Bempedoic acid (Tablets) Instructions for Use

Marketing Authorization Holder

Salyutfarma, LLC (Russia)

Manufactured By

OHFK, JSC (Russia)

ATC Code

C10AX15 (Bempedoic acid)

Active Substance

Bempedoic acid (Rec.INN registered by WHO)

Dosage Form

Bempedoic acid

Film-coated tablets 180 mg: 10, 28, 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; on the cross-section, the tablet core is white or almost white.

Excipients: lactose monohydrate, microcrystalline cellulose type 102, sodium carboxymethyl starch, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide.

Shell composition polyvinyl alcohol, titanium dioxide (E171), talc, macrogol.

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
28 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
90 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agents; other hypolipidemic agents

Pharmacological Action

Bempedoic acid is an adenosine triphosphate-citrate lyase (ATP-citrate lyase) inhibitor that suppresses cholesterol synthesis and reduces LDL-C by inhibiting cholesterol synthesis in the liver. ATP-citrate lyase is an enzyme that works upstream of HMG-CoA reductase in the cholesterol synthesis cascade. Bempedoic acid requires CoA for activation, upon attachment of which ETC-1002-CoA is formed. The reaction is catalyzed by long-chain acetyl-CoA synthetase 1 (ACSVL1). ACSVL1 is expressed primarily in the liver, not in skeletal muscle. Inhibition of ATP-citrate lyase by ETC-1002-CoA leads to reduced cholesterol synthesis in the liver and reduced blood LDL-C levels through activation of LDL receptors. Furthermore, inhibition of ATP-citrate lyase by ETC-1002-CoA leads to concomitant suppression of fatty acid biosynthesis in the liver.

Use of bempedoic acid as monotherapy and in combination with other lipid-modifying drugs reduces LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), and total cholesterol (TC) in patients with hypercholesterolemia or mixed dyslipidemia.

Since patients with diabetes are at increased risk of atherosclerotic cardiovascular disease, patients with diabetes mellitus were included in the clinical trials of bempedoic acid. In the subgroup of patients with diabetes, lower HbA_1c levels were observed compared to placebo (on average 0.2%). In patients without diabetes, no differences in HbA_1c levels were observed between bempedoic acid and placebo, and there were no differences in the incidence of hypoglycemia.

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

Pharmacokinetics

Bempedoic acid is absorbed with a mean time to reach C_max of 3.5 hours when taken as tablets containing 180 mg of bempedoic acid. Bempedoic acid can be considered a prodrug that is activated intracellularly by ACSVL1 to ETC-1002-CoA. Steady-state C_max and AUC after multiple administration in patients with hypercholesterolemia were 24.8 (6.9) µg/ml and 348 (120) µg×h/ml, respectively. Pharmacokinetics were generally linear over the dose range of 120-220 mg. After repeated administration at the recommended dose, the pharmacokinetics of bempedoic acid were time-independent, and the steady state of bempedoic acid was reached after 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. Food slows the rate of absorption of bempedoic acid; the absorption rate constant of bempedoic acid with food is 0.32/h.

The apparent V_d of bempedoic acid is 18 L. Plasma protein binding of bempedoic acid, its glucuronide, and its active metabolite ESP15228 is 99.3%, 98.8%, and 99.2%, respectively. Bempedoic acid does not penetrate into erythrocytes.

In vitro metabolic interaction studies suggest that Bempedoic acid, as well as its active metabolite and glucuronide forms, are not metabolized, do not inhibit, and do not induce cytochrome P450 enzymes.

The main route of elimination of bempedoic acid is metabolism to an acyl glucuronide. Bempedoic acid is also reversibly converted to an active metabolite (ESP15228) based on aldoketoreductase activity observed in vitro in human liver.

The steady-state clearance of bempedoic acid, determined by population pharmacokinetic analysis in patients with hypercholesterolemia, was 12.1 ml/min after once-daily administration; renal clearance of unchanged bempedoic acid is less than 2% of total clearance. The mean T_1/2 of bempedoic acid in humans was 19 h (10) at steady state.

After a single oral dose of 240 mg of bempedoic acid (1.3 times the approved recommended dose), 62.1% of the total dose (Bempedoic acid and its metabolites) was excreted in the urine, mainly as the acyl glucuronide conjugate of bempedoic acid, and 25.4% was found in feces. Less than 5% of the administered dose was excreted as unchanged bempedoic acid in feces and urine.

Indications

Primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia as an adjunct to diet in combination with HMG-CoA reductase inhibitors (statins) or statins used concomitantly with other hypolipidemic drugs in patients unable to achieve the target LDL-C level with the maximum tolerated dose of a statin; as monotherapy or in combination with other hypolipidemic drugs in patients with statin intolerance or in patients for whom they are contraindicated.

Cardiovascular diseases (in adult patients with established or high risk of atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels (as an adjunct to correction of other risk factors): in patients receiving the maximum tolerated dose of a statin, in combination with ezetimibe or without it; in patients with statin intolerance, or for whom statins are contraindicated, as monotherapy or in combination with ezetimibe.

ICD codes

Dosage Regimen

Take orally once daily.

The recommended dose is 180 mg (one tablet).

Take with or without food.

Swallow the tablet whole; do not split, crush, or chew.

For primary hypercholesterolemia or mixed dyslipidemia, use as an adjunct to diet.

Use in combination with a statin in patients not achieving LDL-C target on a maximum tolerated statin dose.

Use as monotherapy or in combination with other lipid-lowering drugs in patients with statin intolerance or contraindications.

For cardiovascular risk reduction in adults, use in patients on a maximum tolerated statin dose, with or without ezetimibe.

In patients with statin intolerance, use as monotherapy or combined with ezetimibe.

Do not co-administer with simvastatin at doses exceeding 40 mg/day.

Monitor for adverse reactions related to statins when used concomitantly.

Discontinue treatment if persistent liver enzyme elevations (ALT/AST) greater than 3 times the upper limit of normal occur.

Discontinue if symptomatic hyperuricemia or gout develops.

Women of childbearing potential must use effective contraception during therapy.

Adverse Reactions

Blood and lymphatic system disorders common – anemia; uncommon – decreased hemoglobin.

Metabolism and nutrition disorders common – gout, hyperuricemia (includes increased uric acid and its salts (urates) in the blood), weight loss (Bempedoic acid did not reduce weight in patients with baseline BMI<25 kg/m²).

Hepatobiliary disorders common – increased AST activity; uncommon – increased ALT activity, increased liver function test results (includes prothrombin time, aPTT, albumin, bilirubin (direct and indirect)).

Musculoskeletal and connective tissue disorders common – limb pain.

Renal and urinary disorders: uncommon – increased blood creatinine, urea, decreased glomerular filtration rate.

Contraindications

Hypersensitivity to the components of the drug; pregnancy; breastfeeding period; concomitant use with simvastatin taken in doses above 40 mg/day.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Women of childbearing potential should use effective contraception during bempedoic acid administration. Women should be advised to discontinue its use if they plan to become pregnant.

Pediatric Use

The safety and efficacy of bempedoic acid in children aged 0 to 18 years have not been established. No data available.

Special Precautions

Bempedoic acid increases the plasma concentration of statins when taken concomitantly. Patients receiving bempedoic acid as add-on therapy to statins should be monitored for the development of adverse reactions associated with the use of high doses of statins. Statins sometimes cause myopathy. In rare cases, myopathy may take the form of rhabdomyolysis with the development of acute renal failure, secondary to myoglobinuria or without it, which can be fatal. All patients receiving bempedoic acid in addition to statins should be informed about the increased risk of myopathy and should immediately report any unexplained muscle pain or weakness, as well as muscle tenderness on palpation. If such symptoms occur during treatment with bempedoic acid in combination with statins, consideration should be given to reducing the statin dose or switching to alternative lipid-lowering therapy under careful monitoring of lipid levels and adverse reactions, discontinuing bempedoic acid. If the development of myopathy is confirmed by an increase in CK activity exceeding 10 times the ULN, bempedoic acid and any concomitantly taken statins should be discontinued immediately.

However, myositis with CK activity >10×ULN is rarely observed with the use of bempedoic acid and background therapy with simvastatin at a daily dose not exceeding 40 mg. Simvastatin doses >40 mg should not be used together with bempedoic acid.

Bempedoic acid may increase serum uric acid levels due to inhibition of OAT in the renal tubules and may cause (worsen) hyperuricemia, leading to exacerbation of gout in patients with a history of gout or accelerate its development in predisposed patients. Treatment with bempedoic acid should be discontinued if hyperuricemia accompanied by symptoms of gout appears.

In clinical trials of bempedoic acid, cases of liver enzyme elevations (ALT and AST) greater than 3×ULN were reported. These elevations were asymptomatic and not accompanied by a significant increase in bilirubin levels (≥2×ULN) or cholestasis, and returned to baseline with continued treatment or after discontinuation of therapy. Liver function tests should be performed at the start of therapy. Treatment with bempedoic acid should be discontinued if liver enzyme elevations greater than 3×ULN persist.

Experience with bempedoic acid in patients with severe renal impairment (eGFR <30 ml/min/1.73 m²) is limited, and in patients on dialysis is absent. Additional monitoring for adverse reactions may be required when using bempedoic acid in such patients.

Experience with bempedoic acid in patients with severe hepatic impairment (Child-Pugh class C) is absent. Patients with severe hepatic impairment should undergo periodic liver function tests.

Use in pediatrics

The safety and efficacy of bempedoic acid in children aged 0 to 18 years have not been established. No data available.

Effect on ability to drive and operate machinery

Bempedoic acid has no or negligible influence on the ability to drive and use machines.

Drug Interactions

Bempedoic acid, as well as its active metabolite and glucuronide derivative, are not substrates of commonly described drug transporters, with the exception of bempedoic acid glucuronide, which is a substrate of OAT3.

Concomitant use of probenecid inhibits glucuronide conjugation. Administration of 180 mg bempedoic acid with probenecid resulted in a 1.7-fold increase in the steady-state AUC of bempedoic acid and a 1.9-fold increase in the AUC of the active metabolite of bempedoic acid (ESP15228). These increases in AUC are not clinically significant and do not affect dosing recommendations.

Clinical studies evaluated pharmacokinetic interactions between bempedoic acid (180 mg) and statins: simvastatin (40 mg), atorvastatin (80 mg), pravastatin (80 mg), and rosuvastatin (40 mg). Administration of a single 40 mg dose of simvastatin against the background of constant bempedoic acid intake (steady state) led to a 2-fold increase in the AUC of simvastatin acid. Concomitant use with bempedoic acid resulted in a 1.4-1.5-fold increase in the AUC of atorvastatin, pravastatin, and rosuvastatin (upon single administration) and/or their major metabolites. A greater increase in the AUC of these statins was observed with concomitant administration of bempedoic acid at a dose of 240 mg.

Bempedoic acid and its glucuronide at clinically relevant concentrations weakly inhibit OATP1B1 and OATP1B3. Concomitant use of bempedoic acid with drugs that are substrates of OATP1B1 or OATP1B3, for example, bosentan, fimasartan, asunaprevir, glecaprevir, grazoprevir, voxilaprevir or statins – atorvastatin, pravastatin, fluvastatin, pitavastatin, rosuvastatin and simvastatin may lead to an increase in the plasma concentration of these drugs.

Bempedoic acid inhibits OAT2 in vitro, which may be the mechanism responsible for the minor increase in serum creatinine and uric acid levels. Inhibition of OAT2 by bempedoic acid may also potentially increase the plasma concentration of drugs that are substrates of OAT2. Bempedoic acid at clinically relevant concentrations may also weakly inhibit OAT3.

AUC and C_max of total ezetimibe (ezetimibe and its glucuronide) and ezetimibe glucuronide increased approximately 1.6 and 1.8 times, respectively, when ezetimibe was taken as a single dose against the background of bempedoic acid steady state. This increase is likely due to inhibition of OATP1B1 by bempedoic acid, leading to reduced hepatic uptake and consequently reduced elimination of ezetimibe glucuronide. The increase in AUC and C_max for ezetimibe was less than 20%. These increases are not clinically significant and do not affect the dosing regimen.

Bempedoic acid does not affect the pharmacodynamics and pharmacokinetics of metformin, nor the pharmacokinetics of oral contraceptives (norethindrone/ethinyl estradiol).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.