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

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

            All Interactions Sort By:
             activity indicator 

            Contraindicated (0)

              Serious - Use Alternative (1)

              • cyclosporine

                cyclosporine, ezetimibe. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Monitor for potential adverse effects of cyclosporine and ezetimibe if coadministered, especially in patients with severe renal impairment.

              Monitor Closely (8)

              • apalutamide

                apalutamide will decrease the level or effect of ezetimibe by increasing elimination. Use Caution/Monitor. Apalutamide induces UGT and weakly induces OATP1B1 and may decrease systemic exposure of drugs that are substrates of both UGT and OATP1B1.

              • cholestyramine

                cholestyramine decreases levels of ezetimibe by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Separate by 2-4 hours.

              • fostemsavir

                fostemsavir will increase the level or effect of ezetimibe by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits OATP1B1/3 transporter. If possible, avoid coadministration or modify dose of OATP1B1/3 substrates coadministered with fostemsavir.

              • glecaprevir/pibrentasvir

                glecaprevir/pibrentasvir will increase the level or effect of ezetimibe by Other (see comment). Use Caution/Monitor. Coadministration with glecaprevir/pibrentasvir may increase plasma concentration of drugs that are substrates of OATP1B1 or OATP1B3

              • letermovir

                letermovir increases levels of ezetimibe by Other (see comment). Use Caution/Monitor. Comment: Letermovir, an OATP1B1/3 inhibitor may increase plasma concentrations of coadministered OATP1B1/3 substrates.

              • pravastatin

                bempedoic acid increases levels of pravastatin by unknown mechanism. Modify Therapy/Monitor Closely. Avoid concomitant use with pravastatin dose 40 mg.

              • simvastatin

                bempedoic acid increases levels of simvastatin by unknown mechanism. Modify Therapy/Monitor Closely. Avoid concomitant use with simvastatin dose >20 mg.

              • sofosbuvir/velpatasvir

                sofosbuvir/velpatasvir increases levels of ezetimibe by Other (see comment). Use Caution/Monitor. Comment: Velpatasvir inhibits OATP1B1, OATP1B3, and OATP2B1 transporters. .

              Minor (5)

              • fenofibrate

                fenofibrate increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.

              • fenofibrate micronized

                fenofibrate micronized increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.

              • fenofibric acid

                fenofibric acid increases levels of ezetimibe by unspecified interaction mechanism. Minor/Significance Unknown.

              • gemfibrozil

                gemfibrozil increases levels of ezetimibe by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              • voclosporin

                voclosporin will increase the level or effect of ezetimibe by Other (see comment). Minor/Significance Unknown. Information suggests voclosporin (an OATP1B1 inhibitor) may increase in the concentration of OATP1B1 substrates is possible. Monitor for adverse reactions of OATP1B1 substrates when coadministered with voclosporin.

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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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              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

              Pregnancy Categories

              A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

              B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

              C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

              D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

              X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

              NA: Information not available.

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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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              Patient Handout

              A Patient Handout is not currently available for this monograph.
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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.
              3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
              4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
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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.