Nustendi

HOS-287557 · has-adverse-reaction-information · PDF-Seite 8

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). 8 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 Anaemiaa Common disorders Decreased haemoglobin Metabolism and nutrition Hyperuricaemiaa,b Common disorders Decreased appetite Common Nervous system disorders Dizziness Common Headache Vascular disorders Hypertension Common Respiratory, thoracic and Cough Common mediastinal disorders Gastrointestinal disorders Constipation Common Diarrhoea

Auszug; vollständigen Abschnitt im Original lesen.

HOS-287553 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to the active substances 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. 3

HOS-287552 · has-indication-information · PDF-Seite 2

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. 2

HOS-287555 · has-interaction-information · PDF-Seite 5

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 5 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

Auszug; vollständigen Abschnitt im Original lesen.

HOS-287556 · has-pregnancy-information · PDF-Seite 7

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 7 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).

HOS-287554 · has-warning-information · PDF-Seite 4

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, conse

Auszug; vollständigen Abschnitt im Original lesen.