Lipfendra

LIPFENDRA ® 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). Cardiovascular outcomes trials have demonstrated that reducing LDL-C lowers the risk for major adverse cardiovascular events (MACE) in adults at increased risk when treated with statins or monoclonal antibody proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors as an add-on to statin therapy. LIPFENDRA is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor 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). Cardiovascular outcomes trials have demonstrated that reducing LDL-C lowers the risk for major adverse cardiovascular events (MACE) in adults at increased risk when treated with statins or monoclonal antibody PCSK9 inhibitors as an add-on to statin therapy. ( 1 )

Tablets: 20 mg enlicitide, white to off-white with grey specks, oval-shaped, film-coated, debossed with “119” on one side and the corporate logo on the other side Film-Coated Tablets: 20 mg enlicitide ( 3 )

None. None. ( 4 )

The frequencies of adverse reactions in adults with hypercholesterolemia were similar between those treated with LIPFENDRA and those receiving placebo. The most common adverse reactions in a study of adults with HeFH treated with LIPFENDRA were diarrhea and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 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. Adverse Reactions in Adults with Hypercholesterolemia The safety of LIPFENDRA was evaluated in Trial 1 (CORALreef Lipids, NCT05952856), a 52-week, multicenter, double-blind, randomized, placebo-controlled trial in 2,904 patients with hypercholesterolemia (including those with and without HeFH) and a history of a major atherosclerotic cardiovascular disease (ASCVD) event or increased risk for development of a first major ASCVD event [see Clinical Studies (14) ] . In Trial 1, the frequencies of adverse reactions in adults with hypercholesterolemia were similar between those treated with LIPFENDRA and those receiving placebo. Similar proportions of LIPFENDRA-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction. Adverse Reactions in Adults with HeFH The safety of LIPFENDRA was evaluated in Trial 2 (CORALreef HeFH, NCT05952869), a 52-week multicenter, double-blind, randomized, placebo-controlled trial in 303 patients with HeFH [see Clinical Studies (14) ] . In Trial 2, the most common adverse reactions in adults with HeFH treated with LIPFENDRA that occurred at higher frequencies compared to placebo were diarrhea (LIPFENDRA 7%, placebo 2%) and dizziness (LIPFENDRA 9%, placebo 4%). Similar proportions of LIPFENDRA-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction. The safety profile observed in adults with HeFH in Trial 2 was otherwise generally consistent with that observed in adults with hypercholesterolemia in Trial 1.

8.1 Pregnancy Risk Summary Discontinue LIPFENDRA when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Alternatively, consider the ongoing therapeutic needs of the individual patient. Enlicitide 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, LIPFENDRA may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . There are insufficient data on the use of LIPFENDRA in pregnant patients to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Consider the benefits and risks of LIPFENDRA when prescribing LIPFENDRA to pregnant women. In animal reproduction studies, no adverse embryofetal developmental effects were observed in pregnant rats and rabbits administered enlicitide subcutaneously during organogenesis (up to 58- and 51-fold, respectively, the human exposure at the recommended human dose (RHD), based on AUC) (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 to 4% and 15 to 20%, respectively. Data Animal Data In the embryofetal developmental rat toxicity study, pregnant rats were administered enlicitide subcutaneously at 0.5, 3, or 10 mg/kg/day during the period of organogenesis (Gestational Days (GD) 6 through 17). No adverse embryofetal or maternal effects were observed up to 10 mg/kg/day (58-fold the human exposure at the RHD, based on AUC). In the embryofetal developmental rabbit toxicity study, pregnant rabbits were administered enlicitide subcutaneously at 0.2, 0.5, or 3 mg/kg/day during the period of organogenesis (GD7 through 19). No adverse embryofetal or maternal effects were observed up to 3 mg/kg/day (51-fold the human exposure at the RHD, based on AUC). In the rat pre- and postnatal developmental toxicity study, enlicitide was administered subcutaneously at 0.5, 3, or 10 mg/kg/day daily from GD 6 through lactation day (LD) 20. No adverse developmental or maternal effects were observed up to 10 mg/kg/day (58-fold the human exposure at the RHD, based on AUC). Enlicitide crosses the placenta and was detected in rat fetal plasma at concentrations that were 3 to 5% of mean maternal plasma concentrations.

8.2 Lactation Risk Summary There is no information on the presence of enlicitide in human milk, the effects on the breastfed infant, or the effects on milk production. Enlicitide was detected at low concentrations in the plasma of nursing pups from lactating rats administered subcutaneous enlicitide (see Data ) . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LIPFENDRA and any potential adverse effects on the breastfed child from LIPFENDRA or from the underlying maternal condition [see Clinical Pharmacology (12.1) ] . Data Animal Data Enlicitide was detected in the plasma of nursing pups (LD 7) from lactating rats administered enlicitide subcutaneously at 0.5, 3, and 10 mg/kg/day from GD 6 to LD 7, with the majority of individual pup-to-maternal plasma concentrations ≤0.7% across doses.

8.4 Pediatric Use The safety and effectiveness of LIPFENDRA have not been established in pediatric patients.

8.5 Geriatric Use Of the 2,137 patients treated with LIPFENDRA in placebo-controlled trials, 960 (45%) patients were 65 years of age and older, and 252 (12%) 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.

Enlicitide is a macrocyclic peptide that binds to PCSK9. PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. By inhibiting the binding of PCSK9 to LDLR, enlicitide increases the number of LDLRs available to clear LDL-C, thereby lowering LDL-C levels.