INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATORVASTATIN 10 ANANTA, ATORVASTATIN 20 ANANTA (ATORVASTATIN 10 ANANTA, ATORVASTATIN 20 ANANTA)

Composition:

Active ingredient: atorvastatin;

One tablet contains atorvastatin calcium equivalent to atorvastatin 10 mg or 20 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; magnesium stearate; sodium croscarmellose; corn starch; hydroxypropylcellulose; hydroxypropylmethylcellulose; polyethylene glycol; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets, film-coated.

Pharmacotherapeutic group. Hypolipidemic agents, single-component. HMG-CoA reductase inhibitors. ATC code C10AA05.

Pharmacological properties.

Pharmacodynamics.

Atorvastatin is a synthetic hypolipidemic medicinal product. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing 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 animal experimental 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, thereby enhancing the uptake and catabolism of LDL; atorvastatin also reduces the production of LDL and the number of these 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, rather than the systemic concentration of the drug, correlates better with the reduction in LDL cholesterol levels. Individual dose titration should be performed based on the therapeutic response (see section "Dosage and administration").

Pharmacokinetics.

Absorption. Atorvastatin is rapidly absorbed after oral administration, and maximum plasma concentration is reached within 1–2 hours. The extent of absorption increases proportionally with the dose of the drug. 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 pre-systemic clearance in the intestinal mucosa and/or pre-systemic metabolism in the liver. Although food reduces the rate and extent of drug absorption by approximately 25% and 9%, respectively, as measured by Cmax and AUC (area under the concentration-time curve), the reduction in LDL cholesterol levels is similar when atorvastatin is taken with or without food. When atorvastatin is administered in the evening, its plasma concentration is lower (by approximately 30% for Cmax and AUC) compared to morning administration. However, the reduction in LDL cholesterol levels is similar regardless of the time of administration (see section "Dosage and administration").

Distribution. The mean volume of distribution of the drug 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 observations in rats, 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 products of beta-oxidation. In vitro studies show that the inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of the circulating HMG-CoA reductase inhibitory activity is attributable to active metabolites. In vitro studies indicate that metabolism of atorvastatin by cytochrome P450 3A4 is significant, consistent with increased plasma concentrations of the drug 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 excreted 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 is 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 for hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 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.

Special patient populations

Elderly patients. Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (aged 65 years and older) compared to younger adults. Clinical 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 8-week study including children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29).

Gender. Drug plasma concentrations in women differ from those in men (approximately 20% higher Cmax and 10% lower 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 plasma concentrations of atorvastatin or the reduction in LDL cholesterol; therefore, dose adjustment in patients with renal impairment is not required (see sections "Dosage and administration" and "Special precautions").

Hemodialysis. Although no studies have been conducted in patients with end-stage renal disease, hemodialysis is not considered to significantly enhance drug clearance due to the extensive plasma protein binding of atorvastatin.

Hepatic impairment. Plasma concentrations of atorvastatin 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").

Table 1

Effect of concomitantly administered drugs on the pharmacokinetics of atorvastatin

Concomitantly administered drugs and dosing regimen	Atorvastatin
Concomitantly administered drugs and dosing regimen	Dose (mg)	Ratio AUC&	Ratio Cmax&
#Cyclosporine 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 S.D. (single dose)	9.36	8.58
#Telaprevir 750 mg every 8 hours, 10 days	20 mg S.D.	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 S.D.	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 twice daily, 14 days	10 mg once daily for 28 days	1.74	2.22
#Grapefruit juice, 240 ml once daily*	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 four times daily, 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 four times daily, 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 four times daily, 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
#Rifampicin 600 mg once daily, 7 days (co-administered) †	40 mg once daily	1.12	2.90
#Rifampicin 600 mg once daily, 5 days (separate 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 three times daily, 7 days	40 mg once daily	2.32	2.66
Glecaprevir 400 mg once daily / pibrentasvir 120 mg once daily, 7 days ***	10 mg once daily for 7 days	3
#Elbasvir 50 mg once daily / grazoprevir 200 mg once daily, 13 days	10 mg twice daily	95

& Comparison by treatment methods (concomitant use of the medicinal product with atorvastatin compared to atorvastatin used alone).

For information on clinical significance, see sections «Special warnings and precautions for use» and «Interaction with other medicinal products and other forms of interaction».

* Higher increases in AUC (AUC ratio up to 2.5) and/or Cmax (Cmax ratio up to 1.71) have been reported with excessive consumption of grapefruit juice (750 ml – 1.2 litres per day or more).

** Ratios based on single samples taken 8–16 hours after dose administration.

*** Concomitant treatment with glecaprevir/pibrentasvir is contraindicated (see section «Contraindications»).

† Due to the dual interaction mechanism of rifampicin, concomitant use of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after rifampicin has been associated with a significant decrease in plasma concentrations of atorvastatin.

‡ The dose of the saquinavir + ritonavir combination used in this study is not a clinically applicable dose. The increase in atorvastatin exposure under clinical use is likely to be higher than that observed in this study. Therefore, the product should be used with caution and at the lowest necessary dose.

Table 2

Effect of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products

Atorvastatin	Concomitant drug and dosing regimen
Atorvastatin	Drug/dose (mg)	Ratio AUC	Ratio Cmax
80 mg once daily for 15 days	Antipyrine 600 mg single dose	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 forms of interaction".

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases in adults

For adult patients without clinically evident ischemic heart disease but with multiple risk factors for developing ischemic heart disease, such as age, tobacco smoking, arterial hypertension, low HDL-C levels, or a family history of premature ischemic heart disease, the medicinal product is indicated for:

reduction of the risk of myocardial infarction;
reduction of the risk of stroke;
reduction of the need for revascularization procedures and angina.

For adult patients with type 2 diabetes mellitus and without clinically evident ischemic heart disease, but with multiple risk factors for developing ischemic heart disease, such as retinopathy, albuminuria, tobacco smoking, or arterial hypertension, the medicinal product is indicated for:

reduction of the risk of myocardial infarction;
reduction of the risk of stroke.

For adult patients with clinically evident ischemic heart disease, the medicinal product is indicated for:

reduction of the risk of non-fatal myocardial infarction;
reduction of the risk of fatal and non-fatal stroke;
reduction of the need for revascularization procedures;
reduction of the risk of hospitalization due to congestive heart failure;
reduction of the risk of angina.

Hyperlipidemia

In adults

As an adjunct to diet to reduce elevated total cholesterol, LDL-C, apolipoprotein B, and triglyceride levels, and to increase HDL-C levels 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 measures are insufficiently effective.
To reduce total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis), or when such therapies are unavailable.

In children

As an adjunct to diet to reduce levels of total cholesterol, LDL-C, and apolipoprotein B in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy the following criteria are met:

a) LDL-C remains ≥ 190 mg/dL (4.91 mmol/L), or

b) LDL-C ≥ 160 mg/dL (4.41 mmol/L) and:

there is a family history of premature cardiovascular disease, or
two or more other cardiovascular risk factors are present in the pediatric patient.

Contraindications.

Active liver disease, which may include persistent elevations of serum transaminases of unknown etiology.

Hypersensitivity to any component of this medicinal product.

Pregnancy.

Breastfeeding.

Concomitant treatment with the hepatitis C antiviral agents glecaprevir/pibrentasvir.

Interaction with other medicinal products and other forms of interaction.

The risk of developing myopathy during statin therapy increases when used concomitantly with fibrates, lipid-modifying doses of niacin, cyclosporine, or potent CYP3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, itraconazole) (see sections "Special warnings and precautions for use" and "Pharmacological properties").

Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 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 "Pharmacological properties").

Concomitant use of medicinal products that are inhibitors of CYP3A4 or transporters may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk may also be increased when atorvastatin is used concomitantly with other medicinal products that may potentially induce myopathy, such as fibrates and ezetimibe (see section "Special warnings and precautions for use").

Potent CYP3A4 inhibitors. Concomitant use of atorvastatin with potent CYP3A4 inhibitors may result in increased plasma concentrations of atorvastatin (see Table 3 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, hepatitis C virus (HCV) antivirals (e.g., elbasvir/grazoprevir), and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided if possible. If concomitant use 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 3).

Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, 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 administration of these drugs with atorvastatin may lead to increased atorvastatin exposure. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to using 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 atorvastatin 80 mg was coadministered with clarithromycin (500 mg twice daily) compared to atorvastatin alone (see section "Pharmacological properties"). Therefore, patients taking clarithromycin should use atorvastatin doses above 20 mg with caution (see sections "Special warnings and precautions for use" and "Posology and method of administration").

Combination of protease inhibitors. AUC values of atorvastatin were significantly increased when atorvastatin was coadministered with several combinations of HIV protease inhibitors, as well as with the hepatitis C virus protease inhibitor telaprevir, compared to atorvastatin alone. Therefore, patients taking the HIV protease inhibitor tipranavir + ritonavir or the hepatitis C virus protease inhibitor telaprevir should avoid concomitant use of atorvastatin. The medicinal product should be used with caution in patients taking the HIV protease inhibitor lopinavir + ritonavir and should be administered at the lowest necessary dose. For patients taking HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the atorvastatin dose should not exceed 20 mg; their use should be cautious (see sections "Special warnings and precautions for use" and "Posology and method of administration"). When used in patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, the atorvastatin dose should not exceed 40 mg, and careful clinical monitoring of patients is recommended.

Itraconazole. AUC values of atorvastatin were significantly increased when atorvastatin 40 mg was coadministered with itraconazole 200 mg (see section "Pharmacological properties"). Therefore, patients taking itraconazole should be cautious if atorvastatin doses exceed 20 mg (see sections "Special warnings and precautions for use" and "Posology and method of administration").

Cyclosporine. Atorvastatin and its metabolites are substrates of the OATP1B1 transporter. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase atorvastatin bioavailability. AUC values of atorvastatin were significantly increased when atorvastatin 10 mg was coadministered 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 warnings and precautions").

Medical recommendations for the use of interacting medicinal products are summarized in Table 3 (see also sections "Posology and method of administration", "Special warnings and precautions for use", "Pharmacological properties").

Table 3.

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis

Drugs that interact	Medical recommendations for use
Cyclosporine, HIV protease inhibitors (tipranavir + ritonavir), hepatitis C virus protease inhibitor (telaprevir)	Avoid use of atorvastatin
HIV protease inhibitor (lopinavir + ritonavir)	Use with caution and at the lowest necessary dose
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir)	Do not exceed 20 mg of atorvastatin per day
HIV protease inhibitor (nelfinavir) Hepatitis C virus protease inhibitor (boceprevir)	Do not exceed 40 mg of atorvastatin per day

*Use with caution and at the lowest necessary dose.

Gemfibrozil. Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are administered concomitantly with gemfibrozil, the combination of atorvastatin with gemfibrozil should be avoided (see section "Special precautions").

Other fibrates. Since the risk of developing myopathy during treatment with HMG-CoA reductase inhibitors increases when other fibrates are coadministered, atorvastatin should be used with caution when prescribed concomitantly with other fibrates (see section "Special precautions").

Niacin. The risk of adverse effects on skeletal muscles may increase when atorvastatin is used in combination with niacin; therefore, under such conditions, dose reduction of atorvastatin should be considered (see section "Special precautions").

Rifampicin or other cytochrome P450 3A4 inducers. Concomitant administration of atorvastatin with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampicin) may lead to unstable decreases in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, concurrent administration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after rifampicin dosing has been shown to result in a significant reduction in atorvastatin plasma concentrations.

Hydrochloride diltiazem

Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) results in increased atorvastatin plasma concentrations.

Cimetidine

No signs of interaction between atorvastatin and cimetidine were observed in clinical studies.

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 was not altered.

Colestipol

Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when coadministered with colestipol. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect achieved by each drug 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.

Transporter inhibitors

Inhibitors of transporter proteins (e.g., cyclosporine) may increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of uptake transporter proteins on atorvastatin concentrations in liver cells is unknown. If concomitant administration cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).

Ezetimibe

Ezetimibe monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, when ezetimibe is used concomitantly with atorvastatin, the risk of such events increases. Appropriate clinical monitoring of these patients is recommended.

Fusidic acid

Concomitant systemic use of fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic, pharmacokinetic, or both) is currently unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination.

If systemic fusidic acid therapy is necessary, atorvastatin should be discontinued for the entire duration of fusidic acid treatment (see section "Special precautions").

Digoxin. Concomitant administration of multiple doses of atorvastatin and digoxin increases steady-state digoxin plasma concentrations (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 considered when selecting an oral contraceptive for a woman taking atorvastatin.

Warfarin. Atorvastatin had no clinically significant effect 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 with caution when used 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").

Other medicinal products. Clinical studies have shown that concomitant use of atorvastatin with antihypertensive agents and its use during estrogen replacement therapy were not associated with clinically significant adverse effects. Interactions with other drugs have not been studied.

Special precautions for use.

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 dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients require closer monitoring for skeletal muscle effects.

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 the upper limit of normal. Concomitant use of higher doses of atorvastatin with certain drugs, such as cyclosporine and potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV 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. IMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; muscle biopsy reveals necrotizing myopathy without significant inflammation; improvement is observed with immunosuppressive therapy.

The possibility of myopathy should be considered in any patient presenting with diffuse myalgias, muscle tenderness or weakness, and/or markedly elevated CPK levels. 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. Treatment should be discontinued in the event of markedly elevated CPK levels, or if myopathy is diagnosed or suspected.

The risk of myopathy during treatment with this class of drugs increases with concomitant use of cyclosporine, fibrates, erythromycin, clarithromycin, the hepatitis C virus protease inhibitor telaprevir, combinations of HIV protease inhibitors (including saquinavir + ritonavir, lopinavir + rit combustible, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir, and fosamprenavir + ritonavir), as well as niacin or azole antifungals. Physicians considering combination therapy with atorvastatin and fibrates, 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 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 initial and maintenance doses of atorvastatin when coadministered with the aforementioned drugs (see section "Interaction with other medicinal products and other forms of interaction"). In such situations, periodic CPK monitoring may be considered, although there is no guarantee that such monitoring will prevent cases of severe myopathy.

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, atorvastatin should be prescribed with caution in patients receiving colchicine (see section "Interaction with other medicinal products and other forms of interaction").

Treatment should be temporarily or permanently discontinued in any patient with an acute, serious condition suggestive of developing myopathy, or in the presence of risk factors for renal failure due to rhabdomyolysis (e.g., severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, 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 "Adverse reactions"). In case of symptom exacerbation, atorvastatin should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Liver function

Statins, like some other lipid-lowering agents, have been associated with abnormalities in liver function tests. Persistent elevations (more than three times the upper limit of normal, occurring on two or more occasions) of serum transaminases were observed in 0.7% of patients receiving 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 are data indicating that jaundice developed in one patient receiving the drug. Elevated liver function test (LFT) results in other patients were not associated with jaundice or other clinical symptoms. Transaminase levels returned to pre-treatment or near pre-treatment levels after dose reduction, temporary interruption, or discontinuation of the drug, without adverse consequences. Eighteen of 30 patients with persistent elevations in liver function tests continued atorvastatin treatment at reduced doses.

Prior to initiating therapy, baseline liver enzyme test results should be obtained and repeated as clinically indicated. Rare post-marketing reports 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 immediately discontinued. Reinitiation of therapy should not occur 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 theoretically may reduce adrenal and/or gonadal steroid secretion. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied in a sufficient number of patients. It is unknown whether the drug affects, or has any effect on, the hypothalamic-pituitary-gonadal axis in premenopausal women. Caution should be exercised when coadministering statins with medicinal products that may reduce 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 ischemic heart disease who had a history of stroke or transient ischemic attack within the previous 6 months, treatment with atorvastatin 80 mg was associated with a higher incidence of hemorrhagic stroke compared to placebo. The incidence of fatal hemorrhagic stroke was similar across all treatment groups. The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group compared to placebo. Certain baseline characteristics, including a history of hemorrhagic and lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.

Among patients aged 65–75 years receiving atorvastatin, no overall differences in safety and efficacy were observed compared to younger patients, nor were there differences in treatment response between elderly and younger patients. However, increased sensitivity in some elderly patients cannot be ruled out. Since advanced age (≥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 hepatic transaminases of unknown etiology (see sections "Contraindications" and "Pharmacological properties").

Before starting treatment

Atorvastatin should be prescribed with caution in patients predisposed to rhabdomyolysis. Prior to initiating statin therapy in patients predisposed to rhabdomyolysis, creatine kinase (CK) 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 (≥70 years), the need for these measures should be evaluated considering the presence of other risk factors for rhabdomyolysis.

Increased plasma concentrations of the drug may occur, particularly due to drug interactions or in specific patient populations, including those with genetic disorders.

In such cases, a risk-benefit assessment of treatment is recommended, along with clinical monitoring of patients. If CK levels are markedly elevated (more than five times the upper limit of normal) prior to treatment initiation, therapy should not be started.

Measurement of creatine kinase levels

CK levels should not be measured following strenuous physical exertion or in the presence of any possible alternative causes of elevated CK, as this may complicate interpretation of results. If baseline CK levels are markedly elevated (more than five times the upper limit of normal), 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, CK levels should be measured. If CK levels are markedly elevated (more than five times the upper limit of normal), treatment should be discontinued.

Discontinuation of therapy should also be considered if CK elevation does not exceed five times the upper limit of normal but muscle symptoms are severe, persist daily, and cause significant discomfort.

After symptom resolution and normalization of CK levels, reinitiation of atorvastatin therapy or initiation of an alternative statin may be considered, provided the lowest possible dose is used and close patient monitoring is maintained.

Atorvastatin therapy must be discontinued if clinically significant CK elevation (more than 10 times the upper limit of normal) is observed, or if rhabdomyolysis is diagnosed or suspected.

Concomitant use with other medicinal products

The risk of rhabdomyolysis increases with concomitant use of atorvastatin and certain drugs that may increase atorvastatin plasma concentrations. Examples include potent CYP3A4 or transporter protein inhibitors: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including 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 (that do not interact with atorvastatin) should be used instead of the above-mentioned agents.

If concomitant therapy with atorvastatin and the above-mentioned 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, consideration should be given to using a lower initial dose of atorvastatin. Appropriate clinical monitoring of these patients is also recommended.

Atorvastatin must not be coadministered with systemic fusidic acid or within 7 days of stopping fusidic acid treatment. In patients requiring systemic fusidic acid, statin therapy should be suspended for the 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 symptoms of muscle weakness, pain, or tenderness.

Statin therapy may be resumed 7 days after the last dose of fusidic acid.

In exceptional circumstances requiring long-term systemic fusidic acid treatment (e.g., for severe infections), concomitant use of atorvastatin and fusidic acid should only be considered on an individual basis and under strict medical supervision.

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Temporary discontinuation of atorvastatin should be considered 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 should be closely monitored for any signs or symptoms suggestive of myopathy.

Interstitial lung disease

Rare cases of interstitial lung disease have been reported with some statins, particularly during long-term treatment. Manifestations 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.

Excipients

The drug 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 therapy for patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when dietary restriction of saturated fats and cholesterol, and other non-pharmacological measures, have been insufficient. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, drug therapy may be initiated concurrently with dietary measures.

Limitations of use

Atorvastatin has not been studied in conditions where the primary lipoprotein abnormality is elevated chylomicrons (Fredrickson types I and V).

Use during pregnancy or breastfeeding

Pregnancy

Assessment of risks

The drug is contraindicated in pregnant women, as safety during 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. Treatment should be discontinued as soon as pregnancy is confirmed (see section "Contraindications").

The background risk of major congenital malformations and miscarriages in the specified population is unknown. In the general US population, the estimated background risk of major congenital malformations and miscarriages 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 childbearing potential should be informed of the need for effective contraception during treatment with this drug.

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 miscarriages.

Rare reports of congenital anomalies have been reported following intrauterine 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 pregnancies under prospective surveillance, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Lactation

The drug is contraindicated during breastfeeding. There is no information on the effect of the drug on the breastfed infant or on lactation. It is unknown whether atorvastatin passes into human breast milk, although another drug in this class has been shown to be excreted in breast milk; atorvastatin is present in rat milk. Because statins may potentially cause serious adverse reactions in breastfed infants, women requiring treatment with this drug should not breastfeed (see section "Contraindications").

Ability to influence reaction speed when driving or operating machinery

Has a negligible effect on the ability to drive or operate machinery.

Dosage and Administration

Hyperlipidemia and Mixed Dyslipidemia

The recommended starting dose is 10 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 atorvastatin dosage range is 10 to 80 mg once daily. The drug can be administered as a single dose at any time of day and independently of food intake. Initial and maintenance doses should be individually adjusted according to treatment goals and patient response. Lipid levels should be analyzed 2 to 4 weeks after initiation of treatment and/or dose titration, and the dose should be adjusted accordingly.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (Aged 10 to 17 Years)

The recommended starting dose is 10 mg/day. The usual dosage range is 10 to 20 mg orally once daily. Doses should be individually adjusted according to treatment goals. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous Familial Hypercholesterolemia

The atorvastatin dose for patients with homozygous familial hypercholesterolemia ranges from 10 to 80 mg daily. The drug 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

The drug may be used concomitantly with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Special Warnings and Precautions for Use", "Interactions with Other Medicinal Products and Other Forms of Interactions").

Dosing in Patients with Renal Impairment

Renal disease does not affect plasma concentrations or LDL-C reduction with the use of this drug; therefore, dose adjustment in patients with renal impairment is not required (see sections "Special Warnings and Precautions for Use", "Pharmacokinetics").

Dosing in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors

Treatment with this drug should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus (HCV) protease inhibitors (telaprevir). Atorvastatin should be administered with caution to HIV patients receiving lopinavir + ritonavir and used at the lowest necessary dose. For patients taking clarithromycin, itraconazole, or HIV patients receiving combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the atorvastatin dose should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure the use of the lowest necessary dose.

In patients receiving the hepatitis C virus protease inhibitor elbasvir/grazoprevir concomitantly with atorvastatin, the atorvastatin dose should not exceed 20 mg/day (see sections "Special Warnings and Precautions for Use" and "Interactions with Other Medicinal Products and Other Forms of Interactions").

For patients taking the HIV protease inhibitor nelfinavir or the HCV protease inhibitor boceprevir, atorvastatin therapy should be limited to a dose of 40 mg, and appropriate clinical monitoring is recommended to ensure the use of the lowest necessary dose (see sections "Special Warnings and Precautions for Use" and "Interactions with Other Medicinal Products and Other Forms of Interactions").

Children

In patients aged 10 to 17 years with heterozygous familial hypercholesterolemia, namely adolescent boys and girls after onset of menstruation, no clinically significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls has been observed (see sections "Adverse Reactions", "Dosage and Administration"). Adolescent girls should be advised about acceptable contraceptive methods during treatment with the drug (see section "Use in Pregnancy and Lactation").

The efficacy and safety of atorvastatin for use in children under 10 years of age have not been established. Therefore, use of the drug in this age group is not recommended.

Overdose.

There is no specific antidote for atorvastatin overdose. In case of overdose, patients should be treated symptomatically and supportive measures applied as needed. Due to the high degree of plasma protein binding of the drug, enhanced clearance of atorvastatin by hemodialysis is not expected to be significant.

Adverse Reactions

Table 4 summarizes the incidence of clinical adverse reactions, regardless of causal relationship, reported in 2% or more of patients and at a higher incidence than in the placebo group, among patients receiving atorvastatin treatment (n=8755), based on data from 17 placebo-controlled studies.

Clinical adverse reactions occurring in more than 2% of patients receiving any dose of atorvastatin and at a higher incidence than in the placebo group, regardless of causal relationship (% of patients).

Table 4

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 more than in the placebo group

Other adverse reactions include:

General disorders: chest pain, facial swelling, fever, asthenia, neck muscle rigidity, weakness, photosensitivity reactions, generalized edema, malaise, pyrexia, peripheral edema, fatigue;
Nervous system disorders: insomnia, dizziness, paresthesia, somnolence, amnesia, sleep disorders, nightmares, decreased libido, emotional lability, coordination disorders, peripheral neuropathy, torticollis, facial nerve paralysis, hyperkinesia, depression, hypesthesia, hypertension, headache, dysgeusia;
Gastrointestinal disorders: gastroenteritis, liver function disorders, colitis, vomiting, nausea, gastritis, dry mouth, rectal hemorrhage, esophagitis, glossitis, oral ulcers, anorexia, increased appetite, stomatitis, cheilitis, duodenal ulcers, dysphagia, enteritis, melena, gingival bleeding, gastric ulcers, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice, diarrhea, abdominal pain, dyspepsia, constipation, flatulence, epigastric discomfort, eructation, cholestasis;
Musculoskeletal and connective tissue disorders: arthritis, myopathy, myalgia, myositis, muscle cramps; bursitis, tenosynovitis, myasthenia, tendon contracture, musculoskeletal pain, muscle spasms, increased muscle fatigue, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture), joint pain, back pain, rhabdomyolysis;
Metabolism and nutrition disorders: peripheral edema, hyperglycemia, increased creatine phosphokinase levels, gout, weight gain, hypoglycemia, anorexia, elevated transaminases, abnormal liver function tests, increased blood alkaline phosphatase levels;
Hepatobiliary disorders: hepatic failure;
Skin and subcutaneous tissue disorders: alopecia, pruritus, contact dermatitis, dry skin, increased sweating, acne, urticaria, eczema, seborrhea, skin ulcers, rash, angioedema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome and toxic epidermal necrolysis; drug-induced lichenoid reaction;
Respiratory, thoracic and mediastinal disorders: throat and laryngeal pain, bronchitis, rhinitis, pneumonia, dyspnea, asthma, epistaxis, nasopharyngitis;
Blood and lymphatic system disorders: ecchymoses, anemia, lymphadenopathy, thrombocytopenia, petechiae;
Immune system disorders: allergic reactions; anaphylaxis;
Sensory organ disorders: amblyopia, parosmia, taste loss, taste distortion;
Eye disorders: blurred vision, visual disturbances, dry eyes, refractive disorders, cataract, ocular hemorrhage, glaucoma, visual clouding;
Ear and labyrinth disorders: tinnitus, deafness;
Renal and reproductive system disorders: urinary tract infection, hematuria, albuminuria, frequent urination, cystitis, dysuria, urolithiasis, nocturia, epididymitis, mastopathy, vaginal hemorrhage, uterine bleeding, breast enlargement, metrorrhagia, nephritis, urinary incontinence, urinary retention, acute urinary retention, impotence, ejaculation disorders, leukocyturia, gynecomastia;
Cardiovascular system disorders: palpitations, vasodilation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina pectoris attack, hypotension, vasculitis;
Laboratory test abnormalities: frequently: abnormal liver function tests, increased serum creatine phosphokinase activity; infrequently: positive urine leukocyte test.

As with other HMG-CoA reductase inhibitors, elevated serum transaminase activity was observed in patients treated with atorvastatin. These changes were generally mild, transient, and did not require intervention or treatment. Clinically significant increases in serum transaminase activity (more than three times the upper limit of normal) were observed in 0.8 % of patients treated with atorvastatin. This increase was dose-dependent and reversible in all patients.

An increase in serum creatine kinase activity more than three times the upper limit of normal was observed in 2.5 % of patients treated with atorvastatin. This is consistent with observations during clinical trials with other HMG-CoA reductase inhibitors. In 0.4 % of patients receiving atorvastatin, levels exceeded the upper limit of normal by more than ten times.

Adverse reactions observed during clinical trials: urinary tract infection, diabetes mellitus, stroke.

Pediatric patients (10–17 years). Adverse events observed in patients treated with atorvastatin were similar to those in the placebo group. The most common adverse event observed in both groups, regardless of causal relationship, was infections.

Post-marketing experience.

During post-marketing use of atorvastatin, the adverse reactions listed below have been reported. Since these reactions were 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 reported after the drug was marketed, regardless of assessment of causality, include: anaphylaxis, angioedema, bullous rashes (including exudative multiform erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis), rhabdomyolysis, myositis, increased fatigue, tendon rupture, fatal and non-fatal hepatic 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 precautions").

Rare post-marketing reports of cognitive disorders (such as memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders were reported during use of all statins. Generally, they were not considered serious adverse reactions and were reversible upon discontinuation of statins, with variable onset time (from 1 day to several years) and resolution (median duration of 3 weeks).

With some statins, adverse events such as sexual dysfunction have been described; rare cases of interstitial lung disease, particularly during long-term treatment, have also been reported.

The following adverse reactions have been reported during post-marketing surveillance.

Blood and lymphatic system disorders: thrombocytopenia.

Immune system disorders: allergic reactions, anaphylaxis (including anaphylactic shock).

Metabolism and nutrition disorders: weight gain.

Nervous system disorders: headache, hypesthesia, dysgeusia; myasthenia gravis (frequency unknown).

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Eye disorders: ocular myasthenia (frequency unknown).

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain.

General disorders: chest pain, peripheral edema, malaise, fatigue.

Laboratory test abnormalities: increased alanine aminotransferase activity, increased serum creatine phosphokinase activity.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister, 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. Ananta Medicare Limited.

Manufacturer's address and site of operations.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udiog Vihar, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorization Holder.

Ananta Medicare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

INSTRUCTION

for medical use of the medicinal product

ATORVASTATIN 10 ANANTA,

ATORVASTATIN 20 ANANTA

(ATORVASTATIN 10 ANANTA,

ATORVASTATIN 20 ANANTA)

Composition:

Active substance: atorvastatin;

1 tablet contains atorvastatin calcium equivalent to atorvastatin 10 mg or 20 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; magnesium stearate; sodium croscarmellose; corn starch; hydroxypropylcellulose; hydroxypropyl methylcellulose; polyethylene glycol; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex film-coated tablets.

Pharmacotherapeutic group. Lipid-lowering agents, single-component. HMG-CoA reductase inhibitors. ATC code: C10AA05.

Pharmacological Properties

Pharmacodynamics

Atorvastatin is a synthetic hypolipidemic medicinal agent. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing 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 conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols including cholesterol.

In animal experimental 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 receptor molecules 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 LDL clearance. The dose of the drug correlates better with LDL cholesterol reduction than systemic drug concentrations. Dose titration should be individualized based on therapeutic response (see section "Dosage and Administration").

Pharmacokinetics

Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations reached within 1–2 hours. The extent of absorption increases proportionally with the dose. Absolute bioavailability of atorvastatin is approximately 14%, while systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. The low systemic availability 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, as measured by Cmax and AUC (area under the concentration-time curve), LDL cholesterol reduction is similar when atorvastatin is taken with or without food. When administered in the evening, atorvastatin plasma concentrations were lower (approximately 30% lower for Cmax and AUC) compared to morning dosing. However, LDL cholesterol reduction is equivalent regardless of the time of administration (see section "Dosage and Administration").

Distribution. The average volume of distribution of the drug 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 observations in rats, atorvastatin is considered capable of entering breast milk (see sections "Contraindications" and "Special Warnings").

Metabolism. Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro studies show that the HMG-CoA reductase inhibition by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to active metabolites. In vitro studies indicate that metabolism of atorvastatin by cytochrome P450 3A4 is significant, consistent with increased plasma concentrations of atorvastatin observed when co-administered with erythromycin, a known inhibitor of this isoenzyme (see section "Interaction with Other Medicinal Products and Other Forms of Interactions").

Excretion. Atorvastatin and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic metabolism; however, 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 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.

Special Patient Populations

Elderly patients. Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (aged 65 years and older) compared to younger adults. Clinical data indicate greater LDL reduction with any dose of the drug in elderly patients compared to younger patients (see section "Special Warnings").

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 8-week study in children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29).

Renal impairment. Renal disease does not affect atorvastatin plasma concentrations or LDL cholesterol reduction; therefore, dose adjustment in patients with renal impairment is not required (see sections "Dosage and Administration" and "Special Warnings").

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").

Table 1

Effect of concomitantly administered medicinal products on the pharmacokinetics of atorvastatin

Concomitantly administered drugs and dosing regimen	Atorvastatin
Concomitantly administered drugs and dosing regimen	Dose (mg)	Ratio AUC&	Ratio Cmax&
#Cyclosporine 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 SD (single dose)	9.36	8.58
#Telaprevir 750 mg every 8 hours, 10 days	20 mg SD	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 SD	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 twice daily, 14 days	10 mg once daily for 28 days	1.74	2.22
#Grapefruit juice, 240 ml once daily*	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 four times daily, 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 four times daily, 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 four times daily, 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
#Rifampicin 600 mg once daily, 7 days (concomitant administration) †	40 mg once daily	1.12	2.90
#Rifampicin 600 mg once daily, 5 days (separate 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 three times daily, 7 days	40 mg once daily	2.32	2.66
Glecaprevir 400 mg once daily / pibrentasvir 120 mg once daily, 7 days ***	10 mg once daily for 7 days	3
#Elbasvir 50 mg once daily / grazoprevir 200 mg once daily, 13 days	10 mg twice daily	95

& Comparison by treatment methods (concomitant use of the medicinal product with atorvastatin compared to atorvastatin use alone).

For information on clinical significance, see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction".

* Greater increases in AUC (AUC ratio up to 2.5) and/or Cmax (Cmax ratio up to 1.71) have been reported with excessive consumption of grapefruit juice (750 mL – 1.2 L per day or more).

** Ratios based on single samples taken 8–16 hours after dose administration.

*** Concomitant treatment with glecaprevir/pibrentasvir is contraindicated (see section "Contraindications").

‡ The dose of the saquinavir + ritonavir combination used in this study is not a clinically applicable dose. The increase in atorvastatin exposure under clinical use is likely to be higher than that observed in this study. Therefore, the medicinal product should be used with caution and at the lowest necessary dose.

Table 2

Effect of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products

Atorvastatin	Concomitant drug and dosing regimen
Atorvastatin	Drug/Dose (mg)	Ratio AUC	Ratio Cmax
80 mg once daily for 15 days	Antipyrine 600 mg single dose	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 µg	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 forms of interaction".

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases in adults

For adult patients without clinically evident ischemic heart disease but with multiple risk factors for developing ischemic heart disease, such as age, tobacco smoking, arterial hypertension, low HDL cholesterol levels, or a family history of premature ischemic heart disease, the medicinal product is indicated for:

reduction of the risk of myocardial infarction;
reduction of the risk of stroke;
reduction of the need for revascularization procedures and angina.

reduction of the risk of myocardial infarction;
reduction of the risk of stroke.

For adult patients with clinically evident ischemic heart disease, the medicinal product is indicated for:

reduction of the risk of non-fatal myocardial infarction;
reduction of the risk of fatal and non-fatal stroke;
reduction of the need for revascularization procedures;
reduction of the risk of hospitalization due to congestive heart failure;
reduction of the risk of angina.

Hyperlipidemia

In adults

As an adjunct to diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides, and to increase HDL cholesterol levels 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 measures are insufficiently effective.
To reduce total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis), or when such therapies are unavailable.

In children

As an adjunct to diet to reduce levels of total cholesterol, LDL cholesterol, and apolipoprotein B in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy the following laboratory results persist:

a) LDL cholesterol remains ≥ 190 mg/dL (4.91 mmol/L), or

b) LDL cholesterol ≥ 160 mg/dL (4.41 mmol/L) and:

there is a family history of premature cardiovascular disease, or
two or more other cardiovascular risk factors are present in the pediatric patient.

Contraindications.

Active liver disease, including persistent elevations of hepatic transaminases of unknown etiology.

Hypersensitivity to any component of this medicinal product.

Pregnancy.

Breastfeeding.

Concomitant use of the antiviral hepatitis C agents glecaprevir/pibrentasvir.

Interaction with other medicinal products and other forms of interaction.

The risk of developing myopathy during statin therapy increases with concomitant use of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, itraconazole) (see sections "Special warnings and precautions for use" and "Pharmacological properties").

Concomitant use of medicinal products that are inhibitors of CYP3A4 or transporters may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk may also be increased when atorvastatin is used concomitantly with other medicinal products that may potentially induce myopathy, such as fibric acid derivatives and ezetimibe (see section "Special warnings and precautions for use").

Strong CYP3A4 inhibitors. Concomitant use of atorvastatin with strong CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 3 and detailed information below). The extent of interaction and effect enhancement depends on the variability of the effect on CYP3A4. Concomitant use with strong CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, hepatitis C virus (HCV) antiviral agents (e.g., elbasvir/grazoprevir), and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use 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 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 developing 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 administration of these agents with atorvastatin may lead to increased atorvastatin exposure. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to using lower maximum doses of atorvastatin and conducting clinical monitoring of the patient. Clinical monitoring is also recommended after initiating treatment with an inhibitor or after adjusting its dose.

Grapefruit juice. Contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of atorvastatin, particularly with excessive consumption of grapefruit juice (more than 1.2 liters per day).

Clarithromycin. AUC values of atorvastatin were significantly increased when atorvastatin 80 mg was coadministered 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 warnings and precautions for use" and "Posology and method of administration").

Combination of protease inhibitors. AUC values of atorvastatin were significantly increased when atorvastatin was coadministered with several combinations of HIV protease inhibitors, as well as with the hepatitis C virus protease inhibitor telaprevir, compared to atorvastatin alone. Therefore, patients taking the HIV protease inhibitor tipranavir + ritonavir or the hepatitis C virus protease inhibitor telaprevir should avoid concomitant use of atorvastatin. The medicinal product should be used cautiously in patients taking the HIV protease inhibitor lopinavir + ritonavir and administered at the lowest necessary dose. For patients taking HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the atorvastatin dose should not exceed 20 mg; use should be cautious (see sections "Special warnings and precautions for use" and "Posology and method of administration"). When used in patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, the atorvastatin dose should not exceed 40 mg, and careful clinical monitoring of patients is recommended.

Itraconazole. AUC values of atorvastatin were significantly increased when atorvastatin 40 mg was coadministered 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 warnings and precautions for use" and "Posology and method of administration").

Cyclosporine. Atorvastatin and its 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 coadministered 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 warnings and precautions for use").

Table 3.

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis

Drugs that interact	Medical recommendations for use
Cyclosporine, HIV protease inhibitors (tipranavir + ritonavir), hepatitis C virus protease inhibitor (telaprevir)	Avoid use of atorvastatin
HIV protease inhibitor (lopinavir + ritonavir)	Use with caution and at the lowest necessary dose
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir)	Do not exceed 20 mg of atorvastatin per day
HIV protease inhibitor (nelfinavir) Hepatitis C virus protease inhibitor (boceprevir)	Do not exceed 40 mg of atorvastatin per day

*Use with caution and at the lowest necessary dose.

Gemfibrozil. Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are administered concomitantly with gemfibrozil, the combined use of atorvastatin with gemfibrozil should be avoided (see section "Special instructions").

Other fibrates. Since it is known that the risk of developing myopathy during treatment with HMG-CoA reductase inhibitors increases when other fibrates are used concomitantly, the drug should be used with caution when coadministered with other fibrates (see section "Special instructions").

Niacin. The risk of skeletal muscle-related adverse effects may increase when the drug is used in combination with niacin; therefore, under such conditions, dose reduction of atorvastatin should be considered (see section "Special instructions").

Rifampicin or other cytochrome P450 3A4 inducers. Concomitant use of the drug with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampicin) may lead to variable decreases in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, simultaneous administration of atorvastatin with rifampicin is recommended, as delayed administration of the drug after rifampicin dosing has been shown to result in a significant reduction in atorvastatin plasma concentrations.

Diltiazem hydrochloride

Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) results in increased atorvastatin plasma concentrations.

Cimetidine

Clinical studies have not revealed signs of interaction between atorvastatin and cimetidine.

Antacids

Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminium hydroxide results in approximately a 35% reduction in atorvastatin plasma concentrations. However, the hypolipidemic effect of atorvastatin remains unchanged.

Colestipol

Atorvastatin plasma concentrations were lower (atorvastatin concentration ratio 0.74) when atorvastatin was coadministered with colestipol. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect achieved with either drug administered alone.

Azithromycin

Concomitant administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not associated with changes in atorvastatin plasma concentrations.

Transporter inhibitors

Inhibitors of transport proteins (e.g., cyclosporine) 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 drugs cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).

Ezetimibe

Fusidic acid

If systemic use of fusidic acid is necessary, atorvastatin should be discontinued for the entire duration of fusidic acid treatment (see section "Special instructions").

Digoxin. When multiple doses of atorvastatin and digoxin are used concomitantly, steady-state digoxin plasma concentrations increase (see section "Pharmacokinetics"). Patients taking digoxin should be appropriately monitored.

Oral contraceptives. Concomitant use of atorvastatin with oral contraceptives increases the AUC for norethisterone and ethinylestradiol (see section "Pharmacological properties"). These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.

Warfarin. Atorvastatin had no clinically significant effect on prothrombin time in patients undergoing long-term warfarin therapy.

Other medicinal products. Clinical studies have shown that concomitant use of atorvastatin with antihypertensive agents and its use during estrogen replacement therapy were not associated with clinically significant adverse effects. Studies on interactions with other drugs have not been conducted.

Special precautions for use.

Skeletal muscles

Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been reported during treatment 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. 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.

Myopathy should be considered in any patient presenting with diffuse myalgia, muscle pain or weakness, and/or markedly elevated CPK levels. 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. Treatment should be discontinued in cases of marked CPK elevation, or if myopathy is diagnosed or suspected.

The risk of myopathy during treatment with statins increases with concomitant use of cyclosporine, fibrates, erythromycin, clarithromycin, the hepatitis C virus 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 antifungal azole agents. Physicians considering combination therapy with atorvastatin and fibrates, erythromycin, clarithromycin, saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, antifungal azoles, or lipid-modifying doses of niacin should carefully weigh potential benefits against 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 initial and maintenance doses of atorvastatin when coadministered with the aforementioned medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). Periodic CPK monitoring may be considered in such situations, although there is no guarantee that such monitoring will prevent cases of severe myopathy.

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, coadministration of atorvastatin with colchicine should be done with caution (see section "Interaction with other medicinal products and other forms of interaction").

Treatment should be temporarily or permanently discontinued in any patient with an acute serious condition suggestive of developing 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, or uncontrolled seizures).

In isolated cases, statins have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, atorvastatin should be discontinued. Recurrences have been reported upon rechallenge with the same or another statin.

Liver function

Statins, like some other hypolipidemic therapeutic agents, have been associated with abnormalities in liver function tests. Persistent elevation (more than 3 times the upper limit of normal, occurring on two or more occasions) of serum transaminases was observed in 0.7% of patients receiving 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 are data indicating that jaundice developed in one patient during treatment with the drug. Elevated liver function test (LFT) values in other patients were not associated with jaundice or other clinical symptoms. Upon dose reduction, temporary interruption, or discontinuation of the drug, transaminase levels returned to pre-treatment levels or approximately to these levels without adverse consequences. Eighteen of 30 patients with persistent elevation of liver function tests continued treatment with atorvastatin at lower doses.

Before initiating therapy, baseline liver enzyme levels should be obtained and retested as clinically indicated. Rare post-marketing reports of fatal and non-fatal hepatic failure have been received in patients taking statins, including atorvastatin. In case of serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice during atorvastatin treatment, therapy should be immediately discontinued. Reinitiation of treatment should not be considered unless an alternative etiology is identified.

Atorvastatin should be prescribed with caution to 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 use of HMG-CoA reductase inhibitors, including atorvastatin.

Statins inhibit cholesterol synthesis and may theoretically impair adrenal and/or gonadal steroid hormone secretion. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied in a sufficient number of patients. It is unknown whether the drug affects, or has any effect at all on, the "gonadal gland-pituitary-hypothalamus" system in premenopausal women. Caution should be exercised when coadministering statin-class drugs with medicinal products that may reduce 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 ischemic heart disease who had a history of stroke or transient ischemic attack within the previous 6 months, treatment with atorvastatin 80 mg was associated with a higher incidence of hemorrhagic stroke compared to placebo. The incidence of fatal hemorrhagic stroke was similar across all treatment groups. The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group compared to placebo. Some baseline characteristics, including a history of hemorrhagic and lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.

In patients aged 65–75 years receiving atorvastatin, no overall differences in safety and efficacy were observed compared to younger patients, nor were there differences in response to treatment between elderly and younger patients. However, increased sensitivity in some older individuals cannot be ruled out. Since advanced age (≥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 "Contraindications" and "Pharmacological properties").

Before starting treatment

Atorvastatin should be prescribed with caution in patients predisposed to developing rhabdomyolysis. Prior to initiating statin therapy in such patients, creatine kinase (CK) levels should be measured in the following cases:

renal impairment;
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 (≥70 years), the need for these measures should be evaluated based on the presence of other risk factors for rhabdomyolysis.

Increased plasma levels of the drug may occur, particularly due to drug interactions or in specific patient populations, including those with inherited disorders.

In such cases, a risk-benefit assessment of treatment is recommended, along with clinical monitoring of patients. If baseline CK levels are markedly elevated (more than 5 times the upper limit of normal), treatment should not be initiated.

Measurement of creatine kinase levels

CK levels should not be measured following intense physical exertion or in the presence of any other possible alternative causes of elevated CK, as this may complicate interpretation of results. If markedly elevated CK levels (more than 5 times the upper limit of normal) 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 treatment with atorvastatin, CK levels should be measured. If CK levels are markedly elevated (more than 5 times the upper limit of normal), treatment should be discontinued.

Discontinuation of treatment should also be considered if CK elevation does not exceed fivefold the upper limit of normal but muscle symptoms are severe and cause daily discomfort.

After symptoms resolve and CK levels normalize, reinitiation of atorvastatin therapy or initiation of an alternative statin may be considered, provided the lowest possible dose is used and close monitoring is maintained.

Atorvastatin therapy must be discontinued if clinically significant elevation of CK (more than 10 times the upper limit of normal) is observed or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use with other medicinal products

The risk of rhabdomyolysis is increased when atorvastatin is coadministered with certain medicinal products that may increase plasma concentrations of atorvastatin. Examples include potent CYP3A4 or transporter protein inhibitors: 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 medicinal products (not interacting with atorvastatin) should be used instead of the above-mentioned agents.

If concomitant therapy with atorvastatin and these agents is necessary, the benefit-risk ratio should be carefully evaluated. If patients are taking drugs that increase atorvastatin plasma concentrations, a reduction in atorvastatin dose to the minimum recommended level is advised. Additionally, when using potent CYP3A4 inhibitors, consideration should be given to using a lower initial dose of atorvastatin. Appropriate clinical monitoring of these patients is also recommended.

Atorvastatin must not be coadministered with systemic fusidic acid or within 7 days of stopping fusidic acid treatment. For 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 concomitantly (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.

Under exceptional circumstances, such as when long-term systemic fusidic acid therapy is required (e.g., for treatment of severe infections), concomitant use of atorvastatin and fusidic acid should only be considered on an individual basis and under strict medical supervision.

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Temporary discontinuation of atorvastatin should be considered in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times per week, and patients should be closely observed for any signs or symptoms suggestive of myopathy.

Interstitial lung disease

Excipients

The drug contains lactose. This medication should not be taken by patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. Lipid-modifying therapy should be part of a comprehensive treatment strategy in patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when dietary restriction of saturated fats and cholesterol, along with other non-pharmacological measures, has been insufficient. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, drug therapy may be initiated concurrently with dietary changes.

Limitations of use

Atorvastatin has not been studied in conditions where the primary lipoprotein abnormality is elevated chylomicron levels (Fredrickson types I and V).

Use during pregnancy or breastfeeding

Pregnancy

Risk assessment

The background risk of major congenital malformations and miscarriage in the indicated population is unknown. In the general U.S. 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 harm the fetus if used during pregnancy. Women of childbearing potential should be informed of the need for effective contraception during treatment with this drug.

Clinical data

Rare reports of congenital anomalies have been received following in utero exposure to other HMG-CoA reductase inhibitors. Prospective follow-up of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed no increase in the frequency of fetal congenital anomalies, miscarriages, or intrauterine deaths/stillbirths compared to the general population. The number of cases is sufficient to exclude a ≥3–4-fold increase in fetal congenital anomalies compared to the background rate. In 89% of the prospectively followed pregnancies, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Lactation

The drug is contraindicated during breastfeeding. There is no information on the effect of the drug on the breastfed infant or on lactation. It is unknown whether atorvastatin is excreted in human milk, although another drug in this class has been shown to pass into breast milk; atorvastatin is present in rat milk. Since statins may potentially cause serious adverse reactions in breastfed infants, women requiring treatment with this drug should not breastfeed (see section "Contraindications").

Ability to influence reaction speed when driving or operating machinery

Has a negligible influence on the ability to drive or operate machinery.

Dosage and Administration

Hyperlipidemia and Mixed Dyslipidemia

The recommended starting dose of the drug is 10 or 20 mg once daily. For patients who require a large reduction in LDL cholesterol levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily. The atorvastatin dosage range is from 10 to 80 mg once daily. The drug can be administered as a single dose at any time of day and independently of food intake. Initial and maintenance doses should be individually adjusted based on treatment goals and patient response. After initiation of therapy and/or dose titration, lipid levels should be analyzed within 2 to 4 weeks and the dose adjusted accordingly.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (Aged 10 to 17 Years)

The recommended starting dose is 10 mg/day. The usual dose range is 10 to 20 mg orally once daily. Doses should be individually adjusted according to treatment goals. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous Familial Hypercholesterolemia

The atorvastatin dose for patients with homozygous familial hypercholesterolemia ranges from 10 to 80 mg daily. The drug should be used as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such lipid-lowering treatments are unavailable.

Concomitant Lipid-Lowering Therapy

The drug may be coadministered with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be prescribed with caution (see sections "Special Precautions", "Interaction with Other Medicinal Products and Other Forms of Interaction").

Dosing in Patients with Renal Impairment

Renal disease does not affect plasma concentrations or the reduction in LDL cholesterol levels with the use of the drug; therefore, dose adjustment is not required in patients with impaired renal function (see sections "Special Precautions", "Pharmacokinetics").

Dosing in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors

Treatment with the drug should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitors (telaprevir). Atorvastatin should be prescribed with caution in HIV patients taking lopinavir + ritonavir and should be used at the lowest necessary dose. For patients taking clarithromycin, itraconazole, or HIV patients taking combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the therapeutic dose of atorvastatin should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose.

In patients taking the hepatitis C virus protease inhibitor elbasvir/grazoprevir concomitantly with atorvastatin, the atorvastatin dose should not exceed 20 mg/day (see section "Special Precautions" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

For patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, atorvastatin therapy should be limited to a dose of 40 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose (see section "Special Precautions" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

In patients aged 10 to 17 years with heterozygous familial hypercholesterolemia, specifically adolescent boys and girls after onset of menstruation, no clinically significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls has been observed (see sections "Adverse Reactions", "Dosage and Administration"). Adolescent girls should be counseled regarding acceptable contraceptive methods during treatment with the drug (see section "Use in Pregnancy or Lactation").

The efficacy and safety of atorvastatin for treatment in children under 10 years of age have not been studied. Therefore, use of the drug in this age group is not recommended.

Overdose.

There is no specific antidote for atorvastatin overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be administered as needed. Due to the high degree of plasma protein binding of the drug, significant enhancement of atorvastatin clearance by hemodialysis is not expected.

Adverse Reactions

Table 4 summarizes the incidence of clinical adverse reactions, regardless of causal relationship, reported in 2% or more of patients and at a higher incidence than in the placebo group, among patients treated with atorvastatin (n=8755), from data from 17 placebo-controlled studies.

Clinical adverse reactions occurring in more than 2% of patients treated with any dose of atorvastatin and at a higher incidence than in the placebo group, regardless of causal relationship (% of patients).

Table 4

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 more than in the placebo group

Other adverse reactions include:

General disorders: chest pain, facial swelling, fever, asthenia, neck muscle rigidity, weakness, photosensitivity reactions, generalized edema, malaise, pyrexia, peripheral edema, fatigue;
Nervous system disorders: insomnia, dizziness, paresthesia, somnolence, amnesia, sleep disorders, nightmares, decreased libido, emotional lability, coordination disorders, peripheral neuropathy, torticollis, facial nerve paralysis, hyperkinesia, depression, hypesthesia, hypertension, headache, dysgeusia;
Gastrointestinal disorders: gastroenteritis, liver function disorders, colitis, vomiting, nausea, gastritis, dry mouth, rectal hemorrhage, esophagitis, glossitis, oral ulceration, anorexia, increased appetite, stomatitis, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gingival bleeding, gastric ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice, diarrhea, abdominal pain, dyspepsia, constipation, flatulence, epigastric discomfort, eructation, cholestasis;
Musculoskeletal and connective tissue disorders: arthritis, myopathy, myalgia, myositis, muscle cramps, bursitis, tenosynovitis, myasthenia, tendon contracture, musculoskeletal pain, muscle spasms, increased muscle fatigue, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture), arthralgia, back pain, rhabdomyolysis;
Metabolism and nutrition disorders: peripheral edema, hyperglycemia, increased creatine phosphokinase levels, gout, weight gain, hypoglycemia, anorexia, elevated transaminases, abnormal liver function tests, increased blood alkaline phosphatase levels;
Hepatobiliary disorders: hepatic failure;
Skin and connective tissue disorders: alopecia, pruritus, contact dermatitis, dry skin, increased sweating, acne, urticaria, eczema, seborrhea, skin ulceration, rash, angioedema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome and toxic epidermal necrolysis; drug-induced lichenoid reaction;
Respiratory, thoracic and mediastinal disorders: throat and laryngeal pain, bronchitis, rhinitis, pneumonia, dyspnea, asthma, epistaxis, nasopharyngitis;
Blood and lymphatic system disorders: ecchymoses, anemia, lymphadenopathy, thrombocytopenia, petechiae;
Immune system disorders: allergic reactions; anaphylaxis;
Sensory organ disorders: amblyopia, parosmia, taste loss, taste distortion;
Eye disorders: blurred vision, visual disturbance, dry eyes, refractive disorder, cataract, ocular hemorrhage, glaucoma, visual clouding;
Ear and labyrinth disorders: tinnitus, deafness;
Renal and reproductive system disorders: urinary tract infection, hematuria, albuminuria, frequent urination, cystitis, dysuria, urolithiasis, nocturia, epididymitis, mastopathy, vaginal hemorrhage, uterine bleeding, breast enlargement, metrorrhagia, nephritis, urinary incontinence, urinary retention, acute urinary retention, impotence, ejaculation disorder, leukocyturia, gynecomastia;
Cardiovascular disorders: palpitations, vasodilation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina attack, hypotension, vasculitis;
Laboratory test abnormalities: common: abnormal liver function tests, increased serum creatine phosphokinase activity; uncommon: positive urine leukocyte test.

As with other HMG-CoA reductase inhibitors, elevated serum transaminase activity has been observed in patients taking atorvastatin. These changes were generally mild, transient, and did not require intervention or treatment. Clinically significant elevations in serum transaminase activity (more than 3 times the upper limit of normal) were observed in 0.8% of patients receiving atorvastatin. This elevation was dose-dependent and reversible in all patients.

Elevated serum creatine kinase activity, more than 3 times the upper limit of normal, was observed in 2.5% of patients taking atorvastatin. This is consistent with observations during clinical trials with other HMG-CoA reductase inhibitors. In 0.4% of patients receiving atorvastatin, levels exceeded the upper limit of normal by more than 10 times.

Adverse reactions observed during clinical trials: urinary tract infection, diabetes mellitus, stroke.

Children (10–17 years). Adverse events observed in patients taking atorvastatin were similar to those in the placebo group. The most common adverse event observed in both groups, regardless of causality, was infections.

Post-marketing experience.

During post-marketing use of atorvastatin, the following adverse reactions have been identified. Because these 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 reported after marketing authorization, regardless of causal assessment, include: anaphylaxis, angioedema, bullous rashes (including exudative multiform erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis), rhabdomyolysis, myositis, increased fatigue, tendon rupture, fatal and non-fatal hepatic 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 precautions").

Rare post-marketing reports of cognitive disorders (such as memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders have been reported with all statins. Overall, they were not considered serious adverse reactions and were reversible upon discontinuation of statins, with variable onset time (from 1 day to several years) and resolution (median duration of 3 weeks).

With the use of some statins, adverse events such as sexual dysfunction have been described; rare cases of interstitial lung disease, particularly during long-term treatment, have also been reported.

Adverse reactions reported during post-marketing surveillance:

Blood and lymphatic system disorders: thrombocytopenia.

Immune system disorders: allergic reactions, anaphylaxis (including anaphylactic shock).

Metabolism and nutrition disorders: weight gain.

Nervous system disorders: headache, hypesthesia, dysgeusia; myasthenia gravis (frequency unknown).

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Eye disorders: ocular myasthenia (frequency unknown).

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain.

General disorders: chest pain, peripheral edema, malaise, fatigue.

Laboratory test abnormalities: increased alanine aminotransferase activity, increased serum creatine phosphokinase activity.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister, 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. Arthura Pharmaceuticals Pvt. Ltd.

Manufacturer's address and location of its business operations.

1505 Portia Road, Sri City SEZ, Setyavedu Mandal, Chittoor District – 517 588, Andhra Pradesh, India.

Marketing Authorization Holder.

Ananta Medikare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Atorvastatin 10 ananta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATORVASTATIN 10 ANANTA, ATORVASTATIN 20 ANANTA (ATORVASTATIN 10 ANANTA, ATORVASTATIN 20 ANANTA)

Composition:

Pharmacological properties.

For information on clinical significance, see sections «Special warnings and precautions for use» and «Interaction with other medicinal products and other forms of interaction».

For information on clinical significance, see section "Interaction with other medicinal products and other forms of interaction".

Clinical characteristics.

Special precautions for use.

Dosage and Administration

Adverse Reactions

Composition:

Pharmacological Properties

For information on clinical significance, see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction".

For information on clinical significance, see section "Interaction with other medicinal products and other forms of interaction".

Clinical characteristics.

Special precautions for use.

Dosage and Administration

Adverse Reactions