Nexlizet

NEXLIZET- bempedoic acid and ezetimibe tablet, film coated
Esperion Therapeutics, Inc.

1 INDICATIONS AND USAGE

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

2.1 Recommended Dosage

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 [see Drug 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

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 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 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:

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 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) [see Clinical 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
Adverse Reaction Bempedoic acid + Statin and ± Other Lipid Lowering Therapies (N = 2009) % Placebo (N = 999) %
*
Hyperuricemia includes hyperuricemia and blood uric acid increased.
Abdominal pain or discomfort includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
Elevated liver enzymes includes AST increased, ALT increased, hepatic enzyme increased, and liver function test increased.
Upper respiratory tract infection 4.5 4.0
Muscle spasms 3.6 2.3
Hyperuricemia * 3.5 1.1
Back pain 3.3 2.2
Abdominal pain or discomfort 3.1 2.2
Bronchitis 3.0 2.5
Pain in extremity 3.0 1.7
Anemia 2.8 1.9
Elevated liver enzymes 2.1 0.8

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.

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 4.7% placebo) had increases in platelet counts of 100× 109 /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.

Increase in Creatine 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
Adverse Reaction Ezetimibe 10 mg(%)N = 2396 Placebo(%)N = 1159
Upper respiratory tract infection 4.3 2.5
Diarrhea 4.1 3.7
Arthralgia 3.0 2.2
Sinusitis 2.8 2.2
Pain in extremity 2.7 2.5
Fatigue 2.4 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 [see Clinical 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.

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).

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