4.1. Therapeutic indications

Hypercholesterolaemia and mixed dyslipidaemia

Nilemdo is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non‑familial) or mixed dyslipidaemia, as an adjunct to diet:

• in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach low-density lipoprotein cholesterol (LDL‑C) goals with the maximum tolerated dose of a statin (see sections 4.2, 4.3, and 4.4) or,

• alone or in combination with other lipid-lowering therapies in patients who are statin‑intolerant, or for whom a statin is contraindicated.

Cardiovascular disease

Nilemdo is indicated in adults with established or at high risk for atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels, as an adjunct to correction of other risk factors:

• in patients on a maximum tolerated dose of a statin with or without ezetimibe or,

• alone or in combination with ezetimibe in patients who are statin-intolerant, or for whom a statin is contraindicated.

For study results with respect to effects on LDL-C, cardiovascular events and populations studied see section 5.1.

4.2. Posology and method of administration

Posology

The recommended dose of Nilemdo is one film-coated tablet of 180 mg taken once daily.

Concomitant simvastatin therapy

When Nilemdo is coadministered with simvastatin, simvastatin dose should be limited to 20 mg daily (or 40 mg daily for patients with severe hypercholesterolaemia and high risk for cardiovascular complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks) (see sections 4.4 and 4.5).

Special populations

Elderly patients

No dose adjustment is necessary in elderly patients (see section 5.2).

Patients with renal impairment

No dose adjustment is necessary in patients with mild or moderate renal impairment. There are limited data available in patients with severe renal impairment (defined as estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2), and patients with end-stage renal disease (ESRD) on dialysis (see section 5.2). Additional monitoring for adverse reactions may be warranted in these patients when Nilemdo is administered (see section 4.4).

Patients with hepatic impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B). No data are available in patients with severe hepatic impairment (Child-Pugh C). Periodic liver function tests should be considered for patients with severe hepatic impairment (see section 4.4).

Paediatric population

The safety and efficacy of Nilemdo in children aged less than 18 years have not yet been established. No data are available.

Method of administration

Each film-coated tablet should be taken orally with or without food. Tablet should be swallowed whole.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Pregnancy (see section 4.6).

• Concomitant use with simvastatin > 40 mg daily (see sections 4.2, 4.4, and 4.5).

4.4. Special warnings and precautions for use

Potential risk of myopathy with concomitant use of statins

Bempedoic acid increases plasma concentrations of statins (see section 4.5). Patients receiving Nilemdo as adjunctive therapy to a statin should be monitored for adverse reactions that are associated with the use of high doses of statins. Statins occasionally cause myopathy. In rare cases, myopathy may take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and can lead to fatality. All patients receiving Nilemdo in addition to a statin should be advised of the potential increased risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness. If such symptoms occur while a patient is receiving treatment with Nilemdo and a statin, a lower maximum dose of the same statin or an alternative statin, or discontinuation of Nilemdo and initiation of an alternative lipid-lowering therapy should be considered under close monitoring of lipid levels and adverse reactions. If myopathy is confirmed by a creatine phosphokinase (CPK) level > 10× upper limit of normal (ULN), Nilemdo and any statin that the patient is taking concomitantly should be immediately discontinued.

Myositis with a CPK level > 10× ULN was rarely reported with bempedoic acid and background simvastatin 40 mg therapy. Doses of simvastatin > 40 mg should not be used with Nilemdo (see sections 4.2 and 4.3).

Concomitant use of fibrates

Concomitant administration of fibrates with bempedoic acid resulted in increased triglycerides and decreased high-density lipoprotein cholesterol (HDL-C) in some patients in clinical studies and post-marketing reports. High-density lipoprotein cholesterol and triglycerides should be monitored (see section 4.5).

Increased serum uric acid

Bempedoic acid may raise the serum uric acid level due to inhibition of renal tubular OAT2 and may cause or exacerbate hyperuricaemia and precipitate gout in patients with a medical history of gout or predisposed to gout (see section 4.8). Treatment with Nilemdo should be discontinued if hyperuricaemia accompanied with symptoms of gout appear.

Elevated liver enzymes

In clinical trials, elevations of > 3× ULN in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported with bempedoic acid. These elevations have been asymptomatic and not associated with elevations ≥ 2× ULN in bilirubin or with cholestasis and have returned to baseline with continued treatment or after discontinuation of therapy. Liver function tests should be performed at initiation of therapy. Treatment with Nilemdo should be discontinued if an increase in transaminases of > 3× ULN persists (see section 4.8).

Renal impairment

There is limited experience with bempedoic acid in patients with severe renal impairment (defined as eGFR < 30 mL/min/1.73 m2), and patients with ESRD on dialysis (see section 5.2). Additional monitoring for adverse reactions may be warranted in these patients when Nilemdo is administered.

Hepatic impairment

Patients with severe hepatic impairment (Child-Pugh C) have not been studied (see section 5.2). Periodic liver function tests should be considered for patients with severe hepatic impairment.

Contraception measures in women of child-bearing potential

Before initiating treatment in women of child-bearing potential, appropriate advice on effective methods of contraception should be provided, and effective contraception initiated.

Patients taking oestrogen-based oral contraceptives should be advised about possible loss of effectiveness due to diarrhoea and/or vomiting. Patients should be advised to immediately contact their physician and stop treatment if they are planning to become pregnant or if they become pregnant (see section 4.6).

Excipients

Nilemdo 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 180 mg film-coated tablet (daily dose), i.e. essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on bempedoic acid

Transporter-mediated drug interactions

In vitro drug interaction studies suggest bempedoic acid, as well as its active metabolite and glucuronide form, are not substrates of commonly characterised drug transporters with the exception of bempedoic acid glucuronide, which is an OAT3 substrate.

Probenecid

Probenecid, an inhibitor of glucuronide conjugation, was studied to evaluate the potential effect of these inhibitors on the pharmacokinetics of bempedoic acid. Administration of bempedoic acid 180 mg with steady-state probenecid resulted in a 1.7-fold increase in bempedoic acid area under the curve (AUC) and a 1.9-fold increase in bempedoic acid active metabolite (ESP15228) AUC. These elevations are not clinically meaningful and do not impact dosing recommendations.

Effects of bempedoic acid on other medicinal products

Statins

The 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 trials. Administration of a single dose of simvastatin 40 mg with steady-state bempedoic acid 180 mg resulted in a 2-fold increase in simvastatin acid exposure. Elevations of 1.4-fold to 1.5-fold in AUC of atorvastatin, pravastatin, and rosuvastatin (administered as single doses) and/or their major metabolites were observed when coadministered with bempedoic acid 180 mg. Higher elevations have been observed when these statins were coadministered with a supratherapeutic 240 mg dose of bempedoic acid (see section 4.4).

Transporter-mediated drug interactions

Bempedoic acid and its glucuronide weakly inhibit OATP1B1 and OATP1B3 at clinically relevant concentrations. Coadministration 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 4.4]) may result in increased plasma concentrations of these medicinal products.

Bempedoic acid inhibits OAT2 in vitro, which may be the mechanism responsible for minor elevations in serum creatinine and uric acid (see section 4.8). 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 ezetimibe (ezetimibe and its glucuronide form) and ezetimibe glucuronide AUC and C maximum serum concentration (Cmax) increased approximately 1.6- and 1.8-fold, respectively, when a single dose of ezetimibe was taken with steady-state bempedoic acid. This increase is likely due to inhibition of OATP1B1 by bempedoic acid, which results in decreased hepatic uptake and subsequently decreased elimination of ezetimibe‑glucuronide. Increases in AUC and Cmax for ezetimibe were less than 20%. These elevations are not clinically meaningful and do not impact dosing recommendations.

Fibrates

Concomitant administration of fibrates with bempedoic acid resulted in increased triglycerides and decreased HDL-C in some patients in clinical studies and post-marketing reports. Reversibility of both increased triglycerides and decreased HDL-C levels were observed when either bempedoic acid or fibrate therapy was discontinued.

Triglycerides and HDL-C levels should be monitored at four weeks and periodically thereafter when bempedoic acid is used concomitantly with a fibrate (see section 4.4).

If clinically relevant increased triglycerides or decreased HDL-C levels are detected, bempedoic acid or fibrate therapy should be discontinued based on clinical judgement. Triglycerides and HDL-C levels should be monitored until levels return to baseline.

Increases in the incidences of anaemia and hyperuricaemia have been observed in patients with the concomitant use of bempedoic acid and fibrates (see section 4.8).

Other interactions studied

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

4.6. Fertility, pregnancy and lactation

Pregnancy

Nilemdo is contraindicated during pregnancy (see section 4.3).

There are no or limited amount of data from the use of bempedoic acid in pregnant women. Studies in animals with bempedoic acid have shown reproductive toxicity (see section 5.3).

Because bempedoic acid decreases cholesterol synthesis and possibly the synthesis of other cholesterol derivatives needed for normal foetal development, Nilemdo may cause foetal harm when administered to pregnant women. Nilemdo should be discontinued prior to conception or as soon as pregnancy is planned or recognized (see section 4.3).

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment (see section 4.4).

Breast‑feeding

Bempedoic acid and its active metabolite are excreted in human milk in very low amounts (mean relative infant dose (RID) of approximately 0.5% for bempedoic acid), therefore, at therapeutic doses of Nilemdo no effects on the breastfed newborns/infants are anticipated (see section 5.2).

The use of Nilemdo during breast-feeding may be considered, weighing the benefit of breast-feeding for the child against the benefit of therapy for the woman.

Fertility

No data on the effect of Nilemdo on human fertility are available. Based on animal studies, no effect on reproduction or fertility is expected with Nilemdo (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with bempedoic acid during pivotal trials were hyperuricaemia (3.8%), pain in extremity (3.1%), anaemia (2.5%), and gout (1.4%). More patients on bempedoic acid compared to placebo discontinued treatment due to muscle spasms (0.7% versus 0.3%), diarrhoea (0.5% versus <0.1%), pain in extremity (0.4% versus 0), and nausea (0.3% versus 0.2%), although differences between bempedoic acid and placebo were not significant.

Tabulated list of adverse reactions

Adverse reactions reported with bempedoic acid, based on incidence rates from phase 3 primary hyperlipidaemia studies and exposure adjusted incidence rates from CLEAR Outcomes study, are displayed by system organ class and frequency in table 1.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (cannot be estimated from the available data).

Table 1: Adverse reactions

System organ class (SOC)

Adverse reactions

Frequency categories

Blood and lymphatic system disorders

Anaemiaa

Common

Haemoglobin decreased

Uncommon

Metabolism and nutrition disorders

Gout

Common

Hyperuricaemiab

Common

Weight decreasedc

Uncommon

Hepatobiliary disorders

Aspartate aminotransferase increased

Common

Alanine aminotransferase increased

Uncommon

Liver function test increased

Uncommon

Musculoskeletal and connective tissue disorders

Pain in extremity

Common

Renal and urinary disorders

Glomerular filtration rate decreased

Common

Blood creatinine increased

Uncommon

Blood urea increased

Uncommon

a. See section 4.5

b. Hyperuricaemia includes hyperuricaemia and blood uric acid increased

c. (CLEAR Outcomes study) Weight decrease was observed only in patients with a baseline body mass index (BMI) of ≥30 kg/m2, with a mean body weight reduction of -2.28 kg at month 36. Mean reduction in body weight 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 of < 25 kg/m2

Description of selected adverse reactions

Hepatic enzyme elevations

Increases in serum transaminases (AST and/or ALT) have been reported with bempedoic acid. In the phase 3 primary hyperlipidaemia studies, the incidence of elevations (≥ 3× ULN) in hepatic transaminase levels was 0.7% for patients treated with bempedoic acid and 0.3% for placebo. In the CLEAR Outcomes study, the incidence of elevations ≥ 3× ULN in hepatic transaminase levels also occurred more frequently in bempedoic acid-treated patients (1.6%) than in placebo-treated patients (1.0%). These elevations in transaminases were not associated with other evidence of liver dysfunction (see section 4.4).

Increased serum uric acid

Increases in serum uric acid were observed in clinical trials with bempedoic acid possibly related to inhibition of renal tubular OAT2 (see section 4.5). In the phase 3 primary hyperlipidemia studies, a mean increase of 47.6 micromole/L (0.8mg/dL) in uric acid compared to baseline was observed with bempedoic acid at week 12. The elevations in serum uric acid usually occurred within the first 4 weeks of treatment and returned to baseline following discontinuation of treatment. In the phase 3 primary hyperlipidemia studies, gout was reported in 1.4% of patients treated with bempedoic acid and 0.4% of patients treated with placebo (see section 4.4). In the CLEAR Outcomes study, a mean increase of 47.6 micromole/L (0.8 mg/dL) in uric acid compared to baseline was observed in bempedoic acid-treated patients at month 3, and gout was also reported more frequently in bempedoic acid-treated patients (3.1%) than placebo-treated patients (2.1%). In both treatment groups, patients who reported gout were more likely to have a medical history of gout and/or baseline levels of uric acid above the ULN. An increase in the incidence of hyperuricaemia was observed in patients treated concomitantly with bempedoic acid and a fibrate. In the CLEAR Outcomes study, hyperuricaemia was reported more frequently in bempedoic acid-treated patients taking a fibrate at baseline (19.5%) compared to patients not taking a fibrate (10.4%), see section 4.5. There was no increase in the incidence of gout in bempedoic acid-treated patients taking a fibrate at baseline (1.1%) compared to patients not taking a fibrate (3.2%).

Effects on serum creatinine and blood urea nitrogen

Bempedoic acid has been shown to increase serum creatinine and blood urea nitrogen (BUN). In the phase 3 primary hyperlipidemia studies, a mean increase of 4.4 micromole/L (0.05mg/dL) in serum creatinine and a mean increase of 0.61 mmol/L (1.7 mg/dL) in BUN compared to baseline was observed with bempedoic acid at week 12. The elevations in serum creatinine and BUN usually occurred within the first 4 weeks of treatment, remained stable, and returned to baseline following discontinuation of treatment. Similar mean increases in serum creatinine (5.8 micromole/L (0.066 mg/dL)) and BUN (0.82 mmol/L (2.3 mg/dL)) were observed with bempedoic acid in the CLEAR Outcomes study.

The observed elevations in serum creatinine may be associated with bempedoic acid inhibition of OAT2‑dependent renal tubular secretion of creatinine (see section 4.5), representing a drug-endogenous substrate interaction and does not appear to indicate worsening renal function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients on Nilemdo therapy, particularly in patients with medical conditions or receiving medicinal products that require monitoring of estimated creatinine clearance.

Decreased haemoglobin

Decreases in haemoglobin were observed in clinical trials with bempedoic acid. In the phase 3 primary hyperlipidaemia studies, a decrease in haemoglobin from baseline of ≥ 20 g/L and < lower limit of normal (LLN) was observed in 4.6% of patients in the bempedoic acid group compared with 1.9% of patients on placebo. Greater than 50 g/L and < LLN decreases in haemoglobin were reported at similar rates in bempedoic acid and placebo groups (0.2% versus 0.2%, respectively). The decreases in haemoglobin usually occurred within the first 4 weeks of treatment and returned to baseline following discontinuation of treatment. Among patients who had normal haemoglobin values at baseline, 1.4% in the bempedoic acid group and 0.4% in the placebo group experienced haemoglobin values below LLN while on treatment. In the phase 3 primary hyperlipidemia studies, anaemia was reported in 2.5% of patients treated with bempedoic acid and 1.6% of patients treated with placebo. In the CLEAR Outcomes study, similar decreases in haemoglobin were observed, and anaemia was also reported more frequently in bempedoic acid-treated patients (4.7%) compared to placebo-treated patients (3.9%). An increase in the incidence of anaemia was observed in patients treated concomitantly with bempedoic acid and a fibrate. In the CLEAR outcomes study, anaemia was reported more frequently in bempedoic acid-treated patients taking a fibrate at baseline (9.6%) compared to patients not taking a fibrate (4.5%).

Elderly population

Of the 3 621 patients treated with bempedoic acid in the phase 3 primary hyperlipidemia studies, 2 098 (58%) were > 65 years old. In the CLEAR Outcomes study, 4 141 patients (59%) treated with bempedoic acid were ≥65 years of age and 1 066 patients (15%) treated with bempedoic acid were ≥75 years of age. No overall difference in safety was observed between elderly and the younger population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Doses up to 240 mg/day (1.3 times the approved recommended dose) have been administered in clinical trials with no evidence of dose limiting toxicity.

No adverse events were observed in animal studies at exposures up to 14-fold higher than those in patients treated with bempedoic acid at 180 mg once daily.

There is no specific treatment for a Nilemdo overdose. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.