Instructions Atorvastatin film-coated tablets 20 mg blister No. 30
Composition
active ingredient: atorvastatin;
1 film-coated tablet contains 10.36 or 20.72, or 41.44 mg of atorvastatin calcium, which corresponds to 10 or 20 or 40 mg of atorvastatin, respectively;
excipients: mannitol (E 421), microcrystalline cellulose, calcium carbonate, povidone, croscarmellose sodium, sodium lauryl sulfate, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide (E 171), macrogol 6000, talc.
Dosage form
Film-coated tablets.
Main physicochemical properties:
10 mg: film-coated tablets, white, round biconvex, 7 mm in size;
20 mg: film-coated tablets, white, round biconvex, 9 mm in size;
40 mg: film-coated tablets, white, oval biconvex, 8.2×17 mm in size.
Pharmacotherapeutic group
Drugs that lower serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. ATC code C10A A05.
Pharmacological properties
Pharmacodynamics.
Atorvastatin is a synthetic lipid-lowering drug. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early, rate-limiting step in cholesterol biosynthesis.
Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that is responsible for the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream complexed with lipoproteins. These complexes are separated by ultracentrifugation into HDL (high-density lipoprotein), LDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the blood plasma for transport to peripheral tissues. LDL is formed from VLDL and catabolized by interaction with high-affinity LDL receptors. Clinical and pathological studies show that elevated levels of total cholesterol (TC), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) in blood plasma contribute to the development of atherosclerosis in humans and are risk factors for cardiovascular disease, while elevated levels of HDL-cholesterol are associated with a reduced risk of cardiovascular disease.
Elevated levels of total cholesterol, LDL cholesterol, and apo B (the membrane complex for LDL cholesterol) are associated with the development of atherosclerosis. Similarly, decreased levels of HDL cholesterol (and its transport complex, apo B) are associated with the development of atherosclerosis.
Epidemiological studies have established that cardiovascular morbidity and mortality vary directly proportionally with total cholesterol and LDL cholesterol levels and inversely proportionally with HDL cholesterol levels.
Atorvastatin reduces total cholesterol, LDL-cholesterol, and apo B in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial hypercholesterolemia, and mixed dyslipidemia. Atorvastatin also reduces VLDL-cholesterol and TG, and causes transient increases in HDL-cholesterol and apolipoprotein A-1. Atorvastatin reduces total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, triglycerides, and non-HDL-cholesterol, and increases HDL-cholesterol in patients with isolated hypertriglyceridemia. Atorvastatin reduces LDL-C in patients with dysbetalipoproteinemia.
Like LDL, cholesterol- and triglyceride-rich lipoproteins, including VLDL, HDL, and remnants, may also contribute to atherosclerosis. Elevated plasma triglyceride levels are often found in the triad of low HDL-C and small LDL particles, and in association with nonlipid metabolic risk factors for coronary heart disease. Total plasma triglycerides per se have not been consistently shown to be an independent risk factor for coronary heart disease. Furthermore, no independent effect of increasing HDL or decreasing triglycerides on the risk of coronary and cardiovascular morbidity and mortality has been established.
Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The main site of action of atorvastatin is the liver, which plays a major role in cholesterol synthesis and LDL clearance. The dose of the drug, in contrast to the systemic concentration of the drug, correlates better with the reduction in LDL cholesterol levels. Individual selection of the dose of the drug should be carried out depending on the therapeutic response (see section "Method of administration and dosage").
Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. The extent of absorption increases in proportion to the dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, and the systemic bioavailability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability of the drug is attributed to presystemic clearance in the gastrointestinal mucosa and/or presystemic biotransformation in the liver. Although food reduces the rate and extent of absorption of the drug by approximately 25% and 9%, respectively, based on Cmax and AUC, the reduction in LDL-C is similar whether atorvastatin is taken with or without food. When atorvastatin was administered in the evening, its plasma concentration was lower (approximately 30% for Cmax and AUC) than when administered in the morning. However, the reduction in LDL-C was the same regardless of the time of administration (see section 4.2).
Distribution. The mean volume of distribution of the drug is approximately 381 liters. More than 98% of the drug is bound to plasma proteins. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes. 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 instructions”).
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro studies have shown that the inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of the circulating inhibitory activity against HMG-CoA reductase is associated with the active metabolites. In vitro studies suggest the importance of metabolism by cytochrome P450 3A4 (CYP 3A4), which is consistent with the increased plasma concentrations of atorvastatin in humans after concomitant administration with erythromycin, a known inhibitor of this isoenzyme (see section 4.5).
Excretion: Atorvastatin and its metabolites are eliminated primarily in the bile after hepatic and/or extrahepatic metabolism, but the drug does not appear to undergo enterohepatic recirculation. The mean elimination half-life of the drug from human plasma is approximately 14 hours, but the half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of the dose is excreted in the urine after oral administration.
Elderly: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly patients (aged 65 years and older) than in young adults. Clinical data suggest that at any dose, atorvastatin is more effective in lowering LDL-C in elderly patients compared with young adults (see section 4.4).
Children: Pharmacokinetic data in pediatric patients are not available.
Gender: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC). However, there is no clinically significant difference in LDL-C reduction between men and women with atorvastatin.
Renal impairment: Renal disease has no effect on plasma concentrations of atorvastatin or LDL-C reduction, and therefore no dose adjustment is required in patients with renal impairment (see Dosage and Administration, Precautions).
Hemodialysis: Although not studied in patients with end-stage renal disease, hemodialysis is not expected to significantly increase drug clearance because the drug is highly bound to plasma proteins.
Hepatic impairment: Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. The values of Cmax and AUC in
4-fold higher in patients with Child-Pugh Class A liver disease. In patients with Child-Pugh Class B liver disease, Cmax and AUC values are increased approximately 16-fold and 11-fold, respectively (see Contraindications).
Drug interaction studies. Atorvastatin is a substrate of the hepatic transporters OATP1B1 and OATP1B3. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin has also been identified as a substrate of the efflux transporter breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.
Effect of concomitant medications on the pharmacokinetics of atorvastatin
Table 1
| Concomitant medications and dosage regimen | Atorvastatin |
| Dose (mg) | Correlation AUC& | Correlation Cmax& |
| #Cyclosporin 5.2 mg/kg/day, stable dose | 10 mg once daily for 28 days | 8.69 | 10.66 |
| 10 mg single dose | 9.36 | 8.58 |
| # Glecaprevir 400 mg once daily/ pibrentasvir 120 mg once daily, 7 days | 10 mg once daily for 7 days | 8.28 | 22.00 |
| #Telaprevir 750 mg every 8 hours, 10 days | 20 mg single dose | 7.88 | 10.60 |
| #, ‡Saquinavir 400 mg twice daily/ritonavir 400 mg twice daily, 15 days | 40 mg once daily for 4 days | 3.93 | 4.31 |
| # Elbasvir 50 mg once daily/ grazoprevir 200 mg once daily, 13 days | 10 mg single dose | 1.94 | 4.34 |
| # Simeprevir 150 mg once daily, 10 days | 40 mg single dose | 2.12 | 1.70 |
| #Clarithromycin 500 mg twice daily, 9 days | 80 mg once daily for 8 days | 4.54 | 5.38 |
| #Darunavir 300 mg twice daily/ritonavir 100 mg twice daily, 9 days | 10 mg once daily for 4 days | 3.45 | 2.25 |
| #Itraconazole 200 mg once daily, 4 days | 40 mg single dose | 3.23 | 1.20 |
| Letermovir 480 mg once daily, 10 days | 20 mg single dose | 3.29 | 2.17 |
| #Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days | 10 mg once daily for 4 days | 2.53 | 2.84 |
| #Fosamprenavir 1400 mg twice daily, 14 days | 10 mg once daily for 4 days | 2.30 | 4.04 |
| #Nelfinavir 1250 mg 2 times a day, 14 days | 10 mg once daily for 28 days | 1.74 | 2.22 |
| #Grapefruit juice, 240 ml once a day* | 40 mg once daily | 1.37 | 1.16 |
| Diltiazem 240 mg once daily, 28 days | 40 mg once daily | 1.51 | 1.00 |
| Erythromycin 500 mg 4 times a day, 7 days | 10 mg once daily | 1.33 | 1.38 |
| Amlodipine 10 mg, single dose | 80 mg once daily | 1.18 | 0.91 |
| Cimetidine 300 mg 4 times a day, 2 weeks | 10 mg once daily for 2 weeks | 1.00 | 0.89 |
| Colestipol 10 g twice daily, 24 weeks | 40 mg once daily for 8 weeks | Not applicable | 0.74** |
| Maalox TC® 30 ml 4 times a day, 17 days | 10 mg once daily for 15 days | 0.66 | 0.67 |
| Efavirenz 600 mg once daily, 14 days | 10 mg for 3 days | 0.59 | 1.01 |
| #Rifampin 600 mg once daily, 7 days (when used concomitantly) † | 40 mg once daily | 1.12 | 2.90 |
| #Rifampin 600 mg once daily, 5 days (in divided doses) † | 40 mg once daily | 0.20 | 0.60 |
| #Gemfibrozil 600 mg twice daily, 7 days | 40 mg once daily | 1.35 | 1.00 |
| #Fenofibrate 160 mg once daily, 7 days | 40 mg once daily | 1.03 | 1.02 |
| #Boceprevir 800 mg 3 times a day, 7 days | 40 mg once daily | 2.32 | 2.66 |
& Treatment ratio (concurrent use of the drug with atorvastatin compared to atorvastatin alone).
# For information on clinical significance, see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”.
* Larger increases in AUC (AUC ratio of 2.5) and/or Cmax (Cmax ratio of 1.71) have been reported with excessive consumption of grapefruit juice (750 ml - 1.2 liters per day or more).
**Ratio based on a single sample taken 8–16 hours after dosing.
† Due to the dual interaction mechanism of rifampin, concomitant use of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after rifampin has been shown to be associated with a significant decrease in atorvastatin plasma concentrations.
‡ The dose of saquinavir + ritonavir in this study is not the clinically applicable dose. The increase in atorvastatin exposure in clinical use is likely to be greater than that observed in this study. Therefore, the drug should be used with caution and at the lowest dose necessary.
Effect of atorvastatin on the pharmacokinetics of concomitant medications
Table 2
| Atorvastatin | Concomitant drug and dosage regimen |
| Drug/dose (mg) | Correlation AUC | Correlation Cmax |
| 80 mg once daily for 15 days | Antipyrine 600 mg once | 1.03 | 0.89 |
| 80 mg once daily for 10 days | #Digoxin 0.25 mg once daily, 20 days | 1.15 | 1.20 |
| 40 mg once daily for 22 days | Oral contraceptives once daily, 2 months norethisterone 1 mg ethinylestradiol 35 mcg | 1.28 1.19 | 1.23 1.30 |
| 10 mg once daily | Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 7 days | 1.08 | 0.96 |
| 10 mg once daily for 4 days | Fosamprenavir 1400 mg twice daily, 14 days | 0.73 | 0.82 |
| 10 mg once daily for 4 days | Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days | 0.99 | 0.94 |
# For information on clinical significance, see section “Interaction with other medicinal products and other types of interactions”.
Indication
Prevention of cardiovascular disease in adults
For adult patients without clinically evident 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, Atorvastatin 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, Atorvastatin is indicated for:
reducing the risk of myocardial infarction;
reducing the risk of stroke.
For adult patients with clinically significant coronary heart disease, Atorvastatin is indicated for:
reducing the risk of non-fatal myocardial infarction;
reducing the risk of fatal and non-fatal stroke;
reducing the risk of revascularization procedures;
reducing the risk of hospitalization due to congestive heart failure;
reducing the risk of angina pectoris.
Hyperlipidemia
In adult patients
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 for the treatment of patients with elevated serum triglyceride levels (type IV according to the Fredrickson classification).
For the treatment of patients with primary dysbetalipoproteinemia (type III according to the Fredrickson classification) in cases where diet is not effective enough.
To reduce total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g. LDL apheresis) or when such therapies are unavailable.
In children
As an adjunct to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B levels in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if, after appropriate diet therapy, the test results are as follows:
a) LDL cholesterol remains ≥ 190 mg/dL (4.91 mmol/L) or
b) LDL cholesterol ≥ 160 mg/dL (4.14 mmol/L) and:
family history of early cardiovascular disease or
two or more other risk factors for cardiovascular disease are present in the pediatric patient.
Contraindication
Active liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology.
Hypersensitivity to any of the components of this medicinal product.
Pregnancy.
Breast-feeding.
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 inhibitors of cytochrome P450 3A4 (CYP 3A4) (e.g. clarithromycin, HIV and hepatitis C protease inhibitors, and itraconazole) (see sections 4.4 and 5.1).
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1). 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 CYP3A4 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 CYP3A4 inhibitors. Clinical monitoring of the patient is also recommended. Clinical monitoring of the patient is also recommended after initiation of treatment with an inhibitor or after dose adjustment. Clinical monitoring is also 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 grapefruit juice consumption (more than 1.2 liters per day).
Clarithromycin: Atorvastatin AUC was significantly increased when atorvastatin 80 mg was co-administered with clarithromycin (500 mg twice daily) compared to atorvastatin alone (see section 5.1). Therefore, atorvastatin doses above 20 mg should be used with caution in patients taking clarithromycin (see sections 4.4 and 4.2).
Combination of protease inhibitors. The AUC of atorvastatin was significantly increased when the drug was used simultaneously with several combinations of HIV protease inhibitors, as well as with the hepatitis C virus protease inhibitor telaprevir compared to the use of atorvastatin alone (see section "Pharmacological properties"). In patients taking the HIV protease inhibitors tipranavir + ritonavir or glecaprevir + pibrentasvir, simultaneous use with atorvastatin should be avoided. The drug should be prescribed with caution to patients taking the HIV protease inhibitors lopinavir + ritonavir, and used at the lowest necessary dose. For patients taking the HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir or elbasvir + grazoprevir, the dose of atorvastatin should not exceed 20 mg, these drugs should be used with caution. 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, and careful clinical monitoring of the patient's condition is also recommended (see sections "Special instructions for use" and "Method of administration and dosage").
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 is a substrate of hepatic transporters. Metabolites of atorvastatin 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 10 mg of the drug 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”).
Letermovir: Co-administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased exposure to atorvastatin (AUC ratio: 3.29) (see section 5.2).
Letermovir is an inhibitor of the efflux transporters P-gp, BCRP, MRP2, OAT2 and the hepatic transporter OATP1B1/1B3, thus increasing the exposure of atorvastatin. The dose of atorvastatin should not exceed 20 mg per day (see section 4.2).
The extent of CYP3A4 and OATP1B1/1B3-mediated drug interactions on concomitant medications may vary when letermovir is co-administered with cyclosporine. The use of atorvastatin is not recommended in patients taking letermovir concomitantly with cyclosporine.
Glecaprevir and pibrentasvir, elbasvir and grazoprevir: Concomitant use of glecaprevir and pibrentavir or elbasvir and grazoprevir may result in increased plasma concentrations of atorvastatin and an increased risk of myopathy.
When elbasvir and grazoprevir are co-administered with atorvastatin, plasma concentrations of atorvastatin are increased up to 1.9-fold, partly due to BCRP, OATP1B1/1B3 and CYP3A4 inhibition, therefore the dose of atorvastatin should not exceed 20 mg/day when used in patients concomitantly taking medicinal products containing elbasvir and grazoprevir (see sections 4.2 and 4.4).
Medical recommendations for the use of interacting drugs are summarized in Table 3 (see also sections “Method of administration and dosage”, “Special instructions for use”, “Pharmacological properties”).
Drug interactions associated with an increased risk of myopathy/rhabdomyolysis
Table 3
| Interacting drugs | Medical recommendations for use |
| Cyclosporine, tipranavir + ritonavir, glecaprevir + pibrentasvir, letermovir when used concomitantly with cyclosporine | Avoid using atorvastatin |
| Clarithromycin, itraconazole, saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, letermovir | Do not exceed a dose of 20 mg of atorvastatin per day. |
| Nelfinavir | Do not exceed a dose of 40 mg of atorvastatin per day. |
| Lopinavir + ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine | Use with caution and in the lowest dose necessary. |
*Use in the smallest dose necessary.
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 is 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).
Rifampin or other cytochrome P450 3A4 inducers. Concomitant use of the drug with cytochrome P450 3A4 inducers (e.g. efavirenz, rifampin) may result in unstable decreases in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampin, concomitant use of atorvastatin 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
Simultaneous 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 (approximately 25%) when atorvastatin and colestipol were coadministered. 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.
Transport protein inhibitors
Transporter protein inhibitors (e.g. cyclosporine, letermovir) may increase systemic exposure to atorvastatin. The effect of inhibition of storage transporters on atorvastatin concentrations in liver cells is unknown. If concomitant administration of these drugs cannot be avoided, a dose reduction and clinical monitoring of atorvastatin efficacy is recommended.
Ezetimibe
The use of ezetimibe as monotherapy has been associated with the development of muscular events, including rhabdomyolysis. Therefore, the risk of these events is increased when ezetimibe and atorvastatin are co-administered. Appropriate clinical monitoring of these patients is recommended.
Fusidic acid
Interaction studies with atorvastatin and fusidic acid have not been conducted. As with other statins, muscle events (including rhabdomyolysis) have been reported in post-marketing experience with concomitant use of atorvastatin and fusidic acid. The mechanism of this interaction remains unknown. Patients should be monitored closely and temporary interruption of atorvastatin treatment may be necessary.
Oral contraceptives: Concomitant use of atorvastatin with oral contraceptives increased the AUC values for norethisterone and ethinylestradiol (see section 5.1). These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
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 caution should be exercised when atorvastatin is administered 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.
Application features
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 is 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, defined as muscle pain or weakness in association with an elevation of creatine phosphokinase (CPK) >10 times 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 and hepatitis C 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 reveals necrotizing myopathy without significant inflammation; and positive dynamics are observed with the use of immunosuppressive agents.
The possibility of myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or marked elevations in CPK. Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise, fever, or if signs of muscle disease persist after discontinuation of atorvastatin. Treatment should be discontinued if CPK levels are significantly elevated, or if myopathy is diagnosed or suspected.
The risk of myopathy with this class of drugs is increased by concomitant use of the drugs listed in Table 3. Physicians considering the combination of atorvastatin and any of these drugs should carefully weigh the potential benefits and risks and monitor patients closely for any symptoms of muscle pain, tenderness, or weakness, especially during the initial months of therapy and during any up-titration periods for either drug. Low initial and maintenance doses of atorvastatin should be considered when co-administered with the above drugs (see Interactions). Periodic monitoring of CPK may be considered in such situations, but there is no guarantee that such monitoring will prevent severe myopathy.
Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of
