Bempedoicside effects

The following clinically significant adverse reactions are described elsewhere in the labeling: Hyperuricemia Tendon Rupture Common adverse reactions with NEXLIZET in the primary hypercholesterolemia trials (incidence ≥ 2% and more frequently than placebo) were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza. The common adverse reaction associated with bempedoic acid in the cardiovascular outcomes trial (incidence ≥ 2% and more frequently than placebo) were hyperuricemia, renal impairment, anemia, elevated liver enzymes, muscle spasms, gout, and cholelithiasis. To report SUSPECTED ADVERSE REACTIONS, contact Esperion at 833-377-7633 (833 ESPRMED) 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 clinical practice. Bempedoic acid The data in Table 1 reflect exposure to bempedoic acid in two placebo-controlled primary hypercholesterolemia trials that included 2,009 patients treated with bempedoic acid for 52 weeks (median treatment duration of 52 weeks). The mean age for bempedoic acid-treated patients was 65 years, 29% were female, 95% were White, 3% were Black or African American, 1% were Asian, and 1% were other races; 3% identified as Hispanic or Latino ethnicity. All patients received bempedoic acid 180 mg orally once daily plus maximally tolerated statin therapy alone or in combination with other lipid-lowering therapies. At baseline, 97% of patients had CVD and about 4% had a diagnosis of HeFH. Patients on simvastatin 40 mg/day or higher were excluded from the trials. In the primary hypercholesterolemia trials, adverse reactions led to discontinuation of treatment in 11% of bempedoic acid-treated patients and 8% of placebo-treated patients. The most common reasons for bempedoic acid treatment discontinuation were muscle spasms (0.5% versus 0.3% placebo), diarrhea (0.4% versus 0.1% placebo), and pain in extremity (0.3% versus 0.0% placebo). Adverse reactions reported in at least 2% of bempedoic acid-treated patients and more frequently than in placebo-treated patients are shown in Table 1. Table 1. Adverse Reactions (≥ 2% and greater than placebo) in Bempedoic Acid-Treated Patients with Primary Hypercholesterolemia and CVD or HeFH (Trials 2 and 3) Adverse Reaction Placebo Background therapy included statin ± other lipid-lowering therapies (N = 999) % Bempedoic acid (N = 2,009) % Upper respiratory tract infection 4.0 4.5 Muscle spasms 2.3

3.6 Hyperuricemia

Grouped term that includes other related terms 1.1 3.5 Back pain 2.2 3.3 Abdominal pain or discomfort 2.2 3.1 Bronchitis 2.5 3.0 Pain in extremity 1.7 3.0 Anemia 1.9 2.8 Elevated liver enzymes 0.8 2.1 In the cardiovascular outcomes trial in which 7,001 patients were exposed to bempedoic acid and 6,964 patients were exposed to placebo for a median of 3.1 years, adverse reactions led to discontinuation of treatment in 11% of bempedoic acid-treated patients and 10% of placebo-treated patients. Adverse reactions reported in at least 2% of bempedoic acid-treated patients and more frequently than placebo are shown in Table 2. Table 2. Adverse Reactions (≥ 2% and 0.5% greater than placebo) in Bempedoic Acid-Treated Patients with CVD or at High Risk for CVD (Trial 4) Adverse Reaction Placebo (N=6,964) % Bempedoic Acid (N=7,001) % Hyperuricemia Grouped term that includes other related terms 8 16 Renal impairment Renal impairment includes laboratory related terms including glomerular filtration rate decreased, blood creatinine increased and hematuria 9 11 Anemia 4 5 Elevated liver enzymes 3 4 Muscle spasms 3 4 Gout 2 3 Cholelithiasis 1 2 Other Adverse Reactions Tendon Rupture In the hypercholesterolemia trials, tendon rupture occurred in 0.5% of bempedoic acid-treated patients versus 0% of placebo-treated patients. In the cardiovascular outcomes trial, tendon rupture events occurred in 1.2% of bempedoic acid-treated patients versus 0.9% of placebo-treated patients. Gout In the hypercholesterolemia trials, gout occurred in 1.5% of bempedoic acid-treated patients versus 0.4% of placebo-treated patients. In the cardiovascular outcomes trial, gout occurred in 3.2% of bempedoic acid-treated patients versus 2.2% of placebo-treated patients. Laboratory Tests Bempedoic acid was associated with persistent changes in multiple laboratory tests that occurred within the first 4 weeks of treatment, and returned to baseline following discontinuation of treatment. Increase in Creatinine and Blood Urea Nitrogen In the hypercholesterolemia trials, there was a mean increase in serum creatinine of 0.05 mg/dL compared to baseline with bempedoic acid at Week 12. Approximately 3.8% of patients treated with bempedoic acid had blood urea nitrogen values that doubled (versus 1.5% placebo), and about 2.2% of patients had creatinine values that increased by 0.5 mg/dL (versus 1.1% placebo). In the cardiovascular outcomes trial, 7.1% of patients had creatinine values that increased by 0.5 mg/dL (versus 5.5% placebo) and 9.5% of patients in the bempedoic acid group had BUN values that increased ≥ 2× baseline (versus 6.2% placebo). Decrease in Hemoglobin and Leukocytes In the hypercholesterolemia trials, approximately 5.1% of patients treated with bempedoic acid (versus 2.3% placebo) had decreases in hemoglobin levels of 2 or more g/dL and below the lower limit of normal on one or more occasion. Anemia was reported in 2.8% of patients treated with bempedoic acid and 1.9% of patients treated with placebo. Approximately 9.0% of bempedoic acid-treated patients with normal baseline leukocyte count had a decrease to less than the lower limit of normal on one or more occasion (versus 6.7% placebo). Leukocyte decrease was generally asymptomatic and did not require medical intervention. In the hypercholesterolemia trials, there was a small imbalance in skin or soft tissue infections, including cellulitis (0.8% versus 0.4%), but there was no imbalance in other infections. In the cardiovascular outcomes trial, 10.8% of patients (versus 7.4% placebo) had a decrease in hemoglobin of 2 or more g/dL and below the lower limit of normal. Anemia was reported in 4.7% of patients treated with bempedoic acid and 3.9% of patients treated with placebo. There were 9.3% of bempedoic acid-treated patients with a leukocyte count below the lower limit of normal (and normal at baseline) at any point (versus 6.8% placebo). Increase in Platelet Count In the hypercholesterolemia trials, approximately 10.1% of bempedoic acid-treated patients (versus 4.7% placebo) had increases in platelet counts of 100× 10 9 /L or more on one or more occasion. In the cardiovascular outcomes trial, 18.6% of patients in the bempedoic acid-treated group (versus 10.2% placebo) had an increase in platelet count of 100 × 10 9 /L or more. Platelet count increase was asymptomatic and did not result in increased risk for thromboembolic events. Increase in Liver Enzymes In the hypercholesterolemia trials, increases in hepatic transaminases (AST and/or ALT) were observed with bempedoic acid. In most cases, the elevations were transient and resolved or improved with continued therapy or after discontinuation of therapy. Increases to more than 3× the upper limit of normal (ULN) in AST occurred in 1.4% of patients treated with bempedoic acid versus 0.4% of placebo patients, and increases to more than 5× ULN occurred in 0.4% of bempedoic acid- treated versus 0.2% of placebo-treated patients. Increases in ALT occurred with similar incidence between bempedoic acid- and placebo-treated patients. Elevations in transaminases were generally asymptomatic and not associated with elevations ≥ 2× ULN in bilirubin or with cholestasis. In the cardiovascular outcomes trial, the incidence of repeated and confirmed ALT and/or AST >3× ULN was 1.6% in the bempedoic acid-treated group (versus 1.0% placebo). A higher percentage of patients in the bempedoic acid-treated group had hepatic enzyme elevations versus placebo (4.5% versus 3.0%, respectively). Increase in Creatine Kinase In the hypercholesterolemia trials, approximately 1.0% of patients (versus 0.6% placebo) had elevations of CK levels of 5 or more times the normal value on one or more occasions, and 0.4% of patients (versus 0.2% placebo) had elevations of CK levels of 10 or more times. Ezetimibe In 10 double-blind, placebo-controlled clinical trials, 2,396 patients with primary hypercholesterolemia (age range 9 to 86 years, 50% were female, 90% were White, 5% were Black or African American, 2% were Asian, 3% other races; 3% identified as Hispanic or Latino ethnicity) and elevated LDL-C were treated with ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥ 2% of patients treated with ezetimibe and at an incidence greater than placebo in placebo-controlled studies of ezetimibe are shown in Table 3. Table 3. Adverse Reactions Occurring in ≥ 2% and greater than placebo in Ezetimibe-treated Patients Adverse Reaction Placebo (%) N = 1,159 Ezetimibe 10 mg (%) N = 2,396 Upper respiratory tract infection 2.5 4.3 Diarrhea 3.7 4.1 Arthralgia 2.2 3.0 Sinusitis 2.2 2.8 Pain in extremity 2.5 2.7 Fatigue 1.5 2.4 Influenza 1.5

2.0 NEXLIZET

In a 4-arm, 12-week, randomized, double-blind, placebo-controlled, parallel group, factorial trial, 85 patients received NEXLIZET (180 mg of bempedoic acid and 10 mg of ezetimibe) once daily. The mean age for NEXLIZET-treated patients was 62 years, 51% were female, 78% were White, 19% were Black or African American, 2% were Asian, and 1% were American Indian or Alaska Native; 11% identified as Hispanic or Latino ethnicity. At baseline, 61% of patients had CVD and/or a diagnosis of HeFH. All patients received NEXLIZET plus maximally tolerated statin therapy. Patients taking simvastatin 40 mg/day or higher and patients taking non-statin lipid-lowering therapy (including fibrates, niacin, bile acid sequestrants, ezetimibe, and PCSK9 inhibitors) were excluded from the trial. Adverse reactions led to discontinuation of treatment in 8% of patients on NEXLIZET, 5% of patients on placebo, 10% of patients on bempedoic acid, and 12% of patients on ezetimibe. The most common reason for NEXLIZET treatment discontinuation was oral discomfort (2% NEXLIZET versus 0% placebo). The most commonly reported adverse reactions (incidence ≥ 3% and greater than placebo) observed with NEXLIZET, but not observed in clinical trials of bempedoic acid or ezetimibe, were urinary tract infection (5.9% NEXLIZET versus 2.4% placebo), nasopharyngitis (4.7% NEXLIZET versus 0% placebo), and constipation (4.7% NEXLIZET versus 0% placebo).

6.2 Postmarketing

Experience The following adverse reactions have been identified during post approval use of ezetimibe and/or bempedoic acid. 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.

Blood Disorders: thrombocytopenia Gastrointestinal Disorders: abdominal pain; pancreatitis; nausea Hepatobiliary Disorders: elevations in liver transaminases, including elevations more than 5× ULN; hepatitis; cholelithiasis; cholecystitis Immune System Disorders: Hypersensitivity reactions including: anaphylaxis, angioedema, wheezing, rash, and urticaria Musculoskeletal Disorders: elevated creatine phosphokinase; myopathy/rhabdomyolysis Nervous System Disorders: dizziness; paresthesia; depression; headache Skin and Subcutaneous Tissue Disorders: erythema multiforme