822) % LEQVIO (N = 1,833) % †includes related terms such as: injection site pain, erythema and rash Injection site reaction† 2 8 Arthralgia 4 5 Bronchitis 3 4 Adverse reactions led to discontinuation of treatment in 2.5% of patients treated with LEQVIO and 1.9% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with LEQVIO were injection site reactions (0.2% versus 0% for LEQVIO and placebo, respectively). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of LEQVIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity: angioedema, rash, and urticaria.