Instructions Atorvastatin 20 Ananta film-coated tablets 20 mg blister No. 30
Composition
active ingredient: atorvastatin;
1 tablet contains atorvastatin calcium equivalent to atorvastatin 10 mg or 20 mg;
Excipients: lactose monohydrate; microcrystalline cellulose; magnesium stearate; croscarmellose sodium; corn starch; hydroxypropylcellulose; hydroxypropylmethylcellulose; polyethylene glycol; titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties: white or almost white, round biconvex tablets, film-coated.
Pharmacotherapeutic group
Hypolipidemic agents, monocomponent. HMG-CoA reductase inhibitors. ATC code C10A A05.
Pharmacological properties
Pharmacodynamics
Atorvastatin is a synthetic lipid-lowering drug. It 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 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, 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").
Pharmacokinetics
Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1–2 hours. The extent of absorption is dose-proportional. The absolute bioavailability of atorvastatin 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 when atorvastatin is taken with or without food. 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 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" 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 atorvastatin metabolism by cytochrome P450 3A4, which is consistent with the increased drug concentrations in human plasma 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 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.
Elderly: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (aged 65 years and older) than in young adult subjects. Clinical data suggest that at any dose, atorvastatin is more effective in lowering LDL-C in elderly patients 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 (aged 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 LDL-C, and therefore no dose adjustment is required in patients with renal impairment (see Dosage and Administration, Precautions).
Hemodialysis: Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly increase clearance of the drug, as 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-fold and 11-fold, respectively, in patients with Child-Pugh Class B liver disease (see Contraindications).
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 RD (single dose) | 9.36 | 8.58 |
| #Telaprevir 750 mg every 8 hours, 10 days | 20 mg RD | 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 |
| #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 RD | 3.32 | 1.20 |
| #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 (with concomitant use) † | 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).
* 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 HDL, 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 adult 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 treatments (e.g. LDL apheresis) or if such treatments 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 (4.41 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 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 protease inhibitors, and itraconazole) (see sections 4.4 and 5.1).
Potent CYP 3A4 inhibitors. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant use of atorvastatin with potent CYP 3A4 inhibitors may result in increased plasma concentrations of atorvastatin (see Table 3 and detailed information below). The extent of interaction and potentiation is dependent on the variability of CYP 3A4 effects. Concomitant use with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use of these drugs with atorvastatin cannot be avoided, lower starting and maximum doses of atorvastatin should be considered. Appropriate clinical monitoring of the patient is also recommended (see Table 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 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 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 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 atorvastatin was co-administered with several combinations of HIV protease inhibitors and with the hepatitis C protease inhibitor telaprevir compared to atorvastatin alone. Therefore, concomitant use of atorvastatin should be avoided in patients taking the HIV protease inhibitor tipranavir + ritonavir or the hepatitis C protease inhibitor telaprevir. The drug should be prescribed with caution to patients taking the HIV protease inhibitor lopinavir + ritonavir and used at the lowest necessary dose. For patients taking the HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir, the dose of atorvastatin should not exceed 20 mg; they should be used with caution (see sections “Special instructions” and “Dosage and administration”). When used in patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin should not exceed 40 mg, and close clinical monitoring of patients is recommended.
Itraconazole: The AUC of atorvastatin was significantly increased when atorvastatin 40 mg was co-administered with itraconazole 200 mg (see section 5.1). Therefore, caution should be exercised when atorvastatin doses greater than 20 mg are administered to patients taking itraconazole (see sections 4.4 and 4.2).
Cyclosporine. Atorvastatin and its metabolites are substrates of the OATP1B1 transporter. OATP1B1 inhibitors (e.g. cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin was significantly increased when atorvastatin 10 mg was co-administered with cyclosporine 5.2 mg/kg/day compared to atorvastatin alone (see section 5.1). The concomitant use of atorvastatin and cyclosporine should be avoided (see section 4.4).
Medical recommendations for the use of interacting drugs are summarized in Table 3 (see also sections “Method of administration and dosage”, “Special instructions for use”, “Pharmacological properties”).
Table 3.
Drug interactions associated with increased risk of myopathy/rhabdomyolysis
| Interacting drugs | Medical recommendations for use |
Cyclosporine, HIV protease inhibitors (tipranavir + ritonavir), hepatitis C virus protease inhibitor (telaprevir) | Avoid using atorvastatin | | HIV protease inhibitor (lopinavir + ritonavir) | Use with caution and in the lowest dose necessary. |
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir) | Do not exceed a dose of 20 mg of atorvastatin per day. |
HIV protease inhibitor (nelfinavir) Hepatitis C virus protease inhibitor (boceprevir) | Do not exceed a dose of 40 mg of atorvastatin per day. |
*Use with caution and in the lowest 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 it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased by concomitant administration of other fibrates, the drug 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, 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
Simultaneous oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide is accompanied by a decrease in the concentration of atorvastatin in the blood plasma by approximately 35%. The hypolipidemic effect of atorvastatin was not changed.
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
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
Inhibitors of transport proteins (e.g. cyclosporine) may increase the systemic exposure of atorvastatin (see Table 1). The effect of inhibition of storage transport proteins on the concentration of atorvastatin in liver cells is unknown. If concomitant administration of these drugs cannot be avoided, a dose reduction and clinical monitoring of the effectiveness of atorvastatin is 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 of these patients is recommended.
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: 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.
Colchicine: Myopathy, including rhabdomyolysis, has been reported with concomitant use of atorvastatin and colchicine, and therefore caution should be exercised when atorvastatin is administered with colchicine.
Other medicinal products: Clinical studies have shown that concomitant use of atorvastatin with antihypertensive drugs and its use during estrogen replacement therapy was not accompanied by clinically significant side effects. Interaction studies with other medicinal products 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 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. Concomitant use of higher doses of atorvastatin with certain medicinal products such as cyclosporine and potent CYP3A4 inhibitors (e.g. clarithromycin, itraconazole and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
Rare cases of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use, have been reported. IMMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase 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 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 signs and symptoms of muscle disease persist after discontinuation of atorvastatin. Treatment with the drug should be discontinued if CPK levels are significantly elevated, myopathy is diagnosed, or myopathy is suspected.
The risk of myopathy during treatment with drugs of this class is increased with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir and fosamprenavir + ritonavir, as well as niacin or azole antifungals. Physicians considering the combination of atorvastatin and fibric acid derivatives, erythromycin, clarithromycin, saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and monitor patients closely for any signs of muscle pain, tenderness, or weakness, especially during the initial months of therapy and during any up-titration periods of either drug. Low initial and maintenance doses of atorvastatin should be considered when co-administered with the above-mentioned drugs (see Interactions). In such situations, periodic CPK determination may be considered, but there is no guarantee that such monitoring will help prevent cases of severe myopathy.
Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin with colchicine, therefore atorvastatin with colchicine should be prescribed with caution to patients (see section "Interaction with other medicinal products and other types of interactions").
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.
Statins, like some other lipid-lowering therapeutic agents, have been shown to be associated with abnormalities in biochemical parameters of liver function. 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 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, 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
Increased HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Statins inhibit cholesterol synthesis and theoretically may reduce adrenal steroid secretion and/or gonadal steroid secretion. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentrations or impair adrenal reserve. The effect of statins on sperm fertilisation has not been studied in a sufficient number of patients. It is not known how, or if, the drug affects the gonadal-pituitary-hypothalamic axis in premenopausal women. Caution should be exercised when co-administering statins with medicinal products that may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.
Use in patients with recent stroke or transient ischemic attack
In patients without coronary artery disease who had a history of stroke or transient ischemic attack within the previous 6 months, a higher incidence of hemorrhagic stroke was observed with atorvastatin 80 mg compared with placebo. The incidence of fatal hemorrhagic stroke was similar in all treatment groups. The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group compared with the placebo group. Several baseline characteristics, including the presence of hemorrhagic and lacunar stroke at baseline, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.
No overall difference in safety was observed among patients aged 65–75 years receiving atorvastatin.
