Nexlizet

1 INDICATIONS AND USAGE NEXLIZET, a combination of bempedoic acid and ezetimibe, is indicated: as an adjunct to diet and exercise to reduce LDL-C in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). Bempedoic acid, a component of NEXLIZET, is indicated: to reduce the risk of major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, or coronary revascularization) in adults at increased risk for these events who are unable to take recommended statin therapy (including those not taking a statin). NEXLIZET, a combination of bempedoic acid, an adenosine triphosphate citrate lyase (ACL) inhibitor, and ezetimibe, a dietary cholesterol absorption inhibitor, is indicated: As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). ( 1 ) Bempedoic acid, a component of NEXLIZET, is indicated: To reduce the risk of major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, or coronary revascularization) in adults at increased risk for these events who are unable to take recommended statin therapy (including those not taking a statin). ( 1 )

2 DOSAGE AND ADMINISTRATION Administer one tablet (180 mg bempedoic acid and 10 mg ezetimibe) orally once daily with or without food. ( 2.1 ) Swallow the tablet whole. ( 2.1 ) Coadministration with Bile Acid Sequestrants: Administer at least 2 hours before or at least 4 hours after bile acid sequestrants. ( 2.2 ) 2.1 Recommended Dosage and Administration The recommended dosage of NEXLIZET is one tablet orally once daily. One tablet of NEXLIZET contains 180 mg of bempedoic acid and 10 mg of ezetimibe. Swallow the tablet whole. NEXLIZET can be taken with or without food. If a dose is missed, take the missed dose as soon as possible. Do not double the next dose. After initiation of NEXLIZET, analyze lipid levels within 8 to 12 weeks. 2.2 Coadministration with Bile Acid Sequestrants Administer NEXLIZET either at least 2 hours before or at least 4 hours after administration of a bile acid sequestrant [see Drug Interactions (7) ].

4 CONTRAINDICATIONS NEXLIZET is contraindicated in patients with a prior hypersensitivity to ezetimibe or bempedoic acid or any of the excipients in NEXLIZET [see Adverse Reactions (6.2) ] . Serious hypersensitivity reactions, such as anaphylaxis, angioedema, rash and urticaria have been reported with ezetimibe or bempedoic acid. Known hypersensitivity to ezetimibe or bempedoic acid or any of the excipients in NEXLIZET. ( 4 , 6.2 )

5 WARNINGS AND PRECAUTIONS Hyperuricemia: Elevations in serum uric acid have occurred. Assess uric acid levels periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate. ( 5.1 ) Tendon Rupture: Tendon rupture has occurred. Discontinue NEXLIZET at the first sign of tendon rupture. Avoid NEXLIZET in patients who have a history of tendon disorders or tendon rupture. ( 5.2 ) 5.1 Hyperuricemia Bempedoic acid, a component of NEXLIZET, inhibits renal tubular OAT2 and may increase blood uric acid levels [see Clinical Pharmacology (12.3) ] . In the primary hypercholesterolemia trials [see Clinical Studies (14.1) ] , 26% of bempedoic acid-treated patients with normal baseline uric acid values (versus 9.5% placebo) experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction (versus 1.1% placebo). Increases in uric acid levels usually occurred within the first 4 weeks of treatment initiation, persisted throughout treatment, and returned to baseline following discontinuation of treatment. After 12 weeks of treatment, the mean placebo-adjusted increase in uric acid compared to baseline was 0.8 mg/dL for patients treated with bempedoic acid. In the cardiovascular outcomes trial [see Clinical Studies (14.2) ] , 16.4% of bempedoic acid-treated patients experienced clinically significant hyperuricemia reported as an adverse reaction (versus 8.2% placebo). Elevated blood uric acid may lead to the development of gout. In the primary hypercholesterolemia trials, gout was reported in 1.5% of patients treated with bempedoic acid versus 0.4% of patients treated with placebo. In the cardiovascular outcomes trial, gout was reported in 3.2% of patients treated with bempedoic acid and 2.2% treated with placebo. Advise patients to contact their healthcare provider if symptoms of hyperuricemia occur. Assess serum uric acid when clinically indicated. Monitor patients for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate. 5.2 Tendon Rupture Bempedoic acid, a component of NEXLIZET, is associated with an increased risk of tendon rupture or injury. In the primary hypercholesterolemia trials [see Clinical Studies (14.1) ] , tendon rupture occurred in 0.5% of patients treated with bempedoic acid versus 0% of placebo-treated patients and involved the rotator cuff (the shoulder), biceps tendon, or Achilles tendon. Tendon rupture occurred within weeks to months of starting bempedoic acid. In the cardiovascular outcomes trial [see Clinical Studies (14.2) ] , tendon rupture events occurred in 1.2% of bempedoic acid-treated patients versus 0.9% of placebo-treated patients. Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders. Discontinue NEXLIZET immediately if the patient experiences rupture of a tendon. Consider discontinuing NEXLIZET if the patient experiences joint pain, swelling, or inflammation. Advise patients to rest at the first sign of tendinitis or tendon rupture and to contact their healthcare provider if tendinitis or tendon rupture symptoms occur. Consider alternative therapy in patients with a history of tendon disorders or tendon rupture.

7 DRUG INTERACTIONS No specific pharmacokinetic drug interaction studies with NEXLIZET have been conducted. Table 4 lists drug interactions with NEXLIZET that have been identified in studies with bempedoic acid or ezetimibe. Table 4. Clinically Important Drug Interactions with NEXLIZET Simvastatin Clinical Impact: Concomitant use of NEXLIZET with simvastatin causes an increase in simvastatin concentration and may increase the risk of simvastatin-related myopathy [see Clinical Pharmacology (12.3) ] . Intervention: Avoid concomitant use of NEXLIZET with simvastatin greater than 20 mg. Pravastatin Clinical Impact: Concomitant use of NEXLIZET with pravastatin causes an increase in pravastatin concentration and may increase the risk of pravastatin-related myopathy [see Clinical Pharmacology (12.3) ] . Intervention: Avoid concomitant use of NEXLIZET with pravastatin greater than 40 mg. Cyclosporine Clinical Impact: Concomitant use of NEXLIZET and cyclosporine increases ezetimibe and cyclosporine concentrations. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency [see Clinical Pharmacology (12.3) ] . Intervention: Monitor cyclosporine concentrations in patients receiving NEXLIZET and cyclosporine. In patients treated with cyclosporine, weigh the potential effects of the increased exposure to ezetimibe from concomitant use against the benefits of alterations in lipid levels provided by NEXLIZET. Fibrates Clinical Impact: Both fenofibrate and ezetimibe (a component of NEXLIZET) may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of NEXLIZET with fibrates other than fenofibrate is not recommended [see Adverse Reactions (6.1) ] . Intervention: If cholelithiasis is suspected in a patient receiving NEXLIZET and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. Clinical Impact: Concomitant administration of fibrates with bempedoic acid (a component of NEXLIZET) resulted in increased triglycerides and decreased high-density lipoprotein cholesterol (HDL-C) in some patients in clinical studies and post-marketing reports. Reversibility of both increased triglycerides and decreased HDL-C levels was observed when either bempedoic acid or fibrate therapy was discontinued. Intervention: Monitor triglycerides and HDL-C four weeks after initial concomitant use of NEXLIZET and a fibrate and periodically thereafter. If increased triglycerides or decreased HDL-C levels are detected, discontinue NEXLIZET or fibrate therapy based on clinical judgment. Monitor triglycerides and HDL-C levels until levels return to baseline. Cholestyramine Clinical Impact: Concomitant use of NEXLIZET and cholestyramine decreases ezetimibe concentration. This may result in a reduction of efficacy [see Clinical Pharmacology (12.3) ]. Intervention: Administer NEXLIZET either at least 2 hours before or at least 4 hours after bile acid sequestrants [see Dosage and Administration (2.2) ] . Simvastatin: Avoid concomitant use of NEXLIZET with simvastatin greater than 20 mg. ( 7 ) Pravastatin: Avoid concomitant use of NEXLIZET with pravastatin greater than 40 mg. ( 7 ) Cyclosporine: Monitor cyclosporine concentrations. ( 7 ) Fibrates: If cholelithiasis is suspected in a patient receiving NEXLIZET and fenofibrate, consider alternative lipid-lowering therapy. ( 6.2 , 7 ) Concomitant use of NEXLIZET with fibrates may increase triglycerides and decrease high-density lipoprotein cholesterol. ( 7 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hyperuricemia [see Warnings and Precautions (5.1) ] Tendon Rupture [see Warnings and Precautions (5.2) ] Common adverse reactions with NEXLIZET in the primary hypercholesterolemia trials (incidence ≥ 2% and more frequently than placebo) were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza. ( 6.1 ) The common adverse reaction associated with bempedoic acid in the cardiovascular outcomes trial (incidence ≥ 2% and more frequently than placebo) were hyperuricemia, renal impairment, anemia, elevated liver enzymes, muscle spasms, gout, and cholelithiasis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Esperion at 833-377-7633 (833 ESPRMED) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Bempedoic acid The data in Table 1 reflect exposure to bempedoic acid in two placebo-controlled primary hypercholesterolemia trials that included 2,009 patients treated with bempedoic acid for 52 weeks (median treatment duration of 52 weeks) [see Clinical Studies (14.1) ] . The mean age for bempedoic acid-treated patients was 65 years, 29% were female, 95% were White, 3% were Black or African American, 1% were Asian, and 1% were other races; 3% identified as Hispanic or Latino ethnicity. All patients received bempedoic acid 180 mg orally once daily plus maximally tolerated statin therapy alone or in combination with other lipid-lowering therapies. At baseline, 97% of patients had CVD and about 4% had a diagnosis of HeFH. Patients on simvastatin 40 mg/day or higher were excluded from the trials. In the primary hypercholesterolemia trials, adverse reactions led to discontinuation of treatment in 11% of bempedoic acid-treated patients and 8% of placebo-treated patients. The most common reasons for bempedoic acid treatment discontinuation were muscle spasms (0.5% versus 0.3% placebo), diarrhea (0.4% versus 0.1% placebo), and pain in extremity (0.3% versus 0.0% placebo). Adverse reactions reported in at least 2% of bempedoic acid-treated patients and more frequently than in placebo-treated patients are shown in Table 1. Table 1. Adverse Reactions (≥ 2% and greater than placebo) in Bempedoic Acid-Treated Patients with Primary Hypercholesterolemia and CVD or HeFH (Trials 2 and 3) Adverse Reaction Placebo Background therapy included statin ± other lipid-lowering therapies (N = 999) % Bempedoic acid (N = 2,009) % Upper respiratory tract infection 4.0 4.5 Muscle spasms 2.3 3.6 Hyperuricemia Grouped term that includes other related terms 1.1 3.5 Back pain 2.2 3.3 Abdominal pain or discomfort 2.2 3.1 Bronchitis 2.5 3.0 Pain in extremity 1.7 3.0 Anemia 1.9 2.8 Elevated liver enzymes 0.8 2.1 In the cardiovascular outcomes trial in which 7,001 patients were exposed to bempedoic acid and 6,964 patients were exposed to placebo for a median of 3.1 years [see Clinical Studies (14.2) ] , adverse reactions led to discontinuation of treatment in 11% of bempedoic acid-treated patients and 10% of placebo-treated patients. Adverse reactions reported in at least 2% of bempedoic acid-treated patients and more frequently than placebo are shown in Table 2. Table 2. Adverse Reactions (≥ 2% and 0.5% greater than placebo) in Bempedoic Acid-Treated Patients with CVD or at High Risk for CVD (Trial 4) Adverse Reaction Placebo (N=6,964) % Bempedoic Acid (N=7,001) % Hyperuricemia Grouped term that includes other related terms 8 16 Renal impairment Renal impairment includes laboratory related terms including glomerular filtration rate decreased, blood creatinine increased and hematuria 9 11 Anemia 4 5 Elevated liver enzymes 3 4 Muscle spasms 3 4 Gout 2 3 Cholelithiasis 1 2 Other Adverse Reactions Tendon Rupture In the hypercholesterolemia trials, tendon rupture occurred in 0.5% of bempedoic acid-treated patients versus 0% of placebo-treated patients. In the cardiovascular outcomes trial, tendon rupture events occurred in 1.2% of bempedoic acid-treated patients versus 0.9% of placebo-treated patients. Gout In the hypercholesterolemia trials, gout occurred in 1.5% of bempedoic acid-treated patients versus 0.4% of placebo-treated patients. In the cardiovascular outcomes trial, gout occurred in 3.2% of bempedoic acid-treated patients versus 2.2% of placebo-treated patients. Laboratory Tests Bempedoic acid was associated with persistent changes in multiple laboratory tests that occurred within the first 4 weeks of treatment, and returned to baseline following discontinuation of treatment. Increase in Creatinine and Blood Urea Nitrogen In the hypercholesterolemia trials, there was a mean increase in serum creatinine of 0.05 mg/dL compared to baseline with bempedoic acid at Week 12. Approximately 3.8% of patients treated with bempedoic acid had blood urea nitrogen values that doubled (versus 1.5% placebo), and about 2.2% of patients had creatinine values that increased by 0.5 mg/dL (versus 1.1% placebo). In the cardiovascular outcomes trial, 7.1% of patients had creatinine values that increased by 0.5 mg/dL (versus 5.5% placebo) and 9.5% of patients in the bempedoic acid group had BUN values that increased ≥ 2× baseline (versus 6.2% placebo). Decrease in Hemoglobin and Leukocytes In the hypercholesterolemia trials, approximately 5.1% of patients treated with bempedoic acid (versus 2.3% placebo) had decreases in hemoglobin levels of 2 or more g/dL and below the lower limit of normal on one or more occasion. Anemia was reported in 2.8% of patients treated with bempedoic acid and 1.9% of patients treated with placebo. Approximately 9.0% of bempedoic acid-treated patients with normal baseline leukocyte count had a decrease to less than the lower limit of normal on one or more occasion (versus 6.7% placebo). Leukocyte decrease was generally asymptomatic and did not require medical intervention. In the hypercholesterolemia trials, there was a small imbalance in skin or soft tissue infections, including cellulitis (0.8% versus 0.4%), but there was no imbalance in other infections. In the cardiovascular outcomes trial, 10.8% of patients (versus 7.4% placebo) had a decrease in hemoglobin of 2 or more g/dL and below the lower limit of normal. Anemia was reported in 4.7% of patients treated with bempedoic acid and 3.9% of patients treated with placebo. There were 9.3% of bempedoic acid-treated patients with a leukocyte count below the lower limit of normal (and normal at baseline) at any point (versus 6.8% placebo). Increase in Platelet Count In the hypercholesterolemia trials, approximately 10.1% of bempedoic acid-treated patients (versus 4.7% placebo) had increases in platelet counts of 100× 10 9 /L or more on one or more occasion. In the cardiovascular outcomes trial, 18.6% of patients in the bempedoic acid-treated group (versus 10.2% placebo) had an increase in platelet count of 100 × 10 9 /L or more. Platelet count increase was asymptomatic and did not result in increased risk for thromboembolic events. Increase in Liver Enzymes In the hypercholesterolemia trials, increases in hepatic transaminases (AST and/or ALT) were observed with bempedoic acid. In most cases, the elevations were transient and resolved or improved with continued therapy or after discontinuation of therapy. Increases to more than 3× the upper limit of normal (ULN) in AST occurred in 1.4% of patients treated with bempedoic acid versus 0.4% of placebo patients, and increases to more than 5× ULN occurred in 0.4% of bempedoic acid- treated versus 0.2% of placebo-treated patients. Increases in ALT occurred with similar incidence between bempedoic acid- and placebo-treated patients. Elevations in transaminases were generally asymptomatic and not associated with elevations ≥ 2× ULN in bilirubin or with cholestasis. In the cardiovascular outcomes trial, the incidence of repeated and confirmed ALT and/or AST >3× ULN was 1.6% in the bempedoic acid-treated group (versus 1.0% placebo). A higher percentage of patients in the bempedoic acid-treated group had hepatic enzyme elevations versus placebo (4.5% versus 3.0%, respectively). Increase in Creatine Kinase In the hypercholesterolemia trials, approximately 1.0% of patients (versus 0.6% placebo) had elevations of CK levels of 5 or more times the normal value on one or more occasions, and 0.4% of patients (versus 0.2% placebo) had elevations of CK levels of 10 or more times. Ezetimibe In 10 double-blind, placebo-controlled clinical trials [see Clinical Studies (14.1) ] , 2,396 patients with primary hypercholesterolemia (age range 9 to 86 years, 50% were female, 90% were White, 5% were Black or African American, 2% were Asian, 3% other races; 3% identified as Hispanic or Latino ethnicity) and elevated LDL-C were treated with ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥ 2% of patients treated with ezetimibe and at an incidence greater than placebo in placebo-controlled studies of ezetimibe are shown in Table 3. Table 3. Adverse Reactions Occurring in ≥ 2% and greater than placebo in Ezetimibe-treated Patients Adverse Reaction Placebo (%) N = 1,159 Ezetimibe 10 mg (%) N = 2,396 Upper respiratory tract infection 2.5 4.3 Diarrhea 3.7 4.1 Arthralgia 2.2 3.0 Sinusitis 2.2 2.8 Pain in extremity 2.5 2.7 Fatigue 1.5 2.4 Influenza 1.5 2.0 NEXLIZET In a 4-arm, 12-week, randomized, double-blind, placebo-controlled, parallel group, factorial trial, 85 patients received NEXLIZET (180 mg of bempedoic acid and 10 mg of ezetimibe) once daily [see Clinical Studies (14.1) ] . The mean age for NEXLIZET-treated patients was 62 years, 51% were female, 78% were White, 19% were Black or African American, 2% were Asian, and 1% were American Indian or Alaska Native; 11% identified as Hispanic or Latino ethnicity. At baseline, 61% of patients had CVD and/or a diagnosis of HeFH. All patients received NEXLIZET plus maximally tolerated statin therapy. Patients taking simvastatin 40 mg/day or higher and patients taking non-statin lipid-lowering therapy (including fibrates, niacin, bile acid sequestrants, ezetimibe, and PCSK9 inhibitors) were excluded from the trial. Adverse reactions led to discontinuation of treatment in 8% of patients on NEXLIZET, 5% of patients on placebo, 10% of patients on bempedoic acid, and 12% of patients on ezetimibe. The most common reason for NEXLIZET treatment discontinuation was oral discomfort (2% NEXLIZET versus 0% placebo). The most commonly reported adverse reactions (incidence ≥ 3% and greater than placebo) observed with NEXLIZET, but not observed in clinical trials of bempedoic acid or ezetimibe, were urinary tract infection (5.9% NEXLIZET versus 2.4% placebo), nasopharyngitis (4.7% NEXLIZET versus 0% placebo), and constipation (4.7% NEXLIZET versus 0% placebo). 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ezetimibe and/or bempedoic acid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood Disorders: thrombocytopenia Gastrointestinal Disorders: abdominal pain; pancreatitis; nausea Hepatobiliary Disorders: elevations in liver transaminases, including elevations more than 5× ULN; hepatitis; cholelithiasis; cholecystitis Immune System Disorders: Hypersensitivity reactions including: anaphylaxis, angioedema, wheezing, rash, and urticaria Musculoskeletal Disorders: elevated creatine phosphokinase; myopathy/rhabdomyolysis Nervous System Disorders: dizziness; paresthesia; depression; headache Skin and Subcutaneous Tissue Disorders: erythema multiforme

8.1 Pregnancy Risk Summary Discontinue NEXLIZET when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. There are insufficient data on bempedoic acid use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are insufficient data on ezetimibe use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction 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 oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of maternal toxicity or embryo-fetal teratogenic or toxicologic effects at exposures up to 10 and 150 times the human exposure, respectively, based on AUC (see Data ) . NEXLIZET decreases cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol; therefore, NEXLIZET may cause fetal harm when administered to pregnant women based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hypercholesterolemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia for most patients. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Report pregnancies to the Esperion Therapeutics, Inc. Adverse Event reporting line at 1-833-377-7633. Data Animal Data Bempedoic acid Bempedoic acid was not teratogenic when given orally at doses of 60 and 80 mg/kg/day, resulting in 11 and 12 times the systemic exposure in humans at the maximum recommended human dose (MRHD) of 180 mg to pregnant rats and rabbits, respectively. In an embryofetal development study in rats, bempedoic acid was given orally to pregnant rats at 10, 30, and 60 mg/kg/day during the period of organogenesis from gestation day 6 to 17. There were increases in the incidence of non-adverse fetal skeletal variations (bent long bones and bent scapula and incomplete ossification) at doses ≥ 10 mg/kg/day (less than the clinical exposure) in the absence of maternal toxicity. At maternally toxic doses, bempedoic acid caused decreases in the numbers of viable fetuses, increases in post-implantation loss, and increased total resorptions at 60 mg/kg/day (11 times MRHD) and reduced fetal body weight at ≥ 30 mg/kg/day (4 times the MRHD). No adverse development effects were observed when bempedoic acid was given to pregnant rabbits during the period of organogenesis (gestation day 6 to 18) at doses up to 80 mg/kg/day (12 times MRHD). In a pre- and post-natal development study in pregnant rats given oral doses of bempedoic acid at 5, 10, 20, 30 and 60 mg/kg/day throughout pregnancy and lactation (gestation day 6 to lactation day 20), there were adverse effects on delivery in the presence of maternal toxicity, including: increases in stillborn pups, reductions in numbers of live pups, pup survival, pup growth and slight delays in learning and memory at ≥ 10 mg/kg/day (at exposures equivalent to the MRHD). Ezetimibe In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats (gestation days 6-15) and rabbits (gestation days 7-19), there was no evidence of maternal toxicity or embryolethal effects at the doses tested (250, 500, 1,000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1,000 mg/kg/day (approximately 10 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1,000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). The animal-to-human exposure multiple for total ezetimibe at the no-observed effect level was 6 times for rat and 134 times for rabbit. Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using a maternal dose of 1,000 mg/kg/day. The fetal maternal plasma exposure ratio (total ezetimibe) was 1.5 for rats on gestation day 20 and 0.03 for rabbits on gestation day 22. The effect of ezetimibe on prenatal and postnatal development and maternal function was evaluated in pregnant rats at doses of 100, 300 or 1,000 mg/kg/day from gestation day 6 through lactation day 21. No maternal toxicity or adverse developmental outcomes were observed up to and including the highest dose tested (17 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis resulted in higher ezetimibe and statin exposures. Reproductive findings occurred at lower doses in combination therapy compared to monotherapy. Bempedoic acid/ezetimibe fixed combination drug product (FCDP) In a combination embryofetal development study in rats, bempedoic acid and ezetimibe were given orally at 4 and 112-times MRHD (based on AUC) during the period of organogenesis (gestation day 6 to 17) in pregnant rats. Bempedoic acid in combination with ezetimibe did not alter the effects on embryo-fetal development profile of bempedoic acid or ezetimibe.