bempedoic acid/ezetimibe (Rx)

Brand and Other Names:Nexlizet
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

bempedoic acid/ezetimibe

tablet

  • 180mg/10mg

Hypercholesterolemia

Indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein cholesterol (LDL-C)

1 tablet (bempedoic acid 180 mg/ezetimibe 10 mg) PO qDay

Dosage Modifications

Renal impairment

Mild or moderate (eGFR ≥30 mL/min/1.73 m2): No dosage adjustment required

Severe (eGFR <30 mL/min/1.73 m2): Data are limited

End-stage renal disease with dialysis: Not studied

Hepatic impairment

Mild (Child-Pugh A): No dosage adjustment required

Moderate or severe (Child-Pugh B or C): Not recommended owing to unknown effects of increased ezetimibe exposure

Dosing Considerations

Limitations of use: Effect on cardiovascular morbidity and mortality not determined

Monitoring: After initiating, analyze lipid levels within 8-12 weeks

Safety and efficacy not established

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Interactions

Interaction Checker

and bempedoic acid/ezetimibe

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    Contraindicated

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            Adverse Effects

            >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
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            Warnings

            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
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            Pharmacology

            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%)
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            Administration

            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

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.