Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
Skeletal muscle effects
Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with rosuvastatin in post-marketing use is higher at the 40 mg dose.
In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known to be associated with increased risk of rhabdomyolysis.

If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level, Rosetemib S.K and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Rosetemib S.K should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness (see section 4.8).

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Rosetemib S.K should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

Creatine kinase measurement
Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.

Before treatment
Caution should be exercised in patients with pre-disposing factors for myopathy/rhabdomyolysis.
Such factors include:
- renal impairment,
- hypothyroidism,
- personal or family history of hereditary muscular disorders,
- previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate, - alcohol abuse,
- age >70 years,
- situations where an increase in plasma levels may occur (see sections 4.2, 4.5 and 5.2), - concomitant use of fibrates.
In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN) treatment should not be started.

Whilst on treatment
Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients.
Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are  30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/l.

Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Severe cutaneous adverse reactions
Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of this reaction appears, Rosetemib S.K must be discontinued immediately and an alternative treatment should be considered.

If the patient has developed a serious reaction such as SJS or DRESS with the use of Rosetemib S.K, treatment with Rosetemib S.K must not be restarted in this patient at any time.

Protease inhibitors
Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Rosetemib S.K in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating rosuvastatin doses in patients treated with protease inhibitors.
The concomitant use with certain protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted (see sections 4.2 and 4.5).

Fibrates
The safety and efficacy of ezetimibe administered with fibrates have not been established (see above and sections 4.3 and 4.5).

If cholelithiasis is suspected in a patient receiving Rosetemib S.K and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see sections 4.5 and 4.8).

Anticoagulants
If Rosetemib S.K is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).

Fusidic acid
Rosetemib S.K must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.
In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Rosetemib S.K and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Race
Pharmacokinetic studies show an increase in exposure of rosuvastatin in Asian subjects compared with Caucasians (see sections 4.2, 4.3 and 5.2).

Paediatric population
Rosetemib S.K is not recommended for use in children and adolescents of less than 18 years of age, due to insufficient data on safety and efficacy.

Rosetemib S.K contains lactose and sodium
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Effects on Driving

4.7   Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.