HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NEXLIZET™ safely and effectively. See full prescribing information for
NEXLIZET.
•
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)
NEXLIZET (bempedoic acid and ezetimibe) tablets, for oral use
Initial U.S. Approval: 2020
--------------------------------ADVERSE REACTIONS----------------------------
Most common (incidence ≥2% and greater than placebo) adverse reactions
are 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)
----------------------------INDICATIONS AND USAGE--------------------------
NEXLIZET, which contains an adenosine triphosphate-citrate lyase (ACL)
inhibitor and a cholesterol absorption inhibitor, is indicated as an adjunct to
diet and maximally tolerated statin therapy for the treatment of adults with
heterozygous familial hypercholesterolemia or established atherosclerotic
cardiovascular disease who require additional lowering of LDL-C. (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.
Limitations of Use: The effect of NEXLIZET on cardiovascular morbidity and
mortality has not been determined. (1)
------------------------------DRUG INTERACTIONS------------------------------
•
Simvastatin: Avoid concomitant use of NEXLIZET with simvastatin
great 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)
-----------------------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, 7)
•
•
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Tablets: 180 mg bempedoic acid/10 mg ezetimibe (3)
----------------------USE IN SPECIFIC POPULATIONS------------------------
•
•
Pregnancy: Based on mechanism of action, may cause fetal harm. (8.1)
Lactation: Breastfeeding is not recommended with NEXLIZET. (8.2)
--------------------------------CONTRAINDICATIONS----------------------------
•
Known hypersensitivity to ezetimibe tablets. (4, 6.2)
SEE 17 FOR PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling
REVISED: 02/2020
-----------------------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)
FULL PRESCRIBING INFORMATION: CONTENTS*
1
2
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
8.4
8.5
8.6
8.7
Pediatric Use
Geriatric Use
Renal Impairment
Hepatic Impairment
2.1
2.2
Recommended Dose
Coadministration with Bile Acid Sequestrants
3
4
5
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
10
11
12
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
5.1
5.2
Hyperuricemia
Tendon Rupture
6
ADVERSE REACTIONS
6.1
6.2
DRUG INTERACTIONS
USE IN SPECIFIC POPULATIONS
8.1
8.2
Clinical Trials Experience
Postmarketing Experience
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES
HOW SUPPLIED/STORAGE AND HANDLING
PATIENT COUNSELING INFORMATION
7
8
14
16
17
*Sections or subsections omitted from the full prescribing information
are not listed.
Pregnancy
Lactation
Reference ID: 4567018
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
1
NEXLIZET is indicated as an adjunct to diet and maximally tolerated statin therapy for the
treatment of adults with heterozygous familial hypercholesterolemia or established
atherosclerotic cardiovascular disease who require additional lowering of LDL-C.
Limitations of Use
The effect of NEXLIZET on cardiovascular morbidity and mortality has not been determined.
2
DOSAGE AND ADMINISTRATION
Recommended Dosage
2.1
The recommended dosage of NEXLIZET, in combination with maximally tolerated statin
therapy, 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.
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 bile acid
sequestrants[seeDrug Interactions (7)].
3
DOSAGE FORMS AND STRENGTHS
NEXLIZET is available as:
• Tablets: 180 mg/10 mg, blue, oval shaped, debossed with “818” on one side and “ESP”
on the other side.
4
CONTRAINDICATIONS
NEXLIZET is contraindicated in patients with a known hypersensitivity to ezetimibe tablets [see
Adverse Reactions (6.2)]. Hypersensitivity reactions including anaphylaxis, angioedema, rash
and urticaria have been reported with ezetimibe.
5
WARNINGS AND PRECAUTIONS
Hyperuricemia
5.1
Bempedoic acid, a component of NEXLIZET, inhibits renal tubular OAT2 and may increase
blood uric acid levels[seeClinical Pharmacology (12.3)]. In clinical trials, 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
Reference ID: 4567018
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 and persisted throughout
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.
Elevated blood uric acid may lead to the development of gout. In clinical trials, gout was
reported in 1.5% of patients treated with bempedoic acid versus 0.4% of patients treated with
placebo. The risk for gout events was higher in patients with a prior history of gout (11.2%
bempedoic acid versus 1.7% placebo), although gout also occurred more frequently than placebo
in patients treated with bempedoic acid who had no prior gout history (1.0% bempedoic acid
versus 0.3% 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 clinical trials, 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. 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.
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Hyperuricemia[seeWarnings and Precautions (5.1)]
• Tendon Rupture[seeWarnings and Precautions (5.2)]
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.
Reference ID: 4567018
Bempedoic acid
The data described below reflect exposure to bempedoic acid in two placebo-controlled trials
that included 2009 patients treated with bempedoic acid for 52 weeks (median treatment duration
of 52 weeks)[seeClinical Studies (14)]. The mean age for bempedoic acid-treated patients was
65.4 years, 29% were women, 3% were Hispanic, 95% White, 3% Black, 1% Asian, and 1%
other races. 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 clinical atherosclerotic cardiovascular disease (ASCVD) and about 4% had a
diagnosis of heterozygous familial hypercholesterolemia (HeFH). Patients on simvastatin
40 mg/day or higher were excluded from the 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 ASCVD and HeFH
Bempedoic acid + Statin
and ± Other Lipid Lowering
Therapies
(N = 2009)
%
4.5
3.6
Placebo
(N = 999)
%
4.0
2.3
Adverse Reaction
Upper respiratory tract infection
Muscle spasms
Hyperuricemia
Back pain
a
3.5
3.3
1.1
2.2
Abdominal pain or discomfort
Bronchitis
b
3.1
3.0
2.2
2.5
Pain in extremity
Anemia
3.0
2.8
1.7
1.9
Elevated liver enzymes
c
2.1
0.8
a.
b.
Hyperuricemia includes hyperuricemia and blood uric acid increased.
Abdominal pain or discomfort includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal
discomfort.
c.
Elevated liver enzymes includes AST increased, ALT increased, hepatic enzyme increased, and liver function test increased.
Tendon Rupture
Bempedoic acid was associated with an increased risk of tendon rupture, occurring in 0.5% of
bempedoic acid-treated patients versus 0% of placebo-treated patients.
Gout
Bempedoic acid was associated with an increased risk of gout, occurring in 1.5% of bempedoic
acid-treated patients versus 0.4% of placebo-treated patients.
Reference ID: 4567018
Benign Prostatic Hyperplasia
Bempedoic acid was associated with an increased risk of benign prostatic hyperplasia (BPH) or
prostatomegaly in men with no reported history of BPH, occurring in 1.3% of bempedoic acid-
treated patients versus 0.1% of placebo-treated patients. The clinical significance is unknown.
Atrial Fibrillation
Bempedoic acid was associated with an imbalance in atrial fibrillation, occurring in 1.7% of
bempedoic acid-treated patients versus 1.1% of placebo-treated patients.
Laboratory Tests
Bempedoic acid was associated with persistent changes in multiple laboratory tests within the
first 4 weeks of treatment. Laboratory test values returned to baseline following discontinuation
of treatment.
Increase in Creatinine and Blood Urea Nitrogen: Overall, 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).
Decreased Hemoglobin and Leukocytes: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. Hemoglobin decrease was
generally asymptomatic and did not require medical intervention. Decreased leukocyte count was
also observed. 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 clinical 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.
Increase in Platelet Count:Approximately 10.1% of bempedoic acid-treated patients (versus
9
4.7% placebo) had increases in platelet counts of 100 × 10 /L or more on one or more occasion.
Platelet count increase was asymptomatic, did not result in increased risk for thromboembolic
events, and did not require medical intervention.
Increase in Liver Enzymes: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.
Reference ID: 4567018
Increase in Creatinine Kinase: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, 2396 patients with primary hyperlipidemia
(age range 9-86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) 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 led to discontinuation of treatment in 3.3% of ezetimibe-treated patients and
2.9% of placebo-treated patients. The most common reasons for ezetimibe treatment
discontinuation were arthralgia (0.3%), dizziness (0.2%), and gamma-glutamyltransferase
increased (0.2%). Adverse reactions reported in ≥2% of patients treated with ezetimibe and at an
incidence greater than placebo in placebo-controlled studies of ezetimibe, regardless of causality
assessment, are shown in Table 2.
Table 2. Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe
and at an Incidence Greater than Placebo, Regardless of Causality
Ezetimibe 10 mg
Placebo
(%)
N = 1159
2.5
(%)
n = 2369
4.3
Adverse Reaction
Upper respiratory tract infection
Diarrhea
4.1
3.7
Arthralgia
3.0
2.2
Sinusitis
2.8
2.2
Pain in extremity
Fatigue
2.7
2.4
2.5
1.5
Influenza
2.0
1.5
The frequency of less common adverse reactions was comparable between ezetimibe and
placebo.
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
[seeClinical Studies (14)]. The mean age for NEXLIZET-treated patients was 62 years, 51%
were women, 12% Hispanic, 78% White, 19% Black, and 2% Asian. At baseline, 61% of
patients had clinical atherosclerotic cardiovascular disease (ASCVD) and/or a diagnosis of
heterozygous familial hypercholesterolemia. 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.
Reference ID: 4567018
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
Because these reactions are reported voluntarily from a population of uncertain size, it is
generally not possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
The following additional adverse reactions have been reported in postmarketing experience for
ezetimibe:
Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema
multiforme; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis; elevations in
liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness;
paresthesia; depression; headache; cholelithiasis; cholecystitis.
7
DRUG INTERACTIONS
No specific pharmacokinetic drug interaction studies with NEXLIZET have been conducted.
Drug interactions that have been identified in studies with bempedoic acid or ezetimibe
determine the interactions that may occur with NEXLIZET.
Simvastatin
Concomitant use of NEXLIZET with simvastatin causes an increase in
Clinical Impact:
simvastatin concentration and may increase the risk of simvastatin-related
myopathy[seeClinical Pharmacology (12.3)].
Intervention:
Avoid concomitant use of NEXLIZET with simvastatin greater than 20 mg.
Pravastatin
Concomitant use of NEXLIZET with pravastatin causes an increase in
pravastatin concentration and may increase the risk of pravastatin-related
myopathy[seeClinical Pharmacology (12.3)].
Clinical Impact:
Intervention:
Avoid concomitant use of NEXLIZET with pravastatin greater than 40 mg.
Cyclosporine
Reference ID: 4567018
Clinical Impact:
Intervention:
Concomitant use of NEXLIZET and cyclosporine increases ezetimibe and
cyclosporine concentrations[seeClinical Pharmacology (12.3)].
Monitor cyclosporine concentrations in patients receiving NEXLIZET and
cyclosporine. In patients treated with cyclosporine, the potential effects of
the increased exposure to ezetimibe from concomitant use should be
carefully weighed against the benefits of alterations in lipid levels provided
by NEXLIZET.
Fibrates
Clinical Impact:
Both fenofibrate and ezetimibe may increase cholesterol excretion into the
bile, leading to cholelithiasis. Co-administration of NEXLIZET with
fibrates other than fenofibrate is not recommended.
Intervention:
If cholelithiasis is suspected in a patient receiving NEXLIZET and
fenofibrate, gallbladder studies are indicated and alternative lipid-lowering
therapy should be considered.
Cholestyramine
Clinical Impact:
Concomitant use of NEXLIZET and cholestyramine decreases ezetimibe
concentration. This may result in a reduction of efficacy.
Intervention:
Administer NEXLIZET either at least 2 hours before or at least 4 hours after
bile acid sequestrants[seeDosage and Administration (2.2)].
8
USE IN SPECIFIC POPULATIONS
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 no available 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(seeData). 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[seeClinical Pharmacology (12.1)]. In addition, treatment of
Reference ID: 4567018
hyperlipidemia 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 hyperlipidemia 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.
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) during organogenesis, there was no evidence of maternal
toxicity or embryolethality at any of the doses tested (250, 500, 1000 mg/kg/day) at exposures
equivalent to 10 to 150 times the MRHD, based on AUC, in rats and rabbits. In rats, increased
incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical
vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (approximately 10 times the
human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with
ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day
(150 times the human exposure at 10 mg daily based on AUC0-24hr 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.
Reference ID: 4567018
Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent
placental transfer studies conducted using a maternal dose of 1000 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 1000 mg/kg/day (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
AUC0-24hr for total ezetimibe).
Multiple-dose studies of ezetimibe coadministered with statins in rats and rabbits during
organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur 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.
8.2
Lactation
Risk Summary
There is no information regarding the presence of bempedoic acid in human or animal milk, the
effects of the drug on the breastfed infant, or the effects of the drug on milk production. There is
no information about the presence of ezetimibe in human milk. Ezetimibe is present in rat milk
(seeData). When a drug is present in animal milk, it is likely that the drug will be present in
human milk. There is no information about the effects of ezetimibe on the breastfed infant or the
effects on milk production.
NEXLIZET decreases cholesterol synthesis and possibly the synthesis of other biologically
active substances derived from cholesterol and may cause harm to the breastfed infant. Because
of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of
action, advise patients that breastfeeding is not recommended during treatment with NEXLIZET
[seeUse in Specific Populations (8.1), Clinical Pharmacology (12.1)].
Data
Animal Data
Ezetimibe was present in the milk of lactating rats. The pup to maternal plasma ratio for total
ezetimibe was 0.5 on lactation day 12.
8.4
Pediatric Use
The safety and effectiveness of NEXLIZET have not been established in pediatric patients.
Reference ID: 4567018
8.5
Geriatric Use
Of the 301 patients in the clinical trial of NEXLIZET, 149 (50%) were 65 and over, while 49
(16%) were 75 and over. No overall differences in safety or effectiveness were observed
between these patients and younger patients, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients. However, greater
sensitivity of some older individuals cannot be ruled out.
8.6
Renal Impairment
No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is
limited experience with bempedoic acid in patients with severe renal impairment
2
(eGFR < 30 mL/min/1.73 m ), and bempedoic acid has not been studied in patients with
end-stage renal disease (ESRD) receiving dialysis[seeClinical Pharmacology (12.3)].
8.7
Hepatic Impairment
No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh A) [see
Clinical Pharmacology (12.3)]. NEXLIZET is not recommended in patients with moderate or
severe hepatic impairment (Child-Pugh B or C) due to the unknown effects of the increased
exposure to ezetimibe[seeClinical Pharmacology (12.3)].
10.
OVERDOSAGE
There is no clinical experience with NEXLIZET overdosage. In the event of overdose, contact
Poison Control (1-800-222-1222) for latest recommendations.
11.
DESCRIPTION
NEXLIZET tablets, for oral use, contain bempedoic acid, an adenosine triphosphate-citrate lyase
(ACL) inhibitor, and ezetimibe, a dietary cholesterol absorption inhibitor.
The chemical name for bempedoic acid is 8-hydroxy-2,2,14,14-tetramethyl-pentadecanedioic
acid. The molecular formula is C19H36O5, and the molecular weight is 344.5 grams per mole.
Bempedoic acid is a white to off-white crystalline powder that is highly soluble in ethanol,
isopropanol and pH 8.0 phosphate buffer, and insoluble in water and aqueous solutions below
pH 5.
Structural formula:
Reference ID: 4567018
The chemical name for ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)
hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The molecular formula is C24H21F2NO3
and the molecular weight is 409.4 grams per mole. Ezetimibe is a white, crystalline powder that
is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water.
Structural formula:
Each film-coated tablet of NEXLIZET contains 180 mg of bempedoic acid and 10 mg of
ezetimibe, and the following inactive ingredients: colloidal silicon dioxide, hydroxy propyl
cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone K30,
sodium lauryl sulfate, sodium starch glycolate. The film coating comprises of FD&C Blue
#1/Brilliant Blue FCF Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake,
glyceryl monocaprylocaprate, partially hydrolyzed polyvinyl alcohol, sodium lauryl sulfate, talc,
and titanium dioxide.
12.
CLINICAL PHARMACOLOGY
Mechanism of Action
12.1
NEXLIZET contains bempedoic acid and ezetimibe. NEXLIZET reduces elevated LDL-C
through inhibition of cholesterol synthesis in the liver and absorption in the intestine.
Bempedoic acid
Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers
low-density lipoprotein cholesterol (LDL-C) by inhibition of 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. Inhibition of ACL by ETC-1002-CoA results in decreased cholesterol
synthesis in the liver and lowers LDL-C in blood via upregulation of low-density lipoprotein
receptors.
Ezetimibe
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small
intestine. The molecular target of ezetimibe has been shown to be the sterol transporter,
Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and
phytosterols. Ezetimibe localizes at the brush border of the small intestine and inhibits the
absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the
Reference ID: 4567018
liver. This causes a reduction of hepatic cholesterol stores and an increase in LDL receptors,
resulting in clearance of cholesterol from the blood.
12.2
Pharmacodynamics
Administration of bempedoic acid and ezetimibe in combination with maximally tolerated
statins, with or without other lipid modifying agents, decreases LDL-C, non-high density
lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), and total cholesterol (TC) in
patients with hyperlipidemia.
Cardiac Electrophysiology
A QT trial has been conducted for bempedoic acid. At a dose of 240 mg (1.3 times the approved
recommended dose), bempedoic acid does not prolong the QT interval to any clinically relevant
extent.
The effect of ezetimibe or NEXLIZET on QT interval has not been evaluated.
12.3
Pharmacokinetics
Absorption
NEXLIZET
The bioavailability of NEXLIZET tablets was similar relative to that from the individual tablets,
coadministered. Maximum plasma concentration (Cmax) values for bempedoic acid and its active
metabolite (ESP15228) were similar between formulations, but ezetimibe glucuronide and
ezetimibe Cmax values were approximately 22% and 13% lower, respectively, for NEXLIZET
relative to the individual tablets, coadministered. Given a similar overall extent of ezetimibe
glucuronide and ezetimibe exposure (as measured by AUC), a 22% lower Cmax is unlikely to be
clinically significant.
Bempedoic acid
Following single oral administration of NEXLIZET (180 mg of bempedoic acid and 10 mg of
ezetimibe), mean (±SD) Cmax and AUC of bempedoic acid were 12.6 (± 2.80) µg/mL and 202 (±
43.4) µg.hr/mL, respectively; the median time to maximum concentration (Tmax) was 3.0 hours.
Following multiple-dose administration of bempedoic acid monotherapy, the steady-state
maximum plasma concentration (Cmax) and AUC at 180 mg/day were 20.6 ± 6.1 µg/mL and
289.0 ± 96.4 µg∙h/mL, respectively. Bempedoic acid steady-state pharmacokinetics were
generally linear over a range of > 60 mg to 220 mg (approximately 33% to 122% of the
recommended dosage of 180 mg daily). There were no time-dependent changes in bempedoic
acid pharmacokinetics following repeat administration at the recommended dosage, and
bempedoic acid steady-state was achieved after 7 days. The mean accumulation ratio was
approximately 2.3-fold.
The steady-state Cmax and AUC of the active metabolite (ESP15228) of bempedoic acid were
2.8 ± 0.9 µg/mL and 51.2 ± 17.2 µg∙h/mL, respectively. ESP15228 likely made a minor
contribution to the overall clinical activity of bempedoic acid based on systemic exposure,
relative potency, and pharmacokinetic properties.
Reference ID: 4567018
Ezetimibe
After a single dose of NEXLIZET to fasted adults, mean ± SD ezetimibe Cmax of 3.56 ± 1.90
ng/mL were attained with a median Tmax of 5 hr. Ezetimibe-glucuronide mean Cmax values of
107 ± 46 ng/mL were achieved with a median Tmax of 1 hr. For ezetimibe monotherapy, there
was no substantial deviation from dose proportionality between 5 mg and 20 mg (0.5- to 2-fold
the recommended dosage). The absolute bioavailability of ezetimibe cannot be determined, as
the compound is virtually insoluble in aqueous media suitable for injection.
Effect of Food
NEXLIZET
After the administration of NEXLIZET with a high-fat, high calorie breakfast in healthy
subjects, the AUC for bempedoic acid and ezetimibe were comparable to the fasted state.
Compared to the fasted state, the fed state resulted in 30% and 12% reductions in Cmax
and
2-hour and 2.5-hour delays in median time to attain maximum concentration (Tmax) of bempedoic
acid and ezetimibe, respectively. For ezetimibe glucuronide, a 12% and 42% decrease in AUC
and Cmax, respectively, were observed under fed relative to fasted conditions.
This effect of food is not considered to be clinically meaningful.
Distribution
Bempedoic acid
The bempedoic acid apparent volume of distribution (V/F) was 18 L. Plasma protein binding of
bempedoic acid, its glucuronide and its active metabolite, ESP15228, were 99.3%, 98.8% and
99.2%, respectively. Bempedoic acid does not partition into blood cells.
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins.
Elimination
Bempedoic acid
The steady-state clearance (CL/F) of bempedoic acid was 11.2 mL/min after once-daily dosing;
renal clearance of unchanged bempedoic acid represented less than 2% of total clearance. The
mean ± SD half-life for bempedoic acid in humans was 21 ± 11 hours at steady-state.
Ezetimibe
Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of
approximately 22 hours for both.
Metabolism
Bempedoic acid
The primary route of elimination for bempedoic acid is through metabolism to the acyl
glucuronide. Bempedoic acid is also reversibly converted to an active metabolite (ESP15228)
based on aldo-keto reductase activity observedin vitrofrom human liver. Mean plasma AUC
Reference ID: 4567018
metabolite/parent drug ratio for ESP15228 following repeat-dose administration was 18% and
remained constant over time. Both bempedoic acid and ESP15228 are converted to inactive
glucuronide conjugatesin vitroby UGT2B7. Bempedoic acid, ESP15228 and their respective
conjugated forms were detected in plasma with bempedoic acid accounting for the majority
(46%) of the AUC0-48h and its glucuronide being the next most prevalent (30%). ESP15228 and
its glucuronide represented 10% and 11% of the plasma AUC0-48h, respectively.
Ezetimibe
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation
with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in
all species evaluated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe
glucuronide are the major drug-derived compounds detected in plasma, constituting
approximately 10% to 20% and 80% to 90% of the total drug in plasma, respectively. Plasma
concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Excretion
Bempedoic acid
Following single oral administration of 240 mg of bempedoic acid (1.3 times the approved
recommended dose), approximately 70% of the total dose (bempedoic acid and its metabolites)
was recovered in urine, primarily as the acyl glucuronide conjugate of bempedoic acid, and
approximately 30% was recovered in feces. Less than 5% of the administered dose was excreted
as unchanged bempedoic acid in feces and urine combined.
Ezetimibe
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe
(ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity
in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the
feces and urine, respectively, over a 10-day collection period. After 48 hours, there were no
detectable levels of radioactivity in the plasma.
Ezetimibe was the major component in feces, and accounted for 69% of the administered dose,
while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the
administered dose.
Specific Populations
Patients with Renal Impairment
Bempedoic acid
Pharmacokinetics of bempedoic acid was evaluated in a single-dose pharmacokinetic study in
subjects with varying degrees of renal function. The mean bempedoic acid AUC in subjects with
mild renal impairment (n = 8) were 1.5-fold higher compared to those with normal renal function
(n = 6). Relative to those with normal renal function, mean bempedoic acid AUCs were higher
in patients with moderate (n = 5) or severe (n = 5) renal impairment by 2.3-fold and 2.4-fold,
respectively.
Reference ID: 4567018
A population pharmacokinetic analysis was performed on pooled data from all clinical trials
(n = 2261) to further evaluate the effects of renal function on the steady-state AUC of bempedoic
acid. Compared to patients with normal renal function, the mean bempedoic acid exposures
were higher in patients with mild or moderate renal impairment by 1.4-fold (90% CI: 1.3, 1.4)
and 1.9-fold (90% CI: 1.7, 2.0), respectively. These differences were not clinically significant.
Clinical studies of bempedoic acid did not include patients with severe renal impairment
(eGFR < 30 mL/min/1.73 m ) or patients with ESRD on dialysis[seeUse in Specific
2
Populations (8.6)].
Ezetimibe
After a single 10 mg dose of ezetimibe in patients with severe renal disease (n = 8; mean
CrCl ≤ 30 mL/min/1.73 m ), the mean AUC for total ezetimibe, ezetimibe-glucuronide, and
2
ezetimibe increased approximately 1.5-fold, compared to healthy subjects (n = 9). No dosage
adjustment is necessary for the ezetimibe component. However, there is limited experience with
bempedoic acid in patients with severe renal impairment [seeUse in Specific Populations (8.6)].
Patients with Hepatic Impairment
NEXLIZET is not recommended in patients with moderate or severe hepatic impairment due to
the unknown effects of the increased exposure to ezetimibe [seeUse in Specific Populations
(8.7)].
Bempedoic acid
The pharmacokinetics of bempedoic acid and its metabolite (ESP15228) was studied in patients
with normal hepatic function or mild or moderate hepatic impairment (Child-Pugh A or B)
following a single dose (n = 8/group). Compared to patients with normal hepatic function, the
bempedoic acid mean Cmax and AUC were decreased by 11% and 22%, respectively, in patients
with mild hepatic impairment and by 14% and 16%, respectively, in patients with moderate
hepatic impairment. Compared to patients with normal hepatic function, the ESP15228 mean
Cmax and AUC were decreased by 13% and 23%, respectively, in patients with mild hepatic
impairment and by 24% and 36%, respectively, in patients with moderate hepatic impairment.
This is not expected to result in lower efficacy.
Bempedoic acid was not studied in patients with severe hepatic impairment (Child Pugh C).
Ezetimibe
After a single 10 mg dose of ezetimibe, the mean AUC for total ezetimibe increased
approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh A), compared to
healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased
approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate
(Child-Pugh B) or severe hepatic impairment (Child-Pugh C). In a 14-day, multiple-dose study
(10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe
and ezetimibe increased approximately 4-fold on Day 1 and Day 14 compared to healthy
subjects.
Reference ID: 4567018
Other Specific Populations
Bempedoic acid
The pharmacokinetics of bempedoic acid were not affected by age, gender, race, or weight.
Ezetimibe
Geriatrics: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma
concentrations for total ezetimibe were about 2-fold higher in older (≥ 65 years) healthy subjects
compared to younger subjects[seeUse in Specific Populations (8.5)].
Gender: In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma
concentrations for total ezetimibe were slightly higher (< 20%) in women than in men.
Race: The pharmacokinetics of ezetimibe is not affected by race.
Drug Interaction Studies
Bempedoic acid
Cytochrome P450 Substrates
In vitrometabolic interaction studies suggest that bempedoic acid, as well as its active metabolite
and glucuronide forms are not metabolized by and do not interact with cytochrome P450
enzymes.
Transporter-mediated Drug Interactions
In vitrodrug interaction studies suggest bempedoic acid, as well as its active metabolite and
glucuronide form, are not substrates of commonly characterized drug transporters with the
exception of bempedoic acid glucuronide, which is an OAT3 substrate. Bempedoic acid weakly
inhibits OAT3 at high multiples of clinically relevant concentrations, and bempedoic acid and its
glucuronide weakly inhibit OATP1B1, and OATP1B3 at clinically relevant concentrations.
Bempedoic acid weakly inhibits OAT2in vitro, which is likely the mechanism responsible for
minor elevations in serum creatinine and uric acid[seeAdverse Reactions (6.1)].
Probenecid
Administration of bempedoic acid 180 mg with steady-state probenecid resulted in a 1.7- and a
1.2-fold increase in bempedoic acid AUC and Cmax, respectively. AUC and Cmax for bempedoic
acid active metabolite (ESP15228) were increased 1.9- and 1.5-fold, respectively. These
elevations are not clinically meaningful and do not impact dosing recommendations.
Statins
The pharmacokinetic interactions between bempedoic acid (at systemic exposure relevant to the
indicated ASCVD population) and simvastatin 20 mg, atorvastatin 10 mg, pravastatin 40 mg, and
rosuvastatin 10 mg were evaluated in clinical trials.
Simvastatin: Administration of simvastatin 20 mg with 240 mg of bempedoic acid or 40 mg with
180 mg of bempedoic acid in healthy subjects at steady-state resulted in approximately 2-fold
(91% for 20 mg and 96% for 40 mg) and 1.5-fold (54% for 20 mg and 52% for 40 mg) increases
in simvastatin acid AUC and Cmax, respectively[seeDrug Interactions (7)].
Reference ID: 4567018
Pravastatin: Administration of pravastatin 40 mg with steady-state bempedoic acid 240 mg in
healthy subjects resulted in 99% (2-fold) and 104% (2-fold) increases in pravastatin acid AUC
and Cmax, respectively[seeDrug Interactions (7)].
Atorvastatin and Rosuvastatin: Elevations of 1.7-fold in AUC of atorvastatin, and rosuvastatin
and/or their major metabolites were observed, suggesting a weak interaction. These elevations
were generally within the individual statin exposures and do not impact dosing
recommendations.
Warfarin
In vitrostudies indicate that bempedoic acid is not an inhibitor or inducer of CYP2C9. Because
warfarin is primarily eliminated through CYP2C9, its pharmacokinetics is not expected to be
altered by bempedoic acid.
Other
Bempedoic acid had no effect on the pharmacokinetics of metformin or the oral contraceptive
Ortho-Novum 1/35.
Ezetimibe
Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan,
tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6,
2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that
ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is
unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these
enzymes.
Cyclosporine: Administration of ezetimibe with cyclosporine (75–150 mg BID) resulted in a 2.4
and a 2.9-fold increase in total ezetimibe AUC and Cmax, respectively[see Drug Interactions
(7)].
Fibrates: Administration of ezetimibe with fenofibrate (200 mg QD for 14 days) resulted in a
1.48- and a 1.64-fold increase in total ezetimibe AUC and Cmax, respectively. Administration
with gemfibrozil (600 mg BID for 7 days) resulted in a 1.64- and 1.91-fold increase in total
ezetimibe AUC and Cmax, respectively[see Drug Interactions (7)].
Cholestyramine: Administration of ezetimibe with cholestyramine (4 g BID for 14 days) resulted
in a 55% and a 4% decrease in total ezetimibe AUC and Cmax, respectively[see Drug
Interactions (7)].
No clinically meaningful pharmacokinetic interaction was observed following co-administration
of ezetimibe with aluminum & magnesium hydroxide combination antacid, cimetidine, glipizide,
lovastatin, pravastatin, atorvastatin, rosuvastatin, fluvastatin, simvastatin, digoxin, ethyl
estradiol/levonorgestrel, and warfarin.
Reference ID: 4567018
13.
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Bempedoic acid
Bempedoic acid was negative for mutagenicity in an in vitro Ames assay and negative for
clastogenicity in the vitro human lymphocyte chromosome aberration assay. Bempedoic acid
was negative in both in vivo mouse micronucleus and in vivo rat bone marrow
micronucleus/liver comet assay. In a 2-year rat carcinogenicity study, Wistar rats were given
oral doses of bempedoic acid at 3, 10 and 30 mg/kg/day. An increased incidence of liver
hepatocellular adenomas and hepatocellular adenomas combined with carcinomas, thyroid gland
follicular cell adenoma and follicular cell adenomas combined with carcinomas, and pancreatic
islet cell adenomas combined with carcinomas were observed in male rats at the dose of
30 mg/kg/day (exposure equivalent to the maximum recommended human dose (MRHD), based
on AUC). In a 2-year mice carcinogenicity study, CD-1 mice were given oral doses of
bempedoic acid at 25, 75 and 150 mg/kg/day. Bempedoic acid-related increases in the incidence
of liver hepatocellular adenomas, hepatocellular carcinomas and hepatocellular adenomas
combined with carcinomas in male mice were observed at 75 and 150 mg/kg/day (exposures
equivalent to the MRHD). Observations of liver and thyroid tumors are consistent with PPAR
alpha agonism in rodents. The human relevance of pancreatic islet cell tumor findings is
unknown.
In fertility and early embryofetal development study in rats, bempedoic acid was given orally to
male and female rats at 10, 30 and 60 mg/kg/day. Males were dosed for 28 days prior to mating
and females were dosed 14 days prior to mating through gestation day 7. No adverse effects on
fertility were observed in females in the absence of maternal toxicity. No effects were observed
on male fertility outcomes, but decreases in sperm counts were observed at 60 mg/kg/day
(9 times the MRHD).
Ezetimibe
A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to
1500 mg/kg/day (males) and 500 mg/kg/day (females) (approximately 20 times the human
exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary
carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day
(>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There
were no statistically significant increases in tumor incidences in drug-treated rats or mice.
No evidence of mutagenicity was observedin vitroin a microbial mutagenicity (Ames) test with
Salmonella typhimuriumandEscherichia coliwith or without metabolic activation. No evidence
of clastogenicity was observedin vitroin a chromosomal aberration assay in human peripheral
blood lymphocytes with or without metabolic activation. In addition, there was no evidence of
genotoxicity in thein vivomouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of
reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (approximately
7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).
Reference ID: 4567018
14.
CLINICAL STUDIES
The efficacy of NEXLIZET was investigated in a single, multi-center, randomized, double-blind,
placebo-controlled, parallel group trial that enrolled 301 patients with heterozygous familial
hypercholesterolemia, established atherosclerotic cardiovascular disease, or multiple risk factors
for cardiovascular disease on maximally tolerated statin therapy. The efficacy of NEXLIZET in
patients with multiple risk factors for cardiovascular disease has not been established.
Study 1 (NCT03337308) was a 4-arm, 12-week trial that assessed the efficacy of NEXLIZET in
301 patients randomized 2:2:2:1 to receive either NEXLIZET (180 mg of bempedoic acid and
10 mg of ezetimibe) (n = 86), bempedoic acid 180 mg (n = 88), ezetimibe 10 mg (n = 86), or
placebo (n = 41) once daily as add-on to maximally tolerated statin therapy. Patients were
stratified by cardiovascular risk and baseline statin intensity. Patients on simvastatin 40 mg per
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.
Overall, the mean age at baseline was 64 years (range: 30 to 87 years), 50% were ≥ 65 years old,
50% were women, 12% Hispanic, 81% White, 17% Black, and 1% Asian. Sixty-two percent
(62%) of patients had clinical atherosclerotic cardiovascular disease (ASCVD) and/or a
diagnosis of heterozygous familial hypercholesterolemia (HeFH). The mean baseline LDL-C
was 149.7 mg/dL. At the time of randomization, 65% of patients were receiving statin therapy;
and 35% were receiving high intensity statin therapy.
The primary efficacy outcome measure of the study was the percent change from baseline to
Week 12 in LDL-C. The difference between NEXLIZET and placebo in mean percent change in
LDL-C from baseline to Week 12 was -38% (95% CI: -47%, -30%; p < 0.001). High-density
lipoprotein (HDL) and triglycerides (TG) were examined as exploratory endpoints and were not
included in the statistical hierarchy. The difference between NEXLIZET and placebo in mean
percent change from baseline to Week 12 was -5% for HDL and median percent change from
baseline to Week 12 was -11% for TG. The maximum LDL-C lowering effect was observed at
Week 4. For additional results see Table 3.
Table 3. Effects of NEXLIZET on Lipid Parameters in Patients on Maximally Tolerated
Statin Therapy (Mean % Change from Baseline to Week 12 in Study 1)
a
LDL-C
LS Mean
non-HDL-C
LS Mean
apo B
LS Mean
TC
LS Mean
NEXLIZET
(180 mg/10 mg; n = 86 )
-36
-32
-25
-26
b
Bempedoic acid
-17
-14
-12
-12
(180 mg; n = 88 )
b
Ezetimibe
b
(10 mg; n = 86 )
-23
2
-20
2
-15
6
-16
1
Placebo
(n = 41 )
b
Mean Difference of
-38 (-47, -30)
-34 (-44, -23)
-30 (-40, -20)
-27 (-35, -19)
NEXLIZET versus Placebo
(95% CI)
Reference ID: 4567018
apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol;
LS = least squares; SE = standard error; TC = total cholesterol.
Background statin: atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin.
a.
3.5% of subjects on NEXLIZET, 6.8% of subjects on bempedoic acid, 7% of subjects on ezetimibe and 2.4% of subjects
on placebo had missing LDL-C data at Week 12. Percent change from baseline was analyzed using analysis of covariance
(ANCOVA), with treatment and randomization strata (high intensity statin versus other and (ASCVD and/or HeFH versus
multiple CV risk factors) as factors and baseline lipid parameter as a covariate. Missing data for LDL-C, non-HDL-C, TC
and apo B were imputed through multiple imputation using a pattern mixture model (PMM) account for treatment
adherence.
b.
Number of randomized subjects at baseline
Examination of age, gender, and race subgroups did not identify differences in response to
NEXLIZET among these subgroups in any of the trials.
Bempedoic Acid
In two 52-week trials that included 3009 adult patients with heterozygous familial
hypercholesterolemia or established atherosclerotic cardiovascular disease on maximally
tolerated statin therapy, the difference between bempedoic acid and placebo in mean percent
change in LDL-C from baseline to Week 12 was -17% to -18%. Bempedoic acid also
significantly lowered non-HDL-C (-13%), apo B (-12% to -13%), and TC (-11%) compared with
placebo.
Ezetimibe
Ezetimibe Added to On-going Statin Therapy: In a multicenter, double-blind, placebo-controlled,
8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or
multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had
not met their NCEP ATP II target LDL-C goal, were randomized to receive either ezetimibe or
placebo in addition to their on-going statin therapy.
Ezetimibe, added to on-going statin therapy, significantly lowered TC (-17%), LDL-C (-25%),
apo B (-19%), non-HDL-C (-23%), and TG (-14%), and increased HDL-C (+3%) relative to
baseline and compared with a statin administered alone. LDL-C reductions induced by ezetimibe
were generally consistent across all statins.
Ezetimibe Initiated Concurrently with a Statin: In four, multicenter, double-blind, placebo-
controlled, 12-week trials, in 2382 hyperlipidemic patients, ezetimibe or placebo was
administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.
When all patients receiving ezetimibe with a statin were compared to all those receiving the
corresponding statin alone, ezetimibe significantly lowered LDL-C (ezetimibe + all atorvastatin
doses [-56%] versus all atorvastatin doses alone [-44%]; ezetimibe + all simvastatin doses [
51%] versus all simvastatin doses alone [-36%]; ezetimibe + all pravastatin doses [-39%] versus
all pravastatin doses alone [-25%]; ezetimibe + all lovastatin doses [-40%] versus all lovastatin
doses alone [-25%]). LDL-C reductions induced by ezetimibe were generally consistent across
all statins.
Reference ID: 4567018
16.
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
NEXLIZET (bempedoic acid and ezetimibe) tablets are supplied as follows:
Tablet Strength
Description
Package Configuration
NDC No.
blue, oval shaped,
debossed with “818” on
one side and “ESP” on the
other side
Bottle of 30 tablets with
child-resistant cap
72426-818-03
180 mg of bempedoic
acid and 10 mg of
ezetimibe
Bottle of 90 tablets with
child-resistant cap
72426-818-09
Storage and Handling
Store at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see
USP Controlled Room Temperature]. Store and dispense in the original package protected from
extreme heat and humidity. Do not discard desiccant.
17.
PATIENT COUNSELING INFORMATION
Advise patients to read the FDA-approved patient labeling.
Risk of Hyperuricemia
Advise patients of the risk of elevated serum uric acid levels, including development of gout.
Inform patients that serum uric acid levels may be monitored during treatment with NEXLIZET.
Patients with signs or symptoms of hyperuricemia should contact their healthcare provider if
symptoms occur[SeeWarnings and Precautions (5.2)]
Risk of Tendon Rupture
Inform patients of the risk of tendon rupture. Advise patients to rest at the first sign of tendinitis
or tendon rupture and to immediately contact their healthcare provider if tendinitis or tendon
rupture symptoms occur[seeWarnings and Precautions (5.3)].
Risk of Myopathy with Concomitant Use of Simvastatin or Pravastatin
Advise patients to notify their healthcare provider(s) if they are taking, or plan to take
simvastatin or pravastatin. The risk of myopathy occurring with the use of simvastatin or
pravastatin may be increased when taken with NEXLIZET.[seeDrug Interactions (7)].
Pregnancy
Advise pregnant women of the potential risk to a fetus based on NEXLIZET’s mechanism of
action. Advise females to inform their healthcare provider of a known or suspected pregnancy
[seeUse in Specific Populations (8.1)].
Manufactured by:
Piramal Pharma Solutions
(Piramal Enterprises Limited)
Reference ID: 4567018
Madhya Pradesh 454 775 India
Manufactured for:
Esperion Therapeutics, Inc.
3891 Ranchero Drive, Suite 150
Ann Arbor, MI 48108
NEXLIZET
TM
(bempedoic acid and ezetimibe)
© 2020 Esperion Therapeutics, Inc.
Reference ID: 4567018
Patient Information
NEXLIZET
TM
(NEX-lee-zet)
(bempedoic acid and ezetimibe)
tablets, for oral use
What is NEXLIZET?
NEXLIZET is a prescription medicine that contains 2 cholesterol lowering medicines, bempedoic acid
and ezetimibe. NEXLIZET is used along with diet and other lipid-lowering medicines in the treatment
of adults with:
• heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited condition that causes high
levels of “bad” cholesterol called low density lipoprotein (LDL).
• known heart disease who need additional lowering of “bad” cholesterol (LDL-C) levels.
It is not known if NEXLIZET can decrease problems from high cholesterol, such as heart attacks,
stroke, death, or other heart problems.
It is not known if NEXLIZET is safe and effective in people with severe kidney problems including
people with end-stage kidney disease who are on dialysis.
It is not known if NEXLIZET is safe and effective in people with moderate to severe liver problems.
It is not known if NEXLIZET is safe and effective in children under 18 years of age.
Do not take NEXLIZET if you are allergic to ezetimibe tablets. Ezetimibe, one of the active
ingredients in NEXLIZET, can cause serious allergic reactions such as anaphylaxis, angioedema,
rash, and urticaria. Stop taking NEXLIZET, call your healthcare provider or go to the nearest
hospital emergency room right away if you have any signs or symptoms of an allergic reaction
including:
•
•
•
•
swelling of your face, lips, mouth or tongue
wheezing
severe itching
•
•
•
trouble breathing
skin rashes, redness, or swelling
dizziness or fainting
fast heart beat or pounding in your chest
See the end of this leaflet for a complete list of ingredients in NEXLIZET.
Before you start taking NEXLIZET, tell your healthcare provider about all your medical
conditions, including if you:
•
•
•
have or had gout.
have or had tendon problems.
are pregnant or think you may be pregnant. Tell your healthcare provider right away if you become
pregnant while taking NEXLIZET. You and your healthcare provider will decide if you should take
NEXLIZET while you are pregnant.
•
are breastfeeding or plan to breastfeed. It is not known if NEXLIZET passes into your breast milk.
You and your healthcare provider should decide if you will take NEXLIZET or breastfeed. You
should not do both.
•
•
have severe kidney problems.
have moderate or severe liver problems.
NEXLIZET may affect the way other medicines work, and other medicines may affect how NEXLIZET
works. Tell your healthcare provider about all the medicines you take, including prescription
and over-the-counter medicines, vitamins, and herbal supplements.
Especially tell your healthcare provider if you take or plan to take:
•
simvastatin or pravastatin (other cholesterol lowering medicines). Taking simvastatin or pravastatin
with NEXLIZET may increase your risk of developing muscle pain or weakness (myopathy).
cyclosporine (often used in organ transplant patients)
fibrates (used to lower cholesterol)
cholestyramine (used to lower cholesterol)
•
•
•
Reference ID: 4567018
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist
when you get a new medicine.
How should I take NEXLIZET?
•
Take NEXLIZET exactly as your healthcare provider tells you to take it. Check with your healthcare
provider or pharmacist if you are not sure.
•
•
•
•
Take 1 NEXLIZET tablet by mouth each day.
Swallow the NEXLIZET tablet whole. Do not cut, chew, or crush the tablet.
You may take NEXLIZET with or without food.
If you take a medicine that lowers cholesterol by binding bile acids, such as colesevelam or
cholestyramine, take NEXLIZET at least 2 hours before or 4 hours after you take bile acid binding
medicines. Ask your healthcare provider if you are not sure if you take these medicines.
If you take too much NEXLIZET, call your poison control center at 1-800-222-1222 or go to the
nearest hospital emergency room right away.
•
What are possible side effects of NEXLIZET?
NEXLIZET may cause serious side effects, including:
•
increased levels of uric acid in your blood (hyperuricemia). This can happen within 4 weeks of
you starting NEXLIZET and continue throughout your treatment. Your healthcare provider may
monitor your blood uric acid levels while you are taking NEXLIZET. High levels of blood uric acid
may lead to gout. Call your healthcare provider if you have the following symptoms of
hyperuricemia and gout:
o severe foot pain especially in the toe joint
o warm joints
o tender joints
o joint redness
o swelling
Gout may happen more in people who have had gout before but also can happen in people who
have never had it before.
•
tendon rupture or injury. Tendon problems can happen in people who take bempedoic acid,
one of the medicines in NEXLIZET. Tendons are tough cords of tissue that connect muscles to
bones. Symptoms of tendon problems may include pain, swelling, tears, and inflammation of
tendons including the arm, shoulder, and back of the ankle (Achilles).
o Tendon rupture can happen while you are taking NEXLIZET. Tendon ruptures can happen
within weeks or months of starting NEXLIZET.
o The risk of getting tendon problems while you take NEXLIZET is higher if you:
. are over 60 years of age
. are taking antibiotics (fluoroquinolones)
. have had tendon problems
. are taking steroids (corticosteroids)
. have renal failure
o Stop taking NEXLIZET immediately and get medical help right away if you get any of the
following signs or symptoms of a tendon rupture:
. hear or feel a snap or pop in a tendon area
. bruising right after an injury in a tendon area
. unable to move the affected area or put weight on the affected area
Stop taking NEXLIZET until tendon rupture has been ruled out by your healthcare provider.
The most common areas of pain and swelling are the rotator cuff (the shoulder), the biceps
tendon (upper arm), and the Achilles tendon at the back of the ankle. This can happen with
other tendons.
o Talk to your healthcare provider about the risk of tendon rupture with continued use of
NEXLIZET. You may need a different lipid-lowering medicine to treat your cholesterol levels.
The most common side effects of NEXLIZET include:
o symptoms of the common cold, flu, or flu-like o muscle spasms
symptoms
o back pain
o bronchitis
o anemia
o stomach pain
o pain in shoulder, legs, or arms
o increased liver enzymes
o fatigue
o diarrhea
Reference ID: 4567018
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of NEXLIZET. Ask your healthcare provider or pharmacist for
more information.
Call your healthcare provider for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store NEXLIZET?
•
Store NEXLIZET in the original package at room temperature between 68ºF to 77ºF (20ºC to
25ºC).
•
•
•
Protect from heat and moisture.
Do not throw away the packet that helps to keep your medicine dry (desiccant).
NEXLIZET comes in a bottle with a child-resistant cap.
Keep NEXLIZET and all medicines out of the reach of children.
General information about the safe and effective use of NEXLIZET.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use NEXLIZET for a condition for which it was not prescribed. Do not give NEXLIZET
to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about NEXLIZET that is written for
healthcare professionals.
What are the ingredients in NEXLIZET?
•
•
Active Ingredients: bempedoic acid and ezetimibe
Inactive Ingredients: colloidal silicon dioxide, hydroxy propyl cellulose, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, povidone K30, sodium lauryl sulfate, sodium starch
glycolate
•
Tablet coating: FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Blue #2/Indigo Carmine
Aluminum Lake, glyceryl monocaprylocaprate, partially hydrolyzed polyvinyl alcohol, sodium lauryl
sulfate, talc, and titanium dioxide
Manufactured by:
Piramal Healthcare UK Limited
Northumberland NE61 3YA
United Kingdom
Manufactured for:
Esperion Therapeutics, Inc.
3891 Ranchero Drive, Suite 150
Ann Arbor, MI 48108
© 2020 Esperion Therapeutics, Inc.
This Patient Package Insert has been approved by the U.S. Food and Drug Administration
Revised: 02/2020
Reference ID: 4567018
