Zevas Adverse Reactions

The safety of this drug was evaluated in the rosuvastatin controlled clinical studies of 369 patients with primary hypercholesterolaemia. The study consists of a treatment duration of 8 weeks and an extension duration of 12 weeks, the extension duration administration of 12 weeks was conducted in 258 patients whose LDL-C level reached the treatment goal according to the risk of cardiovascular disease after completion of the treatment duration of 8 weeks.
Adverse reactions reported in the treatment duration of 8 weeks: The most common adverse reactions in the duration were nasopharyngitis (2.4%), arthralgia (1.4%), headache (1.4%). Adverse reactions related to this drug were 2 cases of ALT elevation 2 cases of AST elevation 2 case of myalgia, 1 case of edema, 1 case of serum bilirubin elevation, 1 case of acne dermatitis and 1 case of pruritus, all were mild or moderate. (See Table 1.)

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Adverse reactions reported in the treatment duration of 12 weeks: The most common adverse reactions in the duration were nasopharyngitis (5.04%), ALT elevation (2.71%), dizziness (1.94%), upper respiratory tract infection (1.55%), myalgia (1.16%), in other all case, the incidence of adverse reactions was less than 1%. As with rosuvastatin controlled clinical studies for 8 weeks, no specific adverse events were observed in this drug alone. The information provided as follows is based on clinical studies of the individual components of Rosuvastatin and Ezetimibe and those collected from post-marketing experience.
Information collected from Rosuvastatin: The reported adverse reactions are generally mild and transient. In controlled clinical studies, less than 4% of rosuvastatin-related patients were withdrawn due to adverse reactions.
Adverse reactions listed as follows are classified according to frequency and system organ class. The frequencies of adverse reactions are ranked according to the following convention: Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data). (See Table 2.)

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As with other statins, the adverse events increased with increasing dose.
Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with rosuvastatin. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Hematuria was observed in patients treated with rosuvastatin and data from clinical trials, but the incidence was low.
Skeletal muscle effects: Effects on skeletal muscle (e.g., myalgia, myopathy including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg. A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5xULN), treatment should be discontinued.
Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.
Overseas Post-marketing experience: In addition to the previously mentioned adverse reactions, the following adverse events have been reported during post-marketing experience.
Nervous system disorders: Very rare: Polyneuropathy, memory loss; Not known: Peripheral neuropathy.
Respiratory, thoracic and mediastinal disorders: Not known: Cough, dyspnea.
Gastrointestinal disorders: Not known: Diarrhoea.
Blood and lymphatic system disorders: Not known: Thrombocytopenia.
Hepatobiliary disorders: Rare: Increased hepatic transaminases: Very rare: Jaundice, hepatitis.
Skin and subcutaneous tissue disorders: Not known: Stevens-Johnson syndrome.
Musculo-skeletal and connective tissue disorders: Very rare: Arthralgia; Not known: Immune-mediated necrotising myopathy.
Renal and urinary disorders: Very rare: Haematuria.
Other: Not known: Oedema.
The following adverse events have been reported with some statins: Nervous system disorders: Not known: Depression sleep disturbances (including insomnia and nightmares).
Respiratory disorders: Exceptional cases of interstitial lung disease, especially with long term therapy.
Reproductive system and breast disorders: Not known: Sexual dysfunction, gynecomastia.
Hepatobiliary disorders: Fatal and non-fatal liver failure.
There have been rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Domestic Post-marketing experience: In Korea, 3,081 people were surveyed for 6years, and the incidence rate of adverse reaction was 10.06% (310 people, 415 cases), 0.78% (24 people, 24 cases) of headache, 0.75% (23 people, 23 cases) of dizziness, 0.58% (18 people, 18 cases) of ALT elevation, 0.49% (15 people, 15 cases) of chest pain, cough, and myalgia were reported and the adverse drug reactions that cannot establish a causal relationship to Rosuvastatin were 2.92% (90 people, 106 cases).
Among the adverse reactions reported, 0.55% (17 people, 17 cases) of ALT elevation, 0.42% (13 people, 13 cases) of myalgia, 0.39% (12 people, 12 cases) of headache, 0.29% (9 people, 9 cases] of CK elevation, 0.26% (8 people, 8 cases) of dizziness, 0.16% (5 people, 5 cases) each of constipation and AST elevation, 0.13% (4 people, 4 cases) of asthenia and arthralgia, 0.10% (3 people, 3 cases) each of fatigue and paresthesia, 0.06% (2 cases, 2 cases) each of sensory abnormality, chest discomfort, nausea, abdominal pain, diarrhea, anorexia, abdominal distension, itching and liver function test abnormality, 0.03% (1 case, 1 case) each of Syncope, systemic pain, muscle spasms, gout, and erectile dysfunction were reported.
Myalgia and arthralgia in one of these patients was a significant adverse reaction, the unexpected adverse reactions that did not appear in pre-marketing were 0.13% (4 people, 4 cases) of arthralgia, 0.10% (3 people, 3 cases) each of fatigue and paresthesia, were (2 cases, 2 cases) each of sensory abnormality, chest discomfort, nausea, abdominal pain, diarrhea, anorexia, abdominal distension, itching and liver function test abnormality, 0.03% (1 people, 1 case) each of syncope, systemic pain, muscle spasms, gout, and erectile dysfunction, 1 case of arthralgia as serious and unexpected adverse reactions was reported.
During the review period, 98 cases of the adverse reactions were reported voluntarily, 2 cases of acute renal failure, 1 case each of oliguria, thrombocytopenia, and increased serum creatinine, were reported as serious and unexpected adverse reactions.
Paediatric patients (10 to 17 years of age): Creatine kinase elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of paediatric patients (10 to 17 years of age), compared to adults. In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.
Information collected from Ezetimibe: The safety of this drug was evaluated in the ezetimibe controlled clinical studies of ≥4700 patients. From the result of clinical studies (Ezetimibe administered alone or co-administered with HMG-CoA reductase inhibitors), adverse reactions were usually mild and transient. The overall incidence of adverse reactions was similar between ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between ezetimibe and placebo.
Monotherapy: Adverse reaction reported in ≥2% of patients treated with ezetimibe and at an incidence greater than placebo in placebo-controlled studies of ezetimibe, regardless of causality assessment, are shown in Table 3. (See Table 3.)

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The incidence of other adverse events with lower frequency than the previously mentioned adverse events was similar between the ezetimibe and placebo groups (see Table 4).
Co-administration with HMG-CoA reductase inhibitors: The safety of ezetimibe was evaluated in the co-administration clinical studies of ≥2000 patients. When co-administered with HMG-CoA reductase inhibitors, adverse reactions were similar compared to HMG-CoA reductase inhibitors administrated alone. But, the incidence of increased transaminases was higher in patients receiving ezetimibe co-administered with HMG-CoA reductase inhibitors than in patients treated with HMG-CoA reductase inhibitors alone. Clinical adverse reactions reported in ≥2% of patients treated with ezetimibe alone or ezetimibe + HMG-CoA reductase inhibitors and at an incidence greater than placebo, regardless of causality assessment, were shown in Table 4. (See Table 4.)

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Co-administration with fenofibrate: 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. 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 co-administered with fenofibrate respectively.
There was no elevation of creatine phosphokinase (> 10 X ULN) in the study.
The following common adverse reactions were reported in patients treated with ezetimibe alone (N=1691), in patients treated with ezetimibe co-administered with a statin (N=1675) and in patients treated with ezetimibe co-administered with a fenofibrate (N=185).
Patients treated with ezetimibe alone: Headache, abdominal pain, diarrhea.
Patients treated with ezetimibe co-administered with a statin: Headache, fatigue, abdominal pain, constipation, diarrhea, flatulence, nausea, ALT and/or AST increased myalgia.
Patients treated with ezetimibe co-administered with a fenofibrate: Abdominal pain.
Post-marketing adverse reactions: The following adverse reactions were reported regardless of causality.
Hypersensitivity including rash and urticaria, anaphylaxis and angio-oedema, erythema multiforme, arthralgia, myalgia, CPK increased, myopathy/rhabdomyolysis (see General Cautions under Precautions), hepatic transaminases increased, hepatitis, abdominal pain, thrombocytopaenia, nausea, pancreatitis, dizziness, senseless, depression, headache, cholelithiasis, cholecystitis.
Domestic Post-marketing experience: In Korea, 3,536 people were surveyed for 6 years, and the incidence rate of adverse reaction was 7.27% (257 people, 422 cases), a commonly occurring (1.0% or more) adverse event is fatigue (37 people, 37 cases) and the adverse drug reactions that cannot establish a causal relationship to ezetimibe were 1.95% (69 people, 108 cases). Among the adverse reactions reported, 0.28% (10 people, 10 cases) of ALT elevation and AST elevation, 0.17% (6 people, 6 cases) of diarrhea, 0.14% (5 people, 5 cases) each of dyspepsia and dizziness, 0.11% (4 people, 4 cases) of nausea were reported and others adverse reactions reported below 0.1% are as follows: General disorders and administration site condition: Fatigue, chest pain, chest discomfort, edema, asthenia, systemic edema.
Nervous system disorders: Headache, paresthesia, diabetic neuropathy, tremor.
Gastrointestinal disorders: Upper abdominal pain, vomiting, abdominal pain, gastritis, constipation, dry mouth, anticardium discomfort, trim, gastrointestinal disorders, gastroesophageal reflux disease, tongue disease.
Cardiovascular disorders: Throbbing, congestive heart failure, myocardial ischemia, flushing.
Respiratory disorders: Cough, sputum, runny nose.
Musculoskeletal and connective tissue disorders: Meralgia, arthralgia.
Metabolism and nutrition disorder: Diabetes, hypoglycemia.
Blood and lymphatic system disorders: Anemia, spleen enlargement.
Skin and subcutaneous tissue disorders: Urticaria, hyperhidrosis, rash, itching.
Infections and infestations: Upper respiratory infection.
Eyes disorder: Conjunctival hyperemia.
Urinary disorder: Renal failure (kidney disease).
Hepatobiliary disorders: Abnormal liver function.
Clinical examination: Increase in serum creatinine, increase in blood pressure, increase in blood factor, increase in CPK, liver function abnormality.