INSTRUCTIONS for medical use of the medicinal product Atorvastatin-Teva (Atorvastatin-Teva)

Composition:

Active substance: atorvastatin;

1 film-coated tablet contains atorvastatin 10 mg or 20 mg, or 40 mg, or 80 mg (as atorvastatin calcium);

Excipients:

core: microcrystalline cellulose, sodium carbonate, maltose, sodium croscarmellose, magnesium stearate;

coating: hypromellose (E 464), hydroxypropylcellulose, triethyl citrate (E 1505), polysorbate 80, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg: white or almost white, elliptical, biconvex, smooth tablets, approximately
9.7 mm × 5.2 mm in size.

20 mg: white or almost white, elliptical, biconvex, smooth tablets, approximately
12.5 mm × 6.6 mm in size.

40 mg: white or almost white, elliptical, biconvex, smooth tablets, approximately
15.6 mm × 8.3 mm in size.

80 mg: white or almost white, elliptical, biconvex, smooth tablets, approximately
18.8 mm × 10.3 mm in size.

Pharmacotherapeutic group. Agents that reduce serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. ATC code C10A A05.

Pharmacological Properties.

Pharmacodynamics.

Atorvastatin is a synthetic hypolipidemic agent. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, the enzyme responsible for the rate-limiting step in 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 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 LDL particles.

Atorvastatin and some of its metabolites are 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 drug dose correlates better with LDL cholesterol reduction than systemic drug concentration. Dose titration should be individualized based on therapeutic response.

Pharmacokinetics.

Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentration (Cmax) reached within 1–2 hours. The extent of absorption increases proportionally with atorvastatin dose. Absolute bioavailability of atorvastatin (parent drug) is approximately 14%, and systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. The low systemic availability of the drug is attributed to pre-systemic clearance in the gastrointestinal mucosa and/or pre-systemic metabolism in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, based on Cmax and AUC (area under the plasma concentration-time curve), LDL cholesterol reduction is similar regardless of whether atorvastatin is administered with food or separately. When atorvastatin is administered in the evening, plasma concentrations are lower (approximately 30% for both Cmax and AUC) compared to morning administration. However, LDL cholesterol reduction is similar regardless of the time of administration.

Distribution. The average volume of distribution of atorvastatin is approximately 381 liters. Over 98% of the drug is bound to plasma proteins. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes. Based on observations in rats, atorvastatin is expected to pass into breast milk.

Metabolism. Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro studies have shown that the HMG-CoA reductase inhibition by ortho- and parahydroxylated 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 atorvastatin concentrations observed in humans when co-administered with erythromycin, a known inhibitor of this isoenzyme.

Excretion. Atorvastatin and its metabolites are primarily eliminated in bile following hepatic and/or extrahepatic metabolism; however, this drug apparently does not undergo enterohepatic recirculation. The mean plasma half-life of atorvastatin in humans is approximately 14 hours, while the half-life of HMG-CoA reduct enzyme 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.

Patient Populations

Elderly Patients. Plasma concentrations of atorvastatin are higher (Cmax approximately 40% higher, AUC 30% higher) in healthy elderly volunteers (aged 65 years and older) compared to younger adult volunteers. Clinical data indicate a greater degree of LDL reduction with any dose of atorvastatin in elderly patients compared to younger individuals.

Children. Oral clearance of atorvastatin in children appears 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 using data from an open-label 8-week study in children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29).

Gender. Atorvastatin plasma concentrations in women differ from those in men (Cmax approximately 20% higher, AUC 10% lower). However, there is no clinically significant difference in LDL cholesterol reduction between men and women when atorvastatin is administered.

Renal Impairment. Renal disease does not affect atorvastatin plasma concentrations or reduction of low-density lipoprotein cholesterol (LDL-C); therefore, dose adjustment in patients with renal impairment is not required.

Hemodialysis. Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance atorvastatin clearance, as the drug is extensively bound to plasma proteins.

Hepatic Impairment. Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC values are fourfold 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.

Drug Interaction Studies. Atorvastatin is a substrate of hepatic transporters OATP1B1 and OATP1B3. Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.

Table 1

Effect of concomitantly administered drugs on the pharmacokinetics of atorvastatin

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

See sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction" for clinical significance.

* 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 L per day or more).

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

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

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

Table 2

Effect of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products

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

Atorvastatin did not clinically significantly affect prothrombin time in patients receiving long-term warfarin therapy.

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases in adults

For adult patients without clinically evident ischemic heart disease (IHD), but with multiple risk factors for IHD such as age, smoking, arterial hypertension, low levels of high-density lipoprotein (HDL) or a family history of premature IHD, atorvastatin is indicated for:

• reducing the risk of myocardial infarction;
• reducing the risk of stroke;
• reducing the risk of revascularization procedures and angina.

For adult patients with type 2 diabetes mellitus and without clinically evident IHD, but with multiple risk factors for IHD such as retinopathy, albuminuria, smoking or arterial hypertension, Atorvastatin-Teva is indicated for:

• reducing the risk of myocardial infarction;
• reducing the risk of stroke.

For adult patients with clinically evident IHD, Atorvastatin-Teva is indicated for:

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

Hyperlipidemia

In adult patients

• As an adjunct to diet to reduce elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglycerides, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification).
• As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (type IV according to Fredrickson classification).
• For the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrickson classification) when dietary measures are insufficient.
• To reduce total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or when such treatments are unavailable.

In children

• As an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy laboratory results are:

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

b) LDL-C ≥ 160 mg/dL (4.14 mmol/L) and:

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

Contraindications.

Hypersensitivity to any component of the medicinal product; active liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology; pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Plasma levels of atorvastatin may be significantly increased when co-administered with inhibitors of CYP3A4 and transporters. Below is a list of medicinal products that may increase atorvastatin exposure and the risk of myopathy and rhabdomyolysis when used concomitantly, along with recommendations for management and prevention of these risks.

Interaction with other medicinal products that may increase the risk of myopathy and rhabdomyolysis during atorvastatin use

Cyclosporine or gemfibrozil. Clinical effect. Plasma levels of atorvastatin were significantly increased when atorvastatin was co-administered with cyclosporine, an inhibitor of CYP3A4 and OATP1B1. Monotherapy with gemfibrozil may cause myopathy. The risk of developing myopathy and rhabdomyolysis is increased when cyclosporine or gemfibrozil is co-administered with atorvastatin. Measures. Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended.

Antiviral agents. Clinical effect. Plasma levels of atorvastatin were significantly increased when atorvastatin was co-administered with many antiviral agents that are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2). Cases of myopathy and rhabdomyolysis have been reported with co-administration of ledipasvir + sofosbuvir with atorvastatin. Measures. · Concomitant use of the combination tipranavir + ritonavir or glecaprevir + pibrentasvir with atorvastatin is not recommended. · In patients receiving lopinavir + ritonavir or simeprevir, the benefit/risk of concomitant use with atorvastatin should be assessed. · In patients receiving saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, or letermovir, the atorvastatin dose should not exceed 20 mg. · In patients receiving nelfinavir, the atorvastatin dose should not exceed 40 mg. · The benefit/risk of concomitant use of ledipasvir + sofosbuvir with atorvastatin should be assessed. · Signs and symptoms of myopathy should be monitored in all patients, especially at the start of treatment and during dose increases of any medicinal product. Examples. Tipranavir + ritonavir, glecaprevir + pibrentasvir, lopinavir + ritonavir, simeprevir, saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, letermovir, nelfinavir, and ledipasvir + sofosbuvir.

Specific azole antifungal agents or macrolide antibiotics. Clinical effect. Plasma levels of atorvastatin were significantly increased when atorvastatin was co-administered with specific azole antifungal agents or macrolide antibiotics due to inhibition of CYP3A4 and/or transporters. Measures. In patients receiving clarithromycin or itraconazole, the atorvastatin dose should not exceed 20 mg. The benefit/risk of concomitant use of specific azole antifungal agents or macrolide antibiotics with atorvastatin should be evaluated. Signs and symptoms of myopathy should be monitored in all patients, especially at the start of therapy and during dose increases of any medicinal product. Examples. Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.

Niacin. Clinical effect. Cases of myopathy and rhabdomyolysis have been observed when lipid-modifying doses of niacin (>1 g/day of niacin) were co-administered with atorvastatin. Measures. Consider whether the benefit of co-administering lipid-modifying doses of niacin with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If co-administration is decided, patients should be monitored for signs and symptoms of myopathy, especially at the start of therapy and during dose increases of either medicinal product.

Fibrates (except gemfibrozil). Clinical effect. Use of fibrates as monotherapy may cause myopathy. The risk of developing myopathy and rhabdomyolysis increases when fibrates are co-administered with atorvastatin. Measures. Consider whether the benefit of co-administering fibrates with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If co-administration is decided, patients should be monitored for signs and symptoms of myopathy, especially at the start of therapy and during dose increases of either medicinal product.

Colchicine. Clinical effect. Cases of myopathy and rhabdomyolysis have been observed during concomitant use of colchicine with atorvastatin. Measures. The benefit/risk of concomitant use of colchicine with atorvastatin should be considered. If co-administration is decided, patients should be monitored for signs and symptoms of myopathy, especially at the start of therapy and during dose increases of either medicinal product.

Grapefruit juice. Clinical effect. Consumption of grapefruit juice, especially in large quantities (more than 1.2 liters per day), may lead to increased plasma levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis. Measures. Avoid consumption of large amounts of grapefruit juice (more than 1.2 liters per day) during atorvastatin use.

Interaction with medicinal products that may reduce atorvastatin exposure

Rifampicin. Clinical effect. Concomitant use of atorvastatin with rifampicin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, may lead to an inconsistent reduction in atorvastatin plasma concentration. Due to the dual interaction mechanism of rifampicin, delayed administration of atorvastatin after rifampicin dosing has been associated with a significant reduction in atorvastatin plasma concentration. Measures. Concomitant administration of atorvastatin and rifampicin is recommended.

Effect of atorvastatin on other medicinal products

Oral contraceptives. Clinical effect. Concomitant use of atorvastatin and oral contraceptives increased plasma concentrations of norethisterone and ethinylestradiol. Measures. This should be considered when selecting an oral contraceptive for patients taking atorvastatin.

Digoxin. Clinical effect. Steady-state digoxin plasma concentrations were increased when multiple doses of atorvastatin and digoxin were co-administered. Measures. Patients taking digoxin should be appropriately monitored.

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

Cimetidine. No evidence of interaction between atorvastatin and cimetidine was observed in 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 lipid-lowering effect of atorvastatin was not altered.

Cholestyramine. Plasma concentration of atorvastatin was lower (by approximately 25%) when atorvastatin and cholestyramine were co-administered. However, the lipid-lowering effect of the combination of atorvastatin and cholestyramine exceeded the effect achieved with either agent alone.

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

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

Ezetimibe. Use of ezetimibe as monotherapy has been associated with adverse reactions affecting the muscular system, including rhabdomyolysis. Therefore, when ezetimibe is co-administered with atorvastatin, the risk of these adverse reactions increases. Appropriate clinical monitoring of such 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 is unknown. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving this combination. If systemic use of fusidic acid is necessary, atorvastatin should be discontinued for the entire duration of fusidic acid therapy.

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

Special precautions for use.

Myopathy and rhabdomyolysis

Atorvastatin may cause myopathy (muscle pain, tenderness or weakness in combination with creatine kinase (CK) elevation more than 10 times the upper limit of normal (ULN)) and rhabdomyolysis (with or without acute renal failure due to myoglobinuria). Rare fatal cases of rhabdomyolysis have been reported with statins, including atorvastatin.

Myopathy risk factors. Risk factors for developing myopathy include age ≥65 years, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher atorvastatin doses.

Measures to reduce or prevent the risk of myopathy and rhabdomyolysis. Exposure to atorvastatin may increase due to drug interactions involving inhibition of cytochrome P450 3A4 (CYP3A4) enzyme and/or transporters (e.g., breast cancer resistance protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3], and P-glycoprotein [P-gp]), leading to an increased risk of myopathy and rhabdomyolysis. Concomitant use of atorvastatin with cyclosporine, gemfibrozil, the combination of tipranavir + ritonavir, or glecaprevir + pibrentasvir is not recommended. Dose adjustments of atorvastatin are recommended for patients taking certain antiviral agents, azole antifungals, or macrolide antibiotics. Cases of myopathy/rhabdomyolysis have been reported with concomitant use of atorvastatin and lipid-modifying doses (>1 g/day) of niacin, fibrates, colchicine, or the combination of ledipasvir + sofosbuvir. The benefit of using these agents should be weighed against the increased risk of myopathy and rhabdomyolysis.

Concomitant consumption of large quantities of grapefruit juice (more than 1.2 L per day) is not recommended in patients taking atorvastatin.

Atorvastatin should be discontinued if markedly elevated CK levels are observed or if myopathy is diagnosed or suspected. Muscle symptoms and elevated CK resolve after discontinuation of atorvastatin. Atorvastatin should be temporarily discontinued in patients with an acute or serious condition associated with a high risk of renal failure due to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disturbances; uncontrolled epilepsy).

Patients should be informed about the risk of developing myopathy and rhabdomyolysis at the beginning of treatment or when the dose of atorvastatin is increased. Patients should be advised to report immediately any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.

Immune-mediated necrotizing myopathy (IMNM). Rare cases of immune-mediated necrotizing myopathy (IMNM)—an autoimmune myopathy associated with statin use—have been reported. IMNM is characterized by: proximal muscle weakness and elevated plasma creatine phosphokinase (CPK) levels that persist despite discontinuation of statin therapy; positive antibodies to HMG-CoA reductase; necrotizing myopathy on muscle biopsy; and improvement with immunosuppressive therapy. Additional neuromuscular and serological investigations may be required. Immunosuppressive therapy may be necessary. The risk of IMNM should be carefully considered before initiating another statin. If another statin is initiated, monitoring for signs and symptoms of IMNM is required.

Myasthenia gravis, ocular myasthenia. There have been several reports of statins inducing de novo myasthenia gravis or exacerbating pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). The drug should be discontinued if symptoms worsen. Recurrences have been reported upon (re)exposure to the same or another statin.

Before starting treatment. Atorvastatin should be prescribed with caution in patients predisposed to developing rhabdomyolysis. Before initiating statin therapy in patients predisposed to rhabdomyolysis, CPK levels should be measured in the presence of: renal impairment, hypothyroidism, personal or family history of hereditary muscle disorders, previous episodes of statin or fibrate-induced myotoxicity, previous liver disease, and/or alcohol abuse.

For elderly patients (over 70 years), the need for these measures should be evaluated considering the presence of other risk factors for rhabdomyolysis.

Increased plasma drug levels may occur, particularly due to drug interactions or in specific patient groups, including patients with hereditary disorders.

In such cases, a risk-benefit assessment of treatment and clinical monitoring of patients is recommended. If baseline CPK levels are significantly elevated (>5 times ULN), treatment should not be initiated.

CPK measurement. CPK levels should not be measured after strenuous physical exertion or in the presence of any other possible alternative causes of elevated CPK, as this may complicate interpretation of results. If markedly elevated CPK levels (>5 times ULN) are observed at baseline, repeat measurement should be performed after 5–7 days to confirm the result.

During treatment. Patients should be aware of the need to report immediately the development of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever. If these symptoms occur during atorvastatin treatment, CPK levels should be measured. If CPK levels are markedly elevated (>5 times ULN), treatment should be discontinued. Discontinuation of therapy should also be considered if CPK elevation does not exceed five times ULN but muscle symptoms are severe and cause daily discomfort. After symptom resolution and normalization of CPK levels, reinitiation of atorvastatin therapy or initiation of an alternative statin may be considered, using the lowest possible dose and with close monitoring of the patient. Atorvastatin therapy should be discontinued if clinically significant elevation of CPK (>10 times ULN) occurs or if rhabdomyolysis (or suspicion thereof) is diagnosed.

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 inhibitors of CYP3A4 or transporter proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, and darunavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibrates, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or the combination telaprevir/ritonavir. If possible, alternative drugs (that do not interact with atorvastatin) should be used instead of the above.

If concomitant use of atorvastatin and the mentioned drugs is necessary, the benefit-risk ratio should be carefully evaluated. If patients are taking drugs that increase atorvastatin plasma concentrations, it is recommended to reduce the atorvastatin dose to the minimum. Additionally, when using potent CYP3A4 inhibitors, a lower initial dose of atorvastatin should be considered. Appropriate clinical monitoring of these patients is also recommended.

Atorvastatin must not be co-administered with systemic fusidic acid or within 7 days of stopping fusidic acid treatment. In patients requiring systemic fusidic acid, statin therapy should be suspended for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination. Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In individual cases where prolonged systemic fusidic acid treatment is required (e.g., for severe infections), the possibility of concomitant use of atorvastatin and fusidic acid should be considered on a case-by-case basis, and such treatment requires careful medical supervision.

Hepatic function. Therapy with statins, as with some other lipid-lowering agents, has been associated with abnormalities in liver biochemical tests. Before initiating atorvastatin therapy, liver enzyme test results should be obtained and repeated as clinically indicated. If any symptoms of liver injury occur, liver function should be assessed. Patients with elevated transaminase levels should be monitored until values normalize. If transaminase levels increase more than 3 times the ULN, it is recommended to reduce the dose or discontinue atorvastatin. Cases of fatal and non-fatal liver 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 use, treatment must be discontinued immediately. Reinitiation of atorvastatin therapy should not be attempted unless an alternative etiology is established. Atorvastatin should be prescribed with caution in patients with alcohol abuse and/or a history of liver disease. Atorvastatin is contraindicated in active liver disease or persistent elevations of hepatic transaminases of unknown etiology.

Endocrine function. Increases in HbA1c and fasting plasma glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Statins inhibit cholesterol synthesis and may theoretically reduce adrenal and/or gonadal steroid hormone synthesis. 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. It is unknown whether the drug affects or has any effect on the hypothalamic-pituitary-gonadal system in premenopausal women. Caution should be exercised when combining statins with drugs that may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Use in patients who recently experienced stroke or transient ischemic attack (TIA). In a retrospective analysis of stroke subtypes in patients without coronary heart disease who recently experienced stroke or TIA, a higher incidence of hemorrhagic stroke was observed with initial atorvastatin 80 mg treatment compared to placebo. A particularly increased risk was noted in patients who had experienced hemorrhagic stroke or lacunar infarction at study entry. For these patients, the benefit-risk balance of using atorvastatin 80 mg is uncertain; therefore, the potential risk of hemorrhagic stroke should be carefully evaluated before initiating treatment.

No differences in treatment response were observed between elderly and younger patients, although increased sensitivity in some elderly patients cannot be excluded. Since elderly patients (over 65 years) are more prone to myopathy, atorvastatin should be prescribed with caution.

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.

Diabetes mellitus. Evidence shows that statins as a class may increase blood glucose levels and may lead to hyperglycemia requiring treatment in some patients at high risk for developing diabetes mellitus. However, this risk should not preclude statin therapy, as the cardiovascular risk reduction with statins outweighs this risk. Patients at risk (fasting glucose 5.6–6.9 mmol/L, BMI >30 kg/m², elevated triglycerides, arterial hypertension) require both clinical and biochemical monitoring.

Excipients. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free."

Use limitations. Atorvastatin has not been studied under conditions where the primary lipoprotein abnormality is elevated chylomicrons (types I and V according to Fredrickson classification).

Use during pregnancy or breastfeeding.

Pregnancy.

Assessment of risks. Atorvastatin is contraindicated in pregnant women, as its 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. Atorvastatin should be discontinued as soon as pregnancy is confirmed. The estimated background risk of major congenital malformations and miscarriages in this 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 harm the fetus when administered to a pregnant woman. Women of reproductive potential should be informed of the need for effective contraception during treatment with this medicinal product.

Clinical data. Limited published data from observational studies, meta-analyses, and case reports on the use of calcium atorvastatin do not indicate an increased risk of major congenital malformations or miscarriages. Rare reports of congenital anomalies have been reported after in utero exposure to other HMG-CoA reductase inhibitors. Prospective follow-up 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 congenital anomalies compared to the background rate. In 89% of the pregnancies followed prospectively, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Breastfeeding. Atorvastatin 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, but 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 atorvastatin therapy should not breastfeed.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Atorvastatin is intended for oral use. The dose should be taken completely once daily at any time of day, regardless of food intake.

Prior to initiating atorvastatin therapy, the patient should begin a standard cholesterol-lowering diet, which should be continued throughout treatment with atorvastatin.

The dose should be individually adjusted based on baseline LDL-C levels, therapeutic goals, and patient response. The maximum dose is 80 mg once daily.

Hyperlipidemia and Mixed Dyslipidemia

The recommended initial dose of atorvastatin is 10 mg or 20 mg once daily. For patients requiring substantial LDL-C reduction (more than 45%), therapy may be initiated with 40 mg once daily. The atorvastatin dosage range is from 10 mg to 80 mg once daily. The drug can be taken as a single dose at any time of day, independent of food intake. Initial and maintenance doses of atorvastatin should be individually titrated according to therapeutic goals and patient response. After initiation of treatment and/or dose adjustment, lipid levels should be analyzed within 2 to 4 weeks and the dose adjusted accordingly.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (Ages 10–17 Years)

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

Homozygous Familial Hypercholesterolemia

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

Concomitant Lipid-Lowering Therapy

Atorvastatin may be coadministered with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution.

Dosing for Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors

Atorvastatin therapy should be avoided in patients taking cyclosporine or the HIV protease inhibitor tipranavir + ritonavir, or the hepatitis C virus protease inhibitor glecaprevir + pibrentasvir, or letermovir when coadministered with cyclosporine. For HIV patients taking lopinavir + ritonavir, atorvastatin should be administered at the lowest necessary dose. For patients taking clarithromycin, itraconazole, elbasvir + grazoprevir, or HIV patients taking combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or letermovir, the atorvastatin therapeutic dose should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose. For patients taking the HIV protease inhibitor nelfinavir, atorvastatin therapy should be limited to a dose of 40 mg.

Patients with Renal Impairment. Renal disease does not affect plasma concentrations or LDL-C reduction with atorvastatin; therefore, dose adjustment in patients with renal impairment is not required.

Patients with Hepatic Impairment. Atorvastatin should be used with caution in patients with hepatic insufficiency. Atorvastatin is contraindicated in patients with active liver disease.

Elderly Patients. There are no differences in safety and efficacy of the drug in patients over 70 years of age at recommended doses compared to the general population.

Children.

Heterozygous Familial Hypercholesterolemia. The safety and efficacy of atorvastatin have been established in children aged 10 to 17 years with heterozygous familial hypercholesterolemia as an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B levels, when after an adequate dietary trial the following criteria are met:

• LDL-C ≥ 190 mg/dL (4.91 mmol/L), or
• LDL-C ≥ 160 mg/dL (4.14 mmol/L) and
  • family history of familial hypercholesterolemia or premature cardiovascular disease in first- or second-degree relatives, or
  • presence of two or more additional cardiovascular risk factors.

Indications for atorvastatin use are supported by clinical studies:

• A 6-month placebo-controlled clinical trial involving 187 boys and girls after onset of menstruation, aged 10 to 17 years. Patients receiving atorvastatin at doses of 10 mg or 20 mg daily had a generally similar adverse reaction profile compared to those receiving placebo. In this limited controlled study, no significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls was observed.
• A 3-year open-label uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, with dose titration aimed at achieving a target LDL-C level < 130 mg/dL (3.36 mmol/L). The safety and efficacy of atorvastatin in lowering LDL-C were generally consistent with those observed in adult patients, despite limitations inherent to the uncontrolled study design.

Girls after onset of menstruation should be counseled regarding contraception, as appropriate for the patient. Long-term efficacy of atorvastatin therapy initiated in childhood for reducing morbidity and mortality in adulthood has not been established. Safety and efficacy of atorvastatin therapy have not been established in children under 10 years of age with heterozygous familial hypercholesterolemia.

Homozygous Familial Hypercholesterolemia. Clinical efficacy of the drug at doses up to 80 mg daily over 1 year was evaluated in a study involving 8 pediatric patients with homozygous familial hypercholesterolemia.

Overdose.

There is no specific antidote for atorvastatin overdose. In case of overdose, symptomatic and supportive treatment should be administered as needed. Liver function tests should be performed and plasma creatine kinase (CK) levels monitored. Due to the high degree of plasma protein binding of atorvastatin, enhanced clearance via hemodialysis is not expected to be significantly effective.

Adverse Reactions

The most common adverse reactions in patients treated with atorvastatin that led to discontinuation of the drug and occurred more frequently than in the placebo group were: myalgia, diarrhea, nausea, increased levels of alanine aminotransferase (ALT), and liver enzymes.

Adverse reactions reported during clinical and post-marketing studies include the following disorders:

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

Gastrointestinal disorders: gastrointestinal discomfort, abdominal pain, belching, flatulence, constipation, diarrhea, pancreatitis, nausea, vomiting, dyspepsia.

Hepatobiliary disorders: hepatitis, cholestasis, hepatic failure (fatal and non-fatal).

Musculoskeletal and connective tissue disorders: musculoskeletal pain, limb pain, muscle spasms, increased muscle fatigue, neck and back pain, myopathy, myositis, rhabdomyolysis, joint pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture), muscle rupture, lupus-like syndrome, immune-mediated necrotizing myopathy.

Metabolism and nutrition disorders: hyperglycemia, hypoglycemia, increased body weight, anorexia.

Laboratory test abnormalities: increased transaminase levels, abnormal liver function tests, increased blood alkaline phosphatase, increased creatine kinase (CK) activity. As with other HMG-CoA reductase inhibitors, elevated plasma transaminase activity has been observed in patients receiving atorvastatin. These changes were generally mild, transient, and did not require intervention or treatment. Clinically significant elevations in plasma transaminase activity (more than 3 times the upper limit of normal [ULN]) were observed in 0.8% of patients treated with atorvastatin. This elevation was dose-dependent and reversible in all patients. Plasma CK levels more than 3 times above ULN were observed in 2.5% of patients in the atorvastatin group, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels exceeding ULN by 10 times were observed in 0.4% of patients in the atorvastatin group.

Nervous system disorders: headache, dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia, peripheral neuropathy, nightmares, depression, insomnia, myasthenia gravis.

Respiratory, thoracic and mediastinal disorders: epistaxis, throat and laryngeal pain, nasopharyngitis, interstitial lung disease.

Skin and subcutaneous tissue disorders: urticaria, skin rashes, pruritus, alopecia; angioedema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome, toxic epidermal necrolysis.

Eye disorders: blurred vision, visual disturbances, clouding of vision, ocular myasthenia.

Ear and labyrinth disorders: tinnitus, hearing loss.

Renal and urinary disorders: leukocyturia.

Reproductive system and breast disorders: gynecomastia.

Blood and lymphatic system disorders: thrombocytopenia.

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

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

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

Interstitial lung disease has been described with some statins, particularly during long-term treatment. Sexual dysfunction has also been reported as an adverse reaction with some statins.

Pediatric population. In a controlled study in boys and girls after onset of menstruation with heterozygous familial hypercholesterolemia (aged 10 to 17 years), the safety and tolerability profile of atorvastatin at doses of 10 mg to 20 mg daily as an adjunct to diet for lowering total cholesterol, LDL-C, and apolipoprotein B levels was generally similar to that of placebo.

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Packaging. Film-coated tablets, 10 mg or 20 mg: 10 tablets in a blister; 3, 6, or 9 blisters in a carton; or 15 tablets in a blister; 2, 4, or 6 blisters in a carton.

Film-coated tablets, 40 mg or 80 mg: 10 tablets in a blister; 3 or 9 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. Teva Pharma S.L.U.

Manufacturer's address and place of business.
Polígono Industrial Malpica c/C nº 4, 50016, Zaragoza, Spain.