Nilemdo · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-098961 · has-adverse-reaction-information · PDF-Seite 6

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. 6 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 Hyperuricaemiaa,b Common Weight decreasedc Uncommon Hepatobiliary disorders Aspartate Common aminotransferase increased Alanine aminotransferase Uncommon increased Liver function test Uncommon increased Musculoskeletal and connective tissue Pain in extremity Common disorders Renal and urinary disorders Glomerular filtration rate Common

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HOS-098957 · has-contraindication-information · PDF-Seite 3

• 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).

HOS-098956 · has-indication-information · PDF-Seite 2

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.

HOS-098959 · has-interaction-information · PDF-Seite 5

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.

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HOS-098960 · has-pregnancy-information · PDF-Seite 6

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).

HOS-098958 · has-warning-information · PDF-Seite 3

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. 3 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 chole

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