Limitations of Use

The effect of NEXLETOL on cardiovascular morbidity and mortality has not been determined.

2.1 Recommended Dosage

The recommended dosage of NEXLETOL, in combination with maximally tolerated statin therapy, 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.

5.1 Hyperuricemia

NEXLETOL inhibits renal tubular OAT2 and may increase blood uric acid levels [see Clinical Pharmacology (12.3)]. In clinical trials, 26% of NEXLETOL-treated patients with normal baseline uric acid values (versus 9.5% placebo) experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction (versus 1.1% placebo). Increases in uric acid levels usually occurred within the first 4 weeks of treatment initiation and persisted throughout treatment. After 12 weeks of treatment, the mean placebo-adjusted increase in uric acid compared to baseline was 0.8 mg/dL for patients treated with NEXLETOL.

Elevated blood uric acid may lead to the development of gout. Gout was reported in 1.5% of patients treated with NEXLETOL and 0.4% of patients treated with placebo. The risk for gout events was higher in patients with a prior history of gout (11.2% NEXLETOL versus 1.7% placebo), although gout also occurred more frequently than placebo in patients treated with NEXLETOL who had no prior gout history (1.0% NEXLETOL versus 0.3% placebo).

Advise patients to contact their healthcare provider if symptoms of hyperuricemia occur. Assess serum uric acid when clinically indicated. Monitor patients for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.

5.2 Tendon Rupture

NEXLETOL is associated with an increased risk of tendon rupture or injury. In clinical trials, tendon rupture occurred in 0.5% of patients treated with NEXLETOL versus 0% of placebo-treated patients and involved the rotator cuff (the shoulder), biceps tendon, or Achilles tendon. Tendon rupture occurred within weeks to months of starting NEXLETOL. Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders.

Discontinue NEXLETOL immediately if the patient experiences rupture of a tendon. Consider discontinuing NEXLETOL if the patient experiences joint pain, swelling, or inflammation. Advise patients to rest at the first sign of tendinitis or tendon rupture and to contact their healthcare provider if tendinitis or tendon rupture symptoms occur. Consider alternative therapy in patients with a history of tendon disorders or tendon rupture.

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.

The data described below reflect exposure to NEXLETOL in two placebo-controlled trials that included 2009 patients treated with NEXLETOL for 52 weeks (median treatment duration of 52 weeks) [see Clinical Studies (14)]. The mean age for NEXLETOL-treated patients was 65.4 years, 29% were women, 3% were Hispanic, 95% White, 3% Black, 1% Asian, and 1% other races. 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 clinical atherosclerotic cardiovascular disease (ASCVD) and about 4% had a diagnosis of heterozygous familial hypercholesterolemia (HeFH). Patients on simvastatin 40 mg/day or higher were excluded from the 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of NEXLETOL. Because these reactions are reported voluntarily from a populationof uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity: angioedema, wheezing, rash, and urticaria.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 3009 patients in clinical trials of NEXLETOL, 1753 (58%) were 65 years and older, while 478 (16%) were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is limited experience with NEXLETOL in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2), and NEXLETOL has not been studied in patients with end-stage renal disease (ESRD) receiving dialysis [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B) [see Clinical Pharmacology (12.3)]. Patients with severe hepatic impairment (Child-Pugh C) have not been studied.

12.1 Mechanism of Action

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Bempedoic acid and its active metabolite, ESP15228, require coenzyme A (CoA) activation by very long-chain acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA and ESP15228-CoA, respectively. ACSVL1 is expressed primarily in the liver. Inhibition of ACL by ETC-1002-CoA results in decreased cholesterol synthesis in the liver and lowers LDL-C in blood via upregulation of low-density lipoprotein receptors.

12.2 Pharmacodynamics

Administration of bempedoic acid in combination with maximally tolerated statins, with or without other lipid modifying agents, decreases LDL-C, non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), and total cholesterol (TC) in patients with hyperlipidemia.

12.3 Pharmacokinetics

Bempedoic acid pharmacokinetic parameters are presented as the mean [standard deviation ± (SD)] unless otherwise specified. The steady-state maximum plasma concentration (Cmax) and area under the curve (AUC) following multiple-dose administration of bempedoic acid at 180 mg/day were 20.6 ± 6.1 µg/mL and 289.0 ± 96.4 µg∙h/mL, respectively. Bempedoic acid steady-state pharmacokinetics were generally linear over a range of > 60 mg to 220 mg (approximately 33% to 122% of the recommended dosage of 180 mg daily). There were no time-dependent changes in bempedoic acid pharmacokinetics following repeat administration at the recommended dosage, and bempedoic acid steady-state was achieved after 7 days. The mean accumulation ratio was approximately 2.3-fold.

The steady-state Cmax and AUC of the active metabolite (ESP15228) of bempedoic acid were 2.8 ± 0.9 µg/mL and 51.2 ± 17.2 µg∙h/mL, respectively. ESP15228 likely made a minor contribution to the overall clinical activity of bempedoic acid based on systemic exposure, relative potency, and pharmacokinetic properties.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Bempedoic acid was negative for mutagenicity in an in vitro Ames assay and negative for clastogenicity in the vitro human lymphocyte chromosome aberration assay. Bempedoic acid was negative in both in vivo mouse micronucleus and in vivo rat bone marrow micronucleus/liver comet assay. In a 2-year rat carcinogenicity study, Wistar rats were given oral doses of bempedoic acid at 3, 10 and 30 mg/kg/day. An increased incidence of liver hepatocellular adenomas and hepatocellular adenomas combined with carcinomas, thyroid gland follicular cell adenoma and follicular cell adenomas combined with carcinomas, and pancreatic islet cell adenomas combined with carcinomas were observed in male rats at the dose of 30 mg/kg/day (exposure equivalent to the maximum recommended human dose (MRHD), based on AUC). In a 2-year mice carcinogenicity study, CD-1 mice were given oral doses of bempedoic acid at 25, 75 and 150 mg/kg/day. Bempedoic acid-related increases in the incidence of liver hepatocellular adenomas, hepatocellular carcinomas and hepatocellular adenomas combined with carcinomas in male mice were observed at 75 and 150 mg/kg/day (exposures equivalent to the MRHD). Observations of liver and thyroid tumors are consistent with PPAR alpha agonism in rodents. The human relevance of pancreatic islet cell tumor findings is unknown.

In fertility and early embryofetal development study in rats, bempedoic acid was given orally to male and female rats at 10, 30 and 60 mg/kg/day. Males were dosed for 28 days prior to mating and females were dosed 14 days prior to mating through gestation day 7. No adverse effects on fertility were observed in females in the absence of maternal toxicity. No effects were observed on male fertility outcomes, but decreases in sperm counts were observed at 60 mg/kg/day (9 times the MRHD).

Study 1 (NCT02666664)

Study 1 was a multi-center, randomized, double-blind, placebo-controlled 52-week trial that evaluated safety and efficacy of bempedoic acid in patients with HeFH and/or ASCVD. Efficacy of NEXLETOL was evaluated at Week 12. The trial included 2230 patients randomized 2:1 to receive either NEXLETOL (n = 1488) or placebo (n = 742) as add-on to a maximally tolerated lipid lowering therapy. Maximally tolerated lipid lowering therapy was defined as a maximally tolerated statin dose alone or in combination with other lipid-lowering therapies. Patients were stratified by presence of HeFH and by baseline statin intensity. Patients on simvastatin 40 mg per day or higher and patients taking PCSK9 inhibitors were excluded from the trial.

Overall, the mean age at baseline was 66 years (range: 24 to 88 years), 61% were ≥ 65 years old, 27% women, 2% Hispanic, 96% White, 3% were Black, and 1% Asian. Ninety-five percent (95%) of patients had established atherosclerotic cardiovascular disease, and 5% of patients had HeFH. Twenty-nine percent (29%) of patients had diabetes at baseline. The mean baseline LDL-C was 103.2 mg/dL. At the time of randomization, all patients were receiving statin therapy and 50% were receiving high-intensity statin therapy.

The primary efficacy outcome measure of the study was the percent change from baseline to Week 12 in LDL-C. The difference between NEXLETOL and placebo in mean percent change in LDL-C from baseline to Week 12 was -18% (95% CI: -20%, -16%; p < 0.001). High-density lipoprotein (HDL) and triglycerides (TG) were examined as exploratory endpoints and were not included in the statistical hierarchy. The difference between NEXLETOL and placebo in mean percent change from baseline to Week 12 was -6% for HDL and median percent change from baseline to Week 12 was +3% for TG. For additional results see Table 2 and Figure 1.

Study 2 (NCT02991118)

Study 2 was a multi-center, randomized, double-blind, placebo-controlled, 52-week trial in patients with HeFH and/or ASCVD. Efficacy of NEXLETOL was evaluated at Week 12. The trial included 779 patients randomized 2:1 to receive either NEXLETOL (n = 522) or placebo (n = 257) as add-on to a maximally tolerated lipid lowering therapy. Maximally tolerated lipid lowering therapy was defined as a maximally tolerated statin dose alone or in combination with other lipid-lowering therapies. Patients were stratified by presence of HeFH and baseline statin intensity. Patients on simvastatin 40 mg/day or higher were excluded from the trial.

Overall, the mean age at baseline was 64 years (range: 28 to 91 years), 51% were ≥ 65 years old, 36% women, 8% Hispanic, 94% White, 5% were Black, and 1% Asian. Ninety-five percent (95%) of patients had established atherosclerotic cardiovascular disease, and 5% of patients had HeFH. Thirty percent (30%) of patients had diabetes at baseline. The mean baseline LDL-C was 120.4 mg/dL. At the time of randomization, 90% of patients were receiving statin therapy, 53% were receiving high-intensity statin therapy, and 0.3% were receiving PCSK9 inhibitors.

The primary efficacy outcome measure of the study was the percent change from baseline to Week 12 in LDL-C. The difference between NEXLETOL and placebo in mean percent change in LDL-C from baseline to Week 12 was -17 % (95% CI: -21%, -14%; p < 0.001). HDL and TG were exploratory endpoints and not included in the statistical hierarchy. The difference between NEXLETOL and placebo in mean percent change from baseline to Week 12 was -6% for HDL and the median percent change from baseline was -2% for TG. For additional results see Table 3 and Figure 1.

LDL-C derived is calculated from the Friedewald equation: LDL-C = TC - HDL-C - TG/5 in mg/dL.
The error bars represent standard error.

How Supplied

NEXLETOL (bempedoic acid) tablets are supplied as follows:

Storage and Handling

Store at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature]. Store and dispense in the original package.

Risk of Hyperuricemia

Advise patients of the risk of elevated serum uric acid levels, including development of gout. Inform patients that serum uric acid levels may be monitored during treatment with NEXLETOL. Patients with signs or symptoms of hyperuricemia should contact their healthcare provider if symptoms occur [See Warnings and Precautions (5.1)]

Risk of Tendon Rupture

Inform patients of the risk of tendon rupture. Advise patients to rest at the first sign of tendinitis or tendon rupture and to immediately contact their healthcare provider if tendinitis or tendon rupture symptoms occur [see Warnings and Precautions (5.2)].

Risk of Myopathy with Concomitant Use of Simvastatin or Pravastatin

Advise patients to notify their healthcare provider(s) if they are taking, or plan to take simvastatin or pravastatin. The risk of myopathy occurring with the use of simvastatin or pravastatin may be increased when taken with NEXLETOL. [see Drug Interactions (7)].

Pregnancy

Advise pregnant women of the potential risk to a fetus based on NEXLETOL's mechanism of action. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women who are exposed to NEXLETOL during pregnancy that there is a pregnancy surveillance study. Encourage these patients to report their pregnancy to Esperion at 1-833-377-7633 [see Use in Specific Populations (8.1)].