Adverse reactions : תופעות לוואי

4.8      Undesirable effects

Tabulated list of adverse reactions (clinical studies and post-marketing experience) In clinical studies of up to 112 weeks duration, Ezetrol 10 mg daily was administered alone in 2396 patients, with a statin in 11,308 patients or with fenofibrate in 185 patients. Adverse reactions were usually mild and transient. The overall incidence of side effects was similar between Ezetrol and placebo.
Similarly, the discontinuation rate due to adverse experiences was comparable between Ezetrol and placebo.

Ezetrol administered alone or co-administered with a statin:

The following adverse reactions were observed in patients treated with Ezetrol (n=2396) and at a greater incidence than placebo (n=1159) or in patients treated with Ezetrol coadministered 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 Ezetrol either administered alone or with a statin.
Adverse reactions observed in clinical studies of Ezetrol (as a monotherapy or co-administered with a statin) or Ezetrol reported from post-marketing use either administered alone or with a statin are listed in Table 1. These reactions are presented by system organ class and by frequency.
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 Recations

System organ class                                  Adverse reaction
Frequency
Blood and lymphatic system disorders
Not known                                           thrombocytopaenia 

Immune system disorders
Not known                                               hypersensitivity; including rash; urticaria; anaphylaxis and angio-oedema
Metabolism and nutrition disorders
Uncommon                                                decreased appetite 
Psychiatric disorders
Not known                                               depression
Nervous system disorders
Common                                                  headache
Uncommon                                                paraesthesia
Not known                                               dizziness
Vascular disorders
Uncommon                                                hot flush; hypertension Respiratory, thoracic and mediastinal disorders
Uncommon                                                cough
Not known                                               dyspnoea
Gastrointestinal disorders
Common                                                  abdominal pain; diarrhoea; flatulence Uncommon                                                dyspepsia; gastrooesophageal reflux disease; nausea; dry mouth; gastritis
Not known                                               pancreatitis; constipation Hepatobiliary disorders
Not known                                               hepatitis; cholelithiasis; cholecystitis Skin and subcutaneous tissue disorders
Uncommon                                                pruritus; rash; urticaria Not known                                               erythema multiforme Musculoskeletal and connective tissue disorders
Common                                                  myalgia
Uncommon                                                arthralgia; muscle spasms; neck pain; back pain; muscular weakness; pain in extremity
Not known                                               myopathy/rhabdomyolysis (see section 4.4) General disorders and administration site conditions
Common                                               fatigue
Uncommon                                             chest pain; pain; asthenia; oedema peripheral Investigations
Common                                               ALT and/or AST increased Uncommon                                             blood CPK increased; gamma-glutamyltransferase increased; liver function test abnormal


Ezetrol monotherapy
System organ class                      Adverse reactions                               Frequency Investigations                          ALT and/or AST increased; blood CPK             Uncommon increased; gamma-glutamyltransferase increased; liver function test abnormal
Respiratory, Thoracic and Mediastinal   cough                                           Uncommon Disorders
Gastrointestinal Disorders              abdominal pain; diarrhoea; flatulence           Common dyspepsia; gastrooesophageal reflux disease;    Uncommon nausea
Musculoskeletal And Connective          arthralgia; muscle spasms; neck pain            Uncommon Tissue Disorders


Metabolism and Nutrition Disorders      decreased appetite                             Uncommon Vascular Disorders                      hot flush; hypertension                        Uncommon General Disorders And                   fatigue                                        Common Administration Site Condition           chest pain, pain                               Uncommon Additional adverse reactions with Ezetrol co-administered with a statin System organ class                      Adverse reactions                              Frequency Investigations                          ALT and/or AST increased                       Common Nervous System Disorders                headache                                       Common paraesthesia                                   Uncommon
Gastrointestinal Disorders              dry mouth; gastritis                           Uncommon Skin And Subcutaneous Tissue            pruritus; rash; urticaria                      Uncommon Disorders
Musculoskeletal And Connective          myalgia                                        Common Tissue Disorders                        back pain; muscular weakness; pain in          Uncommon extremity
General Disorders And                   asthenia; oedema peripheral                    Uncommon Administration Site Condition
Post-marketing Experience (with or without a statin)
System organ class                      Adverse reactions                              Frequency Blood and lymphatic system disorders    thrombocytopaenia                              Not known Nervous system disorders:               dizziness; paraesthesia                        Not known Respiratory, thoracic and mediastinal   dyspnoea                                       Not known disorders
Gastrointestinal disorders              pancreatitis; constipation                     Not known Skin and subcutaneous tissue            erythema multiforme                            Not known disorders
Musculoskeletal and connective tissue   myalgia; myopathy/rhabdomyolysis (see          Not known disorder                                section 4.4)
General disorders and administration    asthenia                                       Not known site conditions
Immune system disorders                 hypersensitivity, including rash, urticaria,   Not known anaphylaxis and angio-oedema
Hepatobiliary disorders                 hepatitis; cholelithiasis; cholecystitis       Not known Psychiatric disorders                   depression                                     Not known 
Ezetrol co-administered with fenofibrate
Gastrointestinal disorders: abdominal pain (common)

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 Ezetrol and fenofibrate completed 12 weeks of therapy, and 230 patients treated with Ezetrol and fenofibrate (including 109 who received Ezetrol 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 Ezetrol 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 Ezetrol co- administered with fenofibrate, respectively (see sections 4.4 and 4.5).

Paediatric (10 to 17 years of age) Patients



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 drug reactions.

Patients with Coronary Heart Disease and ACS Event History
In the IMPROVE-IT study (see section 5.1), 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 section 4.4.) 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 hospitalizations 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) (see section 5.1), involving over 9000 patients treated with a fixed dose combination of Ezetrol 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 Ezetrol combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with Ezetrol combined with simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (> 3X ULN) occurred in 0.7% of patients treated with Ezetrol combined with simvastatin compared with 0.6% of patients treated with placebo. (See section 4.4.) In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for Ezetrol 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 Ezetrol (0.5 %) and placebo (0.3 %). In co-administration trials, the incidence was 1.3 % for patients treated with Ezetrol co- administered 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 section 4.4.).

In clinical trials, CPK >10 X ULN was reported for 4 of 1674 (0.2 %) patients administered Ezetrol alone vs 1 of 786 (0.1 %) patients administered placebo, and for 1 of 917 (0.1 %) patients co-administered 

Ezetrol and a statin vs 4 of 929 (0.4 %) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with Ezetrol compared with the relevant control arm (placebo or statin alone). (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il