Bempedoic acid is an oral adenosine triphosphate-citrate lyase (ACL) inhibitor approved as an adjunct to diet and statin therapy for the treatment of primary hyperlipidemia in adults with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease (CVD) who require additional lowering of low-density lipoprotein cholesterol (LDL-C). Bempedoic acid is also approved for myocardial infarction prophylaxis and reduction of risk of coronary revascularization in adults with established CVD or a high risk for a CVD event without established CVD who are unable to take statin therapy. Bempedoic acid is an inactive prodrug that requires coenzyme A (CoA) activation by very long-chain acyl-CoA synthetase 1 (ACSVL1). Since ACSVL1 is primarily located in the liver and not in adipose tissue or muscle, it is theorized to have reduced adverse effects, such as myotoxicity, due to minimal exposure to non-hepatic tissues. In a 52-week, clinical study involving patients with atherosclerotic CVD, heterozygous familial hypercholesterolemia or both, addition of bempedoic acid to maximally-tolerated statin therapy (with or without additional lipid-lowering therapy) resulted in mean percentage reductions in LDL-C from baseline of 16.5%, 14.9%, and 12.6% at weeks 12, 24, and 52, respectively. LDL-C reductions were significantly greater with bempedoic acid compared to placebo with a difference of -18.1% at week 12 (95% CI:-20 to -16.1; p less than 0.001) and -16.1% at week 24 (95% CI: -18.2 to -14; p less than 0.001). In a cardiovascular outcomes trial, bempedoic acid reduced the occurrence of major cardiovascular events (time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) compared to placebo (p = 0.0037). Hyperuricemia and tendon rupture have been reported with bempedoic acid therapy. This drug may increase the concentrations of pravastatin and simvastatin and increase the risk of statin-induced myopathy; thus, it is recommended to avoid coadministration of bempedoic acid with simvastatin at doses greater than 20 mg and pravastatin at doses greater than 40 mg.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May administer with or without food.
-Store and dispense medication in the original package.
Muscle cramps (muscle spasms) occurred in 3.6%, back pain in 3.3%, and pain in the extremity in 3% of bempedoic acid-treated subjects compared to 2.3%, 2.2%, and 1.7%, respectively, of placebo-treated subjects in primary hyperlipidemia clinical trials. Two of the most common reasons for bempedoic acid discontinuation were muscle pain (0.5%) and pain in the extremity (0.3%). In the cardiovascular outcomes clinical trial, muscle spasms were reported in 4% of bempedoic acid-treated subjects compared to 3% of placebo-treated subjects.
In primary hyperlipidemia clinical trials, tendon rupture, involving the shoulder (rotator cuff), biceps tendon, or Achilles tendon, occurred in 0.5% of bempedoic acid-treated subjects compared to 0% of placebo-treated subjects. In the cardiovascular outcomes trial, tendon rupture events occurred in 1.2% of bempedoic acid-treated subjects compared to 0.9% of placebo-treated subjects. Tendon rupture may occur within weeks to months of starting bempedoic acid. Advise individuals to contact their healthcare provider if tendonitis or tendon rupture develops. Consider discontinuation of therapy if joint pain, swelling, or inflammation occur. Tendon rupture risk may be increased in those over 60 years of age, taking concomitant fluoroquinolones or corticosteroids, with renal failure, or with tendon disorders.
In primary hyperlipidemia trials, hyperuricemia was reported one or more times in 26% of bempedoic acid subjects compared to 9.5% of placebo subjects who had normal uric acid levels at baseline; clinically significant hyperuricemia occurred in 3.5% and 1.1% of bempedoic acid and placebo-treated subjects, respectively. Gout occurred in 1.5% of bempedoic acid-treated subjects and 0.4% of placebo-treated subjects. Assess serum uric acid levels when deemed clinically appropriate. In the cardiovascular outcomes trial, 16.4% of bempedoic acid-treated subjects experienced clinically significant hyperuricemia compared to 8.2% in placebo-treated subjects; gout was reported in 3.2% of bempedoic acid-treated subjects compared to 2.2% of placebo-treated subjects.
In primary hyperlipidemia clinical trials, upper respiratory tract infection and bronchitis were reported in 4.5% and 3% of subjects treated with bempedoic acid versus 4% and 2.5% of subjects treated with placebo. Bempedoic acid-treated subjects had a slight increase in skin or soft tissue infections, such as cellulitis, compared to placebo-treated subjects (0.8% vs 0.4%, respectively).
Adverse changes in multiple laboratory tests were observed within the first 4 weeks of bempedoic acid treatment. In primary hyperlipidemia clinical trials, blood urea nitrogen (BUN) was doubled in 3.8% in bempedoic acid-treated subjects compared to 1.5% placebo. An increase of 0.5 mg/dL in serum creatinine was also reported in 2.2% of bempedoic acid-treated subjects compared to 1.1% placebo. Elevated hepatic enzymes (including aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) were reported in 2.1% of subjects treated with bempedoic acid vs. 0.8% placebo. These elevations in hepatic enzymes were typically transient and resolved or improved with discontinuation of or continued therapy. AST elevations to more than 3 times the upper limit of normal (ULN) and more than 5 times ULN occurred in 1.4% and 0.4% of bempedoic acid-treated subjects, respectively, compared to 0.4% and 0.2% of placebo-treated subjects. Elevations in ALT were similar between the bempedoic acid and placebo groups. Additionally, elevations in creatine kinase (CK) of 5 or more to 10 or more times the normal value occurred in 1% and 0.4% of bempedoic acid-treated subjects, respectively, compared to 0.6% and 0.2% of placebo-treated subjects. In the cardiovascular outcomes clinical trial, 7.1% of bempedoic acid-treated subjects had serum creatinine values that increased by 0.5 mg/dL compared to 5.5% of placebo-treated subjects. Renal impairment (i.e., decreased glomerular filtration rate, increased serum creatinine, and hematuria) was reported in 11% of subjects treated with bempedoic acid compared to 9% placebo. Additionally, elevations in BUN to 2 times or more than baseline were reported in 9.5% of bempedoic acid-treated subjects compared to 6.2% of placebo-treated subjects. Elevated hepatic enzymes (AST and ALT) of 3 times or more the ULN were also reported (1.6% bempedoic acid vs. 1% placebo). Additionally, a higher percentage of bempedoic acid-treated subjects had elevated hepatic enzymes compared to placebo (4.5% vs. 3%, respectively). Cholelithiasis was also reported in bempedoic acid-treated subjects vs. placebo-treated subjects (2% vs 1%, respectively).
In primary hyperlipidemia clinical trials, abdominal pain or discomfort occurred in 3.1% of bempedoic acid-treated subjects compared to 2.2% of placebo-treated subjects. Diarrhea led to treatment discontinuation in 0.4% of bempedoic acid patients and 0.1% of placebo patients.
Hypersensitivity reactions, including angioedema, wheezing, rash, and urticaria, have been reported with postmarketing use of bempedoic acid.
In primary hyperlipidemia clinical trials, a decrease in hemoglobin of 2 g/dL or more and below the lower limit of normal occurred in approximately 5.1% of bempedoic acid-treated subjects on one or more occasions compared to 2.3% of placebo-treated subjects; these reductions were typically asymptomatic and did not require treatment. Anemia was reported in 2.8% of bempedoic acid-treated subjects versus 1.9% of placebo-treated subjects. Reductions in leukocyte count below the lower limit of normal (leukopenia) were reported in 9% and 6.7% of subjects treated with bempedoic acid and placebo, respectively. Thrombocyosis (platelet count elevations) of 100 x 109/L or more were reported on one or more occasions in 10.1% of bempedoic acid-treated subjects and 4.7% of placebo-treated subjects; these elevations were typically asymptomatic and did not require treatment. In the cardiovascular outcomes clinical trial, a decrease in hemoglobin of 2 g/dL or more and below the lower limit of normal was reported in 10.8% of bempedoic acid-treated subjects compared to 7.4% of placebo-treated subjects. Anemia was reported in 4.7% of subjects treated with bempedoic acid compared to 3.9% placebo. Additionally, reductions in leukocyte count below the lower limit of normal occurred in 9.3% of bempedoic acid-treated subjects compared to 6.8% placebo. Thrombocytosis was reported in 18.6% of bempedoic acid-treated subjects compared to 10.2% of placebo-treated subjects. Platelet count elevations were asymptomatic and did not result in increased risk for thromboembolic events.
Hyperuricemia has been reported with bempedoic acid therapy. Bempedoic acid inhibits OAT2 within the renal tubule and may lead to an increase in blood uric acid levels and, subsequently, the development of gout. In clinical trials, elevations in uric acid levels typically occurred within the first 4 weeks and persisted throughout treatment. Monitor patients for signs and symptoms of hyperuricemia and assess serum uric acid levels when clinically indicated. Treatment with urate-lowering drugs may be utilized when deemed appropriate.
Bempedoic acid is associated with an increased risk of tendon rupture or injury. Consider alternate therapy in patients with a history of tendon disorders or tendon rupture. In clinical trials, tendon rupture occurred within weeks to months of starting bempedoic acid. Immediately discontinue therapy if a tendon rupture occurs. Bempedoic acid discontinuation should be considered in treated individuals experiencing joint pain, swelling, or inflammation. Risk of tendon rupture may be increased in those over 60 years of age, taking concomitant fluoroquinolones, taking corticosteroid therapy, with renal failure, and with previous tendon disorders.
Discontinue bempedoic acid once pregnancy is detected unless the benefits of therapy outweigh potential risks to the fetus. There are no available data on bempedoic acid use in human pregnancy to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Bempedoic acid was not teratogenic when orally administered to pregnant rats and rabbits at oral doses that were 11 and 12 times the systemic exposure in humans at the maximum recommended human dose (MHRD). In pregnant rats that received bempedoic acid during organogenesis, fetal body weight reductions were seen at 4 times MRHD and reductions in the number of viable fetuses, increases in post-implantation loss, and increased total resorptions were seen at 11 times MRHD. Adverse effects on delivery, in the presence of maternal toxicity, were observed in rats that received bempedoic acid starting on gestation day 6 through lactation day 20, including increases in stillborn pups, and reductions in the number of live pups, pup survival, and pup growth. At exposures similar to that of the MRHD, there were slight delays in memory and learning. There is a pregnancy surveillance study for bempedoic acid. If bempedoic acid is administered during pregnancy, report exposure by contacting Esperion at 1-833-377-7633.
There is no information regarding the presence of bempedoic acid in human milk, the effects on the breastfed infant, or the effects on milk production. Breast-feeding is not recommended during bempedoic acid therapy. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. Bempedoic acid decreases the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway and may cause adverse effects to a nursing infant. If pharmacotherapy is necessary for the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of primary hyperlipoproteinemia (hyperlipidemia) in adults with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease (atherosclerosis) as an adjunct to diet and statin therapy:
Oral dosage:
Adults: 180 mg PO once daily. Monitor lipid concentrations within 8 to 12 weeks after starting therapy.
For myocardial infarction prophylaxis and reduction of risk of coronary revascularization in adults unable to take statin therapy who have established cardiovascular disease (CVD) or a high risk for a CVD event but without established CVD:
Oral dosage:
Adults: 180 mg PO once daily.
Maximum Dosage Limits:
-Adults
180 mg/day PO.
-Geriatric
180 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Bempedoic acid has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Patients with Renal Impairment Dosing
No dosage adjustment is needed for mild or moderate renal impairment. Specific guidelines for dosage adjustment in patients with severe renal impairment (CrCl less than 30 mL/min) or end-stage renal disease receiving dialysis are not available.
*non-FDA-approved indication
Ezetimibe; Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 40 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and simvastatin against the potential risks. Bempedoic acid increases the simvastatin AUC and Cmax by 2-fold and 1.5-fold, respectively.
Pravastatin: (Major) Do not exceed a pravastatin dose of 40 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving pravastatin 60 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and pravastatin against the potential risks. Bempedoic acid increases the pravastatin AUC and Cmax by 2-fold.
Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 40 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and simvastatin against the potential risks. Bempedoic acid increases the simvastatin AUC and Cmax by 2-fold and 1.5-fold, respectively.
Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) through inhibition of cholesterol synthesis in the liver. Bempedoic acid, an inactive prodrug, and its active metabolite, ESP15228, require coenzyme A (CoA) activation within the liver by very-long-chain acyl CoA synthetase-1 (ACSVL1) to form bempedoic acid-CoA (ETC-1002-CoA) and ESP15228-CoA, respectively. ACSVL1 is primarily expressed in the liver and is absent in adipose tissue and muscles. ACL is an important enzyme that links carbohydrate metabolism to the pathways for cholesterol and fatty synthesis within the liver. Specifically, ACL catalyzes the cleavage of citrate to acetyl-CoA and oxaloacetate within the cholesterol synthesis pathway and is located upstream from HMG-CoA reductase. Both oxaloacetate and acetyl-CoA are important substrates in the synthesis of cholesterol and fatty acids. Thus, inhibition of ACL by bempedoic acid decreases cholesterol and fatty acid synthesis resulting in the upregulation of LDL-C receptors, increased uptake of LDL-C by the liver, and reduced blood LDL-C levels.
Bempedoic acid, in combination with maximally tolerated statins, with or without other lipid-modifying agents, decreases LDL-C, non-high density lipoprotein cholesterol, apolipoprotein B, and total cholesterol.
Bempedoic acid is an orally administered prodrug. Bempedoic acid undergoes reversible conversion to an active metabolite, ESP15228, via aldo-keto reductase activity within the liver and both bempedoic acid and ESP15228 require coenzyme A activation by very long-chain acyl-CoA synthetase 1 (ACSVL1). Bempedoic acid, bempedoic acid glucuronide, and ESP15228 are 99.3%, 98.8%, and 99.2% bound to plasma proteins. Bempedoic acid does not partition into blood cells and has a Vd of 18L. The primary route of elimination for bempedoic acid is through metabolism of the acyl glucuronide. UGT2B7 converts both bempedoic acid and ESP15228 to inactive glucuronide conjugates. After a single oral dose of 240 mg bempedoic acid, approximately 70% of the dose was recovered in the urine, primarily as the acyl glucuronide conjugate of bempedoic acid, and 30% in the feces; less than 5% of the dose was excreted as unchanged bempedoic acid. At steady-state, the half-life of bempedoic acid is 21 +/- 11 hours and the rate of clearance is 11.2 mL/min.
Affected cytochrome P450 (CYP) isoenzymes and drug transporters: OAT3, OATP1B1, OATP1B3, and OAT3
Bempedoic acid is a weak inhibitor of OAT3 at clinically relevant concentrations and bempedoic acid glucuronide is an OAT3 substrate. At clinically relevant concentrations, bempedoic acid and bempedoic acid glucuronide are weak inhibitors of OATP1B1 and OATP1B3. In vitro data indicate that bempedoic acid is a weak inhibitor of OAT2; the likely mechanism behind the minor elevations in serum uric acid and creatinine.
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration of bempedoic acid 180 mg, the median time to maximum concentration is 3.5 hours. At steady-state, following the administration of multiple doses of bempedoic acid 180 mg/day, the Cmax is 20.6 +/- 6.1 mcg/mL and the AUC is 289 +/- 96.4 mcg x h/mL. Steady-state is achieved after 7 days, and the mean accumulation ratio is approximately 2.3-fold. Linear pharmacokinetics were demonstrated during steady-state with bempedoic acid over a dose range of greater than 60 mg to 220 mg. Time-dependent changes were not observed with repeat administration of bempedoic acid. Oral bioavailability was not impacted when bempedoic acid was administered with food. Bempedoic acid, bempedoic acid glucuronide, ESP15228, and ESP15228 glucuronide accounted for 46%, 30%, 10%, and 11% of the drug in plasma.
-Special Populations
Hepatic Impairment
In patients with mild hepatic impairment (Child-Pugh A), the mean Cmax of bempedoic acid and it's active metabolite, ESP15228, was reduced by 11% and 13%, respectively, and the AUC was reduced by 22% and 23%, respectively. In patients with moderate hepatic impairment (Child-Pugh B), the mean Cmax of bempedoic acid and ESP15228 was reduced by 14% and 24%, respectively, and the AUC was reduced by 16% and 36%, respectively. The reductions seen in mild and moderate hepatic impairment are not expected to impact clinical efficacy. Bempedoic acid has not been studied in severe hepatic impairment (Child-Pugh C).
Renal Impairment
In a single-dose pharmacokinetic study, the mean bempedoic acid AUC was 1.5-fold, 2.3-fold, and 2.4-fold higher in patients with mild (n=8), moderate (n=5), and severe (n=5) renal impairment, respectively, compared to patients with normal renal function (n=6). In a population pharmacokinetic study using pooled data from all clinical trials (n=2261), the mean bempedoic acid AUC at steady-state was increased by 1.4-fold (90% CI: 1.3, 1.4) and 1.9-fold (90% CI: 1.7, 2.0) in patients with mild or moderate renal impairment, respectively, compared to patients with normal renal function. Bempedoic acid clinical trials did not include patients with severe renal impairment or end-stage renal disease on dialysis.
Geriatric
Age was not shown to have an effect on the pharmacokinetics of bempedoic acid.
Gender Differences
Gender was not shown to have an effect on the pharmacokinetics of bempedoic acid.
Ethnic Differences
Race was not shown to have an effect on the pharmacokinetics of bempedoic acid.
Obesity
Weight was not shown to have an effect on the pharmacokinetics of bempedoic acid.