Dosing & Uses
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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (4)
- 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.
- leniolisib
leniolisib will increase the level or effect of ezetimibe by Other (see comment). Avoid or Use Alternate Drug. Leniolisib, an OATP1B1 and OATP1B3 inhibitor, may increase systemic exposure of these substrates
- trofinetide
trofinetide will increase the level or effect of ezetimibe by Other (see comment). Avoid or Use Alternate Drug. Trofinetide (an OATP131 and OATP13B inhibitor) may increase plasma levels of OATP131 or OATP13B substrates. Avoid coadministration with sensitive substrates.
- zavegepant intranasal
ezetimibe will increase the level or effect of zavegepant intranasal by Other (see comment). Avoid or Use Alternate Drug. NTCP inhibitors may result in a significant increase in systemic exposure of zavegepant (a NTCP substrate).
Monitor Closely (9)
- 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.
- encorafenib
encorafenib will increase the level or effect of ezetimibe by Other (see comment). Modify Therapy/Monitor Closely. Encorafenib (a OATP1B1 inhibitor) may increase the concentration and toxicities of OATP1B1 substrates. Closely monitor for signs and symptoms of increased exposure and consider adjusting the dose of these substrates.
- 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.
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
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
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.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%)
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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