2.1 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.

5.1 Hyperuricemia

NEXLETOL inhibits renal tubular OAT2 and may increase blood uric acid levels [see Clinical Pharmacology (12.3)]. In the primary hyperlipidemia trials [see Clinical Studies (14.2)], 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, persisted throughout treatment, and returned to baseline following discontinuation of 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. In the cardiovascular outcomes trial [see Clinical Studies (14.1)], 16.4% of NEXLETOL-treated patients experienced clinically significant hyperuricemia reported as an adverse reaction (versus 8.2% placebo).

Elevated blood uric acid may lead to the development of gout. In the primary hyperlipidemia trials, gout was reported in 1.5% of patients treated with NEXLETOL and 0.4% of patients treated with placebo. In the cardiovascular outcomes trial, gout was reported in 3.2% of patients treated with NEXLETOL and 2.2% treated with 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 the primary hyperlipidemia trials [see Clinical Studies (14.2)], 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. In the cardiovascular outcomes trial [see Clinical Studies (14.1)], tendon rupture events occurred in 1.2% of NEXLETOL-treated patients versus 0.9% of placebo-treated patients. 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 in Table 1 reflect exposure to NEXLETOL in two placebo-controlled primary hyperlipidemia trials that included 2,009 patients treated with NEXLETOL for 52 weeks (median treatment duration of 52 weeks) [see Clinical Studies (14.2)]. 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 hyperlipidemia 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.

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 [see Clinical Studies, (14.1)], 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 than placebo are shown in Table 2.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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.

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 3,009 adult patients in the primary hyperlipidemia trials of NEXLETOL, 1,753 (58%) were 65 years of age and older, while 478 (16%) were 75 years of age and older.

Of the 13,970 adult patients in the cardiovascular outcomes trial [see Clinical Studies (14.2)], 8,204 (59%) were 65 years of age and older, while 2,107 (15%) were 75 years of age and older.

No overall differences in safety or effectiveness of NEXLETOL have been observed between patients 65 years of age and older and younger adult patients.

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 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 alone, or in combination with 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).

14.1 Cardiovascular Outcomes Trial in Adults With CVD or at High Risk for CVD

Trial 1 (NCT02993406) was a randomized, double-blind, placebo-controlled, event-driven trial in 13,970 adult patients with established CVD (70%) or at high risk for a CVD event but without CVD (30%) who were not receiving recommended statin dosages. Patients with established CVD had documented history of coronary artery disease, symptomatic peripheral arterial disease, and/or cerebrovascular atherosclerotic disease. Patients without established CVD were considered at high risk for CVD based on meeting at least one of the following criteria:

(1)

Diabetes mellitus (type 1 or type 2) in females over 65 years of age or males over 60 years of age;

(2)

A Reynolds Risk score > 30% or a SCORE Risk score > 7.5% over 10 years. Reynolds risk score and SCORE risk score evaluate a 10-year risk of having a cardiovascular (CV) event. The Reynolds risk score is based on the following risk factors: sex, age, smoking status, systolic blood pressure, total cholesterol, HDL cholesterol, high sensitivity C-reactive protein (hsCRP), and familial history of CVD events. LDL-C is an additional risk factor considered in SCORE risk score; or

(3)

A coronary artery calcium score >400 Agatston units at any time in the past.

Patients were randomized 1:1 to receive either oral NEXLETOL 180 mg per day (n = 6,992) or placebo (n = 6,978), alone or as an add on to other background lipid-lowering therapies. Background therapy could include less than low-intensity statin dosages. Overall, 95.3% of adult patients were followed until the end of the trial or death. The median follow-up duration was 3.4 years.

14.2 Primary Hyperlipidemia Trials in Adults

The efficacy of NEXLETOL as an adjunct to diet and statin therapy, to reduce elevated LDL-C in adults with primary hyperlipidemia (including HeFH) was investigated in two multi-center, randomized, double-blind, placebo-controlled trials that enrolled 3,009 adult patients with HeFH or established CVD who were on maximally tolerated statin therapy (Trials 2 and 3). Demographics and baseline disease characteristics were balanced between the treatment arms in these trials. In both trials, the maximum LDL-C lowering effects occurred at Week 4. These results were consistent across all subgroups studied in any of the trials, including age, sex, race, ethnicity, region, history of diabetes, baseline LDL-C, body mass index (BMI), HeFH status, and background therapies.

How Supplied

NEXLETOL 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 patients that there is a pregnancy safety study that monitors pregnancy outcomes in patients exposed to NEXLETOL during pregnancy. Encourage these patients to report their pregnancy to Esperion at 1-833-377-7633 [see Use in Specific Populations (8.1)].