Bempedoic acid; Ezetimibe is an oral antilipemic combination. Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor. Ezetimibe is a potent cholesterol absorption inhibitor and selectively blocks the intestinal absorption of cholesterol and related phytosterols. This fixed-dose combination medication is indicated 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). The bempedoic acid component is also approved for myocardial infarction prophylaxis and reduction of the 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. A 12-week, double-blind, clinical study the included adult patients at high risk for cardiovascular disease (presence of atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors) was conducted to compare the safety and efficacy of fixed-dose bempedoic acid; ezetimibe, bempedoic acid, ezetimibe, or placebo added to stable, maximally tolerated statin therapy. The mean percentage reduction in LDL-C from baseline to week 12 was significantly greater with bempedoic acid; ezetimibe at 36.2% compared to 17.2% with bempedoic acid (p less than 0.001) and 23.2% with ezetimibe (p less than 0.001). The LDL-C reductions were also significantly greater with bempedoic acid; ezetimibe compared to placebo with a difference of -38% (p less than 0.001). The fixed-dose bempedoic acid; ezetimibe combination produced significantly greater reductions in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B compared to bempedoic acid, ezetimibe, or placebo. In addition, bempedoic acid; ezetimibe therapy was associated with significantly greater reductions in high-sensitivity C-reactive protein compared with ezetimibe (p=0.002) and placebo (p less than 0.001); the difference between combination therapy and bempedoic acid did not reach statistical significance. Additionally, in a cardiovascular outcomes clinical 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).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Bempedoic acid; ezetimibe may be administered with or without food.
-Swallow the tablet whole. Do not cut, chew, or crush the tablet.
-If prescribed concurrently with a bile acid sequestrant, administer bempedoic acid; ezetimibe at least 2 hours before or 4 hours after a dose of the bile acid sequestrant.
-Store and dispense medication in the original package.
In primary hyperlipidemia clinical trials, back pain was reported in 3.3% and pain in the extremity in 3% of bempedoic acid-treated subjects compared to 2.2% and 1.7%, respectively, of placebo-treated subjects. One of the most common reasons for bempedoic acid discontinuation was pain in the extremity (0.3%). Arthralgia occurred in 3%, pain in the extremity in 2.7%, and back pain in 4.1% of ezetimibe-treated subjects compared to 2.2%, 3.9%, and 2.5% of placebo-treated subjects, respectively.
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. Tendon rupture may occur within weeks to months of starting bempedoic acid. Advise persons to contact their healthcare provider if tendonitis or tendon rupture develops. Consider discontinuation of therapy if a patient experiences joint pain, swelling, or inflammation. Tendon rupture risk may be increased in patients over 60 years of age, taking concomitant fluoroquinolones or corticosteroids, with renal failure, or with tendon disorders. In the bempedoic acid cardiovascular outcomes clinical trial, tendon rupture events occurred in 1.2% of bempedoic acid-treated subjects compared to 0.9% of placebo-treated subjects.
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 bempedoic acid cardiovascular outcomes clinical 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 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. Additionally, 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%). In ezetimibe clinical trials, fatigue was reported in 2.4%, influenza in 2%, upper respiratory tract infection in 4.3%, and sinusitis in 2.8% of ezetimibe-treated subjects compared to 1.5%, 1.5%, 2.5%, and 2.2%, respectively, in placebo-treated subjects. Two of the most commonly reported adverse reactions with bempedoic acid; ezetimibe therapy were urinary tract infections (5.9%) and nasopharyngitis/pharyngitis (4.7%) compared to 2.4% and 0%, respectively, in placebo-treated subjects.
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. Abdominal pain and diarrhea occurred in 3% and 4.1%, respectively of ezetimibe-treated subjects compared to 2.8% and 3.7% of placebo-treated subjects. In a single clinical trial, constipation was reported in 4.7% bempedoic acid; ezetimibe subjects compared to 0.9% placebo.
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. In the bempedoic acid 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 hepatic enzyme elevations compared to placebo (4.5% vs. 3%, respectively). Elevated hepatic enzymes, including elevations more than 5 times the ULN, and hepatitis have also been reported during postmarketing experience with ezetimibe and/or bempedoic acid.
Muscle cramps (muscle spasms) occurred in 3.6% of bempedoic acid-treated subjects compared to 2.3% of placebo-treated subjects in primary hyperlipidemia trials. One of the most common reasons for bempedoic acid discontinuation was muscle spasm (0.5%). 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 bempedoic acid cardiovascular outcomes clinical trial, muscle cramps (muscle spasms) were reported in 4% of bempedoic acid-treated subjects compared to 3% of placebo-treated subjects. During post-marketing surveillance with ezetimibe and/or bempedoic acid, increased CK serum concentrations and myopathy/rhabdomyolysis have been reported.
Cholecystitis, cholelithiasis, and pancreatitis have been reported during postmarketing experience with ezetimibe and/or bempedoic acid therapy. Cholelithiasis was also reported in the bempedoic acid cardiovascular outcomes clinical trial (2% bempedoic acid vs. 1% placebo).
During postmarketing experience with ezetimibe and/or bempedoic acid, depression, dizziness, headache, and paresthesias have been reported.
Hypersensitivity reactions, including angioedema, anaphylactoid reactions, wheezing, rash, urticaria, and erythema multiforme have been reported during postmarketing experience with ezetimibe and/or 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 bempedocic 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 also 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. Thrombocytopenia has been reported with post-marketing use of ezetimibe and/or bempedoic acid.
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 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.
Due to the unknown clinical effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic disease (Child-Pugh B or C), bempedoic acid; ezetimibe is not recommended in these patients. Elevations in hepatic enzymes have also been reported with bempedoic acid therapy. These elevations were typically transient and resolved or improved with continued or discontinuation of therapy.
Discontinue bempedoic acid; ezetimibe once pregnancy is detected unless the benefits of therapy outweigh potential risks to the fetus. There are no available data on bempedoic acid and insufficient data on ezetimibe to evaluate for 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, reductions in the number of live pups, pup survival, and pup growth. At exposures similar to that of MRHD, there were slight delays in memory and learning. Ezetimibe was not teratogenic when orally administered to pregnant rats and rabbits at doses that were 10 to 150 times the MRHD. An increase in the incidence of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) was observed in pregnant rats that received 10 times the MRHD of ezetimibe. In pregnant rabbits at doses 150 times MRHD, an increased incidence of extrathoracic ribs was reported. Placental transfer studies found the fetal-maternal plasma exposure ratio for total ezetimibe (conjugated and unconjugated ezetimibe) to be 1.5 for rats and 0.03 for rabbits on gestation day 20 and 22, respectively. When ezetimibe and a statin were coadministered to rats and rabbits during organogenesis, reproductive findings were found to occur at lower doses with combination therapy compared to either agent administered alone. The effects of bempedoic acid or ezetimibe were not altered when coadministered at 4 and 112 times MRHD to pregnant rats during the period of organogenesis (gestation days 6 to 17). There is a pregnancy surveillance study for bempedoic acid; ezetimibe. If bempedoic acid; ezetimibe is administered during pregnancy, report exposure by contacting Esperion at 1-833-377-7633.
There is no information regarding the presence of bempedoic acid or ezetimibe in human milk, the effects on the breastfed infant, or the effects on milk production. Breast-feeding is not recommended during bempedoic acid; ezetimibe 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; ezetimibe 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 vitamines 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: Bempedoic acid 180 mg/ezetimibe 10 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:
NOTE: This indication is based on the bempedoic acid component.
Oral dosage:
Adults: 1 tablet (bempedoic acid 180 mg/ezetimibe 10 mg) PO once daily.
Maximum Dosage Limits:
-Adults
180 mg/day PO bempedoic acid and 10 mg/day PO ezetimibe.
-Geriatric
180 mg/day PO bempedoic acid and 10 mg/day PO ezetimibe.
-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
Mild hepatic impairment (Child-Pugh A): no dosage adjustment is needed.
Moderate or severe hepatic impairment (Child-Pugh B or C): Not recommended because of the unknown effects of elevated ezetimibe concentrations.
Patients with Renal Impairment Dosing
No dosage adjustment is needed in patients with mild or moderate renal impairment. There is limited experience with bempedoic acid in patients with severe renal impairment (CrCl less than 30 mL/min); bempedoic acid has not been studied in patients with end-stage renal disease receiving dialysis.
*non-FDA-approved indication
Aluminum Hydroxide: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aluminum Hydroxide; Magnesium Carbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aluminum Hydroxide; Magnesium Trisilicate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Antacids: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate; Magnesium Hydroxide: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium Carbonate; Simethicone: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Calcium; Vitamin D: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Cholestyramine: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants, such as cholestyramine. The incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively.
Colesevelam: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colesevelam with ezetimibe; however, this potential interaction has not been studied.
Colestipol: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colestipol with ezetimibe; however, this potential interaction has not been studied.
Cyclosporine: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and ezetimibe are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as ezetimibe, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
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.
Fenofibrate: (Moderate) Monitor for cholelithiasis symptoms during concomitant ezetimibe and fenofibrate use. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. If cholelithiasis is suspected, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.
Fenofibric Acid: (Moderate) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
Gemfibrozil: (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
Magnesium Hydroxide: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Magnesium Salts: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Omeprazole; Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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.
Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Warfarin: (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored.
Bepemdoic acid and ezetimibe exhibit complementary mechanisms that reduce LDL-C, non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein (Apo-B), and total cholesterol. When added to maximally tolerated statin therapy, bempedoic acid; ezetimibe resulted in greater LDL-C reductions (36.2%) compared to bempedoic acid (17.2%) or ezetimibe (23.2%). Greater reductions in non-HDL-C, Apo-B, and total cholesterol were also seen with bempedoic acid; ezetimibe compared to bempedoic acid or ezetimibe.
-Bempedoic acid: 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.
-Ezetimibe: Ezetimibe lowers serum cholesterol concentrations by selectively inhibiting the absorption of cholesterol and related phytosterols by the small intestine. Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Ezetimibe localizes at the brush border of the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in the blood clearance of cholesterol. When ezetimibe is given as monotherapy, a compensatory increase in cholesterol synthesis occurs. With ongoing therapy, the overall effects of ezetimibe monotherapy are to reduce total cholesterol (13%), LDL-cholesterol (18%), and Apo-B (16%) in patients with hypercholesterolemia. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols (sitosterol and campesterol). In a 2-week study of 18 hypercholesterolemic patients, ezetimibe has been reported to inhibit intestinal cholesterol absorption by 54% relative to placebo.
Bempedoic acid; ezetimibe is administered orally. The Cmax values for ezetimibe and ezetimibe-glucuronide were approximately 13% and 22% lower, respectively, with bempedoic acid; ezetimibe compared to ezetimibe alone. However, due to similar AUCs for ezetimibe and ezetimibe-glucuronide with bempedoic acid; ezetimibe and ezetimibe alone, the reduced Cmax is not believed to be of any clinical significance. Cmax for bempedoic acid and ESP15228 were similar for bempedoic acid; ezetimibe and bempedoic acid alone. Thus, the bioavailability of bempedoic acid; ezetimibe tablets are similar to the individual components.
-Bempedoic acid: Bempedoic acid is an orally administered prodrug. Bempedoic acid undergoes reversible conversion to an active metabolite, ESP 15228, 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.
-Ezetimibe: Ezetimibe is administered orally. Following systemic absorption, ezetimibe is extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Ezetimibe and ezetimibe-glucuronide are highly bound (greater than 90%) to human plasma proteins. Ezetimibe is rapidly metabolized by glucuronidation to ezetimibe-glucuronide in the small intestines and liver. Metabolism by oxidative metabolism is minimal. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from the plasma with a half-life of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations. After oral administration of radiolabeled ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) accounts for approximately 93% of the total plasma radioactivity. After 48 hours, the plasma radioactivity is undetectable. Over a 10-day period, approximately 78% and 11% of the administered dose is recovered in the feces and urine, respectively. Ezetimibe is the major component recovered in the feces and accounts for 69% of the administered dose, while ezetimibe-glucuronide is the major component recovered in the urine and accounts for 9% of the administered dose.
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. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P450 isoenzymes and transporters.
-Route-Specific Pharmacokinetics
Oral Route
Following administration with a high-fat, high-calorie breakfast in healthy subjects, there was a 2-hour and 2.5-hour delay in Tmax and a 30% and 12% decrease in Cmax for bempedoic acid and ezetimibe, respectively, when compared to administration in the fasting state.
-Bempedoic acid: 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.
-Ezetimibe: Following oral administration of a single ezetimibe dose to fasted adults, the median time to maximum concentration was 5 hours and 1 hour for ezetimibe and ezetimibe-glucuronide, respectively. The Cmax for ezetimibe is 3.56 +/- 1.9 ng/mL. The absolute bioavailability of ezetimibe is not known. The concomitant administration of food (high-fat vs. non-fat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases the Cmax of ezetimibe by 38%.
-Special Populations
Hepatic Impairment
-Bempedoic acid: 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 28%, 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).
-Ezetimibe: Although pharmacokinetic differences have been identified in patients with mild hepatic impairment (Child-Pugh A), no dosage adjustments for ezetimibe are indicated. Significant increases in ezetimibe exposure occur in patients with moderate to severe impairment (Child-Pugh B or C); ezetimibe is not recommended for use in these patients. Following administration with a single 10 mg ezetimibe dose in patients with mild hepatic impairment (Child-Pugh A), the mean AUC for total ezetimibe increased by 1.7-fold compared to healthy subjects. In patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, the mean AUC values for total ezetimibe (unconjugated and conjugated) and ezetimibe increased 3 to 4-fold and 5 to 6-fold, respectively, compared to healthy patients. Compared to patients without hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased by approximately 4-fold following administration of ezetimibe 10 mg PO once daily for 14 days in patients with moderate hepatic impairment.
Renal Impairment
-Bempedoic acid: 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.
-Ezetimibe: Although pharmacokinetic differences have been identified in severe renal impairment, no dosage adjustments for ezetimibe are indicated. In 8 patients with severe renal impairment (mean CrCl 30 mL/min/1.73m2 or lower), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe are increased by approximately 1.5-fold, compared to healthy subjects (n=9).
Geriatric
-Bempedoic acid: Age was not shown to have an effect on the pharmacokinetics of bempedoic acid.
-Ezetimibe: With repeated dosing of 10 mg daily for 10 days, plasma concentrations for total ezetimibe are about 2-fold higher in elderly subjects compared to younger adults; however, no dosage adjustment is recommended in elderly patients.
Gender Differences
-Bempedoic acid: Gender was not shown to have an effect on the pharmacokinetics of bempedoic acid.
-Ezetimibe: Although pharmacokinetic differences have been identified in women, no dosage adjustments for ezetimibe are indicated. In a multiple-dose study of 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (greater than 20%) for women relative to men.
Ethnic Differences
-Race was not shown to have an effect on the pharmacokinetics of bempedoic acid; ezetimibe.[65049
Obesity
-Bempedoic acid: Weight was not shown to have an effect on the pharmacokinetics of bempedoic acid.