bempedoic acid/ezetimibe (Rx)

>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%)

Postmarketing Reports

Ezetimibe

• Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria
• Erythema multiforme
• Myalgia
• Elevated creatinine phosphokinase
• Myopathy/rhabdomyolysis
• Elevated liver transaminases
• Hepatitis
• Abdominal pain
• Thrombocytopenia
• Pancreatitis
• Nausea
• Dizziness
• Paresthesia
• Depression
• Headache
• Cholelithiasis
• Cholecystitis

Contraindications

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

Cautions

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 associated with 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 with joint pain, swelling, or inflammation

Drug interaction overview

• 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 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

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

Absorption

Peak plasma time

• Bempedoic acid: 3 hr
• Ezetimibe: 1 hr
• Ezetimibe glucuronide: 5 hr

Peak plasma concentration

• Bempedoic acid: 12.6 mcg/mL
• Active metabolite, ESP15228: 2.8 mcg/mL
• Ezetimibe: 3.56 ng/mL
• Ezetimibe glucuronide: 107 ng/mL

AUC

• Bempedoic acid: 202 mcgh/mL
• Active metabolite, ESP15228: 51.2 mcgh/mL

Distribution

Vd

• Bempedoic acid: 18 L

Protein bound

• Bempedoic acid: 99.3%
• Bempedoic acid glucuronide metabolite: 99.8%
• Active metabolite, ESP15228: 99.2%
• Ezetimibe: >90%

Metabolism

Bempedoic acid

• Primarily through metabolism of the acyl glucuronide
• Also reversibly converted to an active metabolite (ESP15228) based on aldo-keto reductase activity observed in vitro from human liver

Ezetimibe

• Primarily metabolized in small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion
• Rapidly metabolized to ezetimibe-glucuronide

Elimination

Half-life

• Bempedoic acid: 21 hr
• Ezetimibe and ezetimibe glucuronide: ~22 hr

Excretion

• Bempedoic acid: 70% urine (primarily as the acyl glucuronide conjugate); 30% feces
• Ezetimibe and ezetimibe glucuronide: 11% urine; 78% feces; ezetimibe was the major component in feces (69%), while ezetimibe-glucuronide was the major component in urine (9%)

Oral Administration

May take with or without food

Swallow tablet whole

Storage

Store at 68-77ºF (20-25ºC); excursions permitted to 59-86ºF (15-30ºC)

Store and dispense in the original package

Do not discard desiccant