Instructions Atorvacor film-coated tablets 10 mg blister No. 60
Composition
active ingredient: atorvastatin;
1 tablet contains atorvastatin calcium 10.82 mg or 21.64 mg, or 43.28 mg, or 86.56 mg or in terms of 100% substance (equivalent to atorvastatin) 10 mg or 20 mg, or 40 mg, or 80 mg;
excipients: calcium carbonate; lactose, monohydrate; microcrystalline cellulose; croscarmellose sodium; polysorbate 80; hydroxypropylcellulose; magnesium stearate; Opadry II 85F18422 white (polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171)).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated with a white or almost white film coating.
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 reductase (HMG-CoA reductase). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, the initial and rate-limiting step in cholesterol biosynthesis.
Atorvacor® 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 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-C 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").
Pharmacokinetics.
Absorption. Atorvastatin is rapidly absorbed after oral administration. Peak plasma concentrations (Cmax) are reached within 1–2 hours. The extent of absorption increases proportionally 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 (area under the concentration-time curve), 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 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 animal studies, it is believed that atorvastatin is able to penetrate into human breast milk (see sections "Contraindications" and "Special Instructions").
Metabolism: Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro studies have shown that the inhibition of HMG-CoA reductase by ortho- and para-hydroxylated 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 (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 plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the action 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 volunteers (aged 65 years and older) than in young adult patients. Clinical data suggest that at any dose, atorvastatin reduces LDL-C more than in 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 a population pharmacokinetic model of atorvastatin with data that included children with heterozygous familial hypercholesterolemia (ages 10 to 17 years, n=29) in an open-label 8-week study.
Gender: Plasma concentrations of atorvastatin differ in women compared to men (approximately 20% higher Cmax and 10% lower AUC). However, there is no clinically significant difference in LDL-C reduction between men and women with atorvastatin.
Renal impairment: Renal disease does not affect the plasma concentrations of atorvastatin or the LDL-C reduction, therefore no dose adjustment is required in patients with renal impairment (see sections 4.4 and 4.2).
Hemodialysis: Although studies in patients with end-stage renal disease have not been conducted, hemodialysis is not expected to significantly increase the clearance of atorvastatin because it 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-fold 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) | AUC& ratio | Cmax& ratio |
| #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 mg twice daily, 28 weeks | 40 mg once daily for 28 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 (co-administered) † | 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 | 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 use of 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”.
* Greater 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, caution should be exercised and the lowest dose necessary should be used.
Table 2
Effect of atorvastatin on the pharmacokinetics of concomitant medications
| Atorvastatin | Concomitant drug and dosage regimen |
| Drug/dose (mg) | AUC ratio | Cmax ratio |
| 80 mg once daily for 15 days | Antipyrine 600 mg, single dose | 1.03 | 0.89 |
| 80 mg once daily for 14 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 clinical significance, see section “Interaction with other medicinal products and other forms of interaction”.
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 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 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, Atorvacor® 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-C 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-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (such as LDL apheresis) or when such therapies are unavailable.
In children
As an adjunct to diet to reduce total cholesterol, LDL-C and apolipoprotein B 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
family history of early cardiovascular disease or
two or more other risk factors for cardiovascular disease are present
in a child 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 and breastfeeding.
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 virus protease inhibitors, and itraconazole) (see sections 5.1 and 5.2).
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 Table 1 and detailed information below). The extent of interaction and potentiation is dependent on the effect on CYP 3A4. Concomitant use of atorvastatin with potent CYP3A4 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 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 conducted. Amiodarone and verapamil are known to inhibit CYP3A4 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 CYP3A4 inhibitors and clinical monitoring of the patient should be considered. Clinical monitoring of the patient 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: The AUC of atorvastatin was significantly increased when clarithromycin (500 mg twice daily) was co-administered with 80 mg atorvastatin compared to atorvastatin alone (see section 5.1). Therefore, caution should be exercised when Atorvastatin is administered at doses above 20 mg to patients taking clarithromycin (see sections 4.4 and 4.2).
Combination of protease inhibitors. The AUC of atorvastatin was significantly increased when atorvastatin was co-administered with several protease inhibitor combinations (see section 5.1). Co-administration of Atorvastatin with tipranavir + ritonavir or glecaprevir + pibrentasvir should be avoided in patients taking tipranavir + ritonavir or glecaprevir + pibrentasvir. Atorvastatin should be used at the lowest dose necessary in patients taking lopinavir + ritonavir or simeprevir. For patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir or elbasvir + grazoprevir, the dose of Atorvastatin should not exceed 20 mg. When used in patients taking nelfinavir, the dose of Atorvacor® 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").
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 the drug was co-administered at a dose of 10 mg with cyclosporine at a dose of 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).
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 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 pibrentasvir or elbasvir and grazoprevir may result in increased plasma concentrations of atorvastatin and an increased risk of myopathy.
When glecaprevir and pibrentasvir are co-administered with atorvastatin, the plasma concentration of atorvastatin increases 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 medications containing glecaprevir and pibrentasvir.
When elbasvir and grazoprevir are co-administered with atorvastatin, plasma concentrations of atorvastatin increase up to 1.9-fold, partly due to BCRP, OATP1B1/1B3 and CYP3A inhibition; therefore, the dose of Atorvastatin should not exceed 20 mg/day in patients receiving concomitant medicinal products containing elbasvir and grazoprevir (see sections 4.4 and 4.2).
Medical recommendations for the use of interacting drugs are given in Table 3 (see also sections “Pharmacological properties”, “Special instructions for use” and “Method of administration and dosage”).
Table 3
Drug interactions associated with 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 taken 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 Atorvastatin is used in combination with niacin, therefore, in such conditions, a dose reduction of this medicinal product should be considered (see section "Special warnings and precautions for use").
Rifampin or other cytochrome P450 3A4 inducers. Concomitant use of the drug with cytochrome P450 3A4 inducers (such as efavirenz, rifampin) may result in an unstable decrease 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 a significant decrease 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.
Antacids: Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide resulted in a decrease in plasma concentrations of atorvastatin by 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 coadministered. The lipid-lowering effect of the combination of atorvastatin and colestipol was greater than that of either drug 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.
Transport inhibitors: Transport protein inhibitors (e.g., cyclosporine, letermovir) may increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of storage transport proteins on atorvastatin concentrations in liver cells is unknown. If co-administration cannot be avoided, a 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 currently unknown. Cases of rhabdomyolysis (including fatalities) 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 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 of norethisterone and ethinyl estradiol (see section 5.1). This increase should be taken into account when choosing an oral contraceptive for women 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 with colchicine, and atorvastatin should be administered with caution with colchicine.
Other medicinal products. Clinical studies have shown that the simultaneous use of atorvastatin and antihypertensive drugs and its use in the process of estrogen replacement therapy is not accompanied by clinically significant side effects. Interaction studies with other medicinal products have not been conducted.
Application features
Skeletal muscles
There have been rare reports of rhabdomyolysis with acute renal failure secondary to myoglobinuria with the use of atorvastatin and other drugs of this class. A history of impaired renal function may be a risk factor for the development of 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 drugs, such as cyclosporine and potent CYP3A4 inhibitors (e.g. clarithromycin, itraconazole, and HIV and hepatitis C protease inhibitors), increases the risk of myopathy/rhabdomyolysis.
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 or fever, or if muscle symptoms persist after discontinuation of Atorvastatin. Treatment should be discontinued if CPK levels are significantly elevated or 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 periods of up-titration of either drug. Low initial and maintenance doses of atorvastatin should be considered when co-administered with the above drugs (see Interactions). In such situations, periodic monitoring of CPK may be considered, but there is no guarantee that such monitoring will prevent severe myopathy.
Atorvastatin therapy should be temporarily withheld or 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 therapeutic agents, have been shown to be associated with abnormalities in liver function tests. Persistent elevations (>3 times the upper limit of normal occurring on 2 or more occasions) of serum transaminases occurred 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 mg, 20 mg, 40 mg, and 80 mg doses, respectively.
During clinical trials, one patient developed jaundice. Elevated liver function tests (LFTs) in other patients were not associated with jaundice or other clinical symptoms. Transaminase levels returned to or near pretreatment levels without adverse effects after dose reduction, interruption, or discontinuation of atorvastatin. Eighteen of the 30 patients with persistent elevations in LFTs continued atorvastatin at lower doses.
It is recommended that liver enzyme levels be obtained prior to initiating Atorvastatin and repeated as clinically indicated. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients treated with statins, including atorvastatin. If severe liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Atorvastatin, treatment should be discontinued immediately. Unless an alternative etiology is identified, treatment with the drug should not be restarted.
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
Increases in HbA1c and fasting serum glucose have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Statins prevent
