Statezi 10/10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STATEZY 10/10 (STATEZY 10/10)

Composition:

Active substances: 1 film-coated tablet contains: atorvastatin calcium equivalent to atorvastatin 10 mg, and ezetimibe 10 mg;

Excipients: lactose monohydrate, sodium croscarmellose, calcium carbonate (E 170), hydroxymethylpropylcellulose, microcrystalline cellulose, magnesium stearate, titanium dioxide (E 171), talc, propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Hypolipidemic agents, combinations. HMG-CoA reductase inhibitors in combination with other hypolipidemic agents.

ATC code C10BA05.

Pharmacological Properties

Pharmacodynamics

Staze 10/10 is a combined hypolipidemic agent whose effect is due to the pharmacological properties of its components, atorvastatin and ezetimibe.

Atorvastatin. Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), the enzyme that converts HMG-CoA into mevalonate, a precursor of sterols (including cholesterol). Cholesterol and triglycerides circulate in the blood as components of lipoprotein complexes, which are classified into very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), intermediate-density lipoproteins (IDL), and high-density lipoproteins (HDL). Clinical studies have demonstrated that elevated plasma levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (ApoB) (the protein component of LDL) promote the progression of atherosclerosis and are risk factors for cardiovascular disease and cardiovascular mortality, whereas elevated levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A (ApoA) (the protein component of HDL) are associated with reduced risk. Atorvastatin inhibits HMG-CoA reductase and cholesterol synthesis in the liver and increases the number of hepatic LDL receptors on the cell surface, resulting in enhanced uptake and catabolism of LDL. Atorvastatin reduces plasma concentrations of TC, LDL-C, ApoB, VLDL, and triglycerides (TG), and increases HDL-C and ApoA concentrations in patients with homozygous hypercholesterolemia, heterozygous (familial and non-familial) hypercholesterolemia, mixed dyslipidemia, and isolated hypertriglyceridemia. In patients with dysbetalipoproteinemia, it also reduces plasma levels of intermediate-density lipoprotein cholesterol (IDL-C).

In humans, both atorvastatin and some of its metabolites exhibit pharmacological activity. The primary site of action of atorvastatin is the liver, which plays a central role in cholesterol synthesis and LDL clearance. The reduction in LDL-C levels correlates better with the dose of atorvastatin than with its plasma concentration. Individual dosing of atorvastatin is based on therapeutic response.

In postmenarcheal boys and girls (10–17 years of age) with heterozygous familial hypercholesterolemia or severe hypercholesterolemia, atorvastatin at doses of 10–20 mg once daily significantly reduced plasma levels of TC, LDL-C, TG, and ApoB. No significant effects on growth or sexual maturation in boys or on menstrual cycle length in girls were observed. The safety and efficacy of atorvastatin doses higher than 20 mg for the treatment of children have not been studied. The long-term impact of atorvastatin therapy in childhood on reducing morbidity and mortality in adulthood has not been established.

Prevention of cardiovascular complications. In clinical studies, atorvastatin significantly reduced the incidence of fatal cardiovascular complications and non-fatal myocardial infarction, the overall frequency of cardiovascular complications, the incidence of fatal and non-fatal stroke, and the need for myocardial revascularization procedures. The therapeutic effect was independent of sex, age, or baseline LDL-C levels.

Ezetimibe. Ezetimibe is a selective inhibitor of cholesterol and phytosterol (plant sterols—sitosterol and campesterol) absorption in the small intestine. Upon reaching the small intestine, it localizes at the brush border and reduces the absorption of cholesterol and phytosterols, thereby decreasing their delivery from the intestine to the liver. After two weeks of ezetimibe administration, intestinal cholesterol absorption is reduced by 54% compared to placebo. Ezetimibe does not increase bile acid excretion nor inhibit cholesterol synthesis in the liver. It has no clinically significant effect on plasma concentrations of fat-soluble vitamins A, D, and E, and does not increase corticosteroid hormone production. In patients with hypercholesterolemia, ezetimibe reduces plasma levels of TC, LDL-C, ApoB, and TG, and increases HDL-C levels.

Clinical studies have demonstrated that ezetimibe and HMG-CoA reductase inhibitors (statins) have complementary effects, and their combined use results in a several-fold greater hypolipidemic effect compared to statin monotherapy. Therefore, Staze 10/10 significantly enhances the efficacy of dyslipidemia treatment compared to statin monotherapy.

Pharmacokinetics

Atorvastatin. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations reached within 1–2 hours. The rate and extent of atorvastatin absorption are reduced by approximately 25% and 9%, respectively, when administered with food. Evening administration results in lower plasma concentrations—approximately 30% lower for Cmax (maximum plasma concentration) and AUC (area under the plasma concentration-time curve)—compared to morning administration. However, food and timing of administration do not significantly affect the degree of atorvastatin's hypolipidemic effect. The mean volume of distribution of atorvastatin is approximately 381 L, and more than 98% of the drug is bound to plasma proteins. The erythrocyte/plasma ratio is approximately 0.25, indicating limited penetration into red blood cells. Atorvastatin is metabolized into ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro, the HMG-CoA reductase inhibition by ortho- and para-hydroxylated metabolites is nearly equivalent to that of atorvastatin. Approximately 70% of the inhibitory effect on HMG-CoA reductase is attributed to the activity of circulating metabolites. In vitro studies indicate that hepatic cytochrome P450 3A4 plays a significant role in atorvastatin metabolism, which may result in increased plasma atorvastatin concentrations when co-administered with inhibitors of this enzyme, such as erythromycin. Atorvastatin and its metabolites are primarily excreted via bile following hepatic and/or extrahepatic metabolism, but the drug does not undergo enterohepatic recirculation. The mean elimination half-life of atorvastatin in humans is approximately 14 hours, while the half-life of HMG-CoA reductase inhibitory activity, due to circulating active metabolites, ranges from 20 to 30 hours. Less than 2% of the administered dose is excreted in urine.

Ezetimibe. After oral administration, ezetimibe is rapidly absorbed and extensively conjugated in the small intestine and liver to form the pharmacologically active phenolic glucuronide, ezetimibe-glucuronide. Maximum plasma concentration (Cmax) is reached within 1–2 hours for ezetimibe-glucuronide and within 4–12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined because the compound is practically insoluble in water. Co-administration with food (both high-fat and low-fat meals) does not affect the bioavailability of ezetimibe following oral administration. Ezetimibe can be taken with or without food. Ezetimibe and ezetimibe-glucuronide are bound to human plasma proteins by 99.7% and 88–92%, respectively. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation, followed by biliary excretion. Ezetimibe and ezetimibe-glucuronide are the main components detected in plasma, accounting for approximately 10–20% and 80–90% of total plasma ezetimibe, respectively. The elimination half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours, and enterohepatic recirculation occurs. Approximately 78% and 11% of the administered dose are excreted in feces and urine, respectively, within a 10-day period.

Absorption, metabolism, and other pharmacokinetic parameters of ezetimibe are similar in adolescents aged 10 years and older and in adults; pharmacokinetic data for children under 10 years of age are lacking.

Interaction with HMG-CoA reductase inhibitors. In studies involving healthy hypercholesterolemic (LDL-C 130 mg/dL) adult subjects, co-administration of ezetimibe 10 mg once daily had no significant effect on the bioavailability of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, or rosuvastatin. Conversely, no significant effect on the bioavailability of total ezetimibe or ezetimibe was observed when co-administered with lovastatin (20 mg once daily), pravastatin (20 mg once daily), atorvastatin (10 mg once daily), fluvastatin (20 mg once daily), or rosuvastatin (10 mg once daily).

Clinical characteristics.

Indications.

Dyslipidemias. Ezetimibe 10/10 should be prescribed as part of combination therapy for dyslipidemias along with a cholesterol-lowering diet and other pharmacological and non-pharmacological (e.g., LDL apheresis) lipid-lowering treatments, particularly when monotherapy with HMG-CoA reductase inhibitors is insufficiently effective, in order to reduce plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), intermediate-density lipoprotein cholesterol (IDL-C), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A (ApoA) levels in patients with homozygous and heterozygous familial hypercholesterolemia, non-familial hypercholesterolemia, mixed dyslipidemias, isolated hypertriglyceridemia, and dysbetalipoproteinemia.

Homozygous sitosterolemia. Ezetimibe 10/10 should be prescribed as adjunctive therapy to diet to reduce elevated levels of sitosterol and campesterol in patients with homozygous familial sitosterolemia.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Acute liver disease, or elevated serum transaminase levels of unknown etiology exceeding three times the upper limit of normal. Myopathy. The medicinal product is contraindicated in pregnant women and in women who are breastfeeding. It is also contraindicated in women of childbearing potential who are not using effective contraceptive methods. It may be prescribed to women of childbearing potential only when the possibility of becoming pregnant is highly unlikely, and the patient has been informed about the potential adverse effects on the fetus.

Interaction with other medicinal products and other forms of interaction.

Atorvastatin.

The risk of developing myopathy during statin therapy increases when fibrates, lipid-modifying doses of niacin, cyclosporine, or potent CYP3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, itraconazole) are used concomitantly.

Potent CYP3A4 inhibitors. Ezetimibe 10/10 is metabolized by cytochrome P450 3A4. Concomitant use of Ezetimibe 10/10 with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see table and detailed information below). The extent of interaction and effect enhancement depends on the variability of the impact on CYP3A4. Concomitant use with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use with these agents cannot be avoided, consideration should be given to using a lower initial and maximum dose of atorvastatin. Appropriate clinical monitoring of the patient is also recommended (see table below).

Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase atorvastatin plasma concentrations. Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies evaluating the effect of amiodarone or verapamil on atorvastatin have not been conducted. However, amiodarone and verapamil are known to inhibit CYP3A4 activity; therefore, concomitant administration with atorvastatin may lead to increased atorvastatin exposure. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to prescribing lower maximum doses of atorvastatin. Clinical monitoring of the patient is also recommended. After initiating treatment with an inhibitor or adjusting its dose, clinical monitoring of the patient is advised.

Inducers of CYP3A4. Concomitant use of atorvastatin with CYP3A4 inducers (e.g., phenytoin, efavirenz, rifampicin, St. John’s wort) may lead to decreased plasma concentrations of atorvastatin. Due to the dual mechanism of action of rifampicin (CYP3A4 inducer and inhibitor of the hepatic transporter OATP1B1), concomitant use with atorvastatin is recommended, as delayed administration of atorvastatin after rifampicin therapy has been associated with a significant reduction in atorvastatin plasma concentrations.

Grapefruit juice contains one or more components that inhibit CYP3A4 and may increase atorvastatin plasma concentrations, especially with excessive consumption (more than 1.2 liters per day).

Clarithromycin. AUC values of atorvastatin were significantly increased when atorvastatin 80 mg was administered concomitantly with clarithromycin (500 mg twice daily) compared to atorvastatin alone. Therefore, patients taking clarithromycin should use atorvastatin doses higher than 20 mg with caution.

Combination protease inhibitors. AUC values of atorvastatin were significantly increased when Ezetimibe 10/10 was administered concomitantly with various HIV protease inhibitor combinations, as well as with the hepatitis C virus protease inhibitor telaprevir, compared to Ezetimibe 10/10 alone. Therefore, concomitant use of Ezetimibe 10/10 should be avoided in patients receiving the HIV protease inhibitor combination tipranavir + ritonavir or the hepatitis C virus protease inhibitor telaprevir. The medicinal product should be prescribed with caution to patients receiving the HIV protease inhibitor lopinavir + ritonavir, and the lowest necessary dose should be used. For patients receiving the HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the atorvastatin dose should not exceed 20 mg, and caution is required. When prescribing to patients receiving the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, the atorvastatin dose should not exceed 40 mg, and careful clinical monitoring of patients is recommended.

Itraconazole. AUC values of atorvastatin were significantly increased when atorvastatin 40 mg was administered concomitantly with itraconazole 200 mg. Therefore, patients taking itraconazole should exercise caution if the atorvastatin dose exceeds 20 mg.

Cyclosporine. Atorvastatin and its metabolites are substrates of the OATP1B1 transporter. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase atorvastatin bioavailability. AUC values of atorvastatin were significantly increased when atorvastatin 10 mg was administered concomitantly with cyclosporine 5.2 mg/kg/day compared to atorvastatin alone. Concomitant use of Ezetimibe 10/10 and cyclosporine should be avoided.

Medical recommendations regarding the use of interacting medicinal products are summarized in the table.

Drugs that interact	Medical recommendations for use
Cyclosporine, HIV protease inhibitors (tipranavir + ritonavir), hepatitis C virus protease inhibitor (telaprevir)	Avoid use of atorvastatin
HIV protease inhibitor (lopinavir + ritonavir)	Use with caution and at the lowest necessary dose
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir)	Do not exceed 20 mg of atorvastatin per day
HIV protease inhibitor (nelfinavir) Hepatitis C virus protease inhibitor (boceprevir)	Do not exceed 40 mg of atorvastatin per day

*Use with caution and at the lowest necessary dose.

Gemfibrozil/fibric acid derivatives. Myopathy may occur rarely during monotherapy with fibrates. The risk of atorvastatin-induced myopathy may increase when administered concomitantly with fibric acid derivatives. This interaction may lead to increased plasma concentrations of atorvastatin. Concomitant administration of atorvastatin and gemfibrozil at a dose of 600 mg twice daily increases the bioavailability of atorvastatin by 24%. Due to the increased risk of myopathy/rhabdomyolysis with concomitant use of HMG-CoA reductase inhibitors and gemfibrozil, combination therapy of Statex 10/10 with gemfibrozil should be avoided.

Other fibrates. Since it is known that the risk of developing myopathy during treatment with HMG-CoA reductase inhibitors increases with concomitant use of other fibrates, Statex 10/10 should be used with caution when coadministered with other fibrates. A lower initial dose of atorvastatin is recommended, along with appropriate clinical monitoring of the patient.

Niacin. The risk of adverse effects on skeletal muscles may increase when atorvastatin is used in combination with niacin; therefore, dose reduction of the drug should be considered under such conditions.

Rifampin or other cytochrome P450 3A4 inducers. Concomitant use of atorvastatin with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampin) may result in variable decreases in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after rifampin intake has been shown to result in a significant reduction in atorvastatin plasma concentrations.

Hydrochloride diltiazem. Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) results in increased plasma concentrations of atorvastatin.

Cimetidine. No significant interaction effects between these drugs have been observed.

Antacids. Concomitant use with an oral antacid suspension containing aluminum and magnesium hydroxides reduces atorvastatin plasma concentrations by approximately 35%, although this does not affect the reduction in LDL cholesterol levels.

Colestipol. Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio: 0.74) when atorvastatin was administered concomitantly with colestipol. However, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect of each drug administered separately.

Azithromycin. Concomitant administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not associated with changes in atorvastatin plasma concentrations.

Transport protein inhibitors. Inhibitors of transport proteins (e.g., cyclosporine) may increase systemic exposure to atorvastatin. The impact of inhibition of uptake transport proteins on atorvastatin concentrations in liver cells is unknown. If concomitant administration of these drugs cannot be avoided, dose reduction of atorvastatin and clinical monitoring of its efficacy are recommended.

Ezetimibe. The risk of developing myopathy increases with concomitant use. Appropriate clinical monitoring of patients is recommended during treatment with Statex 10/10.

Fusidic acid. Concomitant systemic use of fusidic acid with statins increases the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic, pharmacokinetic, or both) is still unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination.

If systemic use of fusidic acid is necessary, atorvastatin therapy should be discontinued for the entire duration of fusidic acid treatment.

Digoxin. When multiple doses of atorvastatin and digoxin are administered concomitantly, steady-state digoxin plasma concentrations increase by approximately 20%. Patients receiving digoxin should be appropriately monitored.

Oral contraceptives. Concomitant use with oral contraceptives containing norethindrone and ethinylestradiol increases the AUC of these two components by approximately 30% and 20%, respectively. This effect should be considered when selecting a contraceptive for women taking atorvastatin.

Warfarin. Statex 10/10 had no clinically significant effect on prothrombin time in patients undergoing long-term warfarin therapy.

Colchicine. Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, atorvastatin should be prescribed with caution when used with colchicine.

Daptomycin. Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin. If concomitant use cannot be avoided, appropriate clinical monitoring is recommended (see section "Special precautions").

Amlodipine. Concomitant use of 80 mg atorvastatin and 10 mg amlodipine resulted in an 18% increase in atorvastatin AUC.

Other medicinal products.

In clinical studies, concomitant use of atorvastatin with antihypertensive agents and during estrogen replacement therapy was not associated with clinically significant adverse effects. Studies on interactions with other drugs have not been conducted.

Ezetimibe.

Antacids. Concomitant use with antacids reduces the absorption of ezetimibe, but does not affect its bioavailability.

Cholestyramine. Concomitant use of cholestyramine reduces the AUC of ezetimibe by approximately 55%. Cholestyramine reduces low-density lipoproteins when added to ezetimibe.

Fenofibrate. In patients receiving ezetimibe and fenofibrate, the risk of developing cholelithiasis and gallstone disease increases.

If cholelithiasis is suspected in patients receiving ezetimibe and fenofibrate, gallbladder evaluation is indicated, and treatment should be discontinued.

Concomitant use of fenofibrate or gemfibrozil moderately increases ezetimibe concentrations (approximately 1.5–1.7 times, respectively).

Fibrates may increase biliary cholesterol excretion, leading to cholelithiasis.

Cyclosporine. Caution should be exercised when initiating treatment with ezetimibe and cyclosporine, and ezetimibe levels should be monitored.

Anticoagulants. When ezetimibe is used concomitantly with warfarin, other coumarin-type anticoagulants, or fluindione, INR (International Normalized Ratio) should be monitored.

Special precautions for use.

Effect on skeletal muscles. Atorvastatin, like other HMG-CoA reductase inhibitors, may affect the skeletal muscle system and cause development of myalgia, myositis, and myopathy, and, if progressing, may lead to rhabdomyolysis. Rhabdomyolysis is a life-threatening condition characterized by a 10-fold or greater increase in creatine phosphokinase (CPK) levels above the upper limit of normal, myoglobinemia, myoglobinuria, and subsequent development of renal failure.

Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been reported during treatment with atorvastatin and other drugs of this class. A history of renal dysfunction is a risk factor for the development of rhabdomyolysis. Such patients require closer monitoring for skeletal muscle disorders.

Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle pain or weakness in combination with elevated creatine phosphokinase (CPK) levels more than 10 times above the upper limit of normal. Concomitant use of higher doses of atorvastatin with certain medicinal products, such as cyclosporine and potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors), increases the risk of myopathy/rhabdomyolysis.

Rare cases of immune-mediated necrotizing myopathy (IMNM)—an autoimmune myopathy associated with statin use—have been reported. IMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; muscle biopsy reveals necrotizing myopathy without significant inflammation; a positive response is observed with immunosuppressive therapy.

The possibility of myopathy should be considered in any patient presenting with diffuse myalgia, muscle tenderness or weakness, and/or significantly elevated CPK levels. Patients should be advised to immediately report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if muscle symptoms persist after discontinuation of StatEze 10/10. If these symptoms occur during treatment with atorvastatin, serum CPK levels should be measured. If CPK levels are markedly elevated (≥5 times the upper limit of normal), treatment should be discontinued. If symptoms are severe and cause daily discomfort, discontinuation of therapy should be considered even if CPK levels exceed the upper limit of normal by less than 5 times. Discontinuation should also be considered if CPK elevation is less than 5-fold but muscle symptoms are severe and cause daily discomfort.

If symptoms resolve and CPK levels normalize after discontinuation of the drug, consideration may be given to resuming atorvastatin therapy or switching to another statin at the lowest possible dose under close monitoring.

Treatment with atorvastatin must be discontinued if a clinically significant increase in CPK levels (≥10 times the upper limit of normal) is detected, or if rhabdomyolysis is suspected or confirmed.

The risk of myopathy during treatment with this class of drugs increases with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C virus protease inhibitor telaprevir, combinations of HIV protease inhibitors (including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir, and fosamprenavir + ritonavir), azole antifungals, or niacin. Physicians considering combination therapy with StatEze 10/10 and fibric acid derivatives, erythromycin, clarithromycin, saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits against the risks and closely monitor patients for any symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any dose titration periods. Consideration should be given to using lower initial and maintenance doses of atorvastatin when coadministered with the above-mentioned medicinal products. In such cases, periodic CPK monitoring is recommended, although there is no guarantee that such monitoring will prevent cases of severe myopathy.

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, atorvastatin should be prescribed with caution in patients receiving colchicine.

The risk of rhabdomyolysis increases with concomitant use of atorvastatin and the following medicinal products: telithromycin, delavirdine, stiripentol, voriconazole, posaconazole. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibric acid derivatives, erythromycin, and niacin. If possible, alternative medicinal products should be used.

The risk of myopathy also increases with concomitant use of atorvastatin and ezetimibe. Consideration should be given to alternative therapies with medicinal products that do not interact with atorvastatin. If concomitant use of these drugs with atorvastatin is necessary, the potential benefits and risks of combination therapy should be carefully weighed. When concomitantly using drugs that increase atorvastatin plasma concentrations, it is recommended to reduce the initial dose of atorvastatin. When using cyclosporine, clarithromycin, or itraconazole, the maximum dose of atorvastatin should be reduced, and appropriate clinical monitoring should be ensured.

Treatment with StatEze 10/10 should be temporarily or permanently discontinued in any patient with an acute, serious condition indicating the development of myopathy, or in the presence of risk factors for renal failure due to rhabdomyolysis (e.g., severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Effect on the liver. Liver function tests should be performed before initiating atorvastatin therapy, periodically during treatment, and whenever signs or symptoms of liver injury occur. If transaminase levels are elevated, laboratory monitoring of enzyme concentrations should continue until levels normalize. If transaminase activity increases more than three times the upper limit of normal, treatment should be discontinued.

Cases of fatal and non-fatal hepatic failure have been reported in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, therapy should be immediately discontinued. Unless an alternative etiology is identified, reinitiation of treatment with the drug is not recommended.

The medicinal product should be prescribed with caution in patients who consume alcohol and/or have a history of liver disease. StatEze 10/10 is contraindicated in patients with active liver disease or persistent elevations in liver transaminases of unknown etiology.

Effect on the endocrine system. Increases in HbA1c and fasting plasma glucose levels have been reported with HMG-CoA reductase inhibitors.

Statins may affect cholesterol synthesis and theoretically may reduce adrenal and/or gonadal steroid secretion. Atorvastatin does not reduce baseline plasma cortisol concentration and does not impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied in a sufficient number of patients. It is unknown whether and how the drug affects the "gonadal glands–pituitary–hypothalamus" system in premenopausal women. Caution should be exercised when coadministering statin-class drugs with medicinal products that may reduce levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Hemorrhagic stroke. Use of atorvastatin at a dose of 80 mg in patients without ischemic heart disease who recently experienced a stroke or transient ischemic attack increases the frequency of hemorrhagic stroke. An increased risk of recurrent stroke, particularly in patients who previously had a hemorrhagic stroke before starting therapy, has been observed. For such patients, the risk-benefit ratio should be evaluated before initiating atorvastatin therapy. Since advanced age (over 65 years) is a risk factor for myopathy, the medicinal product should be prescribed with caution in elderly patients.

Hepatic insufficiency

StatEze 10/10 is contraindicated in patients with active liver disease, including persistent elevations in liver transaminases of unknown etiology.

Before initiating treatment

Atorvastatin should be prescribed with caution in patients predisposed to developing rhabdomyolysis. Before initiating statin therapy in patients predisposed to rhabdomyolysis, CPK levels should be measured in the following cases:

• renal dysfunction;
• hypothyroidism;
• family or personal history of inherited muscle disorders;
• previous episodes of statin or fibrate-induced myotoxicity;
• previous liver disease and/or excessive alcohol consumption.

For elderly patients (over 70 years), the need for these measures should be evaluated considering the presence of other risk factors for rhabdomyolysis.

Increased plasma drug levels may occur, particularly due to drug interactions or in specific patient populations, including patients with inherited disorders.

In such cases, the risk-benefit ratio of treatment should be evaluated, and clinical monitoring of patients is recommended. If baseline CPK levels are markedly elevated (more than 5 times the upper limit of normal), treatment should not be initiated.

Measurement of creatine kinase levels

Creatine kinase levels should not be measured after intense physical exertion or in the presence of any possible alternative causes of elevated CK levels, as this may complicate interpretation of results. If a significant elevation in baseline CK levels (more than 5 times the upper limit of normal) is observed, repeat measurement should be performed after 5–7 days to confirm the result.

During treatment

Patients should be informed of the need to immediately report the development of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.

If these symptoms occur during atorvastatin treatment, the patient's CK level should be measured. If CK levels are markedly elevated (more than 5 times the upper limit of normal), treatment should be discontinued.

Discontinuation of therapy should also be considered if CK levels exceed the upper limit of normal by less than 5 times but muscle symptoms are severe and cause daily discomfort.

After resolution of symptoms and normalization of CK levels, consideration may be given to resuming atorvastatin therapy or initiating therapy with an alternative statin, provided the lowest possible dose is used and the patient is closely monitored.

Treatment with atorvastatin must be discontinued in the event of clinically significant elevation of CK levels (more than 10 times the upper limit of normal) or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use of atorvastatin with other medicinal products

The risk of rhabdomyolysis increases with concomitant use of atorvastatin and certain medicinal products that may increase atorvastatin plasma concentrations. Examples include potent CYP3A4 or transporter protein inhibitors: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, and darunavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibric acid derivatives, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or the combination telaprevir/ritonavir. If possible, alternative medicinal products (that do not interact with atorvastatin) should be used instead of the above-mentioned drugs.

If concomitant treatment with atorvastatin and the mentioned drugs is necessary, the benefits and risks of combination therapy should be carefully weighed. If patients are taking medicinal products that increase atorvastatin plasma concentrations, it is recommended to reduce the atorvastatin dose to the minimum. Additionally, when using potent CYP3A4 inhibitors, consideration should be given to using a lower initial dose of atorvastatin. Appropriate clinical monitoring of these patients is also recommended.

Atorvastatin must not be used during systemic administration of fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is necessary, statin therapy should be suspended for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination. Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness.

Statin therapy may be resumed 7 days after the last dose of fusidic acid.

Under exceptional circumstances, when long-term systemic fusidic acid treatment is required (e.g., for treatment of severe infections), concomitant use of StatEze 10/10 and fusidic acid should be considered only on an individual basis and under strict medical supervision.

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Consideration should be given to temporarily discontinuing StatEze 10/10 in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, creatine kinase levels should be monitored 2–3 times per week, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

Concomitant use of ezetimibe with other medicinal products

Fibrates. In patients receiving ezetimibe and fenofibrate who are suspected of having cholelithiasis, gallbladder evaluation is indicated and treatment should be discontinued.

Anticoagulants. When ezetimibe is used concomitantly with warfarin, other coumarin-type anticoagulants, or fluindione, INR (International Normalized Ratio) should be monitored.

Interstitial lung disease

Rare cases of interstitial lung disease have been reported during treatment with some statins, particularly during long-term therapy. Manifestations may include dyspnea, non-productive cough, and general deterioration in health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Data from some studies suggest that statin use may increase plasma glucose levels and contribute to the development of diabetes in patients at high risk for this disease. Before initiating statin therapy in high-risk patients (fasting glucose levels between 5.6 and 6.9 mmol/L, BMI > 30 kg/m², elevated triglycerides, arterial hypertension), evaluation is necessary, and the risk-benefit ratio should be assessed before starting atorvastatin therapy.

Excipients

The medicinal product contains lactose; therefore, it should not be used in patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Lipid-modifying drug therapy should be one component of comprehensive therapy for patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when dietary measures restricting saturated fat and cholesterol intake, along with other non-pharmacological interventions, have been insufficient. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, drug initiation may begin simultaneously with dietary modifications.

Limitations of use

StatEze 10/10 has not been studied under conditions where the primary lipoprotein abnormality is elevated chylomicron levels (Fredrickson types I and V).

Myasthenia

In isolated cases, statins may induce de novo myasthenia gravis or exacerbate existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, StatEze 10/10 should be discontinued. Recurrences have been reported upon re-exposure to the same or another statin.

Use during pregnancy or breastfeeding

Atorvastatin is contraindicated during pregnancy and breastfeeding.

Breastfeeding should be discontinued during treatment with the drug.

Women of childbearing potential must use reliable contraception during treatment and should be informed of the potential adverse effects of therapy on the fetus.

Ability to affect reaction speed when driving or operating machinery.

Dizziness and headache may occur during treatment with the drug; therefore, caution should be exercised when driving or operating machinery.

Dosage and Administration

During treatment with Stazezi 10/10, patients should follow a standard hypocholesterolemic diet. Stazezi 10/10 can be taken at any time of day, regardless of food intake. Stazezi 10/10 may be initiated at the beginning of lipid-lowering therapy or added to atorvastatin monotherapy in cases of insufficient efficacy.

Treatment should be initiated with 1 tablet of Stazezi 10/10 once daily. The lipid-lowering effect becomes apparent within 2 weeks, and maximum effect is achieved within 4 weeks. Lipid profile should be assessed after 2–4 weeks from the start of treatment to evaluate initial therapeutic response.

There are insufficient clinical data on the use of ezetimibe at doses exceeding 10 mg daily, either as monotherapy or in combination with HMG-CoA reductase inhibitors; therefore, increasing the daily dose of Stazezi 10/10 is not recommended. The therapeutic effect of atorvastatin in preventing cardiovascular diseases increases with long-term use; thus, Stazezi 10/10 is recommended to be used long-term after initiation of treatment.

Children

Stazezi 10/10 is contraindicated in children.

Overdose

Symptoms: Myopathy, rhabdomyolysis, liver function abnormalities, nausea, vomiting, diarrhea.

Treatment: There is no specific antidote for overdose with Stazezi 10/10. In case of overdose, gastric lavage and administration of activated charcoal should be performed. Symptomatic and supportive therapy should be provided, including correction of acid-base balance, electrolyte disturbances, and management of intoxication symptoms. Since atorvastatin is highly protein-bound, hemodialysis is not expected to significantly reduce atorvastatin plasma concentrations.

Adverse reactions.

Infections and infestations: nasopharyngitis.

Blood and lymphatic system disorders: thrombocytopenia.

Immune system disorders: hypersensitivity reactions, including anaphylaxis, such as anaphylactic shock.

Metabolism and nutrition disorders: hyperglycemia, hypoglycemia, weight gain, anorexia, decreased appetite, diabetes mellitus.

Renal and urinary disorders: leukocyturia, urinary tract infection.

Psychiatric disorders: insomnia, nightmares, depression.

Nervous system disorders: headache, dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia, peripheral neuropathy, cognitive disorders (e.g., memory impairment, forgetfulness, amnesia, memory disturbance, confusion), myasthenia gravis (frequency not known).

Eye disorders: blurred vision, visual disturbance, ocular myasthenia (frequency not known).

Ear and labyrinth disorders: tinnitus, hearing loss.

Respiratory system disorders: throat pain, pharyngolaryngeal pain, epistaxis, cough, dyspnea.

Gastrointestinal disorders: constipation, flatulence, dyspepsia, nausea, diarrhea, vomiting, abdominal pain (upper and lower), belching, gastroesophageal reflux, pancreatitis, dry mouth, gastritis.

Hepatobiliary disorders: abnormal liver function tests, hepatitis, cholelithiasis, cholecystitis, cholestatic jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: urticaria, rash, pruritus, alopecia, angioneurotic edema, bullous eruptions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme), drug-induced lichenoid reaction (rare).

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, pain, including limb pain, musculoskeletal pain, muscle spasms, joint swelling, back and neck pain, increased muscle fatigue, myopathy, rhabdomyolysis, myositis, tendinopathy, sometimes complicated by tendon rupture.

Reproductive system and breast disorders: impotence, gynecomastia, sexual dysfunction.

Vascular disorders: flushing, arterial hypertension, stroke, vasculitis (rare).

General disorders and administration site conditions: malaise, weakness, asthenia, chest pain, peripheral edema, increased fatigue, fever, rare cases of interstitial lung disease, particularly during long-term treatment.

Investigations: increased serum transaminases, creatine phosphokinase (CPK), gamma-glutamyl transferase, increased alkaline phosphatase in blood, positive test for white blood cells in urine.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25°C, in the original packaging, in a place inaccessible to children.

Packaging.

10 tablets in a blister pack. 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Mepro Pharmaceuticals Private Limited.

Manufacturer's address.

Unit II, Q-Road, Phase IV, GIDC, Wadhwan, Surendranagar, Gujarat, 363 035, India.

Marketing authorization holder.

Mili Healthcare Limited.

Address of the marketing authorization holder.

Fairfax House 15, Fulwood Place, London, WC1V 6AY, Great Britain.