Nexletol Drug Information

Recommended Dosage

The recommended dosage of NEXLETOL is 180 mg administered orally once daily. NEXLETOL can be taken with or without food. After initiation of NEXLETOL, analyze lipid levels within 8 to 12 weeks.

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. The data in Table 1 reflect exposure to NEXLETOL in two placebo-controlled primary hypercholesterolemia trials that included 2,009 patients treated with NEXLETOL for 52 weeks (median treatment duration of 52 weeks) . The mean age for NEXLETOL-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 NEXLETOL 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 NEXLETOL-treated patients and 8% of placebo-treated patients. The most common reasons for NEXLETOL 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 NEXLETOL-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 NEXLETOL-Treated Patients with Primary Hypercholesterolemia and CVD or HeFH (Trials 2 and 3) Adverse Reaction Placebo Background therapy included statin and ± other lipid-lowering therapies (N = 999) % NEXLETOL (N = 2,009) % Upper respiratory tract infection 4.0

Muscle spasms 2.3 3.6 Hyperuricemia Grouped term that includes other related terms

1.1

In the cardiovascular outcomes trial, in which 7,001 patients were exposed to

NEXLETOL 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 NEXLETOL-treated patients and 10% of placebo-treated patients. Adverse reactions reported in at least 2% of NEXLETOL-treated patients and 0.5% greater than placebo are shown in Table 2. Table 2. Adverse Reactions (≥ 2% and 0.5% greater than placebo) in NEXLETOL-Treated Patients with CVD or at High Risk for CVD (Trial 1) Adverse Reaction Placebo (N=6,964) % NEXLETOL (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 NEXLETOL-treated patients versus 0% of placebo-treated patients. In the cardiovascular outcomes trial, tendon rupture events occurred in 1.2% of NEXLETOL-treated patients versus 0.9% of placebo-treated patients.

Gout In the hypercholesterolemia trials, gout occurred in 1.5% of NEXLETOL-treated patients versus 0.4% of placebo-treated patients. In the cardiovascular outcomes trial, gout occurred in 3.2% of NEXLETOL-treated patients versus 2.2% of placebo-treated patients. Laboratory Tests NEXLETOL 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 NEXLETOL at Week 12. Approximately 3.8% of patients treated with NEXLETOL 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 NEXLETOL 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 NEXLETOL (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 NEXLETOL and 1.9% of patients treated with placebo. Approximately 9.0% of NEXLETOL-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 NEXLETOL and 3.9% of patients treated with placebo.

There were 9.3% of NEXLETOL-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 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 NEXLETOL-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 NEXLETOL. 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 NEXLETOL versus 0.4% of placebo patients, and increases to more than 5× ULN occurred in 0.4% of NEXLETOL-treated versus 0.2% of placebo-treated patients. Increases in ALT occurred with similar incidence between NEXLETOL- 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 NEXLETOL-treated group (versus 1.0% placebo). A higher percentage of patients in the NEXLETOL-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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of NEXLETOL. 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. Immune System Disorders: Hypersensitivity reactions including: angioedema, wheezing, rash, and urticaria.

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with NEXLETOL and instructions for preventing or managing them. Table 3. Clinically Important Drug Interactions with NEXLETOL Simvastatin Clinical Impact: Concomitant use of NEXLETOL with simvastatin causes an increase in simvastatin concentration and may increase the risk of simvastatin-related myopathy . Intervention : Avoid concomitant use of NEXLETOL with simvastatin greater than 20 mg. Pravastatin Clinical Impact: Concomitant use of NEXLETOL with pravastatin causes an increase in pravastatin concentration and may increase the risk of pravastatin-related myopathy . Intervention: Avoid concomitant use of NEXLETOL with pravastatin greater than 40 mg.

Fibrates Clinical Impact: Concomitant administration of fibrates with NEXLETOL resulted in increased triglycerides and decreased high-density lipoprotein cholesterol (HDL-C) in some patients in clinical studies and post-marketing reports. Reversibility of both increased triglycerides and decreased HDL-C levels was observed when either NEXLETOL or fibrate therapy was discontinued. Intervention: Monitor triglycerides and HDL-C four weeks after initial concomitant use of NEXLETOL and a fibrate and periodically thereafter.

If increased triglycerides or decreased HDL-C levels are detected, discontinue NEXLETOL or fibrate therapy based on clinical judgment. Monitor triglycerides and HDL-C levels until levels return to baseline. Simvastatin: Avoid concomitant use of NEXLETOL with simvastatin greater than 20 mg.

Pravastatin: Avoid concomitant use of NEXLETOL with pravastatin greater than 40 mg. Fibrates: Concomitant use of NEXLETOL with fibrates may increase triglycerides and decrease high-density lipoprotein cholesterol.

Pregnancy Risk Summary Discontinue NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. There are insufficient data on NEXLETOL use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, bempedoic acid was not teratogenic in rats and rabbits when administered at doses resulting in exposures up to 11 and 12 times, respectively, the human exposures at the maximum clinical dose, based on AUC (see Data ). NEXLETOL decreases cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol; therefore, NEXLETOL may cause fetal harm when administered to pregnant women based on the mechanism of action . 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 primary hypercholesterolemia for most patients. 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.

Report pregnancies to the Esperion Therapeutics, Inc. Adverse Event reporting line at 1-833-377-7633. Data Animal Data Bempedoic acid was not teratogenic when given orally at doses of 60 and 80 mg/kg/day, resulting in 11 and 12 times the systemic exposure in humans at the maximum recommended human dose (MRHD) of 180 mg to pregnant rats and rabbits, respectively. In an embryofetal development study in rats, bempedoic acid was given orally to pregnant rats at 10, 30, and 60 mg/kg/day during the period of organogenesis from gestation day 6 to 17. There were increases in the incidence of non-adverse fetal skeletal variations (bent long bones and bent scapula and incomplete ossification) at doses ≥ 10 mg/kg/day (less than the clinical exposure) in the absence of maternal toxicity.

At maternally toxic doses, bempedoic acid caused decreases in the numbers of viable fetuses, increases in post-implantation loss, and increased total resorptions at 60 mg/kg/day (11 times MRHD) and reduced fetal body weight at ≥ 30 mg/kg/day (4 times the MRHD). No adverse development effects were observed when bempedoic acid was given to pregnant rabbits during the period of organogenesis (gestation day 6 to 18) at doses up to 80 mg/kg/day (12 times MRHD). In a pre- and post-natal development study in pregnant rats given oral doses of bempedoic acid at 5, 10, 20, 30 and 60 mg/kg/day throughout pregnancy and lactation (gestation day 6 to lactation day 20), there were adverse effects on delivery in the presence of maternal toxicity, including: increases in stillborn pups, reductions in numbers of live pups, pup survival, pup growth and slight delays in learning and memory at ≥ 10 mg/kg/day (at exposures equivalent to the MRHD).

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

is contraindicated in patients with a prior serious hypersensitivity reaction to bempedoic acid or any of the excipients in NEXLETOL. Serious hypersensitivity reactions, such as angioedema, have occurred. History of a serious hypersensitivity reaction to bempedoic acid or any of the excipients in NEXLETOL.

There is no clinical experience with NEXLETOL overdose. In the event of an overdosage, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.