Bempedoic acid + Ezetimibe

Indications

Bempedoic acid + Ezetimibe is used for: Hypercholesterolemia

Adult Dose

Oral Primary Hyperlipidemia, Cardiovascular Risk Reduction Indicated as as an adjunct to diet, in combination with other low-density lipoprotein cholesterol (LDL-C) lowering therapies, or alone when concomitant LDL-C lowering therapy is not possible, to reduce LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) Indicated to reduce risk of myocardial infarction and coronary revascularization in adults who are unable to take recommended statin therapy (including those not taking a statin) with established cardiovascular disease (CVD), or a high risk for a CVD event but without established CVD 1 tablet (bempedoic acid 180 mg/ezetimibe 10 mg) once daily

Child Dose

Renal Dose

Renal impairment Mild or moderate (eGFR ?30 mL/min/1.73 m2): No dosage adjustment is required Severe (eGFR <30 mL/min/1.73 m2): Data are limited End-stage renal disease with dialysis: Not studied

Administration

May take with or without food

Contra Indications

Known hypersensitivity to ezetimibe, including anaphylaxis, angioedema, rash, and urticaria

Precautions

Hyperuricemia Bempedoic acid inhibits renal tubular OAT2 and may increase blood uric acid levels Elevated uric acid levels usually occurred within the first 4 weeks of treatment initiation and persisted throughout treatment; elevated blood uric acid may lead to gout Tendon rupture Bempedoic acid is associated with an increased risk of tendon rupture or injury Tendon rupture occurred within weeks to months of initiating May occur more frequently in patients aged >60 yr Discontinue immediately if tendon rupture occurs Consider discontinuing joint pain, swelling, or inflammation

Pregnancy-Lactation

Pregnancy Discontinue bempedoic acid/ezetimibe when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus Decreases cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol; therefore, bempedoic acid/ezetimibe may cause fetal harm when administered to pregnant women based on the mechanism of action No available data regarding use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Note: Statins are contraindicated in pregnant women Clinical considerations Treatment of hyperlipidemia is not generally necessary during pregnancy Cholesterol and cholesterol derivatives are needed for normal fetal development Animal studies Bempedoic acid was not teratogenic in rats and rabbits when administered at doses resulting in exposures up to 11 and 12 times, respectively, the human exposures at the maximum clinical dose, based on AUC In embryofetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of maternal toxicity or embryofetal teratogenic or toxicologic effects at exposures up to 10 and 150 times the human exposure, respectively, based on AUC Lactation Data are not available regarding drug presence of bempedoic acid in human or animal milk, effects on breastfed infants, or effects on milk production; ezetimibe is present in rat milk, and therefore is likely present in human milk Since bempedoic acid and ezetimibe decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, these actions may cause harm to the breastfed infant Based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment

Interactions

Simvastatin or pravastatin Bempedoic acid increases simvastatin or pravastatin serum concentrations which, may increase simvastatin/pravastatin-related myopathy Avoid use with simvastatin doses >20 mg Avoid use with pravastatin doses >40 mg Atorvastatin and rosuvastatin: Elevations of 1.7-fold in AUC of atorvastatin, rosuvastatin, and/or their major metabolites were observed with bempedoic acid coadministration, suggesting a weak interaction; these elevations were generally within the individual statin exposures and do not affect dosing recommendations Cyclosporine Coadministration of cyclosporine and ezetimibe increases both cyclosporine and ezetimibe concentrations If coadministered, monitor cyclosporine concentrations Fibrates Both fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leading to cholelithiasis Coadministration of ezetimibe with fibrates other than fenofibrate is not recommended If cholelithiasis is suspected, gallbladder studies are indicated Consider alternant lipid-lowering therapies Cholestyramine Coadministration of cholestyramine and ezetimibe decreases ezetimibe concentration, which may lead to reduced efficacy Administer ezetimibe-containing products at least 2 hr before or 4 hr after bile acid sequestrants Contraindicated (0) Serious - Use Alternative (6) ceftobiprole medocaril sodium cyclosporine enasidenib leniolisib trofinetide zavegepant intranasal

Adverse Effects

Side effects of Bempedoic acid + Ezetimibe : >10% Bempedoic acid plus statin Upper respiratory tract infection (4.5%) Muscle spasms (3.6%) Hyperuricemia (3.5%) Back pain (3.3%) Abdominal pain or discomfort (3.1%) Bronchitis (3%) Pain in extremity (3%) Anemia (2.8%) Elevated liver enzymes (2.1%) Gout (1.5%) Benign prostatic hyperplasia (1.3%) Atrial fibrillation (1.7%) Ezetimibe Upper respiratory tract infection (4.3%) Diarrhea (4.1%) Arthralgia (3%) Sinusitis (2.8%) Pain in extremity (2.7%) Fatigue (2.4%) Influenza (2%) <1% Bempedoic acid Tendon rupture (0.5%)

Mechanism of Action

Bempedoic acid Adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers LDL-C by inhibiting 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, but absent in most peripheral tissues Ezetimibe Blocks GI cholesterol absorption via NPC1L1 (Niemann-Pick C1-Like 1) inhibition, reducing cholesterol deliver to the liver This action reduces hepatic cholesterol stores and increases LDL receptors, resulting in clearance of cholesterol from the blood NPC1L1 is a sterol transporter that mediates intestinal cholesterol absorption