Lifela

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIFELA (LIFELA)

Composition:

Active substance: bempedoic acid;

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

Excipients: hydroxypropylcellulose low-substituted; lactose monohydrate; sodium starch glycolate (type A); povidone K30; magnesium aluminometasilicate (type A); microcrystalline cellulose (type 102); magnesium stearate; film coating (polyvinyl alcohol, titanium dioxide (E 171), macrogol 4000, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, white or almost white film-coated tablets, embossed with "7P" on one side and "180" on the other.

Pharmacotherapeutic group

Cardiovascular system agents. Hypolipidemic agents. Other hypolipidemic agents. Bempedoic acid. ATC code C10AX15.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase (ACL), which reduces low-density lipoprotein cholesterol (LDL-C) levels by inhibiting hepatic cholesterol synthesis. ACL is an enzyme located upstream of 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 predominantly expressed in the liver and not in skeletal muscle. Inhibition of ACL by ETC-1002-CoA leads to reduced hepatic cholesterol synthesis and lowers circulating LDL-C levels by upregulating low-density lipoprotein receptor expression. Additionally, inhibition of ACL by ETC-1002-CoA results in concomitant suppression of hepatic fatty acid biosynthesis.

Pharmacodynamic Effects

Administration of bempedoic acid, either as monotherapy or in combination with other lipid-modifying agents, 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.

Since patients with diabetes have an increased risk of atherosclerotic cardiovascular disease, clinical trials of bempedoic acid included patients with diabetes. In the subgroup of patients with diabetes, lower levels of glycated hemoglobin (HbA1c) were observed compared to placebo (mean reduction of 0.2%). In patients without diabetes, no differences in HbA1c were 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.

Clinical Efficacy and Safety

Clinical Efficacy and Safety in Primary Hypercholesterolemia and Mixed Dyslipidemia

The efficacy of bempedoic acid was evaluated in four multicenter, randomized, double-blind, placebo-controlled Phase 3 trials in primary hyperlipidemia, involving 3623 adult patients with hypercholesterolemia or mixed dyslipidemia, of whom 2425 patients were randomized to receive bempedoic acid. All patients received bempedoic acid 180 mg or placebo orally once daily. In two of the trials, patients were on background lipid-modifying therapy consisting of the maximally tolerated dose of statins, with or without other lipid-modifying therapies. Two trials included patients with documented statin intolerance. The primary efficacy endpoint in all Phase 3 trials was the mean percent reduction in LDL-C from baseline at Week 12 compared to placebo.

Combination Therapy with Statins

CLEAR Wisdom (Study 1002-047) was a multicenter, randomized, double-blind, placebo-controlled, 52-week Phase 3 trial in patients with hypercholesterolemia or mixed dyslipidemia. Efficacy of bempedoic acid was assessed at Week 12. A total of 779 patients were randomized in a 2:1 ratio to receive bempedoic acid (n=522) or placebo (n=257) as an add-on to maximally tolerated lipid-lowering therapy. Maximally tolerated lipid-lowering therapy was defined as the maximally tolerated dose of statins (including statin regimens other than daily dosing and absent or very low doses), alone or in combination with other lipid-lowering therapies. Patients taking simvastatin 40 mg daily or higher were excluded from the study.

Overall, the mean age at baseline was 64 years (range: 28 to 91 years), 51% were aged ≥65 years, 36% were women, 94% were White, 5% were Black, and 1% were Asian. The mean baseline LDL-C level was 3.1 mmol/L (120.4 mg/dL). At randomization, 91% of patients were receiving statin therapy, and 53% were on high-intensity statin therapy. Bempedoic acid significantly reduced LDL-C levels from baseline to Week 12 compared to placebo (p <0.001). Bempedoic acid also significantly reduced non-HDL-C, apo B, and TC levels.

CLEAR Harmony (Study 1002-040) was a multicenter, randomized, double-blind, placebo-controlled, 52-week Phase 3 trial evaluating the safety and efficacy of bempedoic acid in patients with hypercholesterolemia or mixed dyslipidemia. Efficacy of bempedoic acid was assessed at Week 12. A total of 2230 patients were randomized in a 2:1 ratio to receive either bempedoic acid (n=1488) or placebo (n=742) as an add-on to maximally tolerated lipid-lowering therapy. Maximally tolerated lipid-lowering therapy was defined as the maximally tolerated dose of statins (including statin regimens other than daily dosing and very low doses), alone or in combination with other lipid-lowering therapies. Patients receiving simvastatin 40 mg daily or higher, or those receiving PCSK9 inhibitors, were excluded from the study.

Overall, the mean age at baseline was 66 years (range: 24 to 88 years), 61% were aged ≥65 years, 27% were women, 96% were White, 3% were Black, and 1% were Asian. The mean baseline LDL-C level was 2.7 mmol/L (103.2 mg/dL). At randomization, all patients were receiving statin therapy, and 50% were on high-intensity statin therapy. Bempedoic acid significantly reduced LDL-C levels from baseline to Week 12 compared to placebo (p <0.001). A significantly greater proportion of patients achieved LDL-C levels <1.81 mmol/L (<70 mg/dL) in the bempedoic acid group compared to placebo at Week 12 (32% vs. 9%, P <0.001). Bempedoic acid also significantly reduced non-HDL-C, apo B, and TC levels.

Patients with Statin Intolerance

CLEAR Tranquility (Study 1002-048) was a multicenter, randomized, double-blind, placebo-controlled, 12-week Phase 3 trial evaluating the efficacy of bempedoic acid versus placebo in reducing LDL-C when added to ezetimibe in patients with elevated LDL-C who had a history of statin intolerance and could not tolerate more than the lowest approved starting dose of a statin. A total of 269 patients were 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 women, 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% receiving placebo were on statins at doses ≤ the lowest approved starting dose. Bempedoic acid significantly reduced LDL-C levels from baseline to Week 12 compared to placebo (p <0.001). Bempedoic acid also significantly reduced non-HDL-C, apo B, and TC levels.

CLEAR Serenity (Study 1002-046) was a multicenter, randomized, double-blind, placebo-controlled, 24-week Phase 3 trial evaluating the efficacy of bempedoic acid versus placebo in patients with elevated LDL-C who had statin intolerance or could not tolerate two or more statins, one of which was at the lowest dose. Patients who could tolerate a dose lower than the approved starting dose of a statin were allowed to continue that dose during the study. Efficacy of bempedoic acid was assessed at Week 12. A total of 345 patients were randomized in a 2:1 ratio to receive bempedoic acid (n=234) or placebo (n=111) for 24 weeks. At randomization, 8% of patients receiving bempedoic acid versus 10% receiving placebo were on statins at doses lower than the lowest approved starting dose, and 36% of patients receiving bempedoic acid versus 30% receiving placebo were on other non-statin lipid-modifying agents.

Overall, the mean age at baseline was 65 years (range: 26 to 88 years), 58% were aged ≥65 years, 56% were women, 89% were White, 8% were Black, 2% were Asian, and 1% were other. The mean baseline LDL-C level was 4.1 mmol/L (157.6 mg/dL).

Bempedoic acid significantly reduced LDL-C levels from baseline to Week 12 compared to placebo (p <0.001). Bempedoic acid also significantly reduced non-HDL-C, apo B, and TC levels.

Treatment in the Absence of Lipid-Modifying Therapy

In the CLEAR Serenity trial (Study 1002-046), 133 patients in the bempedoic acid group and 67 patients in the placebo group did not receive background lipid-modifying therapy. Bempedoic acid significantly reduced LDL-C levels from baseline to Week 12 compared to placebo in this subgroup. The difference between bempedoic acid and placebo in the mean percent change in LDL-C from baseline to Week 12 was -22.1% (95% CI: -26.8%, -17.4%; p <0.001).

In all four trials, the maximum LDL-C lowering effect was observed as early as Week 4, and efficacy was maintained throughout the duration of the studies. These results were consistent across all studied subgroups in any of the trials, including age, sex, race, ethnicity, region, history of diabetes, baseline LDL-C level, body mass index (BMI), heterozygous familial hypercholesterolemia (HeFH) status, and background therapy.

Clinical Efficacy and Safety in Cardiovascular Event Prevention

The CLEAR Outcomes trial (Study 1002-043) was a multicenter, randomized, double-blind, placebo-controlled, event-driven trial involving 13,970 adult patients with established atherosclerotic cardiovascular disease (ASCVD) (70%) or at high risk of ASCVD (30%). Patients with established ASCVD had a documented history of ischemic heart disease, symptomatic peripheral artery disease, and/or cerebrovascular atherosclerotic disease. Patients without established ASCVD were considered at high risk 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) Reynolds Risk Score >30% or SCORE risk >7.5% over 10 years, or (3) coronary artery calcium score >400 Agatston units at any time in the past. Patients were randomized in a 1:1 ratio to receive bempedoic acid 180 mg daily (n=6992) or placebo (n=6978), alone or as an add-on to other background lipid-lowering therapies, which could include very low-dose 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 baseline, the mean age was 65.5 years, 48% were women, 91% were White. Selected additional baseline characteristics included hypertension (85%), diabetes (46%), prediabetes (42%), current tobacco use (22%), eGFR <60 mL/min/1.73 m² (21%), and mean BMI 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 on 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). 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 prespecified subgroups (including baseline age, race, ethnicity, sex, LDL-C category, statin use, ezetimibe use, and diabetes). 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 the table below. Kaplan-Meier estimates of cumulative incidence for the primary and secondary MACE-3 endpoints are shown in Figures 1 and 2 below. The cumulative incidence of the primary MACE-4 endpoint is separated at 6 months.

Furthermore, the difference between bempedoic acid and placebo in the mean percent change in LDL-C from baseline to 6 months was -20% (95% CI: -21%, -19%). Impact 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 used with treatment as an explanatory variable.

b. p-value was based on 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 bempedoic acid in children aged 4 to 18 years for the treatment of elevated cholesterol levels. See section "Dosage and administration" for information on use in children.

Pharmacokinetics

Absorption

Pharmacokinetic data indicate that bempedoic acid is absorbed with a median time to maximum concentration of 3.5 hours following administration in tablet form. Pharmacokinetic parameters of 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 hypercholesterolaemia 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 range of 120 mg to 220 mg. No time-dependent changes in bempedoic acid pharmacokinetics 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. Concomitant food intake did not affect the oral bioavailability of bempedoic acid when administered in tablet form. Food slowed the rate of absorption of bempedoic acid; the absorption rate constant with food was 0.32/h.

Distribution

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 into erythrocytes.

Biological transformation

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

The primary route of elimination of bempedoic acid is via metabolism to an acyl glucuronide. Bempedoic acid is also reversibly converted to the active metabolite (ESP15228) via aldo-keto reductase activity observed in vitro in human liver. The mean metabolite/parent AUC ratio in plasma for ESP15228 after repeated dosing was 18% and remained constant over time. Both compounds 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 0–48 hours, followed by its glucuronide (30%). ESP15228 and its glucuronide accounted for 10% and 11% of the plasma AUC 0–48 hours, respectively.

Steady-state Cmax and AUC values of the equi-potent active metabolite (ESP15228) of bempedoic acid in patients with hypercholesterolaemia were 3.0 (1.4) µg/mL and 54.1 (26.4) µg·h/mL, respectively. ESP15228 likely contributes minimally to the overall clinical activity of bempedoic acid based on systemic exposure and pharmacokinetic properties.

Elimination

Steady-state clearance (CL/F) of bempedoic acid, determined by population pharmacokinetic (PK) analysis in patients with hypercholesterolaemia, was 12.1 mL/min following once-daily administration; 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.

Following a single 240 mg oral dose of 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 faeces. Less than 5% of the administered dose was excreted unchanged in urine and faeces combined.

Special patient populations

Renal impairment

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 based on steady-state AUC of bempedoic acid, 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 precautions"). Information in patients with severe renal impairment is 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 bempedoic acid did not include patients with end-stage renal disease on dialysis (see section "Special precautions").

Hepatic impairment

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 hepatic function, mean Cmax and AUC values 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. Therefore, dose adjustment is not required in patients with mild or moderate hepatic impairment.

Bempedoic acid has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Other special patient populations

The pharmacokinetics of bempedoic acid were independent of age, gender, and race. Body weight was a statistically significant covariate. The lowest quartile of body weight (<73 kg) was associated with approximately 30% higher exposure. The increase in exposure was not clinically significant, and dose adjustment based on body weight is not recommended.

Clinical Characteristics

Indications

Hypercholesterolemia and Mixed Dyslipidemia

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

• in combination with statins or statin combined with other lipid-lowering agents in patients in whom adequate LDL-C levels cannot be achieved with the maximum tolerated dose of statin;
• alone or in combination with other lipid-lowering agents in patients who are statin intolerant or for whom statins are contraindicated.

Cardiovascular Diseases

The medicinal product Leqvio is indicated for adults with established or high risk of atherosclerotic cardiovascular diseases to reduce cardiovascular risk by lowering LDL-C levels as an adjunct to correction of other risk factors:

• for patients taking the maximum tolerated dose of statin with or without ezetimibe;
• alone or in combination with ezetimibe in patients who are statin intolerant or for whom statins are contraindicated.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in the composition of the medicinal product. Pregnancy or breastfeeding. Concomitant use with simvastatin at doses > 40 mg daily.

Interaction with Other Medicinal Products and Other Types of Interactions

Effect of Other Medicinal Products on Bempedoic Acid

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

Effect of Bempedoic Acid on Other Medicinal Products

Statins

Pharmacokinetic interactions between bempedoic acid 180 mg and simvastatin 40 mg, atorvastatin 80 mg, pravastatin 80 mg, and rosuvastatin 40 mg were evaluated in clinical studies. Administration of a single dose of simvastatin 40 mg together with steady-state bempedoic acid 180 mg led to a doubling of simvastatin exposure. When co-administered with bempedoic acid 180 mg, AUC increased by 1.4–1.5 times for atorvastatin, pravastatin, and rosuvastatin (single doses administered) and/or their major metabolites. Greater increases were observed when these statins were co-administered with a supratherapeutic dose of bempedoic acid 240 mg (see section "Special Warnings and Precautions for Use").

Drug Interactions Mediated by Transporters

Bempedoic acid and its glucuronide weakly inhibit OATP1B1 and OATP1B3 at clinically relevant concentrations. Concomitant administration of bempedoic acid with medicinal products 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 substrates of OAT2. Bempedoic acid may also weakly inhibit OAT3 at clinically relevant concentrations.

Ezetimibe

Total AUC and maximum concentration (Cmax) of ezetimibe glucuronide in serum (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 together with bempedoic acid at steady state. This increase is likely related to inhibition of OATP1B1 by bempedoic acid, leading to reduced hepatic uptake and consequently reduced elimination of ezetimibe glucuronide. The increase in AUC and Cmax for ezetimibe was less than 20%. This increase is not clinically significant and does not affect dosing recommendations.

Other Interactions

Bempedoic acid had no effect on the pharmacokinetics or pharmacodynamics of metformin or on the pharmacokinetics of the oral contraceptive norethindrone/ethinyl estradiol.

Special precautions for use

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"). Patients receiving the medicinal product as add-on therapy to statins should be monitored for adverse reactions associated with high-dose statin use. Statins may occasionally cause myopathy. In rare cases, myopathy may manifest as rhabdomyolysis with or without acute renal failure due to myoglobinuria, which may lead to fatal outcomes. All patients receiving bempedoic acid in addition to statins should be informed about the potential increased risk of myopathy and should report immediately 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 dose of the statin to the lowest approved dose, switching to an alternative statin, or discontinuing bempedoic acid and initiating alternative lipid-lowering therapy with close monitoring of lipid levels and adverse reactions. If myopathy is confirmed by creatine kinase (CK) levels >10× the upper limit of normal (ULN), treatment with the medicinal product and any concomitantly administered statins should be discontinued immediately. Myositis with CK levels >10 × ULN has been rarely observed with bempedoic acid in combination with background therapy of 40 mg simvastatin. Doses of simvastatin >40 mg should not be used with bempedoic acid (see sections "Dosage and administration" and "Contraindications").

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 shoulder rotator cuff, biceps tendon, or Achilles tendon. Tendon rupture occurred weeks or months after initiation of treatment and may occur more frequently in patients over 60 years of age, those taking corticosteroids or fluoroquinolones, patients with renal impairment, and those with pre-existing 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 advice 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 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"). Treatment with bempedoic acid should be discontinued if symptomatic hyperuricemia or gout occurs.

Elevated liver enzymes

In clinical trials, elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels >3 × ULN have been 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. Liver function tests should be performed at the initiation of therapy. Treatment with bempedoic acid should be discontinued if transaminase elevations >3 × ULN persist (see section "Adverse reactions").

Renal function impairment

Experience with bempedoic acid 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 (see section "Pharmacokinetics"). Additional monitoring for adverse reactions may be required when using the medicinal product in such patients.

Hepatic function impairment

Patients with severe hepatic impairment (Child-Pugh class C) have not been studied (see section "Pharmacokinetics"). Periodic liver function tests should be considered in patients with severe hepatic impairment.

Contraceptive measures in women of reproductive potential

Before initiating treatment in women of reproductive age, appropriate counseling on effective contraceptive methods should be provided, and effective contraception should be initiated.

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

Important information about excipients

The medicinal product contains lactose. Patients with rare hereditary conditions 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 tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product is contraindicated during pregnancy (see section "Contraindications"). Data on the use of bempedoic acid in pregnant women are lacking or limited. Animal studies have shown reproductive toxicity with bempedoic acid. Since bempedoic acid reduces cholesterol synthesis and possibly the synthesis of other cholesterol derivatives necessary for normal fetal development, it may harm the fetus when administered to pregnant women. Treatment with 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 contraception during treatment (see section "Special precautions for use").

Breastfeeding

It is unknown whether bempedoic acid or its 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

There are no data on the effect of bempedoic acid on human fertility. Based on animal studies, no effect of the medicinal product on reproductive function or fertility is expected.

Ability to affect reaction speed while driving or operating machinery

The medicinal product has no effect or a negligible effect on the ability to drive or operate machinery.

Dosage and Administration

Administration

Each film-coated tablet should be taken orally, regardless of food intake. The tablet should be swallowed whole.

Dosage

The recommended dose of the medicinal product is 1 film-coated tablet of 180 mg taken once daily.

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 benefit is expected to outweigh 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

Dose adjustment is not 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 required in these patients when using the medicinal product (see section "Special Warnings and Precautions for Use").

Patients with hepatic impairment

Dose adjustment is not required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Data in patients with severe hepatic impairment are lacking. Patients with severe hepatic impairment should undergo periodic monitoring of liver function tests (see section "Special Warnings and Precautions for Use").

Children

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

Overdose

Symptoms. Doses up to 240 mg/day of bempedoic acid (1.3 times the approved recommended dose) have been used in clinical trials without evidence of dose-limiting 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.

Treatment. There is no specific antidote for bempedoic acid overdose. In case of overdose, symptomatic treatment and supportive measures should be initiated as needed.

Adverse Reactions

Summary of safety profile

The most commonly reported adverse reactions with bempedoic acid in pivotal studies included hyperuricemia (3.8%), limb pain (3.1%), anemia (2.5%), and gout (1.4%). 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 differences between bempedoic acid and placebo were not substantial.

Tabulated list of adverse reactions

Adverse reactions reported during administration of bempedoic acid, based on incidence rates from phase 3 primary hyperlipidemia studies and exposure-adjusted incidence rates from the CLEAR Outcomes study, are listed below by system organ class and frequency. All adverse reactions are categorized by system organ class and frequency as follows: 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 blood uric acid levels.

b (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 from 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 selected adverse reactions

Elevated liver enzymes

Elevations in serum transaminases (AST and/or ALT) have been reported with bempedoic acid use. In phase 3 primary hyperlipidemia studies, the incidence of elevation (≥3 × ULN) of liver transaminases was 0.7% in patients receiving bempedoic acid and 0.3% in placebo. In the CLEAR Outcomes study, the incidence of liver transaminase elevations >3× ULN was also more frequent in patients receiving bempedoic acid (1.6%) compared to placebo (1%). These transaminase elevations were not associated with other signs of hepatic dysfunction (see section "Special precautions for use").

Increased serum uric acid levels

Elevated serum uric acid levels have been observed in clinical trials of bempedoic acid, possibly related to inhibition of renal tubular OAT2 (see section "Interaction with other medicinal products and other forms of interaction"). In phase 3 primary hyperlipidemia studies, a mean increase in serum uric acid of 47.6 micromol/L (0.8 mg/dL) compared to baseline was observed at week 12 of bempedoic acid treatment. Increases in serum uric acid levels typically occurred within the first 4 weeks of treatment and returned to baseline after discontinuation of therapy. In phase 3 primary hyperlipidemia studies, gout was reported in 1.4% of patients receiving bempedoic acid and in 0.4% of patients receiving placebo (see section "Special precautions for use"). In the CLEAR Outcomes study, patients receiving bempedoic acid experienced a mean increase in serum uric acid of 47.6 micromol/L (0.8 mg/dL) compared to baseline at month 3, and gout was also more frequently reported 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 serum uric acid levels above the upper limit of normal.

Effect on serum creatinine and blood urea nitrogen

Bempedoic acid has been shown to increase serum creatinine and blood urea nitrogen (BUN). In phase 3 primary hyperlipidemia studies, a mean increase in serum creatinine of 4.4 micromol/L (0.05 mg/dL) and a mean increase in BUN of 0.61 mmol/L (1.7 mg/dL) compared to baseline were observed at week 12 of bempedoic acid treatment. Increases in serum creatinine and BUN typically occurred within the first 4 weeks of treatment, remained stable, and returned to baseline 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 bempedoic acid's inhibition of OAT2-dependent tubular secretion of creatinine (see section "Interaction with other medicinal products and other forms of interaction"), representing an interaction of bempedoic acid with an endogenous substrate and apparently not indicating worsening renal function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients receiving bempedoic acid therapy, particularly in patients with renal conditions or those receiving medications requiring monitoring of estimated creatinine clearance.

Decreased hemoglobin

Decreased hemoglobin levels have been observed in clinical trials of bempedoic acid. In phase 3 primary hyperlipidemia studies, hemoglobin reductions from baseline of ≥20 g/L and < lower limit of normal (LLN) occurred in 4.6% of patients in the bempedoic acid group compared to 1.9% in the placebo group. Hemoglobin reductions of >50 g/L and <LLN occurred at similar frequencies in the bempedoic acid and placebo groups (0.2% vs. 0.2%, respectively). Hemoglobin reductions typically occurred within the first 4 weeks of treatment and returned to baseline after discontinuation of therapy. Among patients who had normal hemoglobin levels at study initiation, hemoglobin values below LLN were observed in 1.4% in the bempedoic acid group and 0.4% in the placebo group 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 reduction in hemoglobin was observed, and anemia was also more frequently reported in patients receiving bempedoic acid (4.7%) compared to those receiving placebo (3.9%).

Elderly patients

Of the 3621 patients treated with bempedoic acid in phase 3 primary hyperlipidemia studies, 2098 (58%) were aged >65 years. In the CLEAR Outcomes study, 4141 patients (59%) treated with bempedoic acid were aged ≥65 years, and 1066 patients (15%) treated with bempedoic acid were aged ≥75 years. No overall differences in safety between elderly patients and younger populations were observed.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: 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. Sandoz Spain, S.L.

Manufacturer's address and location of operations

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