Leqvio

     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.

     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.

     Pregnancy

Risk Summary

Discontinue LEQVIO when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Inclisiran increases LDL-C uptake and lowers LDL-C levels in the circulation, thus decreasing cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LEQVIO may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of hypercholesterolemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of hypercholesterolemia for most patients.

There are no available data on the use of LEQVIO in pregnant patients to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal reproduction studies, no adverse developmental effects were observed in rats and rabbits with subcutaneous administration of inclisiran during organogenesis at doses up to 5 to 10 times the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison (see Data). No adverse developmental outcomes were observed in offspring of rats administered inclisiran from organogenesis through lactation at 5 times the MRHD based on BSA comparison (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Data

Animal Data

In embryo-fetal development studies conducted in Sprague-Dawley rats and New Zealand White rabbits, inclisiran was administered by subcutaneous injection at dose levels of 50, 100, and 150 mg/kg once daily during organogenesis (rats: Gestation Days 6 to 17; rabbits: Gestation Days 7 to 19). There was no evidence of embryo-fetal toxicity or teratogenicity at doses up to 5 and 10 times, respectively, the MRHD based on BSA comparison/dose. Inclisiran crosses the placenta and was detected in rat fetal plasma at concentrations that were 65 to 154 times lower than maternal levels.

In a pre- and postnatal development study conducted in Sprague-Dawley rats, inclisiran was administered once daily by subcutaneous injection at levels of 50, 100, and 150 mg/kg from Gestation Day 6 through Lactation Day 20. Inclisiran was well-tolerated in maternal rats, with no evidence of maternal toxicity and no effects on maternal performance. There were no effects on the development of the F1 generation, including survival, growth, physical and reflexological development, behavior, and reproductive performance at doses up to 5 times the MRHD, based on BSA comparison/dose.

     Lactation

Risk Summary

There is no information on the presence of inclisiran in human milk, the effects on the breastfed infant, or the effects on milk production. Inclisiran was present in the milk of lactating rats in all dose groups. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Oligonucleotide-based products typically have poor oral bioavailability; therefore, it is considered unlikely that low levels of inclisiran present in milk will adversely impact an infant’s development during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEQVIO and any potential adverse effects on the breastfed infant from LEQVIO or from the underlying maternal condition.

Data

In lactating rats, inclisiran was detected in milk at mean maternal plasma:milk ratios that ranged between 0.361 and 1.79. However, there is no evidence of systemic absorption in the suckling rat neonates.

     Pediatric Use

The safety and effectiveness of LEQVIO have not been established in pediatric patients.

     Geriatric Use

Of the 1,833 patients treated with LEQVIO in clinical studies, 981 (54%) patients were 65 years of age and older, while 239 (13%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.

     Renal Impairment

No dose adjustments are necessary for patients with mild, moderate, or severe renal impairment [see Clinical Pharmacology (12.3)]. LEQVIO has not been studied in patients with end stage renal disease [see Clinical Pharmacology (12.3)].

     Hepatic Impairment

No dose adjustment is necessary in patients with mild to moderate hepatic impairment. LEQVIO has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

     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.

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).

     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.