Etset film-coated tablets 20 mg No. 84

Instructions for Etset film-coated tablets 20 mg No. 84

Composition

active ingredient: atorvastatin;

1 tablet contains atorvastatin calcium equivalent to atorvastatin 20 mg;

excipients: lactose monohydrate, microcrystalline cellulose, calcium carbonate, povidone K30, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, Opadry 03F84827 pink*;

*Opadry 03F84827 pink: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: round biconvex tablets, coated with a pink film coat with the inscription "20" on one side.

Pharmacotherapeutic group

Drugs that lower serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. ATC code C10A A05.

Pharmacological properties

Pharmacodynamics

Etset® contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the rate of conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, which is a precursor of sterols, in particular cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated into very low density lipoprotein (VLDL) molecules, enter the blood plasma and are transported to peripheral tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolized mainly by interaction with high-affinity LDL receptors (LDL receptors).

Atorvastatin reduces plasma cholesterol and serum lipoprotein concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver, and also increases the number of hepatic LDL receptors on the cell surface, leading to increased uptake and catabolism of LDL.

Atorvastatin reduces LDL formation and LDL particle size. Atorvastatin causes a marked and sustained increase in LDL receptor activity combined with favorable changes in the quality of circulating LDL particles. Atorvastatin effectively lowers LDL cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia, a group that has not always responded to lipid-lowering therapy.

In addition to its effect on plasma lipids, atorvastatin has other effects that enhance its antiatherosclerotic effect. It inhibits the synthesis of isoprenoids - substances that act as growth factors on the proliferation of vascular smooth muscle cells, reduces plasma viscosity and the activity of some coagulation and aggregation factors. Due to this action, it improves hemodynamics and contributes to the normalization of blood coagulation processes. In addition, HMG-CoA reductase inhibitors affect the metabolism of macrophages and, thus, inhibit their activation, which reduces the risk of rupture of atherosclerotic plaques.

Atorvastatin has been shown to reduce total cholesterol (30-46%), LDL-C (41-61%), apolipoprotein B (34-50%), and triglycerides (14-33%), with variable increases in HDL-C and apolipoprotein A in a dose-response study. These results are consistent with data in patients with heterozygous familial hypercholesterolemia, non-familial hypercholesterolemia, and mixed hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus.

It has been proven that lowering levels of total cholesterol, LDL-C, and apolipoprotein B reduces the risk of cardiovascular complications and mortality from cardiovascular disease.

Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after oral administration and reaches peak plasma concentrations within 1-2 hours. The extent of absorption and plasma concentrations of atorvastatin depend on the dose of atorvastatin. The bioavailability of atorvastatin in tablet form compared to the solution is 95% and 99%, respectively. The absolute bioavailability of atorvastatin is approximately 14%, and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance in the gastrointestinal mucosa and biotransformation during the first pass through the liver. Food intake reduces the rate and extent of absorption of the drug by approximately 25% and 9%, respectively, as evidenced by the level of maximum concentration and AUC (area under the concentration-time curve). The reduction in LDL-C is independent of the time of administration. Plasma concentrations of atorvastatin after evening dosing are lower than those after morning dosing (approximately 30% higher than peak concentrations and AUC). Despite this, the reduction in LDL-C is independent of the time of day of dosing.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is > 98%. A red blood cell/plasma ratio of approximately 0.25 indicates low penetration of the drug into red blood cells. Based on observations in rats, it is believed that atorvastatin is able to penetrate into breast milk (see sections "Contraindications", "Use during pregnancy or lactation" and "Special warnings and precautions for use").

Atorvastatin is extensively metabolized to form ortho- and parahydroxylated derivatives and various β-oxidation products. In vitro, ortho- and parahydroxylated metabolites exhibit inhibitory activity against HMG-CoA reductase equivalent to that of atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites. In vitro studies confirm the importance of atorvastatin biotransformation under the influence of cytochrome P450 3A4. Simultaneous administration of atorvastatin and erythromycin, an inhibitor of cytochrome P450 3A4, leads to an increase in the concentration of atorvastatin in the blood plasma. In vitro studies also confirm the fact that atorvastatin is a weak inhibitor of cytochrome P450 3A4. With simultaneous use of atorvastatin and terfenadine, which is mainly metabolized by the cytochrome P450 3A4 system, the concentration of the latter in the blood plasma is almost unchanged. Thus, it is unlikely that the use of cytochrome can significantly change the pharmacokinetics of other cytochrome P450 3A4 substrates. In animals, the orthohydroxylated metabolite undergoes further glucuronidation.

Selection

Atorvastatin and its metabolites are mainly excreted in the bile after hepatic and/or extrahepatic biotransformation, but do not undergo gastro-hepatic recirculation. The mean half-life of atorvastatin in humans is approximately 14 hours. Inhibitory activity against HMG-CoA reductase is maintained for 20-30 hours due to the presence of active metabolites. After oral administration, less than 2% of atorvastatin is detected in the urine.

Patient populations

Elderly patients

Plasma concentrations of atorvastatin in healthy elderly subjects (aged > 65 years) are higher than in younger subjects (approximately 40% of the maximum concentration and 30% of the AUC). Available data suggest that efficacy and safety in the elderly do not differ from those in the general population.

Children

Apparent oral clearance of atorvastatin in children was similar to that in adults when scaled allometrically for body weight, as body weight was the only significant covariate in a population pharmacokinetic model of atorvastatin with data that included children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29) in an open-label 8-week study.

Sex

The plasma concentration of atorvastatin in women differs from that in men (the maximum concentration is approximately 20% higher and the AUC is 10% lower). However, these differences are not clinically significant, and the hypolipidemic effect of the drug in men and women is almost the same.

Kidney failure

The route of administration and dose do not affect the plasma concentration of atorvastatin and its hypolipidemic effect. Therefore, there is no need to adjust the dose of the drug.

Hemodialysis

Atorvastatin has not been studied in patients with end-stage renal disease. Because the drug is highly bound to plasma proteins, hemodialysis is unlikely to significantly increase the clearance of atorvastatin.

Liver failure

In patients with alcoholic cirrhosis of the liver, the concentration of atorvastatin in the blood plasma is significantly increased (maximum concentration - approximately 16 times, AUC value - 11 times).

SLOC1B1 polymorphism.

Patients with SLCO1B1 polymorphisms are at risk of increased exposure to atorvastatin, which may lead to an increased risk of rhabdomyolysis.

Indication

Prevention of cardiovascular disease in adults

For adult patients without clinically apparent coronary heart disease but with multiple risk factors for coronary heart disease, such as age, smoking, hypertension, low HDL, or a family history of early coronary heart disease, Etset® is indicated for:

reducing the risk of myocardial infarction; reducing the risk of stroke; reducing the risk of revascularization procedures and angina.

For adult patients with type 2 diabetes mellitus and without clinically significant coronary heart disease, but with multiple risk factors for coronary heart disease, such as retinopathy, albuminuria, smoking or arterial hypertension, Etset® is indicated for:

reducing the risk of myocardial infarction; reducing the risk of stroke.

For adult patients with clinically significant coronary heart disease, Etset® is indicated for:

reduced risk of non-fatal myocardial infarction; reduced risk of fatal and non-fatal stroke; reduced risk of revascularization procedures; reduced risk of hospitalization for congestive heart failure; reduced risk of angina.

Hyperlipidemia

As an adjunct to diet to reduce elevated total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb). As an adjunct to diet to treat patients with elevated serum triglycerides (Fredrickson type IV). For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson type III) when diet is inadequate. To reduce total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or when such treatments are unavailable.

In children

As an adjunct to diet to reduce total cholesterol, LDL-cholesterol, and apolipoprotein B in children 10 to 17 years of age with heterozygous familial hypercholesterolemia, if, after appropriate diet therapy, the test results are as follows: LDL-cholesterol remains ≥ 190 mg/dL (4.91 mmol/L) or LDL-cholesterol ≥ 160 mg/dL (4.14 mmol/L) and: there is a family history of early cardiovascular disease or two or more other risk factors for cardiovascular disease are present in the patient as a child.

Contraindication

Acute liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology. Hypersensitivity to any of the components of this medicinal product. Pregnancy. Lactation.

Interaction with other medicinal products and other types of interactions

The risk of myopathy during statin treatment is increased by concomitant use of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or potent CYP 3A4 inhibitors (e.g. clarithromycin, HIV protease inhibitors, and itraconazole) (see sections 4.4 and 5.1).

Potent CYP 3A4 inhibitors. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant use of atorvastatin with potent CYP 3A4 inhibitors may result in increased plasma concentrations of atorvastatin (see detailed information below). The extent of interaction and potentiation depend on the variability of the effect on CYP 3A4. Concomitant use of atorvastatin 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 of these drugs with atorvastatin cannot be avoided, lower starting and maximum doses of atorvastatin should be considered. Appropriate clinical monitoring of the patient is also recommended (see Table 1).

Moderate CYP 3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase the plasma concentration of atorvastatin.

Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies to evaluate the effects of amiodarone or verapamil on atorvastatin have not been performed. Amiodarone and verapamil are known to inhibit CYP 3A4 activity, and therefore, co-administration of these drugs with atorvastatin may result in increased exposure to atorvastatin. Therefore, lower maximum doses of atorvastatin should be considered when atorvastatin is co-administered with these moderate CYP 3A4 inhibitors. Clinical monitoring of the patient is also recommended. Clinical monitoring of the patient is recommended after initiation of treatment with an inhibitor or after dose adjustment.

Grapefruit juice.

Contains one or more components that inhibit CYP 3A4 and may increase plasma concentrations of atorvastatin, especially with excessive consumption of grapefruit juice (more than 1.2 liters per day).

Combination of protease inhibitors. The AUC of atorvastatin was significantly increased when atorvastatin was co-administered with several combinations of HIV protease inhibitors and with the hepatitis C protease inhibitor telaprevir compared to atorvastatin alone (see section 5.1). Therefore, patients taking the HIV protease inhibitor tipranavir + ritonavir or the hepatitis C protease inhibitor telaprevir should avoid co-administration with Etset®. The drug should be prescribed with caution to patients taking the HIV protease inhibitor lopinavir + ritonavir and used at the lowest necessary dose. For patients taking the HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir, the dose of atorvastatin should not exceed 20 mg and should be used with caution (see sections "Special instructions", "Dosage and administration"). When used in patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin should not exceed 40 mg. Close clinical monitoring of patients is also recommended.

Itraconazole: The AUC of atorvastatin was significantly increased when atorvastatin 40 mg was co-administered with itraconazole 200 mg (see section 5.1). Therefore, caution should be exercised when atorvastatin doses greater than 20 mg are administered to patients taking itraconazole (see sections 4.4 and 4.2).

Cyclosporine. Atorvastatin and its metabolites are substrates of the OATP1B1 transporter. OATP1B1 inhibitors (e.g., cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin was significantly increased when atorvastatin 10 mg was co-administered with cyclosporine 5.2 mg/kg/day compared to atorvastatin alone (see section 5.1). The concomitant use of atorvastatin and cyclosporine should be avoided (see section 4.4).

Medical recommendations for the use of interacting drugs are summarized in Table 1 (see also sections “Method of administration and dosage”, “Special instructions for use”, “Pharmacological properties”).

Gemfibrozil: Due to the increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are administered concomitantly with gemfibrozil, the concomitant use of atorvastatin with gemfibrozil should be avoided (see section 4.4).

Other fibrates: Since the risk of myopathy during treatment with HMG-CoA reductase inhibitors is known to be increased by concomitant use of other fibrates, atorvastatin should be used with caution when used concomitantly with other fibrates (see section 4.4).

Niacin: The risk of skeletal muscle adverse events may be increased when the drug is used in combination with niacin, and therefore, in such conditions, a dose reduction of atorvastatin should be considered (see section 4.4).

Rifampicin or other CYP3A4 inducers. Concomitant use of atorvastatin with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampin) may result in transient decreases in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampin, concomitant use of Etset® with rifampin is recommended, as delayed administration of the drug after rifampin administration has been shown to be associated with significant decreases in atorvastatin plasma concentrations.

Diltiazem hydrochloride: Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) is accompanied by an increase in the concentration of atorvastatin in the blood plasma.

Cimetidine. As a result of the conducted studies, no signs of interaction between atorvastatin and cimetidine were detected.

Antacids: Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide resulted in a decrease in plasma atorvastatin concentrations of approximately 35%. The lipid-lowering effects of atorvastatin were not altered.

Colestipol: Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio: 0.74) when atorvastatin and colestipol were co-administered. The lipid-lowering effect of the combination of atorvastatin and colestipol was greater than that of either drug alone.

Azithromycin.

Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not accompanied by changes in atorvastatin plasma concentrations.

Ezetimibe: Ezetimibe monotherapy has been associated with muscular events, including rhabdomyolysis. Therefore, the risk of these events is increased when ezetimibe and atorvastatin are co-administered. Appropriate clinical monitoring is recommended in these patients.

Fusidic acid. Concomitant systemic use of fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic, or both) is still unknown. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving the combination of these drugs. If systemic use of fusidic acid is necessary, atorvastatin should be discontinued for the duration of fusidic acid use (see section 4.4).

Digoxin: Concomitant administration of multiple doses of atorvastatin and digoxin increased steady-state plasma concentrations of digoxin by approximately 20%. Patients receiving digoxin should be monitored closely.

Oral contraceptives: Concomitant use of atorvastatin with oral contraceptives increased the AUC values for norethisterone and ethinyl estradiol (see section 5.1). These increases should be considered when selecting an oral contraceptive for a woman taking Etset.

Warfarin: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving long-term warfarin therapy.

Colchicine: Myopathy, including rhabdomyolysis, has been reported with concomitant use of atorvastatin and colchicine, and therefore atorvastatin should be administered with caution with colchicine.

Other medicines.

Clinical studies have shown that the simultaneous use of atorvastatin and antihypertensive drugs and its use during estrogen replacement therapy was not accompanied by clinically significant side effects. Interaction studies with other drugs have not been conducted.

Table 1.

*Use with caution and in the lowest dose necessary.

Application features

Effects on skeletal muscles.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and other drugs in this class. A history of renal impairment may be a risk factor for rhabdomyolysis. Such patients should be monitored closely for skeletal muscle abnormalities.

Atorvastatin, like other statins, has occasionally been associated with myopathy, manifested by muscle pain or weakness in association with an elevation of creatine phosphokinase (CPK) >10 times the upper limit of normal (ULN). Concomitant use of higher doses of atorvastatin with certain drugs, such as cyclosporine and potent CYP3A4 inhibitors (e.g. clarithromycin, itraconazole, and HIV protease inhibitors), increases the risk of myopathy/rhabdomyolysis.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use. IMMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy shows necrotizing myopathy without significant inflammation; and positive dynamics are observed with the use of immunosuppressive agents.

The risk of myopathy during treatment with drugs of this class is increased with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir and fosamprenavir + ritonavir, as well as niacin or azole antifungals. Physicians considering the combination of Etset® 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 and risks and monitor patients closely for any signs or symptoms of muscle pain, tenderness, or weakness, especially during the initial months of therapy and during any dose titration period when increasing the dose of the drugs. The use of low initial and maintenance doses of atorvastatin should be considered when co-administered with the above-mentioned drugs (see section "Interaction with other medicinal products and other forms of interaction"). In such situations, it is advisable to periodically determine CPK activity, but there is no guarantee that such monitoring will help prevent the development of severe myopathy.

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin with colchicine, therefore atorvastatin with colchicine should be prescribed with caution to patients (see section "Interaction with other medicinal products and other types of interactions").

Etset® therapy should be temporarily or permanently discontinued in patients with an acute, serious condition indicating the development of myopathy, or in the presence of a risk factor for the development of renal failure due to rhabdomyolysis (e.g., severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, and uncontrolled seizures).

Liver dysfunction.

Statins, like some other hypolipidemic therapeutics, have been reported to be associated with abnormal biochemical parameters of liver function.

After dose reduction, interruption, or discontinuation of atorvastatin, transaminase levels returned to or near pretreatment values without sequelae. It is recommended that liver enzyme levels be obtained before initiating therapy and re-evaluated as clinically indicated. Fatal and non-fatal hepatic failure have been reported in patients receiving statins, including atorvastatin. In the event of severe liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice during treatment with Etset®, treatment should be discontinued immediately. Unless another cause for the serious liver injury is identified, statins should not be restarted.

Etset® should be administered with caution to patients who abuse alcohol and/or have a history of liver disease. Etset® is contraindicated in active liver disease or persistent elevations of hepatic transaminases of unknown etiology (see section "Contraindications").

Endocrine function.

Increased HbA1c and fasting serum glucose concentrations have been reported with HMG-CoA reductase inhibitors, including atorvastatin.

Statins inhibit cholesterol synthesis and theoretically may reduce adrenal and/or gonadal steroid secretion. Atorvastatin does not reduce basal plasma cortisol levels or impair adrenal reserve. The effect of statins on sperm fertilisation has not been studied in a sufficient number of patients. It is not known whether the drug affects the gonadal-pituitary-hypothalamic axis in premenopausal women. Caution should be exercised when co-administering statins with medicinal products that may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

Hemorrhagic stroke.

Treatment with atorvastatin 80 mg in patients without cardiovascular disease who had a stroke or transient ischemic attack within 6 months prior to treatment increased the incidence of hemorrhagic strokes. Patients who had a hemorrhagic stroke at the start of therapy were at increased risk of recurrent hemorrhagic strokes. Atorvastatin 80 mg reduced the total number of strokes and the number of cardiovascular events.

Elderly patients (over 65 years of age).

No overall differences in safety and efficacy were observed between elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out. Since advanced age (over 65 years) is a predisposing factor for myopathy, Etset® should be prescribed with caution in the elderly.

Atorvastatin should be prescribed with caution to patients with factors that contribute to the development of rhabdomyolysis. It is necessary to determine the level of CPK before starting treatment with statins in the following cases: in renal failure; hypothyroidism; the presence of hereditary muscle diseases in an individual or family history; if muscle toxicity was previously observed during treatment with statins or fibrates; if the patient has previously suffered from liver disease and/or drinks alcohol; in elderly patients (aged 70 years and older) the need for this study is determined taking into account the presence of other factors that contribute to the development of rhabdomyolysis; in cases of possible increase in the concentration of atorvastatin in the blood plasma, for example, in interaction with drugs and in special groups of patients, including genetic subpopulations (see section "Pharmacokinetics").

In such situations, the benefit/risk ratio of treatment should be carefully weighed. Careful clinical monitoring is recommended. If the initial CPK level is significantly elevated (more than 5 times the upper limit of normal), treatment with this drug should not be initiated.

Determination of CPK level.

CPK levels should not be measured after intense exercise or in the presence of any other factors that may increase CPK levels, as this may lead to inaccurate results. If the initial CPK level is significantly elevated (more than 5 times the ULN), it is recommended to repeat the test after 5-7 days to confirm the results.

During treatment.

Patients should immediately report to their doctor any cases of muscle pain, cramps or weakness, especially if accompanied by malaise and fever; if such symptoms occur during treatment with atorvastatin, CPK levels should be determined. In the event of a significant increase in this indicator (more than 5 times compared to the ULN), the drug should be discontinued; in the event of severe muscle symptoms that cause significant discomfort, even if the CPK level is less than 5 times higher than the ULN, treatment should be discontinued; if the symptoms completely disappear and the CPK level returns to normal, then atorvastatin or another statin drug can be re-administered, reducing its dose; the patient should be under constant medical supervision; atorvastatin treatment should be discontinued in the event of a clinically significant increase in CPK levels (more than 10 times compared to the ULN) or in the event of diagnosed or suspected rhabdomyolysis.

Concomitant use with other medications.

The risk of rhabdomyolysis is increased when atorvastatin is used concomitantly with certain drugs, such as potent CYP3A4 inhibitors or transport proteins (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir).

Concomitant use with gemfibrozil and other fibric acid derivatives, boceprevir, erythromycin, niacin and ezetimibe, telaprevir or the combination of telaprevir/ritonavir also increases the risk of myopathy. If possible, other drugs (that do not interact with atorvastatin) should be used instead of the above.

If concomitant treatment with atorvastatin and the above-mentioned agents is necessary, the benefits and risks of concomitant use should be carefully weighed. If patients are taking drugs that increase the plasma concentration of atorvastatin, it is recommended to reduce the dose of atorvastatin to the minimum. In addition, in the case of the use of potent CYP3A4 inhibitors, a lower initial dose of atorvastatin should be considered. Appropriate clinical monitoring of these patients is also recommended.

Atorvastatin should not be used concomitantly with systemic fusidic acid or within 7 days of discontinuation of fusidic acid. In patients in whom systemic fusidic acid is considered necessary, statin treatment should be discontinued for the duration of fusidic acid therapy. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination (see section 4.5). Patients should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

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

In exceptional circumstances, when long-term systemic use of fusidic acid is required, for example, for the treatment of severe infections, the need for simultaneous use of Etset® and fusidic acid should only be considered on an individual basis and under close medical supervision.

Interstitial lung disease