Ezecept 10/10

Rx

Indications

• Prevention of cardiovascular events
  Ezecept 10/10 is indicated to reduce the risk of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, or need for revascularization) in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS), whether or not previously treated with a statin.
• Hypercholesterolaemia
  Ezecept 10/10 is indicated as an adjunct treatment to the diet in adult patients with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia when the use of a combination is appropriate:
  – Patients not controlled properly with a statin alone.
  – Patients already receiving a statin and ezetimibe.
• Homozygous familial hypercholesterolaemia (HoFH)
  Ezecept 10/10 is indicated as adjunctive therapy to diet for use in adults with HoFH. Patients may also receive adjunctive treatments (e.g. LDL apheresis).

Dosage

• Hypercholesterolaemia and/or coronary artery disease (with history of acute coronary syndrome)
  During the entire treatment with Ezecept 10/10, the patient must follow an appropriate lipid-lowering diet.
  The dose of atorvastatin/ezetimibe is 10/10 mg per day to 80/10 mg per day. The usual dose is 10/10 mg once a day. LDL-C level, risk factors for coronary artery disease, and the patient’s response to current cholesterol-lowering treatment will be taken into account when starting therapy or adjusting the dose.
  The dosage of atorvastatin/ezetimibe should be individualized and take into account the known efficacy of the different dosages of atorvastatin/ezetimibe as well as the response to the lipid-lowering treatment in progress. Dose adjustments, if necessary, should be made at intervals of 4 weeks or more.
• Homozygous familial hypercholesterolaemia
  The dose of atorvastatin/ezetimibe in patients with homozygous FH is 10/10 mg to 80/10 mg per day. In these patients Ezecept 10/10 can be used as an adjunct to another cholesterol-lowering treatment (e.g. LDL apheresis) or when these treatments are not available.
• Co-administration with other drugs
  Ezecept 10/10 will be administered either ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant.
  In patients taking hepatitis C antiviral medicines elbasvir/grazoprevir concomitantly with atorvastatin/ezetimibe, the dose of atorvastatin/ezetimibe should not exceed 20/10 mg per day.
• No dose adjustment is necessary in elderly patients.
• The safety and efficacy of atorvastatin/ezetimibe in children has not been established. No data are available.
• Atorvastatin/ezetimibe should be used with caution in patients with hepatic impairment.
• Atorvastatin/ezetimibe is contraindicated in patients with active liver disease.
• No dose adjustment is necessary in patients with renal impairment.

Usage

Ezecept 10/10 is for oral administration. It can be administered as a single dose at any time of the day, with or without food.

• Hypersensitivity to any of the ingredients.
• During pregnancy and lactation and in women of reproductive age who do not use appropriate contraceptive methods.
• In patients with active liver disease or unexplained persistent elevations in serum transaminases greater than 3 times the upper limit of normal (ULN).
• In patients treated with hepatitis C antivirals glecaprevir/pibrentasvir.

Common

• Diarrhea,
• Myalgia.

• Myopathy/Rhabdomyolysis
  Since the marketing of ezetimibe, myopathy and rhabdomyolysis have been reported. Most patients who had rhabdomyolysis were also taking a statin in combination with ezetimibe. However, cases of rhabdomyolysis have been very rarely reported with ezetimibe as monotherapy, or when ezetimibe was combined with other drugs known to be associated with an increased risk of rhabdomyolysis.
• Ezecept 10/10 contains atorvastatin. Like other HMG-CoA reductase inhibitors, atorvastatin can in rare cases cause skeletal muscle damage and cause myalgia, myositis and myopathy which can progress to rhabdomyolysis, a life-threatening condition characterized high creatine phosphokinase (CPK) (> 10xULN), myoglobinemia and myoglobinuria which can lead to kidney failure.
• Before treatment:
  Ezecept 10/10 should be prescribed with caution in patients with risk factors for rhabdomyolysis. A CPK assay should be performed before the start of treatment in the following cases:Kidney failure, hypothyroidism, personal or family history of hereditary myopathy, hHistory of muscular toxicity during treatment with a statin or fibrate, history of liver disease and/or excessive alcohol consumption, elderly patients (> 70 years), the need of the metering CPK should be considered depending on the presence of other risk factors for rhabdomyolysis, situations in which plasma concentrations may be increased, for example due to interactions and in special populations including genetic polymorphisms. If the basal CPK value is significantly high (˃ 5xULN), treatment should not be initiated.
• During the treatment:
  Patients should be encouraged to report promptly any pain, muscle cramps or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after stopping Ezecept 10/10.
  If these symptoms occur in a patient during treatment with Ezecept 10/10, a dosing CPK should be performed. If the rate is significantly high (> 5xULN), treatment should be stopped.
  If muscular symptoms are severe and cause daily discomfort, discontinuation of treatment should be considered, even if CK levels are ≤ 5xULN.
  In the event of resolution of symptoms and normalization CPK, resumption of therapy Ezecept 10/10 or another medicine containing a statin may be considered at the lowest dose and under close monitoring.
  Treatment with Ezecept 10/10 must be discontinued if clinically significant elevation of CPK levels (> 10xULN) or diagnosed or suspected rhabdomyolysis.
  Very rare cases of Immune-Mediated Necrotizing Myopathy (IMNM) have been reported during or after treatment with some statins. IMNM is clinically characterized by proximal muscle weakness and elevated serum creatinine kinase, which persist despite discontinuation of statin therapy.
• Because of atorvastatin in Ezecept 10/10, the risk of rhabdomyolysis is increased when Ezecept 10/10 is given in combination with certain medicines which may increase the plasma concentration of atorvastatin, such as strong inhibitors of CYP3A4 or protein transporters (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, …). The risk of myopathy may also be increased in combination with gemfibrozil and other fibrates and the antivirals used in the treatment of hepatitis C (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin or niacin. Therapeutic alternatives (not exhibiting these interactions) should be considered as much as possible.
  If the combination of these drugs with Ezecept 10/10 is necessary, the benefit/risk balance of concomitant therapy should be carefully evaluated. In patients receiving drugs which increase the plasma concentration of atorvastatin, a lower maximum dose of Ezecept 10/10 is recommended. In addition, if strong CYP3A4 inhibitors are administered, a lower starting dose of Ezecept 10/10 should be considered and appropriate clinical monitoring of these patients is recommended.
• Ezecept 10/10 should not be administered simultaneously with fusidic acid in systemic form, and up to 7 days after stopping treatment with fusidic acid. In patients where the use of systemic fusidic acid is considered essential, treatment with statin should be discontinued for the duration of treatment with fusidic acid. Rhabdomyolysis (some of which is fatal) has been reported in patients receiving fusidic acid and a statin in combination. Patients should be informed of the need to seek immediate medical attention if they have symptoms of muscle weakness, pain or tenderness.
  Statin therapy can be reintroduced seven days axer the last dose of fusidic acid. In exceptional circumstances, where prolonged treatment with systemic fusidic acid is necessary, for example for the treatment of serious infections, the need for co-administration of Ezecept 10/10 and fusidic acid should only be considered on a case-by-case and under close medical supervision.
• Daptomycin
  Myopathy and/or rhabdomyolysis have been reported with the co-administration of HMG-CoA reductase inhibitors (such as atorvastatin and ezetimibe/atorvastatin) with daptomycin. Caution is advised when prescribing HMG-CoA reductase inhibitors with daptomycin, as either of these drugs may cause myopathy and/or rhabdomyolysis when administered alone. Temporary discontinuation of Ezecept should be considered in patients treated with daptomycin unless the benefits of co-administration outweigh the risks.
• Liver enzymes
  In clinical studies, elevations in serum transaminases (> 3xULN) have occurred repeatedly in patients receiving ezetimibe and atorvastatin. Liver enzyme tests must be carried out before the initiation of treatment and periodically thereafter. Liver function should be checked in patients who develop signs or symptoms suggestive of liver damage. Patients with elevated transaminase levels should be monitored until the abnormalities are resolved. In case of persistent increase in transaminases > 3xULN, it is recommended to reduce the dose or to stop treatment with Ezecept 10/10.
  Ezecept 10/10 should be used with caution in patients who consume large amounts of alcohol and/or have a history of liver damage.
• In patients with moderate or severe hepatic impairment, as the effects of increased exposure to ezetimibe are not known, Ezecept 10/10 is not recommended.
• The efficacy and safety of ezetimibe administered with fibrates have not been established; therefore, the combination of Ezecept 10/10 with fibrates is not recommended.
• Caution should be exercised if Ezecept 10/10 is started during treatment with ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezecept in combination with ciclosporin.
• If Ezecept 10/10 is combined with warfarin, or another anti-vitamin K anticoagulant or fluindione, the level of prothrombin expressed as international normalized ratio (INR) should be monitored appropriately.
• SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)
  In a post-hoc analysis of stroke subtypes in non-coronary patients with a recent history of stroke or transient ischemic attack (TIA), the incidence of hemorrhagic stroke was higher in patients treated with atorvastatin 80 mg than in patients receiving placebo. The increased risk was observed particularly in patients who had a history of hemorrhagic stroke or lacunar infarction at the time of inclusion in the study. In these patients, the benefit/risk balance of atorvastatin 80 mg is uncertain and the potential risk of hemorrhagic stroke should be carefully considered before initiating therapy.
• Interstitial lung disease
  Exceptional cases of interstitial lung disease have been reported while taking certain statins, especially in the case of long-term treatment. Symptoms are characterized by dyspnea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If interstitial lung disease is suspected in a patient, statin therapy should be discontinued.
• Diabetes
  There is some evidence to suggest that statins, as a pharmacological class, increase blood glucose. In some patients at high risk of developing diabetes, statins may cause hyperglycemia requiring the initiation of anti-diabetic treatment. This risk is nevertheless compensated by the reduction of the vascular risk under statins and therefore, it should not be a reason for stopping statins. Patients at risk (fasting blood sugar between 5.6 and 6.9 mmol/L, BMI > 30 kg/m², increased triglyceride levels, high blood pressure) should be subject to clinical and biological monitoring in accordance to national recommendations.
• Ezecept contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Ezecept is contraindicated during pregnancy. No clinical data are available on the use of Ezecept during pregnancy. Ezecept should not be used during pregnancy, or in a woman who is planning to become pregnant, or in whom pregnancy is suspected. Treatment with Ezecept should be suspended during pregnancy or until it has been established that the woman is not pregnant.
• Because of the potential risk of serious side effects, women treated with Ezecept should not breast-feed.
• Ezecept 10/10 has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or using machines, it should be taken into account that dizziness has been reported.