Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of safety profile
Adverse drug reactions previously reported with one of the individual components (ezetimibe or rosuvastatin) may be potential undesirable effects with Rosetemib S.K.

In clinical studies of up to 112 weeks duration, ezetimibe 10 mg daily was administered alone in 2,396 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 ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between ezetimibe and placebo.

The adverse events seen with rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse events.
Tabulated list of adverse reactions
The frequencies of adverse reactions are ranked according to the following convention: 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).

MedDRA system organ            Frequency        Undesirable effect class
Blood and lymphatic system     rare             thrombocytopenia2 disorders not known        thrombocytopenia5
Immune system disorders        rare             hypersensitivity reactions including angioedema2 not known        hypersensitivity (including rash, urticaria,
anaphylaxis and angioedema) 5
Endocrine disorders            common           diabetes mellitus1, 2 
Metabolism and nutrition       uncommon         decreased appetite3 disorders
Psychiatric disorders          not known        depression2, 5

Nervous system disorders       common           headache2, 4, dizziness2 uncommon         paraesthesia4 very rare        polyneuropathy2, memory loss2 not known        peripheral neuropathy2, sleep disturbances
(including insomnia and nightmares)2,
dizziness5; paraesthesia5, myasthenia gravis2
Eye disorders                  not known        ocular myasthenia2


Vascular disorders             uncommon         hot flush3, hypertension3 Respiratory, thoracic and      uncommon         cough3 mediastinal disorders not known        cough2, dyspnoea2,5

Gastrointestinal disorders     common           constipation2, nausea2, abdominal pain2,3, diarrhoea3, flatulence3 uncommon         dyspepsia3; gastroesophageal reflux disease3;
nausea3, dry mouth4; gastritis4 rare             pancreatitis2 not known        diarrhoea2, pancreatitis5; constipation5
Hepatobiliary disorders        rare             increased hepatic transaminases2 very rare        jaundice2, hepatitis2 not known        hepatitis5, cholelithiasis5, cholecystitis5 uncommon         pruritus2, 4, rash2, 4, urticaria2,4
Skin and subcutaneous tissue       not known         Stevens Johnson syndrome2, erythema disorders                                            multiforme5, drug reaction with eosinophilia and systemic symptoms (DRESS)2
Musculoskeletal and                common            myalgia2, 4 connective tissue disorders uncommon          arthralgia3; muscle spasms3; neck pain3, back pain4; muscular weakness4; pain in extremity4 rare              myopathy (including myositis)2,
rhabdomyolysis2, lupus-like syndrome,
muscle rupture very rare         arthralgia2
 not known         immune-mediated necrotising myopathy2,
tendon disorders, sometimes complicated by rupture2, myalgia5;
myopathy/rhabdomyolysis5 (see section 4.4)
Renal and urinary disorders        very rare         haematuria2
Reproductive system and            very rare         gynaecomastia2 breast disorders
Investigations                     common            ALT and/or AST increased4 uncommon          ALT and/or AST increased3; blood CPK increased3; gamma-glutamyl transferase increased3; liver function test abnormal3
General disorders and              common            asthenia2, fatigue3 administration site conditions                         uncommon          chest pain3, pain3, asthenia4; oedema peripheral4
 not known         oedema2, asthenia5
1
Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/l, BMI > 30 kg/m2, raised triglycerides, history of hypertension) – for rosuvastatin.
2
Adverse reaction profile for rosuvastatin based on data from clinical studies and/ or extensive post- marketing experience.
3
Ezetimibe in monotherapy. Adverse reactions were observed in patients treated with ezetimibe (N=2396) and at a greater incidence than placebo (N=1159).
4
Ezetimibe co administered with a statin. Adverse reactions were observed in patients with ezetimibe co- administered with a statin (N=11308) and at a greater incidence than statin administered alone (N=9361).
5
Additional adverse reactions of ezetimibe, reported in post-marketing experience (with or without statin).

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

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. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease.

Haematuria has been observed in patients treated with rosuvastatin and clinical trial data show that the occurrence is 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 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 (see section 4.4).

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.

The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

The following adverse events have been reported with some statins:
• Sexual dysfunction
• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

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 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 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 section 4.4).

Paediatric population
The safety and efficacy of Rosetemib S.K in children below the age of 18 years have not yet been established (see section 5.1).

Rosuvastatin: Creatine kinase elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of children and adolescents compared to adults. In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.

Ezetimibe: 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 (≥ 3X 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 (≥ 10X 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 drug reactions.

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions
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 https://sideeffects.health.gov.il