Zevas Special Precautions

The following patients should be carefully administrated.
Alcoholics and Patients who have a history of chronic liver disease.
Patients with moderate or severe hepatic dysfunction: Administration of this drug in patients with moderate or severe hepatic dysfunction is not recommended because the increased systemic exposure to rosuvastatin and ezetimibe may result in unexpected effects.
Patients with pre-disposing factors for myopathy/rhabdomyolysis: Renal impairment or history of renal disorders; hypothyroidism; personal or family history of hereditary muscular disorders; previous history of muscular toxicity with statins or fibrate; in case of consuming substantial quantities of alcohol or having history of liver disease; elderly over 70 years of age with factors of rhabdomyolysis; situations where an increase in plasma levels may occur.
Patients who are co-administered with fibrates.
Patients with an acute, serious condition suggestive of myopathy or renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).
General Caution: Myopathy/rhabdomyolysis: CPK levels should be measured in patients with pre-disposing factors for myopathy/rhabdomyolysis before initiation of administration. In these patients, the risk of treatment should be considered with benefit and clinical monitoring is recommended. CPK should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CPK increase which may confound interpretation of the result. If CPK 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.
When initiation of administration, the patient should be informed of the risk of myopathy and should be instructed to report to the physician immediately if fatigue or fever accompanied by myalgia, muscle spasms, or muscle weakness occur during the administration of this drug. In addition, when these symptoms occur, the CPK level should be measured and if the CPK level is significantly increased (>5xULN), the drug should be discontinued.
If the CPK level is less than 5xULN, the drug should be discontinued if the muscle symptoms are severe and cause discomfort in daily life. If symptoms improve and CPK levels return to normal and this drug is re-administered or another statin is administered, the patient should be carefully monitored and administered at the lowest dose.
Rosuvastatin: Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in rosuvastatin-treated patients.
Very rare cases of immune-mediated necrotising myopathy (IMNM) have been reported during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and increased serum creatine kinase, which persist despite discontinuation of statins treatment.
In clinical trials there was no evidence of increased skeletal muscle effects in the small number of patients treated with rosuvastatin and other drug concomitantly.
However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other statins together with fibric acid derivatives (including gemfibrozil), cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with statins. Therefore, the combination of rosuvastatin and gemfibrozil is not recommended. The benefit of the combination use of rosuvastatin with fibrates or niacin should be carefully evaluated with the risk. Dose of rosuvastatin 40 mg is contraindicated with concomitant use of fibrates.
Ezetimibe: The risk of musculoskeletal toxicity increases patients with factors such as concomitant use of a high-dose statin, elderly (≥65 years), hypothyroidism, renal impairment, type of statins administered, and concomitant use of other drugs. In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with co-administrati0n of ezetimibe with other drugs such as fibric acid derivatives known to be associated with increased risk of rhabdomyolysis. If myopathy is suspected based on muscle symptoms or is confirmed by a CPK level >10 times the ULN, co-administration of ezetimibe with fenofibrate should be immediately discontinued.
Liver enzymes: Liver enzymes test should be conducted before initiation of administration, liver function test should be repeated in patients with clinical signs or symptoms of liver disease. For patients with increased transaminases, monitoring should be continued until the adverse symptoms improve. This drug should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the ULN. From post-marketing experience fatal and non-fatal liver failure has reported rarely in patients taking statins, including rosuvastatin. If severe hepatic impairment and/ or hyperbilirubinemia or jaundice occurs during the treatment with clinical signs this drug should be discontinued immediately. If no other pathogen is identified, this drug should not be re-administered.
This drug should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease. Patients with active liver disease or a persistent elevation of serum transaminase which cause is unknown are not treated with this drug.
Ezetimibe: In a controlled clinical study, the incidence of consecutive elevations of transaminases (≥3 X ULN) was 0.5% for ezetimibe and 0.3% for placebo.
In controlled co-administration studies in patients receiving ezetimibe with a statin, the incidence of consecutive elevations of transaminase (≥3 X ULN) was 0.6% for ezetimibe combined with statins. The transaminase elevation was usually not symptomatic, and was not associated with bile, and was returned to baseline after discontinuation or continued administration.
Endocrine system: Increased HbA1c and fasting blood glucose levels have been reported in patients receiving statins, including rosuvastatin. However, the benefit of reduced vascular risk due to statin administration outweighs the risk of hyperglycemia.
Interstitial lung disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy. 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.
Diabetes: Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI >30 kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
Co-administration with other drug: Anticoagulants: If this drug is added to warfarin, another coumarin anticoagulant or fluindione, the International Normalised Ratio (INR) should be appropriately monitored.
If a patient treated with coumarin anticoagulant receives concomitantly with this drug, prothrombin time should be measured prior to administration and should be measured sufficiently frequently at the beginning of treatment to confirm that prothrombin time is not significantly altered.
Fibrates: Fibrates may increase cholesterol release into the bile and cause cholelithiasis. If cholelithiasis is suspected in a patient receiving this drug and fibrates, gallbladder investigations are carried out and alternative therapy of lipid lowering should be considered.
Bile acid binding resin: The drug should be administered 2 hours before or 4 hours after administration of the bile acid-binding resin.
Fusidic acid: Muscle-related adverse events, including rhabdomyolysis have been seen in patients receiving rosuvastatin together with fusidic acid in post-marketing experience. Therefore, the combination of rosuvastatin and fusidic acid is not recommended.
Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. When the drug is administered concomitantly with inhibitors of transporter proteins, care should be taken because the plasma concentration of the drug increases and may increase the risk of myopathy.
Genetic polymorphism: The genotypes of SLC01B1 (OATP1B1) c. 521CC or ABCG2 (BCRP) c.421AA compared to SLCO1B1 cS211T1 and ABCG2 c.421CC are known that can lead to increased rosuvastatin exposure (AUC). Although the safety and efficacy of the drug according to genetic polymorphisms has not been established, it is necessary to control the dose according to the patient's response and tolerance.
Women of childbearing age: Women of child bearing potential should use appropriate contraceptive measures.
Effects on ability to drive and use machines: Studies to determine the effect of the drug on the ability to drive and use machines have not been conducted. However, it should be taken into account that dizziness may occur during treatment.
Hepatic Impairment: This drug is not recommended in patients with active liver disease or a persistent elevation of serum transaminase which cause is unknown (see General Caution as previously mentioned).
Renal Impairment: A history of renal impairment may be a risk factor for the development of rhabdomyolysis. These patients may be closely monitored for skeletal muscle effects (see General Caution as previously mentioned).
Ezetimibe: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; CrCl ≤30 ml/min/1.73 m²), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9). This result is not considered clinically significant. No dosage adjustment is necessary for renally impaired patients.
Use in Children: Administration of this drug is not recommended in paediatric population because the safety and efficacy for pediatric population is not established.
Rosuvastatin: The evaluation of linear growth (height), weight, BMI (body mass index) by Tanner staging in pediatric patients 10 to 17 years of age taking rosuvastatin is limited to a year period.
Ezetimibe: Efficacy and safety of ezetimibe in patients 6 to 10 years of age with heterozygous familial or non-familial hypercholesterolemia have been evaluated in a 12-week placebo-controlled clinical trial. In this study, there was generally no detectable effect on growth or sexual maturation in pediatric population. However, effects of ezetimibe for treatment periods > 12 weeks have not been studied in this age group.
Use in the Elderly: Pre-disposing factors for myopathy are increased in the elderly (≥ 65 years) and care should be taken when administration to elderly. Therefore, no dosage adjustment is necessary in the elderly.