Ezetimibe Sandoz Adverse Reactions

List of adverse reactions (clinical studies and post-marketing experience): In clinical studies of up to 112 weeks duration, ezetimibe 10 mg daily was administered alone in 2396 patients, or with a statin in 11,308 patients with fenofibrate in 185 patients. Adverse reactions were usually mild and transient. The overall incidence of side effects was similar between ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between ezetimibe and placebo.
Ezetimibe administered alone or co-administered with a statin: The following adverse reactions were observed in patients treated with ezetimibe (n=2396) and at a greater incidence than placebo (n=1159) or in patients treated with ezetimibe co-administered with a statin (n=11308) and at a greater incidence than statin administered alone (n=9361): Post-marketing adverse reactions were derived from reports containing ezetimibe either administered alone or with a statin.
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).
Ezetimibe monotherapy: Metabolism and nutrition disorders: Uncommon: Decreased appetite.
Vascula disorders: Uncommon: Hot flush; hypertension.
Respiratory, thoracic and mediastinal disorders: Uncommon: Cough.
Gastrointestinal disorders: Common: Abdominal pain; diarrhoea; flatulence; Uncommon: Dyspepsia; gastrooesophageal reflux disease; nausea.
Musculoskeletal and connective tissue disorders: Uncommon: Arthralgia; muscle spasms; neck pain.
General disorders and administration site condition: Common: Fatigue; Uncommon: Chest pain, pain.
Investigations: Uncommon: ALT and/or AST increased; blood CPK increased; gamma-glutamyltransferase increased; liver function test abnormal.
Additional adverse reactions with ezetimibe coadministered with a statin: Nervous system disorders: Common: Headache; Uncommon: Paraesthesia.
Gastrointestinal disorders: Uncommon: Dry mouth, gastritis.
Skin and subcutaneous tissue disorders: Uncommon: Pruritus, rash, urticaria.
Musculoskeletal and connective tissue disorders: Common: Myalgia; Uncommon: Back pain; muscular weakness; pain in extremity.
General disorders and administration site condition: Uncommon: Asthenia; oedema peripheral.
Investigations: Common: ALT and/or AST increased.
Post-marketing experience (with or without a statin): Blood and lymphatic system disorders: Not known: Thrombocytopenia.
Immune system disorders: Not known: Hypersensitivity, including rash, urticaria, anaphylaxis and angioedema.
Psychiatric disorders: Not known: Depression.
Nervous system disorders: Not known: Dizziness; paraesthesia.
Respiratory, thoracic and mediastinal disorders: Not known: Dyspnoea.
Gastro-intestinal disorders: Not known: Pancreatitis; constipation.
Hepatobiliary disorders: Not known: Hepatitis, cholelithiasis, cholecystitis.
Skin and subcutaneous tissue disorders: Not known: Erythema multiforme.
Musculoskeletal and connective tissue disorders: Not known: Myalgia; myopathy/rhabdomyolysis (see Precautions).
General disorders and administration site conditions: Not known: Asthenia.
Ezetimibe coadministered with fenofibrate: Gastrointestinal disorders: Common: Abdominal pain.
In a multicentre, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidaemia, 625 patients were treated for up to 12 weeks and 576 patients for up to 1 year. In this study, 172 patients treated with ezetimibe and fenofibrate completed 12 weeks of therapy, and 230 patients treated with ezetimibe and fenofibrate (including 109 who received ezetimibe alone for the first 12 weeks) completed 1 year of therapy. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (>3 X ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and ezetimibe co-administered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and ezetimibe coadministered with fenofibrate, respectively (see Precautions and Interactions).
Paediatric (6 to 17 years of age) patients: In a study involving paediatric (6 to 10 years of age) patients with heterozygous familial or non-familial hypercholesterolaemia (n=138), elevations of ALT and/or AST (≥3 x ULN, consecutive) were observed in 1.1% (1 patient) of the ezetimibe patients compared to 0% in the placebo group. There were no elevations of CPK (≥10 x ULN). No cases of myopathy were reported.
In a separate study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n = 248), elevations of ALT and/or AST (≥ 3X ULN, consecutive) were observed in 3% (4 patients) of the ezetimibe/simvastatin patients compared to 2% (2 patients) in the simvastatin monotherapy group; these figures were respectively 2% (2 patients) and 0% for elevation of CPK (≥ 10X ULN). No cases of myopathy were reported.
These trials were not suited for comparison of rare adverse reactions.
Patients with Coronary Heart Disease and ACS Event History: In the IMPROVE-IT study, involving 18,144 patients treated with either ezetimibe/simvastatin 10/40 mg (n=9067; of whom 6% were uptitrated to ezetimibe/simvastatin 10/80 mg) or simvastatin 40 mg (n=9077; of whom 27% were uptitrated to simvastatin 80 mg), the safety profiles were similar during a median follow-up period of 6.0 years. Discontinuation rates due to adverse experiences were 10.6% for patients treated with ezetimibe/simvastatin and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for ezetimibe/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN or two consecutive observations of CK ≥5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for ezetimibe/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 times ULN and <10 times ULN on two consecutive occasions with evidence of renal injury or CK ≥10,000 IU/L without evidence of renal injury. The incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for ezetimibe/simvastatin and 2.3% for simvastatin (see Precautions). Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to ezetimibe/simvastatin and simvastatin, respectively. The incidence of cholecystectomy hospitalisations was 1.5% in both treatment groups. Cancer (defined as any new malignancy) was diagnosed during the trial in 9.4% vs 9.5%, respectively.
Patients with chronic kidney disease: In the Study of Heart and Renal Protection (SHARP), involving over 9000 patients treated with a fixed dose combination of ezetimibe 10 mg with simvastatin 20 mg daily (n=4650) or placebo (n=4620), the safety profiles were comparable during a median follow-up period of 4.9 years. In this trial, only serious adverse events and discontinuations due to any adverse events were recorded.
Discontinuation rates due to adverse events were comparable (10.4% in patients treated with ezetimibe combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with ezetimibe combined with simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (>3 x ULN) occurred in 0.7% of patients treated with ezetimibe combined with simvastatin compared with 0.6% of patients treated with placebo. In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for ezetimibe combined with simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.
Laboratory values: In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥ 3 X ULN, consecutive) was similar between ezetimibe (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with ezetimibe coadministered with a statin and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. (See Precautions.)
In clinical trials, CPK>10 X ULN was reported for 4 of 1,674 (0.2%) patients administered ezetimibe alone vs 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered ezetimibe and a statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone) (see Precautions).