Atorvastatin-darnitsa
Ukraine
Table of Contents
- INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATORVASTATIN–DARNITSA (ATORVASTATIN–DARNITSA)
- Composition:
- Pharmacological properties.
- Clinical characteristics.
- For information on clinical significance, see sections "Interaction with other medicinal products and other forms of interaction" and "Special instructions".
- When multiple doses of atorvastatin and antipyrine are administered concomitantly, changes in antipyrine clearance are minor or not observed.
- Special precautions.
- Method of Administration and Dosage
- Adverse Reactions
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATORVASTATIN–DARNITSA (ATORVASTATIN–DARNITSA)
Composition:
Active substance: atorvastatin;
1 tablet contains atorvastatin calcium equivalent to 10 mg or 20 mg of atorvastatin;
Excipients: calcium carbonate with povidone, microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate, crospovidone, magnesium stearate, Opadry II 85F white.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: white or almost white, round, biconvex film-coated tablets.
Pharmacotherapeutic group. Medicinal products that reduce serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. Atorvastatin.
ATC code C10A A05.
Pharmacological properties.
Pharmacodynamics.
Atorvastatin is a synthetic hypolipidemic agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the 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, the enzyme responsible for 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 cholesterol and lipoprotein levels in plasma 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 uptake and catabolism of LDL; atorvastatin also reduces the production of LDL and the number of LDL particles.
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 central role in cholesterol synthesis and clearance of LDL. The dose of the drug correlates better with LDL cholesterol reduction than systemic drug concentration. Dose titration should be individualized based on therapeutic response (see section "Dosage and administration").
Pharmacokinetics.
Absorption.
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentration (Cmax) is reached within 1–2 hours. The extent of absorption increases proportionally with the dose of atorvastatin. Absolute bioavailability of atorvastatin (parent drug) is approximately 14%, while systemic bioavailability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability of the drug is attributed to pre-systemic clearance in the gastrointestinal mucosa and/or pre-systemic metabolism in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, based on Cmax and AUC (area under the concentration-time curve), LDL cholesterol reduction is similar regardless of whether the drug is taken with food or separately. When atorvastatin is administered in the evening, plasma concentrations are lower (approximately 30% for both Cmax and AUC) compared to morning administration. However, LDL cholesterol reduction is equivalent regardless of the time of drug administration (see section "Dosage and administration").
Distribution.
The mean volume of distribution of atorvastatin is approximately 381 liters. Over 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 observations, atorvastatin is considered capable of passing into breast milk (see sections "Contraindications" and "Special precautions").
Metabolism.
Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro studies show that ortho- and para-hydroxylated metabolites inhibit HMG-CoA reductase to an extent equivalent to atorvastatin. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to active metabolites. In vitro studies indicate that atorvastatin metabolism is significantly mediated by cytochrome P450 3A4, consistent with increased drug plasma concentrations in humans when co-administered with erythromycin, a known inhibitor of this isoenzyme (see section "Interaction with other medicinal products and other forms of interaction").
Excretion.
Atorvastatin and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic metabolism, although this drug apparently does not undergo enterohepatic recirculation. The mean elimination half-life of the drug in human plasma is approximately 14 hours, while the half-life of HMG-CoA reductase inhibitory activity ranges from 20 to 30 hours due to the contribution of active metabolites. Less than 2% of the dose is excreted in urine after oral administration.
Atorvastatin is a substrate of hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and transporter 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.
Patient populations
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) compared to younger patients. Data indicate a greater degree of LDL reduction with any dose of the drug in elderly patients compared to younger patients (see section "Special precautions").
Children. Apparent oral clearance of atorvastatin in children was found to be similar to that in adults when scaled allometrically by body weight, as body weight was the only significant covariate in the population pharmacokinetic model of atorvastatin based on data from an open-label 8-week study including results from children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n=29).
Gender. Atorvastatin plasma concentrations 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 cholesterol reduction between men and women when the drug is administered.
Renal impairment. Renal disease does not affect atorvastatin plasma concentration or reduction of low-density lipoprotein cholesterol (LDL-C); therefore, dose adjustment in patients with renal impairment is not required (see sections "Special precautions" and "Dosage and administration").
Hemodialysis. Although studies in patients with end-stage renal disease have not been conducted, hemodialysis is not expected to significantly enhance atorvastatin clearance, as the drug is extensively bound to plasma proteins.
Hepatic impairment. Atorvastatin plasma concentrations are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC values 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 values are increased approximately 16-fold and 11-fold, respectively (see section "Contraindications").
Clinical characteristics.
Indications.
Prevention of cardiovascular diseases in adults.
For adult patients without clinically evident ischemic heart disease but with multiple risk factors for the development of ischemic heart disease, such as age, smoking, arterial hypertension, low levels of high-density lipoprotein (HDL) or a family history of premature ischemic heart disease, atorvastatin is indicated for:
- reduction in the risk of myocardial infarction;
- reduction in the risk of stroke;
- reduction in the risk of revascularization procedures and angina.
For patients with type 2 diabetes mellitus and without clinically evident ischemic heart disease, but with multiple risk factors for the development of ischemic heart disease, such as retinopathy, albuminuria, smoking, or arterial hypertension, the medicinal product is indicated for:
- reduction in the risk of myocardial infarction;
- reduction in the risk of stroke.
For patients with clinically evident ischemic heart disease, the medicinal product is indicated for:
- reduction in the risk of non-fatal myocardial infarction;
- reduction in the risk of fatal and non-fatal stroke;
- reduction in the risk of revascularization procedures;
- reduction in the risk of hospitalization due to congestive heart failure;
- reduction in the risk of angina.
Hyperlipidemia.
In adult patients.
- As an adjunct to diet to reduce elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), 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 (types IIa and IIb according to Fredrickson classification).
- As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (type IV according to Fredrickson classification).
- For the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrickson classification), when dietary therapy is insufficiently effective.
- For reduction of total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis), or when such treatments are unavailable.
In children.
- As an adjunct to diet to reduce levels of total cholesterol, LDL-C, and apolipoprotein B in boys and girls after onset of menstruation aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy the following test results are observed:
a) LDL-C remains ≥ 190 mg/dL (4.91 mmol/L), or;
b) LDL-C ≥ 160 mg/dL (4.14 mmol/L) and:
- there is a family history of premature cardiovascular disease;
- two or more other cardiovascular risk factors are present in the pediatric patient.
Contraindications.
- Active liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology.
- Hypersensitivity to any component of this medicinal product.
- Treatment of hepatitis C with the antiviral agents glecaprevir/pibrentasvir.
- Pregnancy.
- Breastfeeding.
Interaction with other medicinal products and other forms of interaction.
Effect of concomitantly administered medicinal products on atorvastatin
Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and transporter 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin (see section "Pharmacokinetics"). Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transporter proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk also increases with concomitant use of atorvastatin with other agents that may potentially induce myopathy, such as fibrates and ezetimibe (see sections "Contraindications" and "Special precautions for use").
Potent CYP3A4 inhibitors. Concomitant use of the medicinal product with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 1 and detailed information below). The extent of interaction and effect enhancement depends on the variability of the effect on CYP3A4. Concomitant use with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for treatment of HCV (e.g., elbasvir/grazoprevir), and HIV protease inhibitors, particularly ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use of these medicinal products with atorvastatin cannot be avoided, consideration should be given to using lower initial and maximum doses of atorvastatin. Appropriate clinical monitoring of the patient is also recommended (see Table 1).
Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase atorvastatin plasma concentrations (see Table 1). Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies assessing the effect of amiodarone or verapamil on atorvastatin have not been conducted. It is known that amiodarone and verapamil inhibit CYP3A4 activity; therefore, concomitant use of these medicinal products with atorvastatin may lead to increased atorvastatin exposure. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to prescribing lower maximum doses of atorvastatin and conducting clinical monitoring of the patient. Clinical monitoring is also recommended after initiation of an inhibitor or after dose adjustment.
Grapefruit juice. Contains one or more components that inhibit CYP3A4 and may increase atorvastatin plasma concentrations, especially with excessive consumption of grapefruit juice (more than 1.2 liters per day).
Clarithromycin. AUC values of atorvastatin were significantly increased when the medicinal product was administered at a dose of 80 mg concomitantly with clarithromycin (500 mg twice daily) compared to atorvastatin alone (see section "Pharmacological properties"). Therefore, patients taking clarithromycin should use atorvastatin cautiously at doses exceeding 20 mg (see sections "Special precautions for use" and "Dosage and administration").
Combination of protease inhibitors. AUC values of atorvastatin were significantly increased when the medicinal product was administered concomitantly with several protease inhibitor combinations (see section "Pharmacological properties"). Patients taking tipranavir + ritonavir or glecaprevir + pibrentasvir should avoid concomitant use with atorvastatin. For patients taking lopinavir + ritonavir or simeprevir, the medicinal product 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 medicinal product should not exceed 20 mg. In patients taking nelfinavir, the atorvastatin dose should not exceed 40 mg, and careful clinical monitoring of patients is also recommended (see sections "Special precautions for use" and "Dosage and administration").
Itraconazole. AUC values of atorvastatin were significantly increased when atorvastatin 40 mg was administered concomitantly with itraconazole 200 mg (see section "Pharmacological properties"). Therefore, patients taking itraconazole should be cautious if the atorvastatin dose exceeds 20 mg (see sections "Special precautions for use" and "Dosage and administration").
Cyclosporine. Atorvastatin is a substrate of hepatic transporters. Atorvastatin metabolites are substrates of the OATP1B1 transporter. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase the bioavailability of atorvastatin. AUC values of atorvastatin were significantly increased when atorvastatin 10 mg was administered concomitantly with cyclosporine 5.2 mg/kg/day compared to atorvastatin alone (see section "Pharmacological properties"). Concomitant use of atorvastatin and cyclosporine should be avoided (see section "Special precautions for use").
Letermovir. Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased exposure to atorvastatin (AUC ratio: 3.29) (see section "Pharmacokinetics").
Letermovir is an inhibitor of efflux transporters P-gp, BCRP, MRP2, OAT2, and the hepatic transporter OATP1B1/1B3, thereby increasing atorvastatin exposure. The atorvastatin dose should not exceed 20 mg daily (see section "Dosage and administration").
The extent of CYP3A- and OATP1B1/1B3-mediated drug interactions may vary when letermovir is used concomitantly with cyclosporine. Atorvastatin use 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 lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy.
When glecaprevir and pibrentasvir are used concomitantly with atorvastatin, plasma concentrations of atorvastatin increase up to 8.3-fold, partially due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, concomitant use of atorvastatin is not recommended in patients taking medicinal products containing glecaprevir and pibrentasvir.
When elbasvir and grazoprevir are used concomitantly with atorvastatin, plasma concentrations of atorvastatin increase up to 1.9-fold, partially due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, the atorvastatin dose should not exceed 20 mg daily when administered to patients taking medicinal products containing elbasvir and grazoprevir (see sections "Pharmacokinetics", "Special precautions for use", and "Dosage and administration").
Gemfibrozil. Due to an increased risk of myopathy/rhabdomyolysis with concomitant use of HMG-CoA reductase inhibitors and gemfibrozil, concomitant use of atorvastatin with gemfibrozil should be avoided (see section "Special precautions for use").
Other fibrates. Since the risk of myopathy during treatment with HMG-CoA reductase inhibitors increases with concomitant use of other fibrates, atorvastatin should be used cautiously when co-administered with other fibrates (see section "Special precautions for use").
Niacin. The risk of skeletal muscle-related adverse events may increase when the medicinal product is used in combination with niacin; therefore, consideration should be given to reducing the atorvastatin dose (see section "Special precautions for use").
Rifampicin or other cytochrome P450 3A4 inducers. Concomitant use of the medicinal product with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampicin) may lead to variable decreases in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, concomitant use of the medicinal product with rifampicin is recommended, as delayed administration of the medicinal product after rifampicin administration has been shown to be associated with a significant decrease in atorvastatin plasma concentrations.
Hydrochloride diltiazem. Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) is associated with increased atorvastatin plasma concentrations.
Cimetidine. No signs of interaction between atorvastatin and cimetidine were observed in studies conducted.
Antacids. Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide results in approximately a 35% reduction in atorvastatin plasma concentration. However, the hypolipidemic effect of atorvastatin is not altered.
Cholestyramine. Atorvastatin plasma concentrations were lower (atorvastatin concentration ratio 0.74) when atorvastatin and cholestyramine were administered concomitantly. However, the hypolipidemic effect of the combination of atorvastatin and cholestyramine exceeded the effect achieved with each medicinal product administered separately.
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. Inhibitors of transport proteins (e.g., cyclosporine, letermovir) may increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of uptake transporters on atorvastatin concentrations in liver cells is unknown. If concomitant administration of these medicinal products 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 musculoskeletal events, including rhabdomyolysis. Thus, the risk of such events increases with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of such patients is recommended.
Fusidic acid. Systemic concomitant use of fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic, pharmacokinetic, or both) is not fully understood. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination of medicinal products.
If systemic use of fusidic acid is necessary, atorvastatin use should be discontinued for the entire duration of fusidic acid treatment (see section "Special precautions for use").
Digoxin. Steady-state digoxin plasma concentrations increase when multiple doses of atorvastatin and digoxin are administered concomitantly (see section "Pharmacokinetics"). Patients receiving digoxin should be appropriately monitored.
Oral contraceptives. Concomitant use of atorvastatin with oral contraceptives increases AUC values for norethisterone and ethinylestradiol (see section "Pharmacological properties"). These increases should be taken into account when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin. Atorvastatin did not exert clinically significant effects on prothrombin time in patients undergoing long-term warfarin therapy.
Colchicine. Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, atorvastatin should be prescribed cautiously with colchicine.
Daptomycin. Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin. If concomitant use cannot be avoided, appropriate clinical monitoring is recommended (see section "Special precautions for use").
Other medicinal products. It is known that concomitant use of atorvastatin with antihypertensive agents and its use during estrogen replacement therapy are not associated with clinically significant adverse effects.
No drug interaction studies have been conducted with other medicinal products.
Table 1
Effect of concomitantly administered medicinal products on the pharmacokinetics of atorvastatin
| Concomitantly administered drugs and dosing regimen |
Atorvastatin |
||
| Dose (mg) |
Ratio AUC& |
Clinical recommendations# |
|
| Cyclosporine 5.2 mg/kg/day, stable dose |
10 mg once daily for 28 days |
8.7 |
If coadministration with atorvastatin is necessary, the atorvastatin dose should not exceed 10 mg daily. Clinical monitoring of patients is recommended. |
| Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 7 days |
10 mg, single dose |
9.4 |
|
| Telaprevir 750 mg every 8 hours, 10 days |
20 mg, single dose |
7.9 |
|
| Glecaprevir 400 mg once daily/pibrentasvir 120 mg once daily, 7 days |
10 mg once daily for 7 days |
8.3 |
Concomitant use with products containing glecaprevir or pibrentasvir is contraindicated (see section "Contraindications"). |
| Saquinavir 400 mg twice daily/ritonavir (300 mg twice daily for 5–7 days, increased on day 8 to 400 mg), |
40 mg once daily for 4 days |
3.9 |
If coadministration with atorvastatin is necessary, a reduction in atorvastatin dose is recommended. Clinical monitoring of patients is recommended when dosing exceeds 40 mg. |
| Darunavir 300 mg twice daily/ritonavir 100 mg twice daily, 9 days |
10 mg once daily for 4 days |
3.4 |
|
| Itraconazole 200 mg once daily, 4 days |
40 mg, single dose |
3.3 |
|
| Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days |
10 mg once daily for 4 days |
2.5 |
|
| Fosamprenavir 1400 mg twice daily, 14 days |
10 mg once daily for 4 days |
2.3 |
|
| Elbasvir 50 mg once daily/grazoprevir 200 mg once daily, 13 days |
10 mg, single dose |
1.95 |
The atorvastatin dose should not exceed 20 mg daily when coadministered with products containing elbasvir or grazoprevir. |
| Simeprevir 150 mg once daily, 10 days |
40 mg, single dose |
2.12 |
The atorvastatin dose should not exceed 20 mg daily when coadministered with products containing simeprevir. |
| Lopinavir 400 mg twice daily/ritonavir 100 mg twice daily, 14 days |
20 mg once daily for 4 days |
5.9 |
If coadministration with atorvastatin is necessary, a reduction in atorvastatin dose is recommended. Clinical monitoring of patients is recommended when atorvastatin dosing exceeds 20 mg. |
| Clarithromycin 500 mg twice daily, 9 days |
80 mg once daily for 8 days |
4.5 |
|
| Letermovir 480 mg once daily, 10 days |
20 mg, single dose |
3.29 |
The atorvastatin dose should not exceed 20 mg daily when coadministered with products containing letermovir. |
| Nelfinavir 1250 mg twice daily, 14 days |
10 mg once daily for 28 days |
1.74 |
No specific recommendations. |
| Grapefruit juice, 240 ml once daily* |
40 mg once daily |
1.37 |
Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended. |
| Diltiazem 240 mg once daily, 28 days |
40 mg once daily |
1.51 |
Clinical monitoring of patients is recommended following initiation or dose adjustment of diltiazem. |
| Erythromycin 500 mg four times daily, 7 days |
10 mg once daily |
1.33 |
Reduction of the maximum atorvastatin dose and clinical monitoring of patients is recommended. |
| Amlodipine 10 mg, single dose |
80 mg once daily |
1.18 |
No specific recommendations. |
| Cimetidine 300 mg four times daily, 2 weeks |
10 mg once daily for 2 weeks |
1.00 |
|
| Colestipol 10 g twice daily, 24 weeks |
40 mg once daily for 8 weeks |
0.74** |
|
| Maalox TC® 30 ml four times daily, 17 days*** |
10 mg once daily for 15 days |
0.66 |
|
| Efavirenz 600 mg once daily, 14 days |
10 mg for 3 days |
0.59 |
|
| Rifampicin 600 mg once daily, 7 days (concomitant administration) |
40 mg once daily |
1.12 |
If concomitant administration cannot be avoided, clinical monitoring of patients is recommended. |
| Rifampicin 600 mg once daily, 5 days (separate doses) |
40 mg once daily |
0.20 |
|
| Gemfibrozil 600 mg twice daily, 7 days |
40 mg once daily |
1.35 |
The lowest starting dose of atorvastatin is recommended, along with clinical monitoring of patients. |
| Fenofibrate 160 mg once daily, 7 days |
40 mg once daily |
1.03 |
|
| Boceprevir 800 mg three times daily, 7 days |
40 mg once daily |
2.3 |
The lowest starting dose of atorvastatin is recommended, along with clinical monitoring of patients. The atorvastatin dose should not exceed 20 mg daily during concomitant use with boceprevir. |
& Comparison by treatment methods (concomitant use of the medicinal product with atorvastatin compared to atorvastatin used alone).
For information on clinical significance, see sections "Interaction with other medicinal products and other forms of interaction" and "Special instructions".
* Contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of drugs metabolized by CYP3A4. Drinking one 240 mL glass of grapefruit juice also resulted in a 20.4% reduction in AUC of the active ortho-hydroxy metabolite. Large amounts of grapefruit juice (more than 1.2 L per day for 5 days) increased the AUC of atorvastatin by 2.5 times and the AUC of active HMG-CoA reductase inhibitors (atorvastatin and metabolites) by 1.3 times.
** Ratios based on single samples taken 8–16 hours after dose administration.
*** Accompanied by approximately a 35% reduction in plasma concentration of atorvastatin, but the hypolipidemic effect of atorvastatin remains unchanged.
Table 2
Effect of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products
| Atorvastatin |
Concomitant medicinal product and dosing regimen |
||
| Medicinal product/dose (mg) |
Ratio AUC& |
Clinical recommendations |
|
| 80 mg once daily for 10 days |
Digoxin 0.25 mg once daily, 20 days |
1.15 |
Clinical monitoring of patients is recommended. |
| 80 mg once daily for 15 days |
Antipyrine 600 mg single dose# |
1.03 |
No specific recommendations. |
| 40 mg once daily for 22 days |
Oral contraceptives once daily, 2 months:
|
1.28 1.19 |
|
| 10 mg once daily |
Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 7 days |
1.08 |
|
| 10 mg once daily for 4 days |
Fosamprenavir 1400 mg twice daily, 14 days |
0.73 |
|
| 10 mg once daily for 4 days |
Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days |
0.99 |
|
& Comparison by treatment methods (concomitant use of the medicinal product with atorvastatin compared to use of atorvastatin alone).
When multiple doses of atorvastatin and antipyrine are administered concomitantly, changes in antipyrine clearance are minor or not observed.
Medical recommendations regarding the use of interacting medicinal products are summarized in Table 3 (see also sections «Pharmacological properties», «Special instructions», and «Administration and dosage»).
Table 3
Drug interactions associated with an increased risk of myopathy/rhabdomyolysis
| Medicinal products that interact |
Medical recommendations for use |
| Cyclosporine, tipranavir + ritonavir, glecaprevir + pibrentasvir, ledipasvir when used concomitantly with cyclosporine |
Avoid use of atorvastatin |
| Clarithromycin, itraconazole, saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, ledipasvir |
Do not exceed 20 mg of atorvastatin per day |
| Nelfinavir |
Do not exceed 40 mg of atorvastatin per day |
| Lopinavir + ritonavir, simeprevir, fibrinic acid derivatives, erythromycin, azole antifungal agents, lipid-modifying doses of niacin, colchicine |
Use with caution and at the lowest necessary dose |
- Use at the lowest necessary dose.
Special precautions.
Skeletal muscles
Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been reported with atorvastatin and other drugs of this class. A history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients require closer monitoring for skeletal muscle disorders.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle pain or weakness in combination with elevated creatine phosphokinase (CPK) levels more than 10 times above 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, HIV protease inhibitors, and hepatitis C virus protease inhibitors), increases the risk of myopathy/rhabdomyolysis.
Rare cases of immune-mediated necrotizing myopathy (IMNM) — an autoimmune myopathy associated with statin use — have also been reported. IMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase (CK) levels that persist despite discontinuation of statin therapy; muscle biopsy reveals necrotizing myopathy without significant inflammation; a positive response to immunosuppressive therapy.
The possibility of myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or markedly elevated CPK. Patients should be advised to promptly report any unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever, or if muscle symptoms persist after discontinuation of atorvastatin. The drug should be discontinued in cases of markedly elevated CPK levels, or if myopathy is diagnosed or suspected.
The risk of myopathy during treatment with statins increases with concomitant use of drugs listed in Table 3. Physicians considering combination therapy with atorvastatin and any of these drugs should carefully weigh potential benefits and risks and closely monitor patients for any signs of muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any dose-titration periods. Consideration should be given to using lower starting and maintenance doses of atorvastatin when co-administered with the aforementioned drugs (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, periodic CPK monitoring may be considered, although there is no guarantee that such monitoring will prevent cases of severe myopathy.
Treatment with atorvastatin 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 renal failure due to rhabdomyolysis (e.g., severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine or electrolyte disorders, and uncontrolled seizures).
Hepatic function
Statins, like some other lipid-lowering agents, have been associated with abnormalities in liver function tests. Persistent elevation (more than three times the ULN on two or more occasions) of serum transaminases was observed in 0.7% of patients receiving atorvastatin in clinical trials. The incidence of such abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg doses of the drug, respectively.
Cases of jaundice, elevated liver function tests (LFTs) not associated with jaundice, or other clinical signs and symptoms have been reported with atorvastatin. Transaminase levels usually return to pre-treatment or near pre-treatment levels after dose reduction, interruption, or discontinuation of the drug, without adverse consequences.
Liver enzyme tests should be obtained before initiating therapy and repeated as clinically indicated. Rare cases of fatal and non-fatal hepatic failure have been reported in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during atorvastatin therapy, treatment should be discontinued immediately. The drug should not be restarted unless an alternative etiology is identified.
Atorvastatin should be prescribed with caution in patients who consume alcohol excessively and/or have a history of liver disease. The drug is contraindicated in patients with active liver disease or persistent elevations of hepatic transaminases of unknown etiology (see section "Contraindications").
Endocrine function
Increases in HbA1c and fasting plasma glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Statins inhibit cholesterol synthesis and may theoretically reduce the secretion of adrenal and/or gonadal steroids. It is known that atorvastatin does not reduce baseline plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been studied. The effect of atorvastatin on the hypothalamic-pituitary-gonadal axis in premenopausal women is unknown. Caution should be exercised when combining statins with drugs 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 a post-hoc analysis of the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, in which 4731 patients without ischemic heart disease and with a history of stroke or transient ischemic attack within the previous 6 months received atorvastatin 80 mg versus placebo, a higher incidence of hemorrhagic stroke was observed in the atorvastatin group compared to placebo (55 cases, 2.3% in the atorvastatin group vs. 33 cases, 1.4% in the placebo group; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 and 18 in the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38; 1.6%) compared to placebo (16; 0.7%). Certain baseline characteristics, including a history of hemorrhagic or lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group (see section "Adverse reactions").
Among 39,828 patients who received atorvastatin in clinical trials, 15,813 (40%) were aged 65 years or older, and 2,800 (7%) were aged 75 years or older. No overall differences in safety and efficacy were observed between these patients and younger patients, nor were there differences in treatment response between elderly and younger patients based on other clinical experience; however, increased sensitivity in some older individuals cannot be ruled out. Since advanced age (over 65 years) is a risk factor for myopathy, atorvastatin should be prescribed with caution in elderly patients.
Hepatic impairment
The drug is contraindicated in patients with active liver disease, including persistent elevations of liver transaminases of unknown etiology (see sections "Pharmacological properties" and "Contraindications").
Before starting treatment
Atorvastatin should be prescribed with caution in patients predisposed to rhabdomyolysis. Before initiating statin therapy in patients predisposed to rhabdomyolysis, CPK levels should be measured in the following cases:
- renal dysfunction;
- hypothyroidism;
- personal or family history of hereditary muscle disorders;
- previous history of statin or fibrate-induced myotoxicity;
- previous history of liver disease and/or alcohol abuse.
For elderly patients (aged 70 years or older), the need for these measures should be evaluated considering the presence of other risk factors for rhabdomyolysis.
Increased plasma levels of the drug may occur, particularly due to drug interactions (see section "Interaction with other medicinal products and other forms of interaction") and in special patient populations (see section "Pharmacokinetics"), including patients with inherited disorders.
In such cases, the risk-benefit ratio of treatment should be carefully evaluated, and clinical monitoring of patients is recommended. If baseline CPK levels are markedly elevated (more than five times the ULN), treatment should not be initiated.
Measurement of CPK levels
CPK levels should not be measured after strenuous physical exertion or in the presence of any possible alternative causes of elevated CPK, as this may complicate interpretation of results. If markedly elevated CPK levels (more than five times the ULN) are observed at baseline, repeat testing should be performed after 5–7 days to confirm the result.
During treatment
Patients should be informed of the need to promptly report the onset of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.
If these symptoms occur during atorvastatin therapy, CPK levels should be measured. If CPK levels are markedly elevated (more than five times the ULN), treatment should be discontinued.
Discontinuation of treatment should also be considered if CPK elevation does not exceed five times the ULN but muscle symptoms are severe and cause daily discomfort.
After symptom resolution and normalization of CPK levels, reinitiation of atorvastatin therapy or initiation of an alternative statin may be considered, using the lowest possible dose and with close monitoring of the patient.
Atorvastatin therapy must be discontinued if clinically significant elevation of CPK (more than ten times the ULN) occurs or if rhabdomyolysis is diagnosed or suspected.
Concomitant use with other medicinal products
The risk of rhabdomyolysis is increased when atorvastatin is co-administered with certain drugs that may increase atorvastatin plasma concentrations. Examples include potent inhibitors of CYP3A4 or transporter proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors such as ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibrates, antiviral agents for hepatitis C (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin, or ezetimibe. If possible, alternative drugs (not interacting with atorvastatin) should be used instead.
If concomitant use of atorvastatin and these drugs is necessary, the benefits and risks should be carefully weighed. If patients are taking drugs that increase atorvastatin plasma concentrations, it is recommended to reduce the atorvastatin dose to the minimum. Additionally, when using potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered. Appropriate clinical monitoring of these patients is also recommended.
Atorvastatin must not be co-administered with systemic fusidic acid or within 7 days after discontinuation of fusidic acid. In patients requiring systemic fusidic acid, statin therapy should be suspended for the entire duration of fusidic acid treatment.
Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness.
Statin therapy may be resumed 7 days after the last dose of fusidic acid.
In exceptional circumstances, when long-term systemic fusidic acid therapy is required (e.g., for treatment of severe infections), concomitant use of atorvastatin and fusidic acid should be considered only on an individual basis and under close medical supervision.
The risk of myopathy and/or rhabdomyolysis may be increased when HMG-CoA reductase inhibitors (e.g., atorvastatin) are used concomitantly with daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Consideration should be given to temporarily suspending atorvastatin in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times weekly and patients closely monitored for any signs or symptoms suggestive of myopathy.
Interstitial lung disease
Cases of interstitial lung disease have been reported with some statins, particularly during long-term therapy. Symptoms may include dyspnea, non-productive cough, and general deterioration in health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.
Myasthenia gravis / ocular myasthenia
Rare cases of statin-induced de novo or worsening of pre-existing myasthenia gravis or ocular myasthenia have been reported (see section "Adverse reactions"). If symptoms worsen, atorvastatin should be discontinued. Recurrences have been reported upon rechallenge with the same or another statin.
Important information on excipients.
The medicinal product contains lactose. This medicine should not be taken by patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Lipid-modifying drug therapy should be one component of comprehensive treatment for patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Pharmacological therapy is recommended as an adjunct to diet when dietary measures restricting saturated fat and cholesterol intake, and other non-pharmacological interventions, have been insufficient. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, the drug may be initiated concurrently with dietary measures.
This medicinal product contains sodium compounds; therefore, patients on a sodium-controlled diet should exercise caution when using this medicinal product.
Limitations of use
Atorvastatin has not been studied in conditions where the primary lipid abnormality is elevated chylomicrons (Fredrickson types I and V).
Use during pregnancy or breastfeeding.
Pregnancy.
Risk assessment
Atorvastatin is contraindicated in pregnant women, as its safety in pregnancy has not been established and there is no clear benefit of lipid-lowering drugs during pregnancy. Since HMG-CoA reductase inhibitors reduce cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may have harmful effects on the fetus. Atorvastatin should be discontinued as soon as pregnancy is confirmed (see section "Contraindications").
The background risk of major congenital malformations and miscarriage in the indicated population is unknown. In the general US population, the estimated background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Contraception
Atorvastatin may cause fetal harm when administered to a pregnant woman. Women of reproductive potential should be advised to use effective contraception during treatment with this medicinal product.
Clinical data
Limited published data from observational studies, meta-analyses, and case reports on the use of calcium atorvastatin do not indicate an increased risk of major congenital malformations or miscarriage.
Rare reports of congenital anomalies have been received following in utero exposure to other HMG-CoA reductase inhibitors. Prospective observation of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the rates of fetal congenital anomalies, miscarriages, and intrauterine deaths/stillbirths did not exceed those expected in the general population. The number of cases is sufficient to exclude a ≥3–4-fold increase in fetal developmental anomalies compared to the background rate. In 89% of the pregnant women followed prospectively, drug use started before pregnancy and was discontinued in the first trimester after pregnancy was detected.
Breastfeeding period.
Atorvastatin is contraindicated during breastfeeding. There is no information on the effect of the drug on the breastfed child or on lactation. It is unknown whether atorvastatin passes into human milk, but another drug in this class has been found in breast milk; atorvastatin is present in rat milk. Since statins may potentially cause serious adverse reactions in breastfed infants, women requiring atorvastatin therapy should not breastfeed (see section "Contraindications").
Ability to affect reaction speed when driving or operating machinery.
Has a very minor influence on the ability to drive or operate machinery.
Method of Administration and Dosage
Hyperlipidemia and Mixed Dyslipidemia
The recommended initial dose of atorvastatin is 10 mg or 20 mg once daily. For patients requiring a large reduction in LDL-C levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily. The dosage range of the medicinal product is from 10 mg to 80 mg once daily. The drug can be administered as a single dose at any time of day, independent of food intake. Initial and maintenance doses of atorvastatin should be individually adjusted based on treatment goals and patient response. Lipid levels should be analyzed 2 to 4 weeks after initiating therapy and/or dose titration, and the dose should be adjusted accordingly.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients (Ages 10–17 Years)
The recommended initial dose of the medicinal product is 10 mg/day; the usual dosage range is 10 mg to 20 mg orally once daily. Dosage should be individually adjusted according to the recommended treatment goal. Dose adjustments should be made at intervals of 4 weeks or longer.
Homozygous Familial Hypercholesterolemia
The atorvastatin dosage for patients with homozygous familial hypercholesterolemia ranges from 10 mg to 80 mg daily. Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis), or when such treatments are unavailable.
Concomitant Lipid-Lowering Therapy
Atorvastatin may be coadministered with bile acid sequestrants. Combination therapy of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").
Dosing in Patients with Renal Impairment
Renal disease does not affect plasma concentrations or LDL-C reduction with the use of this medicinal product; therefore, dose adjustment in patients with renal impairment is not required (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").
Dosing in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors
The use of this medicinal product should be avoided in patients taking cyclosporine or HIV protease inhibitors tipranavir + ritonavir, or hepatitis C virus protease inhibitor glecaprevir + pibrentasvir, or letermovir when coadministered with cyclosporine. In HIV patients receiving lopinavir + ritonavir, atorvastatin should be administered at the lowest necessary dose. In patients taking clarithromycin, itraconazole, elbasvir + grazoprevir, or in HIV patients receiving saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, or letermovir, the therapeutic dose of the medicinal product should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose of atorvastatin. In patients taking the HIV protease inhibitor nelfinavir, atorvastatin treatment should be limited to a dose of 40 mg. When atorvastatin is coadministered with other protease inhibitors, appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose of the medicinal product (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").
Pediatric Use
Heterozygous Familial Hypercholesterolemia
The safety and efficacy of the medicinal product have been established in children aged 10 to 17 years with heterozygous familial hypercholesterolemia as an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B levels, when after an adequate dietary trial the following are observed:
- LDL-C ≥ 190 mg/dL (4.91 mmol/L), or
- LDL-C ≥ 160 mg/dL (4.14 mmol/L) and:
- family history of familial hypercholesterolemia or premature cardiovascular disease in first- or second-degree relatives;
- presence of two or more other cardiovascular risk factors.
Indications for atorvastatin use are supported by the following studies:
- A 6-month placebo-controlled clinical trial involving 187 boys and girls who had reached puberty, aged 10 to 17 years. Patients receiving atorvastatin 10 mg or 20 mg daily had an overall adverse reaction profile similar to those receiving placebo. In this small, controlled study, no significant effect of the medicinal product on growth or sexual maturation in boys or on menstrual cycle length in girls was observed.
- A 3-year open-label, uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, in whom dose was titrated to achieve a target LDL-C level <130 mg/dL (3.36 mmol/L). The safety and efficacy of atorvastatin in lowering LDL-C generally corresponded to those observed in adult patients, despite limitations of the uncontrolled study design.
Counseling on contraception should be provided to girls who have reached puberty, if appropriate for the patient.
The long-term efficacy of atorvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.
The safety and efficacy of atorvastatin therapy have not been established in children under 10 years of age with heterozygous familial hypercholesterolemia.
Homozygous Familial Hypercholesterolemia
The clinical efficacy of atorvastatin at doses up to 80 mg/day over 1 year was evaluated in an uncontrolled study involving 8 pediatric patients with homozygous familial hypercholesterolemia.
Overdose.
There is no specific antidote for atorvastatin overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be instituted as required. Due to the high degree of plasma protein binding of atorvastatin, enhanced drug elimination by hemodialysis is not expected to be significant.
Adverse Reactions
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed during clinical trials of a medicinal product cannot be directly compared with those of another medicinal product and may not reflect the rates observed in clinical practice.
According to data from clinical trials of atorvastatin in 16,066 patients (8,755 receiving atorvastatin and 7,311 receiving placebo; age range 10–93 years, 39% women, 91% Caucasian, 3% Black, 2% Asian, 4% other), with a median treatment duration of 53 weeks, 9.7% of patients receiving atorvastatin and 9.5% of patients receiving placebo discontinued the drug due to adverse reactions, regardless of causal relationship to the drug.
The five most common adverse reactions in patients receiving atorvastatin treatment that led to discontinuation of atorvastatin and occurred at a higher frequency than in the placebo group were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and increased liver enzymes (0.4%).
In patients receiving atorvastatin treatment in placebo-controlled trials (n=8,755), the most commonly observed adverse reactions (incidence ≥2% and higher than in the placebo group), regardless of causal relationship, were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), limb pain (6.0%), and urinary tract infection (5.7%).
Table 4 summarizes the frequency of clinical adverse reactions, regardless of causal relationship, reported in 2% or more of patients and at a higher frequency than in the placebo group, among patients receiving atorvastatin treatment (n=8,755), based on data from 17 placebo-controlled trials.
Table 4
Clinical adverse reactions occurring in 2% or more of patients receiving any dose of atorvastatin and at a higher frequency than placebo, regardless of causal relationship (% of patients)
| Adverse reaction* |
Any dose N=8755 |
10 mg N=3908 |
20 mg N=188 |
40 mg N=604 |
80 mg N=4055 |
Placebo N=7311 |
| Nasopharyngitis |
8.3 |
12.9 |
5.3 |
7 |
4.2 |
8.2 |
| Arthralgia |
6.9 |
8.9 |
11.7 |
10.6 |
4.3 |
6.5 |
| Diarrhea |
6.8 |
7.3 |
6.4 |
14.1 |
5.2 |
6.3 |
| Limb pain |
6 |
8.5 |
3.7 |
9.3 |
3.1 |
5.9 |
| Urinary tract infection |
5.7 |
6.9 |
6.4 |
8 |
4.1 |
5.6 |
| Dyspepsia |
4.7 |
5.9 |
3.2 |
6 |
3.3 |
4.3 |
| Nausea |
4 |
3.7 |
3.7 |
7.1 |
3.8 |
3.5 |
| Musculoskeletal pain |
3.8 |
5.2 |
3.2 |
5.1 |
2.3 |
3.6 |
| Muscle spasms |
3.6 |
4.6 |
4.8 |
5.1 |
2.4 |
3 |
| Myalgia |
3.5 |
3.6 |
5.9 |
8.4 |
2.7 |
3.1 |
| Insomnia |
3 |
2.8 |
1.1 |
5.3 |
2.8 |
2.9 |
| Pharyngolaryngeal pain |
2.3 |
3.9 |
1.6 |
2.8 |
0.7 |
2.1 |
| * Adverse reaction > 2% in any dose higher than placebo |
||||||
Other adverse reactions reported during studies include:
Eye disorders: blurred vision, visual disturbance.
Ear and labyrinth disorders: tinnitus.
Respiratory, thoracic and mediastinal disorders: epistaxis.
Gastrointestinal disorders: gastrointestinal discomfort, eructation, flatulence, hepatitis, cholestasis.
Renal and urinary disorders: leucocyturia.
Metabolism and nutrition disorders: increased transaminases, abnormal liver function tests, increased blood alkaline phosphatase, increased creatine kinase (CK) activity, hyperglycaemia.
Nervous system disorders: nightmares.
Skin and subcutaneous tissue disorders: urticaria.
Musculoskeletal, connective tissue and bone disorders: musculoskeletal pain, increased muscle fatigue, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture).
Reproductive system and breast disorders: gynaecomastia.
General disorders: malaise, pyrexia.
All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).
Eye disorders: uncommon – blurred vision.
Respiratory, thoracic and mediastinal disorders: common – throat and larynx pain.
Gastrointestinal disorders: common – constipation; uncommon – pancreatitis, vomiting.
Hepatobiliary disorders: very rare – liver failure.
Metabolism and nutrition disorders: uncommon – hypoglycaemia, weight gain, anorexia.
Nervous system disorders: common – headache; uncommon – dizziness, paraesthesia, hypoaesthesia, dysgeusia, amnesia; rare – peripheral neuropathy.
Cardiac disorders: rare – vasculitis.
Blood and lymphatic system disorders: rare – thrombocytopenia.
Immune system disorders: common – allergic reactions; very rare – anaphylaxis.
Skin and subcutaneous tissue disorders: uncommon – skin rash, pruritus, alopecia; rare – angioneurotic oedema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome and toxic epidermal necrolysis, drug-induced lichenoid reaction.
Musculoskeletal, connective tissue and bone disorders: common – arthralgia, back pain; rare – myopathy, myositis, rhabdomyolysis.
General disorders: uncommon – asthenia, chest pain, peripheral oedema, fatigue.
Investigations: common – abnormal liver function tests, increased blood CK activity; uncommon – positive test for leucocytes in urine.
As with other HMG-CoA reductase inhibitors, elevations in serum transaminase activity have been observed in patients treated with atorvastatin. These changes were generally mild, transient, and did not require intervention or discontinuation of treatment. Clinically significant increases in serum transaminase activity (exceeding the upper limit of normal [ULN] by more than 3 times) were observed in 0.8 % of patients treated with atorvastatin. These increases were dose-dependent and reversible in all patients.
Elevations in serum CK activity exceeding the ULN by more than 3 times were observed in 2.5 % of patients treated with atorvastatin. This is consistent with observations from clinical trials of other HMG-CoA reductase inhibitors. Serum CK levels exceeding the ULN by more than 10 times were observed in 0.4 % of patients receiving atorvastatin.
Adverse reactions observed during studies: urinary tract infection, diabetes mellitus, stroke.
In the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) study, which included 10,305 participants (age range 40–80 years, 19 % women; 94.6 % Caucasian, 2.6 % Black, 1.5 % South Asian, and 1.3 % mixed/other), receiving atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile in patients receiving atorvastatin was comparable to that in the placebo group over a median follow-up period of 3.3 years.
In the CARDS (Collaborative Atorvastatin Diabetes Study), which included 2,838 patients (age range 39–77 years, 32 % women; 94.3 % Caucasian, 2.4 % South Asian, 2.3 % Afro-Caribbean, and 1 % other) with type 2 diabetes, receiving atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 3.9 years. No cases of rhabdomyolysis were reported.
In the TNT (Treating to New Targets) study, which included 10,001 patients (age range 29–78 years, 19 % women; 94.1 % Caucasian, 2.9 % Black, 1.0 % Asian, and 2.0 % other) with clinically evident coronary heart disease, receiving atorvastatin 10 mg daily (n=5,006) or atorvastatin 80 mg daily (n=4,995), more serious adverse reactions and discontinuations due to adverse reactions were observed in the high-dose atorvastatin group (92, 1.8 %; 497, 9.9 %, respectively) compared to the low-dose group (69, 1.4 %; 404, 8.1 %, respectively) over a median follow-up period of 4.9 years. Persistent elevations in transaminase levels (≥3 times ULN on two occasions 4–10 days apart) occurred in 62 (1.3 %) patients receiving atorvastatin 80 mg and in 9 (0.2 %) patients receiving atorvastatin 10 mg. Elevations in CK levels (≥10 times ULN) were generally low but higher in the high-dose atorvastatin group (13, 0.3 %) compared to the low-dose group (6, 0.1 %).
In the IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid Lowering) study, which included 8,888 patients (age range 26–80 years, 19 % women; 99.3 % Caucasian, 0.4 % Asian, 0.3 % Black, and 0.04 % other), receiving atorvastatin 80 mg daily (n=4,439) or simvastatin 20–40 mg daily (n=4,449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 4.8 years.
In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, which included 4,731 patients (age range 21–92 years, 40 % women; 93.3 % Caucasian, 3.0 % Black, 0.6 % Asian, and 3.1 % other) without clinically evident coronary heart disease but with a history of stroke or transient ischaemic attack within the previous 6 months, receiving atorvastatin 80 mg (n=2,365) or placebo (n=2,366), a higher incidence of persistent elevations in liver transaminases (≥3 times ULN on two occasions 4–10 days apart) was observed in the atorvastatin group (0.9 %) compared to the placebo group (0.1 %) over a median follow-up period of 4.9 years. Cases of CK elevation (≥10 times ULN) were rare but more frequent in the atorvastatin group (0.1 %) than in the placebo group (0.0 %). Diabetes mellitus was reported as an adverse reaction in 144 patients (6.1 %) in the atorvastatin group and in 89 patients (3.8 %) in the placebo group (see section "Special warnings and precautions for use").
Post hoc analysis showed that atorvastatin 80 mg reduced the incidence of ischaemic stroke (218 of 2,365, 9.2 % vs. 274 of 2,366, 11.6 %) but increased the incidence of haemorrhagic stroke (55 of 2,365, 2.3 % vs. 33 of 2,366, 1.4 %) compared to placebo. The incidence of fatal haemorrhagic stroke was similar between groups (17 cases in the atorvastatin group vs. 18 in the placebo group). The incidence of non-fatal haemorrhagic stroke was significantly higher in the atorvastatin group (38 non-fatal haemorrhagic strokes) compared to the placebo group (16 non-fatal haemorrhagic strokes). Patients entering the study with a history of haemorrhagic stroke had an increased risk of haemorrhagic stroke (7 (16 %) in the atorvastatin group vs. 2 (4 %) in the placebo group).
No significant differences in all-cause mortality were observed between treatment groups: 216 (9.1 %) in the atorvastatin 80 mg daily group vs. 211 (8.9 %) in the placebo group. The proportion of patients who died from cardiovascular causes was numerically lower in the atorvastatin 80 mg group (3.3 %) than in the placebo group (4.1 %). The proportion of patients who died from non-cardiovascular causes was numerically higher in the atorvastatin 80 mg group (5.0 %) than in the placebo group (4.0 %).
Adverse reactions during clinical studies of atorvastatin use in children
In a 26-week controlled study in boys and girls after onset of menstruation with heterozygous familial hypercholesterolaemia (aged 10 to 17 years) (n=140, 31 % female; 92 % Caucasian, 1.6 % Black, 1.6 % Asian, and 4.8 % other ethnic groups), the safety and tolerability profile of atorvastatin 10–20 mg daily as an adjunct to diet for lowering total cholesterol, LDL cholesterol, and apolipoprotein B levels was generally similar to that of placebo.
Post-marketing experience with atorvastatin
The following adverse reactions have been identified during post-marketing use of atorvastatin. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions associated with atorvastatin treatment, regardless of causal assessment, include: anaphylaxis, angioedema, bullous eruptions (including exudative multiform erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis), rhabdomyolysis, myositis, increased fatigue, tendon rupture, fatal and non-fatal liver failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.
Rare cases of immune-mediated necrotizing myopathy associated with statin use have been reported (see section "Special warnings and precautions for use").
Rare post-marketing reports of cognitive disorders (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders have been reported with all statins. Reports were generally not serious, and symptoms were reversible upon discontinuation of statin therapy, with variable onset time (from 1 day to several years) and symptom resolution (median duration 3 weeks).
With the use of some statins, adverse events such as sexual dysfunction and rare cases of interstitial lung disease, particularly with long-term treatment, have been described.
Adverse reactions reported during post-marketing surveillance are listed below.
All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).
Eye disorders: frequency not known: ocular myasthenia.
Ear and labyrinth disorders: tinnitus.
Gastrointestinal disorders: abdominal pain.
Metabolism and nutrition disorders: weight gain.
Nervous system disorders: headache, hypoaesthesia, dysgeusia; frequency not known: myasthenia gravis.
Blood and lymphatic system disorders: thrombocytopenia.
Immune system disorders: allergic reactions, anaphylaxis (including anaphylactic shock).
Skin and subcutaneous tissue disorders: urticaria.
Musculoskeletal, connective tissue and bone disorders: arthralgia, back pain.
General disorders: chest pain, peripheral oedema, malaise, fatigue.
Investigations: increased ALT activity, increased blood CK activity.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging.
10 tablets in a blister pack; 3 blisters per carton; 14 tablets in a blister pack; 2 blisters per carton.
Prescription status. Prescription only.
Manufacturer. JSC "Pharmaceutical Company "Darnytsia".
Manufacturer's address and location of its operations.
13, Boryspilska Street, Kyiv, 02093, Ukraine.