4.1. Therapeutic indications

Hypercholesterolaemia and mixed dyslipidaemia

Nustendi 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 in patients unable to reach low-density lipoprotein cholesterol (LDL-C) goals with the maximum tolerated dose of a statin in addition to ezetimibe (see sections 4.2, 4.3, and 4.4),

• alone in patients who are either statin-intolerant or for whom a statin is contraindicated, and are unable to reach LDL-C goals with ezetimibe alone,

• in patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets with or without statin.

Cardiovascular disease

Nustendi 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 and not adequately controlled with additional ezetimibe treatment or,

• in patients who are either statin-intolerant, or for whom a statin is contraindicated, and not adequately controlled with ezetimibe treatment or,

• in patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets.

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 Nustendi is one film-coated tablet of 180 mg/10 mg taken once daily.

Coadministration with bile acid sequestrants

Dosing of Nustendi should occur either at least 2 hours before or at least 4 hours after administration of a bile acid sequestrant.

Concomitant simvastatin therapy

When Nustendi 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 Nustendi is administered (see section 4.4).

Patients with hepatic impairment

No dose adjustment is necessary in patients with mild hepatic impairment (Child‑Pugh A). Treatment with Nustendi is not recommended in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment due to the unknown effects of the increased exposure to ezetimibe (see section 4.4).

Paediatric population

The safety and efficacy of Nustendi in children aged less than 18 years have not 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).

• Nustendi coadministered with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

• When Nustendi is coadministered with a statin, please refer to the summary of product characteristics (SmPC) for that particular statin therapy.

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). 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. In postmarketing experience with ezetimibe, very rare cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe.

Patients receiving Nustendi as adjunctive therapy to a statin should be monitored for adverse reactions that are associated with the use of high doses of statins. All patients receiving Nustendi 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 Nustendi and a statin, a lower maximum dose of the same statin or an alternative statin, or discontinuation of Nustendi 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), Nustendi 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 Nustendi (see sections 4.2 and 4.3).

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 Nustendi 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. In controlled coadministration trials in patients receiving ezetimibe with a statin, consecutive transaminase elevations (≥ 3× ULN) have been observed. Liver function tests should be performed at initiation of therapy. Treatment with Nustendi should be discontinued if an increase in transaminases of > 3× ULN persists (see sections 4.3 and 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 Nustendi is administered.

Hepatic impairment

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment (Child-Pugh B and C), Nustendi is not recommended in these patients (see section 5.2).

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).

If cholelithiasis is suspected in a patient receiving Nustendi and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see sections 4.5 and 4.8).

The safety and efficacy of ezetimibe administered with fibrates have not been established.

Ciclosporin

Caution should be exercised when initiating Nustendi in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Nustendi and ciclosporin (see section 4.5).

Anticoagulants

If Nustendi is added to warfarin, other coumarin anticoagulants, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).

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).

Patients at high risk of cardiovascular disease

Evidence for the use of the fixed combination medicinal product of bempedoic acid with ezetimibe in patients at high risk of cardiovascular disease is only available for the lipid-lowering effect in absence of any cardiovascular risk reduction estimation for ezetimibe in primary prevention patients (see section 5.1).

Excipients

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

This medicine contains less than 1 mmol sodium (23 mg) per 180 mg/10 mg film-coated tablet (daily dose), that is to say essentially 'sodium free'.

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

No specific pharmacokinetic drug interaction studies with Nustendi have been conducted. Drug interactions that have been identified in studies with bempedoic acid or ezetimibe determine the interactions that may occur with Nustendi.

Effects of other medicinal products on individual components of Nustendi

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).

Concomitant fenofibrate or gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1.5- and 1.7-fold, respectively). Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see section 5.3). A lithogenic risk associated with the therapeutic use of Nustendi cannot be ruled out.

If cholelithiasis is suspected in a patient receiving Nustendi and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered (see section 4.4).

Ciclosporin

In a study of eight post-renal transplant patients with creatinine clearance of > 50 mL/min on a stable dose of ciclosporin, a single 10 mg dose of ezetimibe resulted in a 3.4-fold (range 2.3- to 7.9-fold) increase in the mean area under the curve (AUC) for total ezetimibe compared to a healthy control population, receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal impairment who was receiving ciclosporin and multiple other medicinal products demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100 mg dose of ciclosporin on day 7 resulted in a mean 15% increase in ciclosporin AUC (range 10% decrease to 51% increase) compared to a single 100 mg dose of ciclosporin alone. A controlled study on the effect of coadministered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Caution should be exercised when initiating Nustendi in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Nustendi and ciclosporin (see section 4.4).

Cholestyramine

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe plus ezetimibe glucuronide) approximately 55%. The incremental low-density lipoprotein cholesterol (LDL-C) reduction due to adding Nustendi to cholestyramine may be lessened by this interaction (see section 4.2).

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 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 individual components of Nustendi 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).

No clinically significant pharmacokinetic interactions were seen when ezetimibe was coadministered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.

Transporter-mediated drug interactions

Bempedoic acid and its glucuronide weakly inhibit OATP1B1 and OATP1B3 at clinically relevant concentrations. Coadministration of Nustendi 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.

Anticoagulants

Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been postmarketing reports of increased INR in patients who had ezetimibe added to warfarin or fluindione.

If Nustendi is added to warfarin, other coumarin anticoagulants, or fluindione, INR should be appropriately monitored (see section 4.4).

Other interactions studied

Bempedoic acid had no effect on the pharmacokinetics of oral contraceptive norethindrone/ethinyl estradiol. In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of oral contraceptives ethinyl estradiol and levonorgestrel. Bempedoic acid had no effect on the pharmacokinetics or pharmacodynamics of metformin.

In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, glipizide, tolbutamide, or midazolam, during coadministration.

4.6. Fertility, pregnancy and lactation

Pregnancy

Nustendi is contraindicated during pregnancy (see section 4.3).

There are no or limited amount of data from the use of Nustendi 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, Nustendi may cause foetal harm when administered to pregnant women. Nustendi 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 ezetimibe and their active metabolites are excreted in human milk in very low amounts (mean relative infant dose (RID) of approximately 0.5% for bempedoic acid and 0.04% for ezetimibe), therefore, at therapeutic doses of Nustendi no effects on the breastfed newborns/infants are anticipated (see section 5.2).

The use of Nustendi 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 Nustendi on human fertility are available. Based on animal studies, no effect on reproduction or fertility is expected with Nustendi (see section 5.3).

4.7. Effects on ability to drive and use machines

Nustendi has minor influence on the ability to drive and use machines. When driving vehicles or using machines, it should be taken into account that dizziness has been reported with bempedoic acid and ezetimibe (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in Nustendi were hyperuricaemia (4.7%) and constipation (4.7%).

In placebo-controlled phase 3 primary hyperlipidaemia studies with bempedoic acid, 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.

Serious adverse reactions reported for ezetimibe were myopathy, rhabdomyolysis, hepatitis, hypersensitivity, anaphylaxis, angioedema, erythema multiforme, cholelithiasis, cholecystitis, pancreatitis and thrombocytopenia.

Tabulated list of adverse reactions

Adverse reactions reported with Nustendi are displayed by system organ class and frequency in table 1. Any additional adverse reactions that have been reported with bempedoic acid (based on incidence rates from phase 3 primary hyperlipidaemia studies and exposure adjusted incidence rates from CLEAR Outcomes study), or ezetimibe have also been presented to provide a more comprehensive adverse reaction profile for Nustendi.

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 (clinical studies and post-marketing experience)

System organ class (SOC)

Adverse reactions

Frequency categories

Adverse reactions with Nustendi

Blood and lymphatic system disorders

AnaemiaaDecreased haemoglobin

Common

Metabolism and nutrition disorders

Hyperuricaemiab

Common

Decreased appetite

Common

Nervous system disorders

DizzinessHeadache

Common

Vascular disorders

Hypertension

Common

Respiratory, thoracic and mediastinal disorders

Cough

Common

Gastrointestinal disorders

ConstipationDiarrhoeaAbdominal painNauseaDry mouthFlatulenceGastritis

Common

Hepatobiliary disorders

Liver function test increasedc

Common

Musculoskeletal and connective tissue disorders

Back painMuscle spasmsMyalgiaPain in extremityArthralgia

Common

Renal and urinary disorders

Blood creatinine increased

Common

General disorders and administration site conditions

FatigueAsthenia

Common

Additional adverse reactions with bempedoic acid

Metabolism and nutrition disorders

Gout

Common

Weight decreasede

Uncommon

Hepatobiliary disorders

Aspartate aminotransferase increased

Common

Alanine aminotransferase increased

Uncommon

Renal and urinary disorders

Glomerular filtration rate decreased

Common

Blood urea increased

Uncommon

Additional adverse reactions with ezetimibe

Blood and lymphatic system disorders

Thrombocytopaenia

Not known

Immune system disorders

Hypersensitivity, including rash, urticaria, anaphylaxis and angio-oedema

Not known

Psychiatric disorders

Depression

Not known

Nervous system disorders

Paraesthesiad

Not known

Vascular disorders

Hot flush

Uncommon

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Not known

Gastrointestinal disorders

DyspepsiaGastrooesophageal reflux disease

Uncommon

Pancreatitis

Not known

Hepatobiliary disorders

Aspartate aminotransferase increasedAlanine aminotransferase increasedGammaglutamyltransferase increased

Uncommon

HepatitisCholelithiasisCholecystitis

Not known

Skin and subcutaneous tissue disorders

Pruritusd

Uncommon

Erythema multiform

Not known

Musculoskeletal and connective tissue disorders

Blood CPK increased

Common

Neck painMuscular weaknessd

Uncommon

Myopathy/rhabdomyolysis

Not known

General disorders and administration site conditions

Chest painPainOedema peripherald

Uncommon

a. See section 4.5.

b. Hyperuricaemia includes hyperuricaemia and uric acid increased

c. Liver function test increased includes liver function test increased and liver function test abnormal

d. Adverse reactions with ezetimibe coadministered with a statin

e. (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

Increased serum uric acid

Nustendi increases serum uric acid possibly due to inhibition of renal tubular OAT2 by bempedoic acid (see section 4.5). A mean increase of 35.7 micromole/L (0.6 mg/dL) in uric acid compared to baseline was observed with Nustendi 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. There were no reports of gout with Nustendi. In the phase 3 primary hyperlipidaemia studies of bempedoic acid, gout was reported in 1.4% of patients treated with bempedoic acid and 0.4% of patients treated with placebo. 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 (see section 4.4). 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

Nustendi increases serum creatinine and blood urea nitrogen (BUN). A mean increase of 1.8 micromole/L (0.02 mg/dL) in serum creatinine and a mean increase of 1.0 mmol/L (2.7 mg/dL) in BUN compared to baseline was observed with Nustendi 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 therapy. 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 Nustendi therapy, particularly in patients with medical conditions or receiving medicinal products that require monitoring of estimated creatinine clearance.

Hepatic enzyme elevations

Hepatic transaminase (AST and/or ALT) elevations of ≥ 3× ULN were reported in 2.4% of patients treated with Nustendi compared with no patients on placebo. In four phase 3 primary hyperlipidaemia studies of bempedoic acid, the incidence of elevations (≥ 3× ULN) in hepatic transaminase levels (AST and/or ALT) was 0.7% for patients treated with bempedoic acid and 0.3% for placebo. In controlled clinical combination trials of ezetimibe initiated concurrently with a statin, the incidence of consecutive elevations (≥ 3× ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe administered with statins and 0.4% for patients treated with statins alone. 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%). The elevations in transaminases with bempedoic acid or ezetimibe were not associated with other evidence of liver dysfunction (see section 4.4).

Decreased haemoglobin

In the phase 3 primary hyperlipidaemia studies of bempedoic acid, 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 hyperlipidaemia 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%).

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

In the event of overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

Bempedoic acid

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.

Ezetimibe

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, did not result in an increase in the rate of adverse events. In animals, no toxicity was observed after single oral doses of 5 000 mg/kg of ezetimibe in rats and mice and 3 000 mg/kg in dogs.