Lifelaza

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIFELIZA (LIFELEZA)

Composition:

Active substances: bempedoic acid, ezetimibe;

One film-coated tablet contains 180 mg of bempedoic acid and 10 mg of ezetimibe;

Excipients: lactose monohydrate; microcrystalline cellulose (type 102); sodium starch glycolate (type A); povidone K30; sodium lauryl sulfate; low-substituted hydroxypropyl cellulose; magnesium aluminum metasilicate (type A); magnesium stearate; film coating (Opadry AMB II 88A505030: polyvinyl alcohol, talc, titanium dioxide (E 171), indigo carmine aluminum lake (E 132), glycerol monocaprylocaprate, sodium lauryl sulfate, brilliant blue FCF aluminum lake (E 133)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, blue-colored tablets, with "B7E" embossed on one side.

Pharmacotherapeutic group

Cardiovascular system agents. Combined lipid-lowering agents. Bempedoic acid and ezetimibe. ATC code: C10BA10.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

The medicinal product contains bempedoic acid and ezetimibe, two compounds that lower LDL-C levels with complementary mechanisms of action. It reduces elevated LDL-C levels through dual inhibition of cholesterol synthesis in the liver and cholesterol absorption in the intestine.

Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase (ACL), which lowers LDL-C by inhibiting cholesterol synthesis in the liver. ACL is an enzyme that precedes 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Bempedoic acid requires activation by coenzyme A (CoA) via very long-chain acyl-CoA synthetase 1 (ACSVL1) to form ETC-1002-CoA. ACSVL1 is expressed predominantly in the liver, not in skeletal muscle. Inhibition of ACL by ETC-1002-CoA leads to reduced cholesterol synthesis in the liver and lowers circulating LDL-C levels by upregulating low-density lipoprotein receptors. Additionally, inhibition of ACL by ETC-1002-CoA results in concomitant suppression of hepatic fatty acid biosynthesis. Ezetimibe lowers blood cholesterol levels by inhibiting its absorption in the small intestine. The molecular target of ezetimibe is the Niemann-Pick C1-like 1 (NPC1L1) sterol transporter, which is involved in intestinal uptake of cholesterol and phytosterols. Ezetimibe localizes to the brush border of the small intestine and inhibits cholesterol absorption, thereby reducing intestinal cholesterol delivery to the liver.

Pharmacodynamic Effects

Administration of bempedoic acid and ezetimibe, alone and in combination with other lipid-modifying medicinal products, reduces levels of LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), total cholesterol (TC), and C-reactive protein (CRP) in patients with hypercholesterolemia or mixed dyslipidemia.

Because patients with diabetes have an increased risk of developing atherosclerotic cardiovascular disease, clinical trials of bempedoic acid included patients with diabetes. In the subgroup of patients with diabetes, lower levels of glycated hemoglobin A1c (HbA1c) were observed compared to placebo (mean reduction of 0.2%). In patients without diabetes, no difference in HbA1c was observed between bempedoic acid and placebo, and there was no difference in the frequency of hypoglycemia.

Cardiac Electrophysiology

At a dose of 240 mg (1.3 times the approved recommended dose), bempedoic acid does not prolong the QT interval to a clinically significant extent.

The effect of ezetimibe or the combination treatment with bempedoic acid/ezetimibe on the QT interval has not been evaluated.

Clinical Efficacy and Safety

The reduction of cardiovascular events by ezetimibe 10 mg has been demonstrated. Clinical Efficacy and Safety in Primary Hypercholesterolemia and Mixed Dyslipidemia

The efficacy of the medicinal product was evaluated in a sensitivity analysis involving 301 patients receiving treatment in the CLEAR Combo study (study 1002-053). This analysis excluded all data from 3 sites (81 patients) due to systematic non-adherence of patients to all 4 treatment regimens. The study was a 4-arm, multicenter, randomized, double-blind, parallel-group, 12-week trial involving patients at high cardiovascular risk and with hyperlipidemia. Patients were randomized in a 2:2:2:1 ratio to receive either the medicinal product orally at a dose of 180 mg/10 mg once daily (n=86), bempedoic acid 180 mg once daily (n=88), ezetimibe 10 mg once daily (n=86), or placebo once daily (n=41), as an add-on to maximally tolerated statin therapy. Maximally tolerated statin therapy could include statin regimens different from daily dosing or no statin use. Patients were stratified by cardiovascular risk and baseline statin intensity. Patients taking simvastatin 40 mg daily or higher were excluded from the study. Demographic and disease characteristics at baseline were balanced across treatment groups. Overall, the mean age at baseline was 64 years (range: 30 to 87 years), 50% were aged ≥65 years, 50% were female, 81% were White, 17% Black, 1% Asian, and 1% other. At randomization, 61% of patients receiving bempedoic acid/ezetimibe, 69% receiving bempedoic acid, 63% receiving ezetimibe, and 66% receiving placebo were on statin therapy; 36% of patients receiving bempedoic acid/ezetimibe, 35% receiving bempedoic acid, 29% receiving ezetimibe, and 41% receiving placebo were on high-intensity statin therapy. The mean baseline LDL-C level was 3.9 mmol/L (149.7 mg/dL). The majority of patients (94%) completed the study.

The medicinal product significantly reduced LDL-C levels from baseline to week 12 compared to placebo (-38%; 95% CI: -46.5%, -29.6%; p <0.001). The maximum LDL-C lowering effect was observed as early as week 4, and efficacy was maintained throughout the study. The medicinal product also significantly reduced non-HDL-C, apolipoprotein B, and total cholesterol levels (see Table 1).

Table 1

Effect of the medicinal product on lipid parameters in patients with high cardiovascular risk and hyperlipidemia on background statin therapy (mean % change from baseline to week 12)

apo B = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol; LS = least squares; TC = total cholesterol.

Background statins: atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin.

Initiation of bempedoic acid on a background of ezetimibe therapy

CLEAR Tranquility (study 1002-048) was a multicenter, randomized, double-blind, placebo-controlled, 12-week Phase 3 study evaluating the efficacy of bempedoic acid versus placebo in lowering LDL-C when added to ezetimibe in patients with elevated LDL-C who had a history of statin intolerance and were unable to tolerate more than the lowest approved starting dose of a statin. The study enrolled 269 patients randomized in a 2:1 ratio to receive bempedoic acid (n=181) or placebo (n=88) as an add-on to ezetimibe 10 mg daily for 12 weeks. Overall, the mean age at baseline was 64 years (range: 30 to 86 years), 55% were aged ≥65 years, 61% were female, 89% were White, 8% were Black, 2% were Asian, and 1% were other. The mean baseline LDL-C level was 3.3 mmol/L (127.6 mg/dL). At randomization, 33% of patients receiving bempedoic acid versus 28% of those receiving placebo were receiving statins at doses less than or equal to the lowest approved. Initiation of bempedoic acid in patients on background ezetimibe therapy significantly reduced LDL-C from baseline to Week 12 compared to placebo with ezetimibe (p <0.001). Initiation of bempedoic acid with background ezetimibe therapy also significantly reduced non-HDL-C, apo B, and TC.

Clinical efficacy and safety in the prevention of cardiovascular events
The CLEAR Outcomes study (study 1002-043) was a multicenter, randomized, double-blind, placebo-controlled, event-driven trial involving 13,970 adult patients with established atherosclerotic cardiovascular disease (CVD) (70%) or at high risk for atherosclerotic CVD (30%). Patients with established CVD had a documented history of ischemic heart disease, symptomatic peripheral artery disease, and/or cerebrovascular atherosclerotic disease. Patients without established CVD were considered to be at high risk for CVD based on meeting at least one of the following criteria: (1) diabetes mellitus (type 1 or 2) in women aged ≥65 years or men aged ≥60 years, or (2) a Reynolds Risk Score >30% or a SCORE risk >7.5% over 10 years, or (3) a coronary artery calcium score >400 Agatston units at any time in the past. Patients were randomized in a 1:1 ratio to receive either bempedoic acid 180 mg once daily (n = 6992) or placebo (n = 6978), either alone or as an add-on to other background lipid-lowering therapies, which could include very low doses of statins. Overall, over 95% of patients were followed until the end of the study or death, and less than 1% were lost to follow-up. The median duration of follow-up was 3.4 years.

At study initiation, the mean age was 65.5 years, 48% were women, 91% were White. Selected additional baseline characteristics included hypertension (85%), diabetes (46%), prediabetes (42%), tobacco smoking (22%), eGFR <60 mL/min/1.73 m² (21%), and a mean body mass index of 29.9 kg/m². The mean baseline LDL-C level was 3.6 mmol/L (139 mg/dL). At baseline, 41% of patients were receiving at least one lipid-modifying therapy, including ezetimibe (12%) and very low-dose statins (23%). Bempedoic acid significantly reduced the risk of the primary composite endpoint of major adverse cardiovascular events (MACE-4), consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization, by 13% compared to placebo (hazard ratio: 0.87; 95% CI: 0.79, 0.96; p = 0.0037); and the risk of the key secondary composite endpoint MACE-3 (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) was significantly reduced by 15% compared to placebo (hazard ratio: 0.85; 95% CI: 0.76, 0.96; p = 0.0058). The primary composite endpoint result was generally consistent across pre-specified subgroups (including baseline age, race, ethnicity, sex, LDL-C category, statin use, ezetimibe use, and diabetes). The point estimate of the MACE-4 hazard ratio was 0.94 (95% CI: 0.74; 1.20) in the subgroup of patients using ezetimibe at baseline. For the limited subgroup of patients who were on ezetimibe at baseline and had high cardiovascular risk (n=335), LDL-C reduction was -26.7% (95% CI: -30.9%, -22.4%), but cardiovascular risk reduction could not be assessed.

The effect of bempedoic acid on individual components of the primary endpoint included a 27% reduction in the risk of non-fatal myocardial infarction and a 19% reduction in the risk of coronary revascularization compared to placebo. No statistically significant difference was observed in the reduction of non-fatal stroke or cardiovascular death risk compared to placebo. Results for primary and key secondary efficacy endpoints are presented in Table 2. Kaplan-Meier curve estimates for the cumulative incidence of the primary and secondary MACE-3 endpoints are shown in Figures 1 and 2 below. The cumulative incidence of the primary MACE-4 endpoint diverged by 6 months. Additionally, the difference between bempedoic acid and placebo in the mean percentage change in LDL-C from baseline to Month 6 was -20% (95% CI: -21%, -19%).

Table 2

Effect of bempedoic acid on major adverse cardiovascular events

CI = confidence interval; MACE = major adverse cardiovascular event; NS = not significant.

a. Hazard ratio and corresponding 95% CI were based on the Cox proportional hazards model using treatment as an explanatory variable.

b. p-value was calculated using the log-rank test.

Note: This table also presents time to first occurrence of each MACE component; patients may be included in more than one category.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with the medicinal product in all subsets of the paediatric population for the treatment of elevated cholesterol (see section "Posology and method of administration" for information on use in children).

Pharmacokinetics

Absorption

The bioavailability of bempedoic acid/ezetimibe tablets was similar compared to the bioavailability of the individual tablets taken concomitantly. The maximum serum concentration (Cmax) values for bempedoic acid and its active metabolite (ESP15228) were similar between the different formulations, while the Cmax values for ezetimibe and ezetimibe-glucuronide were approximately 13% and 22% lower, respectively, for bempedoic acid/ezetimibe compared to the individual tablets taken concomitantly. Given the similar overall exposure of ezetimibe and ezetimibe-glucuronide (measured as AUC), the 22% lower Cmax is unlikely to be clinically significant. No clinically significant pharmacokinetic interaction was observed when ezetimibe was co-administered with bempedoic acid. AUC and Cmax of total ezetimibe (ezetimibe and its glucuronide form) and ezetimibe-glucuronide increased approximately 1.6- and 1.8-fold, respectively, when a single dose of ezetimibe was administered with bempedoic acid at steady state. This increase is likely due to inhibition of OATP1B1 by bempedoic acid, resulting in reduced hepatic uptake and, consequently, reduced elimination of ezetimibe-glucuronide. The increase in AUC and Cmax for ezetimibe was less than 20%.

Bempedoic acid

Pharmacokinetic data indicate that bempedoic acid is absorbed with a median time to peak concentration of 3.5 hours following administration of 180 mg tablets. Pharmacokinetic parameters for bempedoic acid are presented as mean [standard deviation (SD)] unless otherwise stated. Bempedoic acid can be considered a prodrug that is intracellularly activated by ACSVL1 to ETC-1002-CoA. Steady-state Cmax and AUC values after multiple dosing in patients with hypercholesterolemia were 24.8 (6.9) µg/mL and 348 (120) µg·h/mL, respectively. The pharmacokinetics of bempedoic acid at steady state were generally linear over the dose range of 120 mg to 220 mg. No time-dependent changes in the pharmacokinetics of bempedoic acid were observed after repeated administration at the recommended dose, and steady state was achieved within 7 days. The mean accumulation ratio of bempedoic acid was approximately 2.3-fold.

Ezetimibe

Following oral administration, ezetimibe is rapidly absorbed and extensively conjugated to its pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean Cmax is reached within 1–2 hours for ezetimibe-glucuronide and between 4 and 12 hours for ezetimibe. Absolute bioavailability of ezetimibe cannot be determined because the compound is practically insoluble in aqueous media suitable for injection. Ezetimibe undergoes significant enterohepatic recycling, and multiple peaks of ezetimibe can be observed.

Effect of food

Following administration of bempedoic acid/ezetimibe with a high-fat, high-calorie breakfast in healthy subjects, AUC for bempedoic acid and ezetimibe was comparable to fasting conditions. Compared to fasting, administration with breakfast resulted in a 30% and 12% reduction in Cmax for bempedoic acid and ezetimibe, respectively. Compared to fasting, administration with breakfast resulted in a 12% and 42% reduction in AUC and Cmax for ezetimibe-glucuronide, respectively. This food effect is not considered clinically significant.

Distribution

Bempedoic acid

The apparent volume of distribution (V/F) of bempedoic acid was 18 L. Plasma protein binding of bempedoic acid, its glucuronide, and its active metabolite ESP15228 was 99.3%, 98.8%, and 99.2%, respectively. Bempedoic acid does not penetrate erythrocytes.

Ezetimibe

Ezetimibe and ezetimibe-glucuronide are bound to human plasma proteins by 99.7% and 88% to 92%, respectively.

Metabolism

Bempedoic acid

In vitro metabolic interaction studies show that bempedoic acid, its active metabolite, and glucuronide forms are not metabolized by cytochrome P450 enzymes and do not inhibit or induce them.

The primary route of elimination of bempedoic acid is metabolism to an acyl glucuronide. Bempedoic acid is also reversibly converted to its active metabolite (ESP15228) via aldo-keto reductase activity observed in vitro in human liver. The mean AUC metabolite/parent ratio in plasma for ESP15228 after repeated dosing was 18% and remained constant over time. Both bempedoic acid and ESP15228 are converted to inactive glucuronide conjugates in vitro by UDP-glucuronosyltransferase-2B7 (UGT2B7). Bempedoic acid, ESP15228, and their respective conjugated forms were detected in plasma, with bempedoic acid accounting for the majority (46%) of the AUC 0–48h, followed by its glucuronide (30%). ESP15228 and its glucuronide accounted for 10% and 11% of the AUC 0–48h in plasma, respectively. Steady-state Cmax and AUC values of the equipotent active metabolite (ESP15228) of bempedoic acid in patients with hypercholesterolemia were 3.0 (1.4) µg/mL and 54.1 (26.4) µg·h/mL, respectively. Based on systemic exposure and pharmacokinetic properties, ESP15228 likely contributes minimally to the overall clinical activity of bempedoic acid.

Ezetimibe

Preclinical studies have shown that ezetimibe does not induce drug-metabolizing cytochrome P450 enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and medicinal products known to be metabolized by cytochrome P450 enzymes 1A2, 2D6, 2C8, 2C9, and 3A4 or by N-acetyltransferase. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (Phase II reaction), followed by biliary excretion. Minimal oxidative metabolism (Phase I reaction) was observed across all species studied. Ezetimibe and ezetimibe-glucuronide are the primary drug-derived compounds detected in plasma, accounting for approximately 10–20% and 80–90% of total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma, with evidence of extensive enterohepatic recirculation.

Elimination

Bempedoic acid

Steady-state clearance (CL/F) of bempedoic acid, determined by population pharmacokinetic (PK) analysis in patients with hypercholesterolemia, was 12.1 mL/min after once-daily dosing; renal clearance of unchanged bempedoic acid accounted for less than 2% of total clearance. The mean (SD) elimination half-life of bempedoic acid in humans was 19 (10) hours at steady state. After a single oral dose of 240 mg bempedoic acid (1.3 times the approved recommended dose), 62.1% of the total dose (bempedoic acid and its metabolites) was excreted in urine, primarily as the acyl glucuronide conjugate of bempedoic acid, and 25.4% in feces. Less than 5% of the administered dose was excreted unchanged in feces and urine combined.

Ezetimibe

Following oral administration of 14C-ezetimibe (20 mg) to humans, total ezetimibe (ezetimibe and ezetimibe-glucuronide) accounted for approximately 93% of total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in feces and urine, respectively, over a 10-day collection period. Plasma levels of radioactivity were not detectable after 48 hours. The elimination half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Special populations

Renal impairment

Bempedoic acid

The pharmacokinetics of bempedoic acid were evaluated in a population pharmacokinetic analysis based on pooled data from all clinical trials (n=2261) to assess renal function effects on steady-state AUC, and in a single-dose pharmacokinetic study in patients with varying degrees of renal function. Compared to patients with normal renal function, mean exposure to bempedoic acid was 1.4-fold (90% PI: 1.3, 1.4) and 1.9-fold (90% PI: 1.7, 2.0) higher in patients with mild and moderate renal impairment, respectively (see section "Special warnings and precautions for use"). Data in patients with severe renal impairment are limited; in a single-dose study, AUC of bempedoic acid increased 2.4-fold in patients (n=5) with severe renal impairment (eGFR <30 mL/min/1.73 m²) compared to those with normal renal function. Clinical studies of the medicinal product did not include patients with end-stage renal disease on dialysis (see section "Special warnings and precautions for use").

Ezetimibe

Following a single 10 mg dose of ezetimibe in patients with severe renal disease (n=8; mean creatinine clearance ≤30 mL/min/1.73 m²), mean AUC for total ezetimibe increased by approximately 1.5-fold compared to healthy subjects (n=9). This finding is not considered clinically significant. One additional patient in this study (post-kidney transplant receiving multiple medications including cyclosporine) had a 12-fold higher exposure to total ezetimibe.

Hepatic impairment

The medicinal product is not recommended for use in patients with moderate or severe hepatic impairment due to unknown effects of increased ezetimibe exposure.

Bempedoic acid

The pharmacokinetics of bempedoic acid and its metabolite (ESP15228) were studied in patients with normal hepatic function or mild to moderate hepatic impairment (Child-Pugh class A or B) after a single dose (n=8/group). Compared to patients with normal liver function, mean Cmax and AUC of bempedoic acid decreased by 11% and 22%, respectively, in patients with mild hepatic impairment, and by 14% and 16%, respectively, in patients with moderate hepatic impairment. This is not expected to result in reduced efficacy. Bempedoic acid has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Ezetimibe

After a single 10 mg dose of ezetimibe, mean AUC for total ezetimibe increased by approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh class A) compared to healthy volunteers. In a 14-day multiple-dose study (10 mg once daily) in patients with moderate hepatic impairment (Child-Pugh class B), mean AUC for total ezetimibe increased by approximately 4-fold on both Day 1 and Day 14 compared to healthy volunteers.

Other special populations

Bempedoic acid

Of the 3,621 patients who received bempedoic acid in placebo-controlled studies, 2,098 (58%) were aged >65 years. No overall differences in safety or efficacy were observed between these patients and younger patients. The pharmacokinetics of bempedoic acid were independent of age, gender, or race. Body weight was a statistically significant covariate. The lowest quartile of body weight (<73 kg) was associated with approximately 30% higher exposure. This increased exposure was not clinically significant, and dose adjustment based on body weight is not recommended.

Ezetimibe

Elderly patients

In a multiple-dose study of ezetimibe 10 mg once daily for 10 days, plasma concentrations of total ezetimibe were approximately twice as high in healthy elderly subjects (≥65 years) compared to younger subjects. LDL-C reduction and safety profile were comparable between elderly patients and younger subjects receiving ezetimibe.

Gender

Plasma concentrations of total ezetimibe are slightly higher (approximately 20%) in females than in males. LDL-C reduction and safety profile are comparable between males and females receiving ezetimibe.

Clinical Characteristics

Indications

Hypercholesterolemia and Mixed Dyslipidemia

The medicinal product is indicated for adult patients with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia as adjunctive therapy to diet:

• in combination with a statin for patients unable to reach the desired LDL-cholesterol level with the maximum tolerated dose of a statin in addition to ezetimibe;
• as monotherapy for patients who either cannot tolerate statins or for whom statins are contraindicated, and who cannot achieve desired LDL-cholesterol levels with ezetimibe alone;
• for patients already receiving a combination of bempedoic acid and ezetimibe as separate medicinal products, with or without a statin.

Cardiovascular Disease

The medicinal product is indicated for adults with established atherosclerotic cardiovascular disease or at high risk of atherosclerotic cardiovascular disease to reduce cardiovascular risk through lowering LDL-cholesterol levels, as an adjunct to correction of other risk factors:

• for patients taking the maximum tolerated dose of a statin and who are not adequately controlled with additional ezetimibe therapy;
• for patients with statin intolerance or for whom statins are contraindicated, and who are not adequately controlled with ezetimibe therapy;
• for patients already receiving a combination of bempedoic acid and ezetimibe as separate medicinal products, as an additional agent to achieve adequate cholesterol control.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Pregnancy or breastfeeding.

Concomitant use with simvastatin >40 mg daily.

The medicinal product Lifelza in combination with a statin is contraindicated in patients with active liver disease or with unexplained persistent elevations in serum transaminases.

Interaction with Other Medicinal Products and Other Forms of Interaction

No specific pharmacokinetic interaction studies with the medicinal product have been conducted. Drug interactions identified in studies with bempedoic acid or ezetimibe define the potential interactions that may occur with the medicinal product.

Effect of Other Medicinal Products on Individual Components of the Medicinal Product

Fibrates

Concomitant administration of fenofibrate or gemfibrozil slightly increased total ezetimibe concentration (approximately 1.5- and 1.7-fold, respectively). Fenofibrate may increase biliary cholesterol excretion, leading to gallstone disease. In preclinical studies in dogs, ezetimibe increased biliary bladder cholesterol levels. A lithogenic risk associated with therapeutic use of the medicinal product cannot be excluded.

If gallstone disease is suspected in a patient receiving the medicinal product and fenofibrate, gallbladder examination is indicated and alternative lipid-lowering therapy should be considered (see section "Special Warnings and Precautions for Use").

• Cyclosporine *

In a study involving eight kidney transplant patients with creatinine clearance >50 ml/min receiving stable doses of cyclosporine, a single 10 mg dose of ezetimibe resulted in a 3.4-fold (range 2.3 to 7.9-fold) increase in mean area under the curve (AUC) for total ezetimibe compared to a healthy control population receiving ezetimibe alone, according to another study (n=17). In another study, a kidney transplant patient with severe renal insufficiency receiving cyclosporine and several other medicinal products showed a 12-fold higher exposure to total ezetimibe compared to a concurrent control group receiving ezetimibe alone. In a two-period crossover study involving 12 healthy volunteers, daily administration of 20 mg ezetimibe for 8 days with a single 100 mg dose of cyclosporine on day 7 led to a mean 15% increase in cyclosporine AUC (range from 10% decrease to 51% increase) compared to a single 100 mg dose of cyclosporine alone. A controlled study evaluating the effect of concomitant ezetimibe on cyclosporine exposure in kidney transplant patients has not been conducted. Caution should be exercised when initiating the medicinal product concomitantly with cyclosporine. Cyclosporine concentrations should be monitored in patients receiving the medicinal product and cyclosporine (see section "Special Warnings and Precautions for Use").

Cholestyramine

Concomitant use of cholestyramine reduced the mean area under the curve (AUC) of total ezetimibe (ezetimibe plus ezetimibe glucuronide) by approximately 55%. The gradual reduction in low-density lipoprotein cholesterol (LDL-C) levels resulting from adding the medicinal product to cholestyramine may be diminished due to this interaction (see section "Dosage and Administration").

Drug Interactions Mediated by Transporters

In vitro drug interaction studies show that bempedoic acid, as well as its active metabolite and glucuronide form, are not substrates of commonly used drug transporters, except for the glucuronide of bempedoic acid, which is a substrate of OAT3.

Probenecid

Probenecid, an inhibitor of glucuronide conjugation, was studied to evaluate the potential impact of such inhibitors on the pharmacokinetics of bempedoic acid. Administration of 180 mg bempedoic acid with steady-state probenecid resulted in a 1.7-fold increase in AUC of bempedoic acid and a 1.9-fold increase in AUC of the active metabolite of bempedoic acid (ESP15228). This increase is not clinically significant and does not affect dosing recommendations.

Effect of Individual Components of the Medicinal Product on Other Agents

Statins

Pharmacokinetic interactions between 180 mg bempedoic acid and 40 mg simvastatin, 80 mg atorvastatin, 80 mg pravastatin, and 40 mg rosuvastatin were evaluated in clinical studies. Administration of a single 40 mg dose of simvastatin with steady-state 180 mg bempedoic acid resulted in a doubling of simvastatin exposure. When co-administered with 180 mg bempedoic acid, AUC increases of 1.4–1.5-fold were observed for atorvastatin, pravastatin, and rosuvastatin (administered as single doses) and/or their major metabolites. Greater increases were observed when these statins were co-administered with a supratherapeutic dose of 240 mg bempedoic acid (see section "Special Warnings and Precautions for Use"). No clinically significant pharmacokinetic interactions were observed when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.

Drug Interactions Mediated by Transporters

Bempedoic acid and its glucuronide weakly inhibit OATP1B1 and OATP1B3 at clinically relevant concentrations. Concomitant administration of the medicinal product with agents that are substrates of OATP1B1 or OATP1B3 (i.e., bosentan, fimasartan, asunaprevir, glecaprevir, grazoprevir, voxilaprevir, and statins such as atorvastatin, pravastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin [see section "Special Warnings and Precautions for Use"]) may lead to increased plasma concentrations of these medicinal products. Bempedoic acid inhibits OAT2 in vitro, which may be the mechanism responsible for the slight increase in serum creatinine and uric acid levels (see section "Adverse Reactions"). Inhibition of OAT2 by bempedoic acid may also potentially increase plasma concentrations of medicinal products that are OAT2 substrates. Bempedoic acid may also weakly inhibit OAT3 at clinically relevant concentrations.

Anticoagulants

Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin or prothrombin time in a study of twelve healthy adult males. However, post-marketing reports have described increased INR in patients receiving ezetimibe added to warfarin or fluindione. If the medicinal product is added to warfarin, other coumarin anticoagulants, or fluindione, INR should be appropriately monitored (see section "Special Warnings and Precautions for Use").

Other Investigated Interactions

Bempedoic acid did not affect the pharmacokinetics of the oral contraceptives norethindrone/ethinyl estradiol. In clinical interaction studies, ezetimibe did not affect the pharmacokinetics of the oral contraceptives ethinyl estradiol and levonorgestrel. Bempedoic acid did not affect the pharmacokinetics or pharmacodynamics of metformin. In clinical interaction studies, ezetimibe did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, glipizide, tolbutamide, or midazolam when co-administered.

Special precautions

Potential risk of myopathy with concomitant use of statins

Bempedoic acid increases plasma concentrations of statins (see section "Interaction with other medicinal products and other forms of interaction"). Statins occasionally cause myopathy. In rare cases, myopathy may manifest as rhabdomyolysis with acute renal failure with or without myoglobinuria, and may lead to fatal outcomes. During the post-marketing period of ezetimibe use, very rare cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking statins concomitantly with ezetimibe. Patients receiving the medicinal product as add-on therapy to statins should be monitored for adverse reactions associated with high-dose statin use. All patients receiving the medicinal product in addition to statins should be informed about the potentially increased risk of myopathy and should immediately report any unexplained muscle pain, tenderness, or weakness. If such symptoms occur during treatment with the medicinal product and a statin, consideration should be given to reducing the maximum dose of the same statin or switching to an alternative statin, or discontinuing the medicinal product and initiating alternative lipid-lowering therapy under close monitoring of lipid levels and adverse reactions. If myopathy is confirmed by creatine phosphokinase (CPK) levels >10 × upper limit of normal (ULN), administration of the medicinal product and any concomitantly used statin should be immediately discontinued. Myositis with CPK levels >10 × ULN has been rarely observed with bempedoic acid in combination with background therapy of 40 mg simvastatin. Simvastatin doses >40 mg should not be used concomitantly with this medicinal product (see sections "Dosage and administration" and "Contraindications").

Elevated serum uric acid levels

Bempedoic acid may increase serum uric acid levels due to inhibition of renal tubular OAT2 and may cause or exacerbate hyperuricemia and trigger gout in patients with a history of gout or predisposition to gout (see section "Adverse reactions"). The medicinal product should be discontinued if hyperuricemia associated with symptoms of gout develops.

Tendon rupture

Use of the medicinal product is associated with an increased risk of tendon rupture or injury. In clinical trials, tendon rupture occurred in 0.5% of patients receiving bempedoic acid compared to 0% of patients receiving placebo, affecting the rotator cuff of the shoulder, biceps tendon of the arm, or Achilles tendon. Tendon rupture occurred weeks or months after initiation of the medicinal product and may occur more frequently in patients over 60 years of age, those taking corticosteroids or fluoroquinolones, patients with renal impairment, and those with prior tendon disorders. Immediate discontinuation of bempedoic acid is recommended if tendon rupture occurs. Consideration should also be given to discontinuing the medicinal product if a patient develops joint pain, swelling, or inflammation. Patients should be advised to rest at the first signs of tendinitis or tendon rupture and to seek medical attention if symptoms of tendinitis or tendon rupture occur. Alternative therapy should be considered for patients with a history of tendon disorders or tendon rupture.

Elevated liver enzymes

In clinical trials, elevations in liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >3 × ULN were reported with bempedoic acid use. These elevations were asymptomatic and not associated with increases in bilirubin ≥2 × ULN or cholestasis, and returned to baseline levels during continued treatment or after discontinuation of therapy. In controlled combination studies in patients receiving ezetimibe with a statin, a consistent increase in transaminase levels (≥3 × ULN) was observed. Liver function tests should be performed at the beginning of therapy. The medicinal product should be discontinued if transaminase elevations >3 × ULN persist (see sections "Contraindications" and "Adverse reactions").

Renal function impairment

Experience with bempedoic acid use in patients with severe renal impairment (defined as eGFR <30 mL/min/1.73 m²) is limited, and patients with end-stage renal disease on dialysis have not been studied with bempedoic acid (see section "Pharmacokinetics"). Additional monitoring for adverse reactions may be required when using the medicinal product in these patients.

Hepatic function impairment

Due to unknown consequences of increased exposure to ezetimibe in patients with moderate and severe hepatic impairment (Child-Pugh class B and C), use of the medicinal product in these patients is not recommended (see section "Pharmacokinetics").

Fibrates

The safety and efficacy of ezetimibe when used with fibrates have not been established. If gallstone disease is suspected in a patient receiving the medicinal product and fenofibrate, gallbladder imaging is indicated and this therapy should be discontinued (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Cyclosporine

Caution is advised when initiating the medicinal product concomitantly with cyclosporine. Cyclosporine concentrations should be monitored in patients receiving the medicinal product and cyclosporine (see section "Interaction with other medicinal products and other forms of interaction").

Anticoagulants

If the medicinal product is added to warfarin, other coumarin anticoagulants, or fluindione, international normalized ratio (INR) should be appropriately monitored (see section "Interaction with other medicinal products and other forms of interaction").

Contraceptive measures in women of reproductive potential

Prior to initiating treatment in women of reproductive potential, appropriate recommendations regarding effective contraceptive methods should be provided and effective contraception initiated.

Women taking estrogen-based oral contraceptives should be advised of the potential loss of contraceptive efficacy due to diarrhea and/or vomiting. Patients should be advised to seek immediate medical advice and discontinue treatment if they plan pregnancy or if pregnancy occurs (see section "Use during pregnancy or breastfeeding").

Patients at high cardiovascular risk

Evidence for use of the fixed-dose combination medicinal product of bempedoic acid with ezetimibe in patients at high cardiovascular risk is available only for lipid-lowering effect, without any assessment of cardiovascular risk reduction for ezetimibe in patients undergoing primary prevention (see section "Pharmacodynamics").

Important information on excipients

The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product is contraindicated during pregnancy (see section "Contraindications"). Data on use of the medicinal product in pregnant women are lacking or limited. Animal studies with bempedoic acid have shown reproductive toxicity. Since bempedoic acid reduces cholesterol synthesis and possibly the synthesis of other cholesterol derivatives necessary for normal fetal development, the medicinal product may cause fetal harm when administered to pregnant women. Administration of the medicinal product should be discontinued prior to conception or as soon as pregnancy is planned or diagnosed (see section "Contraindications").

Women of reproductive potential

Women of reproductive potential should use effective contraceptive methods during treatment (see section "Special precautions").

Breastfeeding

It is unknown whether bempedoic acid or its metabolites, or ezetimibe/metabolites, are excreted in human milk. Due to the potential for serious adverse reactions, women taking the medicinal product should discontinue breastfeeding. The medicinal product is contraindicated during breastfeeding (see section "Contraindications").

Fertility

Data on the effect of the medicinal product on human fertility are lacking. Based on animal studies, no effect of the medicinal product on reproductive function or fertility is expected.

Ability to affect driving and operating machinery

The medicinal product has a minor influence on the ability to drive and use machines. When driving vehicles or operating machinery, it should be considered that dizziness has been reported with use of bempedoic acid and ezetimibe (see section "Adverse reactions").

Dosage and Administration

Administration

Each film-coated tablet should be taken orally, independent of meals. The tablet should be swallowed whole.

Dosage

The recommended dose is 1 film-coated tablet containing 180 mg/10 mg, taken once daily.

Concomitant use with bile acid sequestrants

The dose of the medicinal product should be administered at least 2 hours before or at least 4 hours after administration of a bile acid sequestrant.

Concomitant therapy with simvastatin

When the medicinal product is used concomitantly with simvastatin, the dose of simvastatin should be limited to 20 mg daily (or 40 mg daily for patients with severe hypercholesterolemia and high cardiovascular risk who have not achieved treatment goals with lower doses, and when the expected benefit outweighs potential risks) (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Special Patient Populations

Elderly patients

Dose adjustment in elderly patients is not required (see section "Pharmacokinetics").

Patients with renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. Data in patients with severe renal impairment (defined as estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) are limited, and patients with end-stage renal disease on dialysis have not been studied. Additional monitoring for adverse reactions may be necessary in such patients when using the medicinal product (see section "Special Warnings and Precautions for Use").

Patients with hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Data in patients with severe hepatic impairment are lacking. Periodic monitoring of liver function tests should be performed in patients with severe hepatic impairment (see section "Special Warnings and Precautions for Use").

Children

Safety and efficacy of the medicinal product in children under 18 years of age have not yet been established. Data are lacking.

Overdose

In case of overdose, symptomatic treatment and supportive measures should be initiated as needed.

Bempedoic acid

In clinical trials, doses up to 240 mg/day (1.3 times the approved recommended dose) were administered without signs of toxicity. In animal studies, no adverse effects were observed at exposures up to 14 times higher than those in patients receiving bempedoic acid 180 mg once daily.

Ezetimibe

In clinical studies, administration of ezetimibe at 50 mg/day to 15 healthy subjects for up to 14 days or 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days did not result in increased frequency of adverse effects. In animals, no toxicity was observed after single oral doses of ezetimibe at 5000 mg/kg in rats and mice and 3000 mg/kg in dogs.

Adverse Reactions

Summary of safety profile

The most commonly reported adverse reactions with the medicinal product were hyperuricemia (4.7%) and constipation (4.7%).

In placebo-controlled Phase 3 studies of primary hyperlipidemia with bempedoic acid, more patients receiving bempedoic acid than placebo discontinued treatment due to muscle spasms (0.7% vs. 0.3%), diarrhea (0.5% vs. <0.1%), tendon rupture (0.5% vs. 0%), limb pain (0.4% vs. 0%), and nausea (0.3% vs. 0.2%), although the difference between bempedoic acid and placebo was not substantial.

Serious adverse reactions reported with ezetimibe include myopathy, rhabdomyolysis, hepatitis, hypersensitivity, anaphylaxis, angioedema, erythema multiforme, gallstone disease, cholecystitis, pancreatitis, and thrombocytopenia.

Tabulated list of adverse reactions

Adverse reactions reported with the medicinal product based on incidence rates from Phase 3 primary hyperlipidemia studies and exposure-adjusted incidence rates from the CLEAR Outcomes study or ezetimibe to provide a more comprehensive adverse reaction profile of the medicinal product.

All adverse reactions are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

Adverse reactions

a. Hyperuricemia includes hyperuricemia and elevated levels of uric acid in the blood.

b. Increased liver function tests include elevated liver function parameters and laboratory abnormalities.

c. Adverse reactions with concomitant use of ezetimibe with a statin.

d. (CLEAR Outcomes study) Weight reduction was observed only in patients with a baseline body mass index (BMI) ≥30 kg/m², with a mean weight reduction of -2.28 kg at month 36. Mean weight reduction was ≤0.5 kg in patients with a baseline BMI of 25 to <30 kg/m². Bempedoic acid was not associated with a mean change in body weight in patients with a baseline BMI <25 kg/m².

Description of individual adverse reactions

Elevated serum uric acid levels

The medicinal product increases serum uric acid levels, possibly due to inhibition of the renal tubular OAT2 transporter by bempedoic acid (see section "Interaction with other medicinal products and other forms of interaction"). A mean increase in uric acid levels of 35.7 micromol/L (0.6 mg/dL) compared to baseline was observed at week 12 of treatment. Increased serum uric acid levels typically occurred within the first 4 weeks of treatment and returned to baseline levels after discontinuation of therapy. No cases of gout were reported during treatment with the medicinal product. In phase 3 primary hyperlipidemia studies with bempedoic acid, gout was reported in 1.4% of patients receiving bempedoic acid and in 0.4% of patients receiving placebo. In the CLEAR Outcomes study, patients receiving bempedoic acid showed a mean increase in uric acid levels of 47.6 micromol/L (0.8 mg/dL) compared to baseline at month 3, and gout was also reported more frequently in patients receiving bempedoic acid (3.1%) than in those receiving placebo (2.1%). In both treatment groups, patients who reported gout more frequently had a history of gout and/or baseline uric acid levels above the upper limit of normal (see section "Special precautions for use").

Effect on serum creatinine and blood urea nitrogen (BUN)

The medicinal product increases serum creatinine and blood urea nitrogen (BUN) levels. At week 12 of treatment, a mean increase in serum creatinine of 1.8 micromol/L (0.02 mg/dL) and a mean increase in BUN of 1 mmol/L (2.7 mg/dL) compared to baseline were observed. Increases in serum creatinine and BUN typically occurred within the first 4 weeks of treatment, remained stable, and returned to baseline levels after discontinuation of therapy. A similar mean increase in serum creatinine (5.8 micromol/L (0.066 mg/dL)) and BUN (0.82 mmol/L (2.3 mg/dL)) was observed with bempedoic acid in the CLEAR Outcomes study. The observed increase in serum creatinine may be related to inhibition by bempedoic acid of OAT2-dependent tubular secretion of creatinine (see section "Interaction with other medicinal products and other forms of interaction"), representing a drug interaction with an endogenous substrate, and does not appear to indicate worsening of kidney function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients receiving the medicinal product, particularly in patients with kidney disease or those receiving medications requiring monitoring of estimated creatinine clearance.

Elevation of liver enzymes

Elevations in liver transaminases (AST and/or ALT) ≥3 × ULN were recorded in 2.4% of patients treated with the medicinal product compared to none in the placebo group. In four phase 3 primary hyperlipidemia studies with bempedoic acid, the incidence of transaminase elevations (≥3 × ULN) was 0.7% in patients receiving bempedoic acid and 0.3% in the placebo group. In controlled clinical combination studies of ezetimibe initiated simultaneously with a statin, the incidence of consecutive transaminase elevations (≥3 × ULN) was 1.3% in patients receiving ezetimibe with statins and 0.4% in patients receiving statins alone. In the CLEAR Outcomes study, the incidence of transaminase elevations >3 × ULN was also higher in patients receiving bempedoic acid (1.6%) compared to those receiving placebo (1.0%). Transaminase elevations with bempedoic acid or ezetimibe were not associated with other signs of liver dysfunction (see section "Special precautions for use").

Decreased hemoglobin

In phase 3 primary hyperlipidemia studies with bempedoic acid, a decrease in hemoglobin from baseline of ≥20 g/L and below the lower limit of normal (LLN) was observed in 4.6% of patients in the bempedoic acid group compared to 1.9% in the placebo group. Decreases in hemoglobin of more than 50 g/L and below LLN occurred at similar frequencies in the bempedoic acid and placebo groups (0.2% vs. 0.2%, respectively). Decreased hemoglobin levels typically occurred within the first 4 weeks of treatment and returned to baseline after discontinuation of therapy. Among patients with normal hemoglobin levels at baseline, 1.4% in the bempedoic acid group and 0.4% in the placebo group had hemoglobin levels below LLN during treatment. In phase 3 primary hyperlipidemia studies, anemia was reported in 2.5% of patients receiving bempedoic acid and in 1.6% of patients receiving placebo. In the CLEAR Outcomes study, a similar decrease in hemoglobin was observed, and anemia was also reported more frequently in patients receiving bempedoic acid (4.7%) compared to those receiving placebo (3.9%).

Reporting suspected adverse reactions

Reporting of adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life

2 years.

Storage conditions

No special storage conditions required. Keep out of reach of children.

Packaging

10 tablets per blister, 3 blisters per cardboard pack.

Prescription status

Prescription only.

Manufacturer

Sinteo España, S.L.

Manufacturer's address and location of operations

Calle C/ Castello, n°1, Sant Boi de Llobregat, Barcelona, 08830, Spain.