Instructions for use of STATINAM

Ro-statin

From the urinary system

In patients receiving high doses of rosuvastatin (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. This proteinuria did not indicate acute kidney disease or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function parameters during treatment.

From the musculoskeletal system

The following effects on the musculoskeletal system have been reported with the use of rosuvastatin at all dosages and, in particular, when taking doses of the drug exceeding 20 mg: myalgia, myopathy, and in rare cases, rhabdomyolysis.

Determination of creatine phosphokinase activity

Determination of CPK activity should not be carried out after intense physical exercise or in the presence of other possible reasons for increased CPK activity, which

may lead to incorrect interpretation of the results obtained. If the initial CPK activity is significantly increased (5 times higher than the upper limit of normal), a repeat measurement should be taken after 5-7 days. Therapy should not be started if a repeat test confirms the initial CPK activity (more than 5 times the upper limit of normal).

Before starting therapy

When prescribing the drug Ro-statin, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis; it is necessary to consider the balance of risk and possible benefit of therapy and conduct clinical observation.

During therapy

The patient should be informed to immediately report to the doctor the unexpected onset of muscle pain, muscle weakness or cramps, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (more than 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is less than 5 times the upper limit norms). If symptoms disappear and CPK activity returns to normal, re-prescribing Rostatin or other HMG-CoA reductase inhibitors in lower doses should be considered with careful monitoring of the patient. Routine monitoring of CPK activity in the absence of symptoms is impractical. Very rare cases of immune-mediated necrotizing myopathy have been reported with clinical manifestations in the form of persistent weakness of the proximal muscles and increased CPK activity in the serum during treatment or upon discontinuation of statins, incl. rosuvastatin. Additional studies of the muscular system and nervous system, serological studies, and therapy with immunosuppressive drugs may be required.

There were no signs of increased effects on skeletal muscles when taking the drug Rostatin and concomitant therapy. However, an increase in the number of cases of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g / day), azole antifungals, inhibitors HIV proteases and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used together with certain HMG-CoA reductase inhibitors. Thus, the simultaneous use of Rostatin and gemfibrozil is not recommended. The balance of risk and possible benefit should be carefully weighed when using the drug Rostatin together with fibrates or lipid-lowering doses of nicotinic acid (more than 1 g/day). Taking the drug Rostatin at a dose of 40 mg together with fibrates is contraindicated. 2-4 weeks after the start of treatment and/or when increasing the dose of the drug Ro-statin, monitoring of lipid metabolism parameters is necessary (if necessary, dose adjustment is required). Effect on liver function

It is recommended to determine liver function indicators before starting therapy and 3 months after starting therapy. Taking Rostatin should be stopped or the dose reduced if the activity of hepatic transaminases in the blood serum is 3 times higher than the upper limit of normal.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment for underlying diseases should be carried out before starting treatment with Rostatin. Special populations. Ethnic groups

During pharmacokinetic studies among Chinese and Japanese patients, an increase in systemic concentrations of rosuvastatin was noted compared with values ​​​​obtained among European patients.

HIV protease inhibitors

Concomitant use of the drug with HIV protease inhibitors is not recommended. Lactose

The drug should not be used in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with some statins, especially over long periods of use. Manifestations of the disease may include shortness of breath, non-productive cough and deterioration in general health (weakness, weight loss and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus type 2

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, rosuvastatin therapy was associated with an increased risk of developing type 2 diabetes mellitus.

HMG-CoA reductase inhibitors, incl. Ro-statin may increase blood glucose concentrations.

Instructions for use of STATINAM

Skeletal muscles

Rare cases of rhabdomyolysis with acute renal failure and subsequent myoglobinuria caused by atorvastatin have been reported when taking tablets containing atorvastatin and amlodipine. A risk factor for the development of rhabdomyolysis is the presence of renal failure. For such patients, more careful monitoring of the condition of the skeletal muscles is necessary. Atorvastatin, like other statins, in rare cases can lead to the development of myopathy, manifested by muscle pain or muscle weakness in combination with an increase in CK levels more than 10 times the upper threshold value (UTV). Concomitant use of atorvastatin in higher doses with drugs such as cyclosporine and strong CYP3A4 inhibitors (for example, clarithromycin, itraconazole and an HIV protease inhibitor) increases the risk of developing myopathy/rhabdomyolysis.

Any patient with diffuse myalgia, muscle pain, weakness, or a significant increase in CPK should be evaluated for the presence of myopathy. Patients should be advised to promptly report unexplained muscle pain, soreness, or weakness, especially if accompanied by malaise or fever. It is necessary to stop taking the drug if there is a significant increase in CPK levels, as well as if myopathy is diagnosed or suspected.

The likelihood of developing myopathy during statin treatment increases with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, a combination of ritonavir with saquinavir or lopinavir with ritonavir, niacin, or azole antifungals. For the combinations listed above, the potential benefits and risks should be carefully weighed and patients should be closely monitored for any signs or symptoms of muscle pain, soreness, or weakness, especially during the first months of drug use and during any dosage changes of any drug. When used simultaneously with the above drugs, it is necessary to start with a minimum dose of atorvastatin and maintain it. CPK levels should be measured periodically, but this does not guarantee prevention of the development of severe myopathy.

Patients with acute myopathy and those with risk factors predisposing them to the development of renal failure with subsequent rhabdomyolysis (for example, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances and uncontrolled seizures) should temporarily interrupt or discontinue use of the drug. a drug.

Liver failure

Statins, incl. and atorvastatin, as well as other lipid-lowering drugs, can cause biochemical abnormalities in liver function. Persistent increases (more than 3 times the UL observed in 2 or more measurements) of hepatic transaminases were observed in 0.7% of patients taking atorvastatin in clinical trials. The incidence of such disorders was 0.2%, 0.2%, 0.6% and 2.3% when taking 10, 20, 40 and 80 mg, respectively.

In clinical studies in patients taking the atorvastatin/amlodipine combination, this side effect was not observed. One participant developed jaundice during clinical studies. Changes in liver function tests in other patients were not associated with jaundice or other clinical signs or symptoms. After reducing the dose of the drug, temporarily stopping the drug, or discontinuing the drug, the level of transaminases was restored without any complications or differed slightly from the values ​​​​observed before the start of treatment.

18 of 30 patients with persistently elevated liver transaminases continued to take low-dose atorvastatin.

It is recommended to measure liver function indicators before and 12 weeks after the start of treatment, with any increase in the dose of the drug, and also periodically (for example, every six months). Changes in liver enzyme levels usually occur within the first 3 months after starting treatment with atorvastatin, which is part of Statinam. Patients who have increased transaminase levels should be monitored until the disturbances disappear. If elevated ALT or AST levels persist (more than 3 times the ULN), it is recommended to reduce the dose of the drug or discontinue the drug.

Active liver disease or unexplained persistent elevated levels of transaminase activity are a contraindication to the use of Statinam.

Progression of angina and/or myocardial infarction

Progression of angina pectoris and acute myocardial infarction may develop after increasing the dose of amlodipine, especially in patients with severe obstructive coronary artery disease.

Arterial hypotension

Symptomatic hypotension may develop, especially in patients with severe aortic stenosis. The dose should be selected starting from the minimum, in which case the development of acute arterial hypotension is unlikely.

Beta blocker withdrawal syndrome

Amlodipine, which is part of Statinam, is not a beta-blocker and therefore cannot prevent the development of beta-blocker withdrawal syndrome; if withdrawal syndrome develops, it is necessary to gradually reduce the dose of the beta-blocker.

Endocrine function

Atorvastatin, like other statins, affects cholesterol synthesis and theoretically may reduce levels of adrenal hormones and/or sex steroid hormones. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol levels and does not have a negative effect on adrenal reserve. The effect of statins on male fertility has not been studied in sufficient numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised when prescribing statins with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Toxic effect on the central nervous system

Studies with atorvastatin.

One female dog experienced cerebral hemorrhage when administered atorvastatin calcium salt for 3 months at a dose equivalent to 120 mg atorvastatin/kg/day. Cerebral hemorrhage and optic nerve vacuolation were also observed in another female who, after 11 weeks of atorvastatin administration at a dose equivalent to 280 mg atorvastatin/kg/day, became critically ill. Administration of atorvastatin at a dose of 120 mg/kg resulted in a 16-fold increase in AUC0-24 compared to the AUC for humans when taking the maximum permissible dose of 80 mg/day. In a 2-year study, 2 adult male dogs experienced single tonic seizures (the first received atorvastatin calcium at a dose equivalent to 10 mg atorvastatin/kg/day and the second at a dose equivalent to 120 mg atorvastatin/kg/day). In mice, when atorvastatin calcium was continuously administered for 2 years in doses equivalent to 400 mg of atorvastatin/kg/day and when administered to rats in doses equivalent to 100 mg of atorvastatin/kg/day, no CNS damage was observed. At these doses, AUC0-24 increased 6-11 times (for mice) and 8-16 times (for rats) compared to AUC in humans when taking the maximum recommended dose of atorvastatin 80 mg/day.

CNS vascular lesions characterized by perivascular hemorrhage, edema, and infiltration of mononuclear cells from the perivascular space have been observed in dogs administered other statins. This class of drugs has been associated with optic nerve dystrophy (Wallerian retinogeniculate degeneration) in healthy dogs in a dose-dependent manner at doses that result in plasma drug levels that are approximately 30 times higher than the average plasma drug levels in humans taking the maximum recommended dose of the drug.

Use in patients after a recent stroke or transient ischemic cerebrovascular accident

Studies with atorvastatin

. A retrospective analysis of stroke prevention through active cholesterol lowering compared the effects of atorvastatin 80 mg with placebo in 4731 patients without congenital heart disease who had had a stroke or had a history of transient ischemic cerebrovascular accident within the previous 6 months. A higher rate of hemorrhagic stroke was observed in the atorvastatin 80 mg group (55; 2.3% atorvastatin and 33; 1.4% placebo; OR:

• 1.68;
• 95% CI: 1.09;
• 2.59;
• p=0.0168). The incidence of deaths from hemorrhagic stroke was similar in both groups (17 for atorvastatin and 18 for placebo, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the group taking atorvastatin (38;
• 1.6%) than in the placebo group (16;
• 0.7%). The higher incidence of hemorrhagic stroke in the atorvastatin group was associated with several baseline elevated parameters, including: hemorrhagic and lacunar strokes at the start of the study.

Impact on the ability to drive vehicles and operate machinery

During the treatment period, care should be taken when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.