Instructions for use Limistin 40 film-coated tablets 40 mg No. 30
Composition
active ingredient: atorvastatin;
1 tablet contains atorvastatin calcium equivalent to atorvastatin 20 mg or 40 mg;
excipients: calcium carbonate; microcrystalline cellulose; lactose, monohydrate; croscarmellose sodium; polysorbate 80; hydroxypropylcellulose; magnesium stearate; hydroxypropylmethylcellulose; propylene glycol; polyethylene glycol-6000; talc; titanium dioxide (E 171) – 20 mg tablets;
calcium carbonate; microcrystalline cellulose; lactose, monohydrate; croscarmellose sodium; polysorbate 80; hydroxypropylcellulose; magnesium stearate; crospovidone; sodium lauryl sulfate; hydroxypropylmethylcellulose; polyethylene glycol-6000; talc; titanium dioxide (E 171) - 40 mg tablets.
Dosage form
Film-coated tablets.
Main physicochemical properties:
white or almost white, capsule-shaped, film-coated tablets with a score on one side (20 mg tablets);
White or almost white, round, biconvex, film-coated tablets (40 mg tablets).
Pharmacotherapeutic group
Hypolipidemic agents, monocomponent. 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, 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 reduced 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 reduced 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 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 is dose-proportional. 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, the reduction in LDL-C levels is similar when the drug is taken with or without food, as measured by Cmax and AUC. When atorvastatin was administered in the evening, its plasma concentration was lower (approximately 30% in terms of 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 atorvastatin 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" and "Special Instructions").
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 inhibitory activity against HMG-CoA reductase is 20 to 30 hours due to the action of active metabolites. After oral administration, less than 2% of the dose is excreted in the urine.
Special patient populations
Elderly patients: Plasma concentrations of the drug 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 indicate a greater degree of LDL-C reduction at 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 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 the drug differ in women compared to 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 does not affect the plasma concentrations of atorvastatin or the reduction in low-density lipoprotein cholesterol (LDL-C), therefore, no dose adjustment is required for 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 the drug 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. In patients with Child-Pugh class B liver disease, Cmax and AUC are increased approximately 16- and 11-fold, respectively (see Contraindications).
Drug interaction studies. Atorvastatin is a substrate of the hepatic transporters OATP1B1 and OATP1B3. Atorvastatin metabolites 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 once | 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 once | 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 once | 1.94 | 4.34 |
| #Simeprevir 150 mg once daily, 10 days | 40 mg once | 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 once | 3.32 | 1.20 |
| Letermovir 480 mg once daily, 10 days | 20 mg once | 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 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 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 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, the drug 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, 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 high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb).
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 (e.g. 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
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 pediatric patients.
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 period.
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. Concomitant use of atorvastatin with potent inhibitors of CYP 3A4 may result in increased plasma concentrations of atorvastatin (see Table 3 and detailed information below). The extent of interaction and potentiation of action depend on the potential for CYP 3A4 inhibition. Concomitant use of the drug with potent inhibitors of CYP3A4 (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 if possible. If concomitant use of these drugs 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 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 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 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 the concentration of atorvastatin in the blood plasma, especially with excessive consumption of grapefruit juice (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. Therefore, atorvastatin doses above 20 mg should be used with caution in patients receiving clarithromycin (see sections 4.4 and 4.2).
Combination of protease inhibitors
Atorvastatin AUC 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. The lowest dose necessary should be used in patients taking lopinavir + ritonavir or simeprevir. The dose should not exceed 20 mg in patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir or elbasvir + grazoprevir. The dose should not exceed 40 mg in patients taking nelfinavir and close clinical monitoring is recommended (see sections 4.4 and 4.2).
Atorvastatin AUC 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 receiving 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 with the simultaneous use of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day compared to the use of atorvastatin alone (see section "Pharmacological properties"). The simultaneous use of the drug Limistin and cyclosporine should be avoided (see section "Special instructions").
Letermovir: Co-administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased exposure to atorvastatin (AUC ratio: 3.29) (see Pharmacokinetics).
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 the drug 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. Use of the drug 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 increase by up to 1.9-fold, partly due to BCRP, OATP1B1/1B3 and CYP3A inhibition, therefore the dose of the drug should not exceed 20 mg per day when used in patients concomitantly taking medicinal products containing elbasvir and grazoprevir (see sections “Pharmacokinetics”, “Special instructions for use” and “Method and dosage”).
Medical recommendations for the use of interacting drugs are summarized in Table 3 (see also sections “Pharmacological properties”, “Method of administration and dosage” and “Special instructions for use”).
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 with the simultaneous use of HMG-CoA reductase inhibitors with gemfibrozil, the combined use of Limistin with gemfibrozil should be avoided (see section "Special warnings and precautions for use").
Other fibrates
Since it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors increases with the simultaneous use of other fibrates, Limistin should be used with caution when used concomitantly with other fibrates (see section "Special warnings and precautions for use").
Niacin
The risk of skeletal muscle side effects may increase when the drug is used in combination with niacin, therefore, in such conditions, a dose reduction of Limistin should be considered (see section "Special instructions").
Rifampin or other cytochrome P450 3A4 inducers
Concomitant use of the drug with cytochrome P450 3A4 inducers (e.g., 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
Simultaneous administration of atorvastatin (40 mg) and diltiazem (240 mg) is accompanied by an increase in the concentration of atorvastatin in the blood plasma.
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 coadministered. The lipid-lowering effect of the combination of atorvastatin and colestipol was greater than that of either drug alone.
Azithromycin
Concomitant use 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 (see Table 1). The effect of inhibition of storage transporters on atorvastatin concentrations in liver cells is unknown. If concomitant administration cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).
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 is recommended in such patients.
Fusidic acid
Concomitant systemic administration 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
When multiple doses of atorvastatin are co-administered with digoxin, steady-state plasma concentrations of digoxin are increased (see Pharmacokinetics). Patients receiving digoxin should be monitored closely.
Oral contraceptives
When atorvastatin was co-administered with oral contraceptives, an increase in AUC for norethisterone and ethinylestradiol was observed (see section "Pharmacological properties"), which should be considered when choosing an oral contraceptive for women using atorvastatin.
Warfarin
Atorvastatin had no clinically significant effect on prothrombin time in patients receiving long-term warfarin treatment.
Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin with colchicine, therefore atorvastatin should be prescribed with caution with colchicine.
Other medicines
Clinical studies have shown that the simultaneous use of atorvastatin and antihypertensive drugs and its use in the process of 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 of this class. A history of renal impairment may be a risk factor for rhabdomyolysis. Such patients should be closely monitored for skeletal muscle dysfunction.
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 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 patients 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 signs and symptoms of muscle disease persist after discontinuation of atorvastatin. Treatment with the drug should be discontinued in the event of a marked elevation in CPK, diagnosis or suspicion of myopathy.
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 signs 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.
Therapy with the drug should be temporarily or permanently discontinued in any patient 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).
In isolated cases, statins have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Atorvastatin should be discontinued if symptoms worsen. Relapse has been reported with rechallenge with the same or a different statin.
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 or more times) of serum transaminases were observed in 0.7% of patients treated with atorvastatin. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for atorvastatin doses of 10, 20, 40, and 80 mg, respectively.
There is evidence that one patient developed jaundice while taking the drug. Elevated liver function tests (LFTs) in other patients were not associated with jaundice or other clinical symptoms. After dose reduction, interruption of the drug, or discontinuation of its use, transaminase levels returned to or near pretreatment levels without adverse effects. 18 of 30 patients with persistent elevations in liver function tests continued treatment with atorvastatin at lower doses.
It is recommended that liver enzyme levels be obtained before initiating therapy 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, re-treatment with atorvastatin should not be considered.
