Instructions for Atorvastatin-Darnitsa tablets 20 mg No. 28
Composition
active ingredient: atorvastatin;
1 tablet contains atorvastatin calcium, equivalent to atorvastatin 10 mg or 20 mg;
excipients: calcium carbonate with povidone, microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate, crospovidone, magnesium stearate, Opadry II 85F white.
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated with a white or almost white coating.
Pharmacotherapeutic group
Drugs that lower serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. Atorvastatin.
ATX 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, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the initial and rate-limiting step in cholesterol biosynthesis.
Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that regulates the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.
In experimental animal models, atorvastatin reduces plasma cholesterol and lipoprotein levels by inhibiting hepatic HMG-CoA reductase and cholesterol synthesis and by increasing the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface to enhance LDL uptake and catabolism; atorvastatin also reduces LDL production and particle size.
Atorvastatin, as well as some of its metabolites, is pharmacologically active in humans. The primary 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. Individual selection of the dose of the drug should be carried out depending on the therapeutic response (see section "Method of administration and dosage").
Pharmacokinetics
Absorption.
Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations (Cmax) occurring within 1–2 hours. The extent of absorption increases in proportion to the dose of atorvastatin. 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 (area under the concentration-time curve), the reduction in LDL-C is similar whether the drug is administered 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 atorvastatin 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 animals, it is believed that atorvastatin is able to penetrate into breast milk (see sections "Contraindications" and "Special Instructions").
Metabolism.
Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various β-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 atorvastatin metabolism by cytochrome P450 3A4, which is consistent with the increased plasma concentrations of the drug 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. After oral administration, less than 2% of the dose is excreted in the urine.
Elderly patients: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly volunteers (aged 65 years and older) than in young patients. There is evidence of a greater degree of LDL-C reduction with any dose in elderly patients compared with young patients (see section 4.4).
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 the population pharmacokinetic model of atorvastatin in an open-label, 8-week study that included children with heterozygous familial hypercholesterolemia (ages 10 to 17 years, n=29).
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.
Renal impairment: Renal disease has no effect on plasma concentrations of atorvastatin or on the reduction of low-density lipoprotein cholesterol (LDL-C), therefore, no dose adjustment is required in patients with renal impairment (see sections 4.4 and 4.2).
Hemodialysis: Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly increase the clearance of atorvastatin 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. Cmax and AUC are 4-fold higher in patients with Child-Pugh class A liver disease. Cmax and AUC are increased approximately 16- and 11-fold, respectively, in patients with Child-Pugh class B liver disease (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.
Table 1
Effect of concomitant medications on the pharmacokinetics of atorvastatin
| 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 |
| #Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 7 days | 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 | 3.32 | 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 2 times a day, 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 throughout 3 days | 0.59 | 1.01 |
#Rifampin 600 mg once daily, 7 days (when used concurrently) † | 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 2 times a day, 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 “Interaction with other medicinal products and other types of interactions” and “Special warnings and precautions for use”.
* 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.
Table 2
Effect of atorvastatin on the pharmacokinetics of concomitant medications
| 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 a day, 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 high-density lipoprotein (HDL) cholesterol, 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 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, the drug is indicated for:
reducing the risk of myocardial infarction;
reducing the risk of stroke.
For patients with clinically significant ischemic heart disease, the drug 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 if such therapies are unavailable.
As an adjunct to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B in postmenarcheal boys and girls 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:
there is a family history of early cardiovascular disease;
Two or more other risk factors for cardiovascular disease are present in a 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.
Breastfeeding period.
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 and hepatitis C protease inhibitors, and itraconazole) (see sections 5.1 and 5.2).
Potent CYP 3A4 inhibitors. Atorvastatin is metabolized by cytochrome P450 3A4. Co-administration of the drug with potent CYP 3A4 inhibitors may result in increased plasma concentrations of atorvastatin (see Table 3 and detailed information below). The extent of interaction and potentiation depends on the variability of the effect on CYP 3A4. Co-administration with potent CYP 3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, some antiviral agents for the treatment of HCV (e.g., elbasvir/grazoprevir) and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use of these medicinal products with atorvastatin cannot be avoided, lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended (see Table 3).
Moderate CYP 3A4 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 conducted. Amiodarone and verapamil are known to inhibit CYP 3A4 activity, and concomitant use of these medicinal products 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 and clinical monitoring of the patient should be considered. Clinical monitoring of the patient is also recommended after initiation of treatment with the 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).
Clarithromycin: The AUC of atorvastatin was significantly increased when clarithromycin (500 mg twice daily) was co-administered with 80 mg of atorvastatin compared to atorvastatin alone (see section 5.1). Therefore, caution should be exercised when atorvastatin doses above 20 mg are administered to 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 protease inhibitors (see section "Pharmacological properties"). In patients taking tipranavir + ritonavir or glecaprevir + pibrentasvir, co-administration with atorvastatin should be avoided. In patients taking lopinavir + ritonavir or simeprevir, the drug should be used at the lowest necessary dose. For patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir or elbasvir + grazoprevir, the dose of the drug should not exceed 20 mg. When used in patients taking nelfinavir, the dose of atorvastatin should not exceed 40 mg, and careful clinical monitoring of patients is also recommended (see sections "Special warnings and precautions for use" and "Method of administration and dosage").
Cyclosporine. Atorvastatin is a substrate for hepatic transporters. Metabolites of atorvastatin are substrates for 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). Concomitant use of atorvastatin and cyclosporine should be avoided (see section 4.4).
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).
Letepmovir 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 CYP3A 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 glecaprevir and pibrentavir are co-administered with atorvastatin, plasma concentrations of atorvastatin increase up to 8.3-fold, partly due to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, concomitant use of atorvastatin is not recommended in patients taking concomitant medicinal products containing glecaprevir and pibrentasvir.
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 CYP3A inhibition, therefore the dose of atorvastatin should not exceed 20 mg daily when used in patients taking concomitant medicinal products containing elbasvir and grazoprevir (see sections 4.2, 4.4 and 4.2).
Medical recommendations for the use of interacting drugs are summarized in Table 3 (see also sections “Pharmacological properties”, “Special instructions for use” and “Method of administration and dosage”).
Table 3.
Drug interactions associated with an increased risk of myopathy/rhabdomyolysis.
| 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 co-administered 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, therefore 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 the drug 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.
Colestipol. Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when atorvastatin and colestipol were coadministered. The lipid-lowering effect of the combination of atorvastatin and colestipol was greater than that of either drug given alone.
Azithromycin: Concomitant administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not associated with changes in atorvastatin plasma concentrations.
Transporter protein inhibitors. Transporter protein inhibitors (e.g., cyclosporine, letermovir) may increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of storage transporters on atorvastatin concentrations in liver cells is unknown. If co-administration of these drugs cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).
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 not yet known. Cases of rhabdomyolysis (including fatalities) have been reported in patients receiving the combination of these medicinal products.
If systemic use of fusidic acid is necessary, atorvastatin should be discontinued for the entire period of fusidic acid administration (see section 4.4).
Digoxin: Concomitant administration of multiple doses of atorvastatin and digoxin increases steady-state plasma concentrations of digoxin (see Pharmacokinetics). Patients taking digoxin should be monitored closely.
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 in patients receiving long-term warfarin therapy.
Colchicine: Myopathy, including rhabdomyolysis, has been reported with concomitant use of atorvastatin with colchicine, and therefore atorvastatin should be administered with caution with colchicine.
Other medicinal products: It is known that the simultaneous use of atorvastatin and antihypertensive medicinal products and its use in the process of estrogen replacement therapy is not accompanied by clinically significant side effects.
No interaction studies with other drugs have been conducted.
Application features
Skeletal muscles
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and other medicinal products of 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, defined as 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 medicinal products, such as cyclosporine and potent CYP 3A4 inhibitors (e.g. clarithromycin, itraconazole and HIV and hepatitis C protease inhibitors), increases the risk of myopathy/rhabdomyolysis.
There have also 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 (CK) that 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 risk of myopathy with this class of medicinal products is increased by concomitant use of the medicinal products listed in Table 3. Physicians considering the combination of atorvastatin with any of these medicinal products should carefully weigh the potential benefits and risks and monitor patients closely for any signs of muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any up-titration periods of either medicinal product. Low initial and maintenance doses of atorvastatin should be considered when co-administered with the above medicinal products (see section 4.5). Periodic CPK monitoring may be considered in such situations, but there is no guarantee that such monitoring will prevent severe myopathy.
Atorvastatin therapy should be temporarily or permanently discontinued in any patient with an acute, serious condition suggestive of myopathy or in the presence of a risk factor for renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine, and electrolyte disturbances, and uncontrolled seizures).
Liver dysfunction
Statins, like some other lipid-lowering agents, have been associated with abnormal liver function tests. Persistent elevations (>3 times the upper limit of normal, occurring 2 times or more times) of serum transaminases were observed in 0.7% of patients treated with atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for the 10, 20, 40, and 80 mg doses, respectively.
Jaundice and elevations in liver function tests (LFTs) not associated with jaundice or other clinical signs and symptoms have been reported with atorvastatin. Transaminase levels return to or near pretreatment levels without adverse effects after dose reduction, interruption, or discontinuation of the drug.
It is recommended that liver enzyme levels be obtained before initiating therapy and repeated as clinically indicated. Rare cases of fatal and non-fatal hepatic failure have also 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 atorvastatin, treatment should be discontinued immediately. The drug should not be restarted unless an alternative etiology is identified.
Atorvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease. The drug is contraindicated in active liver disease or persistent elevations of hepatic transaminases of unknown etiology (see section "Contraindications").
Endocrine function
Increased HbA1c levels have been reported
