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Safety profile
For NUSTENDI®
For full safety information, please refer to the NUSTENDI® SmPC before prescribing.1
Tabulated list of adverse reactions
Adverse reactions reported with NUSTENDI® are displayed by system organ class and frequency. Any additional adverse reactions that have been reported with bempedoic acid (based on incidence rates from Phase 3 hyperlipidaemia studies and exposure adjusted incidence rates from the CLEAR Outcomes study), or ezetimibe have also been presented to provide a more comprehensive adverse reaction profile for NUSTENDI®.1,2
In placebo-controlled Phase 3 hyperlipidaemia studies with bempedoic acid, more patients on bempedoic acid compared to placebo discontinued treatment due to muscle spasms (0.7% vs. 0.3%), diarrhoea (0.5% vs. < 0.1%), pain in extremity (0.4% vs. 0), and nausea (0.3% vs. 0.2%) although differences between bempedoic acid and placebo were not significant.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).
Serious adverse reactions reported for ezetimibe were myopathy, rhabdomyolysis, hepatitis, hypersensitivity, anaphylaxis, angioedema, erythema multiforme, cholelithiasis, cholecystitis, pancreatitis and thrombocytopenia.1
*Hyperuricaemia includes hyperuricaemia and blood uric acid increased.1
†Liver function test increased includes liver function test increased and liver function test abnormal.1
‡(CLEAR Outcomes study) Weight decrease was observed only in patients with a baseline 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/m2.1
§Adverse reactions with ezetimibe coadministered with a statin.1
- Concomitant use with simvastatin >40 mg daily is contraindicated; please refer to the SmPC for more information.1
- When NUSTENDI® is co-administered with simvastatin, the simvastatin dose should be limited to 20 mg daily (or 40 mg daily for patients with severe hypercholesterolaemia and who are at high risk for CV complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks)1
- Hypersensitivity to the active substance or to any of the excipients1
- Pregnancy1
- Breastfeeding1
- NUSTENDI® co-administered with a statin in patients with active liver disease or unexplained persistent elevations in serum transaminases1
- When NUSTENDI® is co-administered with a statin, please refer to the SmPC for that particular statin therapy1
Risk of myopathy with concomitant use of statins1
- Monitor 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 whilst 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 >10× 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®
Risk of increased serum uric acid1
- Bempedoic acid may cause or exacerbate hyperuricaemia and precipitate gout in patients with a medical history of gout or predisposed to gout
- Treatment with NUSTENDI® should be discontinued if hyperuricaemia accompanied with symptoms of gout appear
Risk of elevated liver enzymes1
- In clinical trials, elevations of >3× ULN in the liver enzymes ALT and 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 and treatment with NUSTENDI® discontinued if an increase in transaminases of >3× ULN persists
Ciclosporin1
- Caution should be exercised when initiating NUSTENDI® in the setting of ciclosporin. Ciclosporin concentrations should be monitored in these patients
Moderate to severe hepatic impairment1
- 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
Severe renal impairment1
- There is limited experience with bempedoic acid in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), and in patients with end-stage renal disease on dialysis
- Additional monitoring for adverse reactions may be warranted in these patients when NUSTENDI® is administered
Pregnancy & contraception measures in women of child-bearing potential1
- Prior to NUSTENDI® treatment, 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
- Advise patients to immediately contact their physician and stop taking NUSTENDI® if they become or plan to become pregnant. Women of childbearing potential must use effective contraception during treatment
Hereditary problems1
- NUSTENDI® contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take NUSTENDI®
Anticoagulants1
- If NUSTENDI® is added to warfarin, other coumarin anticoagulants, or fluindione, the international normalised ratio should be appropriately monitored
Cholelithiasis1
- The safety and efficacy of ezetimibe administered with fibrates have not been established
- If suspected in patients receiving NUSTENDI® and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued
Driving and use of heavy machinery1
- Has a minor influence (dizziness) on the ability to drive and use machines
Patients at high risk of cardiovascular disease1
- CV risk reduction estimation for ezetimibe in primary prevention patients has not been established. Evidence for the use of NUSTENDI® in patients at high risk of ASCVD is only available for the lipid-lowering effect (see section 5.1 of the NUSTENDI® SmPC)
Administration precaution: Bile acid sequestrants1
- For patients taking NUSTENDI® and bile acid sequestrants concomitantly, dosing of NUSTENDI® should occur either at least 2 hours before or at least 4 hours after administration of a bile acid sequestrant
Please refer to the NUSTENDI® SmPC for more information.1
For NILEMDO®
For full safety information, please refer to the NILEMDO® SmPC before prescribing.3
Tabulated list of adverse reactions
Adverse reactions reported are based on incidence rates from Phase 3 hyperlipidaemia studies and exposure adjusted incidence rates from the CLEAR Outcomes study.2,3
More patients on bempedoic acid compared to placebo discontinued treatment due to muscle spasms (0.7% vs. 0.3%), diarrhoea (0.5% vs. <0.1%), pain in extremity (0.4% vs. 0), and nausea (0.3% vs. 0.2%) although differences between bempedoic acid and placebo were not significant.3,4
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).
*Hyperuricaemia includes hyperuricaemia and blood uric acid increased.3
†(CLEAR Outcomes study) Weight decrease was observed only in patients with a baseline 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/m2.3
- Concomitant use of NILEMDO® with simvastatin >40 mg daily is contraindicated; please refer to the SmPC for more information.3
- When NILEMDO® is co-administered with simvastatin, the simvastatin dose should be limited to 20 mg daily (or 40 mg daily for patients with severe hypercholesterolaemia and who are at high risk for CV complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks)3
- Hypersensitivity to the active substance or to any of the excipients3
- Pregnancy3
- Breastfeeding3
Risk of myopathy with concomitant use of statins3
- Monitor for adverse reactions that are associated with the use of high doses of statins
- 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 whilst 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 CPK level >10× 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®
Risk of increased serum uric acid3
- Bempedoic acid may cause or exacerbate hyperuricaemia and precipitate gout in patients with a medical history of gout or predisposed to gout
- Treatment with NILEMDO® should be discontinued if hyperuricaemia accompanied with symptoms of gout appear
Risk of elevated liver enzymes3
- In clinical trials, elevations of >3× ULN in the liver enzymes ALT and 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 and treatment with NILEMDO® discontinued if an increase in transaminases of >3× ULN persists
Severe renal impairment3
- There is limited experience with bempedoic acid in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), and in patients with end-stage renal disease on dialysis
- Additional monitoring for adverse reactions may be warranted in these patients when NILEMDO® is administered
Pregnancy & contraception measures in women of child-bearing potential3
- Prior to NILEMDO® treatment, 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
- Advise patients to immediately contact their physician and stop taking NILEMDO® if they become or plan to become pregnant. Women of childbearing potential must use effective contraception during treatment
Hereditary problems3
- NILEMDO® contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take NILEMDO®
Severe hepatic impairment3
- Patients with severe hepatic impairment have not been studied. Periodic liver function tests should be considered for patients with severe hepatic impairment (Child-Pugh C)
Please refer to the NILEMDO® SmPC for more information.3
The CLEAR Outcomes study reinforces the benefit-risk profile of bempedoic acid with a consistent long-term safety profile across >48,000 patient-years of follow-up5
CLEAR Outcomes assessed bempedoic acid only. CV risk reduction estimation for ezetimibe in primary prevention patients has not been established.2 Evidence for use of NUSTENDI® in patients at high risk of ASCVD is only available for the lipid-lowering effect (see section 5.1 of the NUSTENDI® SmPC).1
The overall incidences of adverse events, serious adverse events and adverse events leading to discontinuation of the trial regimen did not differ meaningfully between the two trial groups.2
The incidences of adverse events were similar in the two trial groups,2 except for those shown in bold in the table.
*Patients with pre-diabetes at baseline were defined as: No past medical history of diabetes and with glycated haemoglobin level of ≥5.7% and <6.5% or 1 or more measurement of fasting glucose ≥100 mg/dL (5.6 mmol/L), but not more than 1 value of fasting glucose ≥126 mg/dL (7.0 mmol/L). Patients with normoglycemia at baseline did not meet criteria for prediabetes.5
Please refer to the NILEMDO® SmPC for more information.3
Adverse events reported in the primary prevention prespecified sub-analysis of the CLEAR Outcomes trial6
In the primary prevention prespecified sub-analysis of the CLEAR Outcomes trial, there were no differences reported between groups in serious adverse events, or adverse events leading to drug discontinuation.6 Reported Efficacy data.
Subgroup analyses are not adjusted for multiplicity and therefore do not provide definitive conclusions.
All reported adverse events other than the laboratory findings represent the investigator’s judgement. Specific guidance was not provided. Notable differences highlighted by investigators are marked in bold.
Adapted from Nissen SE, et al. 2023.6
*In patients with diabetes at baseline.6
†Patients with prediabetes at baseline were defined as: No past medical history of diabetes and with glycated haemoglobin level of ≥5.7% and <6.5% or 1 or more measurement of fasting glucose ≥100 mg/dL (5.6mmol/L), but not more than 1 value of fasting glucose ≥126 mg/dL (7.0 mmol/L). Patients with normoglycaemia at baseline did not meet criteria for prediabetes.6
In the diabetes prespecified sub-analysis of the CLEAR Outcomes trial, bempedoic acid was generally well tolerated across glycaemic strata7
In the diabetes prespecified sub-analysis of CLEAR Outcomes trial, there was a comparable incidence of adverse events across glycaemic strata vs. placebo.7 Reported Efficacy data.
In the CLEAR Outcomes diabetes sub analysis, there was no increase in the incidence of new-onset diabetes in patients treated with bempedoic acid vs. placebo after a median follow-up of 40.6 months.7 TEAEs, serious AEs and AEs leading to study drug discontinuation in the diabetes sub-analysis were comparable between bempedoic acid and placebo across glycaemia strata and were consistent with the CLEAR Outcomes overall population. Gout and cholelithiasis occurred more frequently with bempedoic acid irrespective of glycaemia strata.7
Subgroup analyses are not adjusted for multiplicity and therefore do not provide definitive conclusions.
Adapted from Ray KK, et al. 2024.7,8
*Normoglycaemia: Did not meet the criteria for either prediabetes or diabetes. Pre-diabetes: HbA1c 5.7–6.4% (39–48 mmol/mol), or ≥1 fasting serum glucose concentration of at least 5.6 mmol/L, but with no more than one value of ≥7.0 mmol/L. Diabetes: Medical history of DM; or use of glucose lowering medication; or HbA1c >6.5% (48 mmol/mol); or two or more fasting serum glucose concentration ≥7.0 mmol/L.7
References
- NUSTENDI® Summary of Product Characteristics.
- Nissen SE, et al. N Engl J Med. 2023;388(15):1353–1364.
- NILEMDO® Summary of Product Characteristics.
- Banach M, et al. JAMA Cardiol. 2020;5(10):1124–1135.
- Bays HE, et al. J Clin Lipidol. 2023;18:e59–e69.
- Nissen SE, et al. JAMA. 2023;330(2):131–140.
- Ray KK, et al. Lancet Diabetes Endocrinol. 2024;12:19–28.
- Ray KK, et al. Lancet Diabetes Endocrinol. 2024;12:19–28. Supplement.
Abbreviations
AE, adverse event; ALT, alanine aminotransferase; ASCVD, atherosclerotic cardiovascular disease; AST, aspartate aminotransferase; BMI, body mass index; CPK, creatine phosphokinase; CV, cardiovascular; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HbA1c, glycated haemoglobin; INR, international normalised ratio; NA, not applicable; SmPC, Summary of Product Characteristics; TEAE, treatment-emergent adverse event; ULN, upper limit of normal.
Job code: UK/BIL/06/25/0006|Date of preparation: July 2025