Tolevas

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOLEVAS® (TOLEVAS)

Composition:

Active substance: atorvastatin;

One tablet contains atorvastatin as atorvastatin calcium trihydrate 10 mg or 20 mg or 40 mg or 80 mg;

Excipients: calcium carbonate, lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, polysorbate 80, hydroxypropylcellulose, magnesium stearate;

Film coating: Opadry AMB OY-B-28920: polyvinyl alcohol, titanium dioxide (E 171), talc, lecithin (E 322), xanthan gum (E 415).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, elongated, film-coated tablets.

Pharmacotherapeutic group.

Medicinal products that reduce serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. ATC code C10AA05.

Pharmacological Properties.

Pharmacodynamics.

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, the key enzyme involved in the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid—a precursor of sterols, including cholesterol. In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed hyperlipidemia, atorvastatin reduces levels of total cholesterol, LDL-C (low-density lipoprotein cholesterol), and apolipoprotein B. Atorvastatin also reduces levels of VLDL-C (very low-density lipoprotein cholesterol) and TG (triglycerides), and leads to variable increases in HDL-C (high-density lipoprotein cholesterol).

Atorvastatin reduces cholesterol and lipoprotein levels in plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, as well as by increasing the number of LDL receptors on hepatocyte membranes, resulting in enhanced uptake and catabolism of LDL. Atorvastatin reduces the formation of LDL and the number of LDL particles. Atorvastatin causes significant and sustained increases in LDL receptor activity in combination with favorable changes in the quality of LDL particles. Atorvastatin reduces LDL-C levels in patients with homozygous familial hypercholesterolemia, who typically do not respond to treatment with lipid-lowering agents.

Atorvastatin and some of its metabolites are pharmacologically active in humans. Atorvastatin primarily affects the liver, as cholesterol synthesis and LDL clearance occur mainly in the liver. The reduction in LDL-C levels is more closely related to the dose of the drug than to its systemic concentration. The individual dose should be selected based on the therapeutic response.

Atorvastatin dose-dependently (10–80 mg) reduces total cholesterol (by 30–40%), LDL-C (by 41–61%), apolipoprotein B (by 34–50%), and triglycerides (by 14–33%) in patients with heterozygous familial hypercholesterolemia, non-familial hypercholesterolemia, and mixed hyperlipidemia, including patients with insulin-independent diabetes mellitus.

In patients with hypertriglyceridemia, atorvastatin reduces levels of total cholesterol, LDL-C, VLDL-C, apolipoprotein B, TG, and increases HDL-C levels. In patients with dysbetalipoproteinemia, atorvastatin reduces levels of IDL-C (intermediate-density lipoprotein cholesterol).

In patients with hyperlipoproteinemia type IIa and IIb according to Fredrickson classification, included in 24 controlled studies, the mean increase in HDL-C levels compared to baseline during atorvastatin treatment (10–80 mg), regardless of dose, was 5.1–8.7%. Furthermore, pooled data analysis demonstrated significant reductions in total cholesterol to HDL-C and LDL-C to HDL-C ratios, ranging from -29% to -44% and from -37% to -55%, respectively.

Atorvastatin significantly reduces the risk of ischemic heart disease and mortality (by 16%). Atorvastatin significantly reduces the risk of rehospitalization due to angina with documented myocardial ischemia (by 26%). The risk of ischemic heart disease and mortality is similarly reduced with atorvastatin use within the range of the maximum allowable LDL-C level. Additionally, atorvastatin reduces the risk of ischemic heart disease and mortality in patients with myocardial infarction other than Q-wave myocardial infarction and unstable angina, regardless of sex and age (< 65 years and > 65 years).

Pharmacokinetics.

Absorption

Atorvastatin is rapidly absorbed after oral administration and reaches peak plasma concentration within 1–2 hours. The extent of absorption and plasma concentration of atorvastatin is dose-dependent. The bioavailability of atorvastatin in tablet form compared to solution is 95% and 99%, respectively. The absolute bioavailability of atorvastatin is approximately 14%, and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance in the gastrointestinal mucosa and biotransformation during first-pass metabolism through the liver. Food intake reduces the rate and extent of drug absorption by approximately 25% and 9%, respectively, as confirmed by reduced peak concentration and AUC. However, the reduction in LDL-C levels is independent of the time of administration. Plasma concentrations of atorvastatin after evening dosing are lower than after morning dosing (peak concentration and AUC are approximately 30% higher after morning dosing). Despite this, the reduction in LDL-C levels is independent of the time of drug administration.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is ≥ 98%. A blood-to-plasma ratio of approximately 0.25 indicates low penetration of the drug into erythrocytes.

Metabolism

Atorvastatin is extensively metabolized, forming ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro, ortho- and para-hydroxylated metabolites exhibit HMG-CoA reductase inhibitory activity equivalent to that of atorvastatin. Approximately 70% of the inhibitory effect of the drug on HMG-CoA reductase is attributed to circulating active metabolites. In vitro studies confirm the importance of atorvastatin biotransformation by cytochrome P450 3A4. Concomitant administration of atorvastatin and erythromycin, an inhibitor of cytochrome P450 3A4, increases atorvastatin plasma concentration. In vitro studies also confirm that atorvastatin is a weak inhibitor of cytochrome P450 3A4. When atorvastatin is coadministered with terfenadine, which is primarily metabolized by the cytochrome P450 3A4 system, the plasma concentration of terfenadine remains almost unchanged. Therefore, it is unlikely that atorvastatin significantly alters the pharmacokinetics of other cytochrome P450 3A4 substrates. In animals, the ortho-hydroxylated metabolite undergoes further glucuronidation.

Excretion

Atorvastatin and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic biotransformation, without undergoing enterohepatic recirculation. The mean elimination half-life of atorvastatin in humans is approximately 14 hours. HMG-CoA reductase inhibitory activity persists for 20–30 hours due to the presence of active metabolites. Less than 2% of orally administered atorvastatin is recovered in urine.

Special Patient Populations

Elderly Patients

Plasma concentrations of atorvastatin in healthy elderly patients (aged ≥ 65 years) are higher than in younger individuals (approximately 40% higher peak concentration and 30% higher AUC). In the ACCESS study, the efficacy of the drug was evaluated in elderly patients to achieve NCEP treatment goals. The study included 1087 patients under 65 years of age, 815 patients aged 65 years and older, and 185 patients aged 75 years and older. Efficacy and safety in elderly patients were comparable to those in the general population.

Pediatric Patients

Pharmacokinetic data on atorvastatin in children are not available.

Gender

Plasma concentrations of atorvastatin in women differ from those in men (peak concentration approximately 20% higher, AUC approximately 10% lower). However, these differences are not clinically significant, and the lipid-lowering effect of the drug is nearly identical in men and women.

Renal Impairment

The route of administration and dosage do not affect atorvastatin plasma concentrations or its lipid-lowering effect. Therefore, dose adjustment is not necessary.

Hemodialysis

Studies with atorvastatin have not been conducted in patients with end-stage renal disease. Due to the high plasma protein binding of the drug, hemodialysis is unlikely to significantly enhance atorvastatin clearance.

Hepatic Impairment

In patients with alcoholic cirrhosis, plasma concentrations of atorvastatin are markedly increased (peak concentration approximately 16-fold higher, AUC approximately 11-fold higher).

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, Tolevas® is indicated for:

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

For 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, atorvastatin is indicated for:

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

For adult patients with clinically evident ischemic heart disease, Tolevas® is indicated for:

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

Hyperlipidemia

In 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 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 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 (4.14 mmol/L) and:

• a family history of premature cardiovascular disease, or
• two or more other risk factors for cardiovascular disease

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.
• Lactation.

Interaction with other medicinal products and other forms of interaction.

The risk of myopathy during statin therapy increases when used concomitantly with fibrates, lipid-modifying doses of niacin, cyclosporine, or potent inhibitors of cytochrome P450 3A4 (CYP3A4) (e.g., clarithromycin, HIV and hepatitis C virus protease inhibitors, and itraconazole) (see sections "Special precautions for use" and "Pharmacological properties").

Potent CYP3A4 inhibitors. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant use of atorvastatin with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 1 and detailed information below). The degree of interaction and effect enhancement depends on the variability of the impact on CYP3A4. Concomitant use with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for HCV treatment (e.g., elbasvir/grazoprevir), and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided if possible. If concomitant use with these agents cannot be avoided, consideration should be given to using lower initial and maximum doses of atorvastatin. Appropriate clinical monitoring of the patient is also recommended (see Table 1).

Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase atorvastatin plasma concentrations. 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. Amiodarone and verapamil are known to 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. Clinical monitoring of the patient is also recommended. After initiating treatment with an inhibitor or adjusting its dose, clinical monitoring of the patient is recommended.

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

Clarithromycin. The AUC of atorvastatin 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 with caution at doses exceeding 20 mg (see sections "Special precautions for use" and "Dosage and administration").

Combination of protease inhibitors. The AUC of atorvastatin significantly increased when atorvastatin was coadministered with several protease inhibitor combinations (see section "Pharmacological properties"). Therefore, concomitant use of Tolevas® should be avoided in patients taking tipranavir + ritonavir or glecaprevir + pibrentasvir. The product should be prescribed with caution to patients taking lopinavir + ritonavir or simeprevir, and the lowest necessary dose should be used. For patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, or elbasvir + grazoprevir, the atorvastatin dose should not exceed 20 mg. When administered to patients, the atorvastatin dose should not exceed 40 mg, and careful clinical monitoring of patients is recommended (see sections "Special precautions for use" and "Dosage and administration").

Itraconazole. The AUC of atorvastatin significantly increased when atorvastatin 40 mg was coadministered with itraconazole 200 mg (see section "Pharmacological properties"). Therefore, caution is advised in patients taking itraconazole if the atorvastatin dose exceeds 20 mg (see sections "Special precautions for use" and "Dosage and administration").

Cyclosporine. Atorvastatin is a substrate of hepatic transporters. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin significantly increased when atorvastatin 10 mg was coadministered with cyclosporine 5.2 mg/kg/day compared to atorvastatin alone. Concomitant use of atorvastatin and cyclosporine should be avoided (see section "Special precautions for use").

Letermovir. Concomitant administration of atorvastatin 20 mg with letermovir 480 mg daily resulted in increased atorvastatin exposure (AUC ratio: 3.29) (see section "Pharmacokinetics").

Letermovir is an inhibitor of efflux transporters P-gp, BCRP, MRP2, OAT2, and the hepatic transporter OATP1B1/1B3, thus increasing atorvastatin exposure. The dose of Tolevas® should not exceed 20 mg daily (see section "Dosage and administration").

The extent of CYP3A- and OATP1B1/1B3-mediated drug interactions may vary when letermovir is coadministered with cyclosporine. The use of Tolevas® is not recommended in patients taking letermovir concomitantly with cyclosporine.

Glecaprevir and pibrentasvir, elbasvir and grazoprevir. Concomitant use of glecaprevir and pibrentasvir or elbasvir and grazoprevir may increase atorvastatin plasma concentrations and increase the risk of myopathy.

When coadministered with atorvastatin, plasma concentrations of atorvastatin increase up to 8.3-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, concomitant use of Tolevas® is not recommended in patients taking concomitant medications containing glecaprevir and pibrentasvir.

When coadministered with atorvastatin, plasma concentrations of atorvastatin increase up to 1.9-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, the dose of Tolevas® should not exceed 20 mg daily when administered to patients taking concomitant medications containing elbasvir and grazoprevir (see sections "Dosage and administration", "Special precautions for use", and "Pharmacokinetics").

Medical recommendations for the use of interacting medicinal products are summarized in Table 1 (see also sections "Dosage and administration", "Special precautions for use", "Pharmacological properties").

Drug interactions associated with increased risk of myopathy/rhabdomyolysis

Table 1

Drugs with which interaction occurs	Medical recommendations for use
Cyclosporine, (tipranavir + ritonavir), glecaprevir + pibrentasvir, ledipasvir when used concomitantly with cyclosporine	Avoid use of atorvastatin
Lopinavir + ritonavir, simeprevir, fibrinic acid derivatives, erythromycin, azole antifungal agents, lipid-modifying doses of niacin, colchicine	Use with caution and at the lowest necessary dose
Clarithromycin, itraconazole, (saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, ledipasvir)	Do not exceed 20 mg of atorvastatin per day
Nelfinavir	Do not exceed 40 mg of atorvastatin per day

*Use with caution and at the lowest necessary dose.

Gemfibrozil. Due to the increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are administered concomitantly with gemfibrozil, combination therapy 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 administered concomitantly with other fibrates (see section "Special precautions").

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

Rifampicin or other cytochrome P450 3A4 inducers. Concomitant use of atorvastatin with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampicin) may lead to variable reductions in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, concomitant 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

Clinical studies have shown no evidence of interaction between atorvastatin and cimetidine.

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 remains unchanged.

Cholestyramine

Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when administered concomitantly with cholestyramine. Nevertheless, the hypolipidemic 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 concentrations.

Transport protein inhibitors

Inhibitors of transport proteins (e.g., cyclosporine, letermovir) can increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of uptake transport proteins on atorvastatin concentrations in hepatocytes 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

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

Fusidic acid

No formal drug interaction studies between atorvastatin and fusidic acid have been conducted. As with other statins, muscle-related adverse events (including rhabdomyolysis) have been reported in the post-marketing period when atorvastatin and fusidic acid are used concomitantly. The mechanism of this interaction remains unknown. Patients require close monitoring, and temporary discontinuation of atorvastatin therapy may be necessary (see section "Special precautions").

Digoxin. Concomitant administration of multiple doses of atorvastatin and digoxin increases the steady-state plasma concentrations of digoxin (see section "Pharmacokinetics"). Patients receiving digoxin should be appropriately monitored.

Oral contraceptives. Concomitant use of atorvastatin with oral contraceptives increases the 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 receiving 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 are not associated with clinically significant adverse effects. Drug interaction studies with other agents have not been conducted.

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 statin drugs, 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 medicinal products such as cyclosporine and potent CYP3A4 inhibitors (e.g. clarithromycin, itraconazole, and HIV and hepatitis C virus protease inhibitors) increases the risk of myopathy/rhabdomyolysis.

Rare cases of immune-mediated necrotizing myopathy (IMNM) – an autoimmune myopathy associated with statin use – have 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; a positive response to immunosuppressive therapy is observed.

The possibility of myopathy should be considered in any patient presenting with diffuse myalgia, muscle tenderness or weakness and/or markedly elevated CPK. Patients should be advised to immediately report any unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever, or if signs and symptoms of muscle disease persist after discontinuation of atorvastatin. Treatment 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 drugs in this class is increased when used concomitantly with medicinal products listed in Table 1. Physicians considering combination therapy with Tolevas® and any of these drugs should carefully weigh the potential benefits against the risks and closely monitor patients for any signs or symptoms 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"). In such situations, periodic CPK monitoring may be considered, although there is no guarantee that such monitoring will prevent cases of severe myopathy.

Atorvastatin therapy should be temporarily or permanently discontinued in any patient with an acute serious condition indicating the development of myopathy, or in the presence of a risk factor for renal failure due to rhabdomyolysis (e.g. severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine or electrolyte 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 "Side effects"). If symptoms worsen, Tolevas® should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Hepatic function

Statins, like some other hypolipidemic agents, have been associated with abnormalities in liver function biochemical parameters. Persistent elevations (more than three times the upper limit of normal range, occurring on two or more occasions) of serum transaminases were observed in 0.7% of patients receiving atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg doses of the drug, respectively.

During clinical trials, one patient developed jaundice. Elevated liver function test (LFT) values in other patients were not associated with jaundice or other clinical symptoms. Transaminase levels returned to pre-treatment levels or approximately to those levels after dose reduction, treatment interruption, or discontinuation of the drug, without adverse consequences. Eighteen of 30 patients with persistent elevations in liver function tests continued treatment with atorvastatin at lower doses.

Prior to initiating atorvastatin therapy, 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 use, treatment should be immediately discontinued. Reinitiation of the drug should not be attempted unless an alternative etiology is identified.

Atorvastatin should be prescribed with caution in patients who consume large amounts of alcohol and/or have a history of liver disease. Atorvastatin is contraindicated in patients with active liver disease or persistent elevations of hepatic transaminases of unknown etiology (see section "Contraindications").

Endocrine function

Increases in HbA1c and fasting plasma glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Statins inhibit cholesterol synthesis and may theoretically impair adrenal and/or gonadal steroid hormone secretion. Clinical studies have shown that atorvastatin does not reduce baseline 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 indeed has any effect on, the hypothalamic-pituitary-gonadal 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.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

Post hoc analysis of stroke subtypes in patients without ischemic heart disease (IHD) who had recently experienced a stroke or transient ischemic attack (TIA) reported a higher incidence of hemorrhagic stroke with atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarction at study entry. For patients with prior hemorrhagic stroke or lacunar infarction, the risk-benefit balance of atorvastatin 80 mg is not established; therefore, the potential risk of hemorrhagic stroke should be carefully evaluated before initiating treatment (see section "Side effects").

Hepatic insufficiency

Atorvastatin 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 developing rhabdomyolysis. Prior to initiating statin therapy in patients predisposed to rhabdomyolysis, CPK levels should be measured in cases of:

-impaired renal function;

-hypothyroidism;

-personal or family history of hereditary muscle disorders;

-prior history of statin or fibrate myotoxicity;

-prior history of liver disease and/or heavy alcohol consumption.

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

Increased plasma drug levels may occur, particularly due to drug interactions (see section "Interaction with other medicinal products and other forms of interaction") and in special patient populations (see section "Pharmacokinetics"), including patients with hereditary diseases.

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

Measurement of creatine kinase levels

Creatine kinase levels should not be measured following strenuous physical exercise or in the presence of any possible alternative causes of elevated CK levels, as this may complicate interpretation of results. If markedly elevated CK levels (exceeding the upper limit of normal by more than 5 times) 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 immediately report the onset of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.

If these symptoms occur during atorvastatin treatment, CK levels should be measured. If CK levels are markedly elevated (exceeding the upper limit of normal by more than 5 times), 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 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 treatment must be discontinued if clinically significant elevation of CK levels (exceeding the upper limit of normal by more than 10 times) occurs or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use with other medicinal products

The risk of developing rhabdomyolysis is increased when atorvastatin is used concomitantly with certain medicinal products 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, and darunavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibric acid derivatives, erythromycin, niacin, and ezetimibe. If possible, alternative medicinal products (that do not interact with atorvastatin) should be used instead of the aforementioned agents.

If concomitant therapy with atorvastatin and these drugs is necessary, the benefits and risks of combination therapy should be carefully weighed. If patients are taking medicinal products 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.

Concomitant administration of atorvastatin and fusidic acid is not recommended; therefore, temporary discontinuation of atorvastatin during fusidic acid therapy should be considered. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness.

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

Under exceptional circumstances, when long-term systemic fusidic acid therapy is required (e.g. for treatment of severe infections), the need for concomitant use of Tolevas and fusidic acid should be considered on an individual basis and conducted 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"). Consideration should be given to temporarily suspending Tolevas in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, creatine kinase levels should be monitored 2–3 times per week, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

Lung interstitial 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, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Excipients

Tolevas® 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 one component of comprehensive treatment for patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Pharmacological therapy is recommended as an adjunct to diet when dietary restriction of saturated fats and cholesterol, and other non-pharmacological measures, have been insufficient. Tolevas® may be initiated concurrently with dietary measures in patients with ischemic heart disease or multiple risk factors for ischemic heart disease.

Limitations of use

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

Use during pregnancy or breastfeeding

Pregnancy

Risk assessment

Tolevas® is contraindicated in pregnant women, as the safety of its use 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 harm the fetus. The drug should be discontinued as soon as pregnancy is confirmed (see section "Contraindications").

The 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 if used during pregnancy. Women of reproductive 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 clinical cases on the use of calcium atorvastatin have not shown an increased risk of serious congenital malformations or miscarriages.

Rare reports of congenital anomalies have been reported after in utero exposure to other HMG-CoA reductase inhibitors. Prospective observation of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the frequency of fetal congenital anomalies, miscarriages, and intrauterine deaths/stillbirths did not exceed the frequency expected in the general population. The number of cases is sufficient to exclude a ≥3–4-fold increase in fetal developmental anomalies compared to the background rate. In 89% of the pregnant women followed prospectively, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Lactation

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 breast milk, although it is known that a small amount of another drug in this class passes into breast milk. Since statins have the potential to cause serious adverse reactions in breastfed infants, women requiring treatment with Tolevas® should not breastfeed their infants (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

Hyperlipidemia

The recommended starting dose of atorvastatin is 10 or 20 mg once daily. For patients who require a large reduction in LDL-C levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily. The dosage range of the drug is from 10 to 80 mg once daily. Atorvastatin can be administered as a single dose at any time of day, with or without food. Initial and maintenance doses of atorvastatin 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 10–17 Years)

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

Homozygous Familial Hypercholesterolemia

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

Concomitant Lipid-Lowering Therapy

Tolevas® may be used with bile acid sequestrants. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections “Special Warnings and Precautions for Use” and “Interaction with Other Medicinal Products”).

Dosing in 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 (see sections “Special Warnings and Precautions for Use” and “Pharmacokinetics”).

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

Treatment with atorvastatin should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or the hepatitis C virus protease inhibitor glecaprevir + pibrentasvir, or letermovir when co-administered with cyclosporine. Atorvastatin should be prescribed with caution in HIV patients receiving lopinavir + ritonavir and used at the lowest necessary dose. For patients taking clarithromycin or itraconazole, or HIV patients receiving 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 of Tolevas®. In patients taking the HIV protease inhibitor nelfinavir, atorvastatin therapy should be limited to a dose of 40 mg. When atorvastatin is co-administered with other protease inhibitors, appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose of Tolevas® (see sections “Special Warnings and Precautions for Use” and “Interaction with Other Medicinal Products and Other Forms of Interaction”).

Pediatric Use

Heterozygous Familial Hypercholesterolemia

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

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

The indication for use of atorvastatin is supported by the following studies:

• A 6-month placebo-controlled clinical trial involving 187 boys and girls who had reached menarche, aged 10 to 17 years. Patients receiving atorvastatin at doses of 10 mg or 20 mg daily had an overall adverse reaction profile similar to those receiving placebo. In this limited controlled trial, 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, in whom doses were titrated to achieve a target LDL-C level < 130 mg/dL (3.36 mmol/L). The safety and efficacy of atorvastatin in lowering LDL-C were generally consistent with those observed in adult patients, despite the limitations of the uncontrolled study design.

Appropriate counseling regarding contraception should be provided to girls after menarche, if relevant to the patient.

The long-term efficacy of atorvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

The safety and efficacy of Tolevas® have not been established in children under 10 years of age with heterozygous familial hypercholesterolemia.

Homozygous Familial Hypercholesterolemia

The clinical efficacy of atorvastatin at doses up to 80 mg/day for 1 year was evaluated in an uncontrolled study involving 8 pediatric patients with homozygous familial hypercholesterolemia.

Overdose

There is no specific antidote for atorvastatin overdose.

In the event of overdose, the patient should be treated symptomatically and supportive measures should be implemented as needed. Due to the high degree of plasma protein binding, significant enhancement of atorvastatin clearance by hemodialysis is not expected.

Adverse Reactions

Because clinical trials are conducted under different conditions, the incidence of adverse reactions observed during clinical trials of a medicinal product cannot be directly compared with figures obtained from clinical trials of another drug and may not reflect the rates observed in clinical practice.

According to clinical trial data on atorvastatin among 16,066 patients over 53 weeks, the most common adverse reactions leading to discontinuation of atorvastatin treatment and occurring at a higher frequency than in the placebo group were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and elevated liver enzymes (0.4%).

The most frequently reported adverse reactions (≥ 2% compared to placebo), regardless of causality, in patients treated with atorvastatin (n = 8,755), were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), limb pain (6.0%), urinary tract infection (5.7%), dyspepsia (4.7%), nausea (4.0%), musculoskeletal pain (3.8%), muscle spasms (3.6%), myalgia (3.5%), insomnia (3.0%), pharyngolaryngeal pain (2.3%).

Adverse reactions reported during placebo-controlled trials include:

General disorders: malaise, pyrexia.

Gastrointestinal disorders: gastrointestinal discomfort, eructation, flatulence, hepatitis, cholestasis.

Musculoskeletal system disorders: musculoskeletal pain, increased muscle fatigue, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture).

Metabolism and nutrition disorders: increased transaminases, abnormal liver function tests, elevated alkaline phosphatase in blood, increased creatine phosphokinase activity, hyperglycemia.

Nervous system disorders: nightmares.

Respiratory system disorders: epistaxis.

Skin and appendages disorders: urticaria.

Eye disorders: blurred vision, visual disturbances.

Ear and balance disorders: tinnitus.

Renal and urinary system disorders: leukocyturia.

Reproductive system and breast disorders: gynecomastia.

The frequency of adverse reactions was defined as follows: common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (frequency cannot be estimated from available data).

Nervous system disorders: common: headache; uncommon: dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia; rare: peripheral neuropathies; not known: myasthenia gravis.

Gastrointestinal disorders: common: constipation; uncommon: pancreatitis, vomiting.

Musculoskeletal and connective tissue disorders: common: joint pain, back pain; rare: myopathy, myositis, rhabdomyolysis.

General disorders: uncommon: asthenia, chest pain, peripheral edema, increased fatigue.

Metabolism and nutrition disorders: uncommon: hypoglycemia, weight gain, anorexia.

Hepatobiliary disorders: very rare: hepatic failure.

Skin and subcutaneous tissue disorders: uncommon: skin rash, pruritus, alopecia; angioedema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome, and toxic epidermal necrolysis; rare: drug-induced lichenoid reaction.

Respiratory, thoracic and mediastinal disorders: throat and laryngeal pain.

Blood and lymphatic system disorders: thrombocytopenia.

Vascular disorders: rare: vasculitis.

Immune system disorders: common: allergic reactions; very rare: anaphylaxis.

Eye disorders: uncommon: blurred vision; not known: ocular myasthenia.

Investigations (laboratory test abnormalities): common: abnormal liver function tests, increased blood creatine phosphokinase activity; uncommon: positive test for leukocytes in urine.

As with other HMG-CoA reductase inhibitors, patients taking atorvastatin have shown increased serum transaminase activity. These changes were generally mild, transient, and did not require intervention or treatment. Clinically significant increases in serum transaminase activity (exceeding the upper limit of normal [ULN] by more than 3 times) were observed in 0.8% of patients taking atorvastatin. This increase was dose-dependent and reversible in all patients.

An increase in serum creatine kinase activity exceeding the ULN by more than 3 times was observed in 2.5% of patients taking atorvastatin. This is consistent with observations during clinical trials of other HMG-CoA reductase inhibitors.

Levels exceeding the ULN by more than 10 times were observed in 0.4% of patients receiving atorvastatin (see section "Special precautions").

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

Children (10–17 years)

Children aged 10 to 17 years receiving atorvastatin had a safety and tolerability profile similar to that of the placebo group. The most common adverse reactions identified in both groups, regardless of causality assessment, were infections. Three-year Tanner-based studies assessing overall child development indicate no clinically significant effect of atorvastatin on growth, body weight, or sexual maturation. The safety and tolerability profile of atorvastatin in children was similar to that in adult patients.

The safety profile database includes 520 children who received atorvastatin, including 7 patients aged < 6 years, 121 patients aged 6 to 9 years, and 392 patients aged 10 to 17 years. Based on available data, the frequency, type, and severity of adverse reactions in children were similar to those in adults.

Post-marketing experience

During post-marketing use of atorvastatin, the adverse reactions listed below have been identified. 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 marketing authorization, regardless of causal assessment, include: anaphylaxis, angioedema, bullous skin eruptions (including exudative multiform erythema, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, increased fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.

Rare post-marketing reports of cognitive disorders (memory loss, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders were reported during use of all statins. Reports were generally not considered serious adverse reactions and the symptoms were reversible after discontinuation of statins, with variable onset time (from 1 day to several years) and symptom 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.

During post-marketing surveillance, the following adverse reactions have been reported.

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, hypoesthesia, dysgeusia.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain.

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

Investigations: increased alanine aminotransferase activity, increased blood creatine phosphokinase activity.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 mg: 15 tablets in a blister; 2 or 6 blisters in a cardboard package.

20 mg or 40 mg: 10 tablets in a blister; 3 or 9 blisters in a cardboard package.

80 mg: 6 tablets in a blister; 5 or 15 blisters in a cardboard package.

Prescription category.

Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of business operations.

Sankaklar Quarter, Eskikarakodja Avenue No. 299, 81100 Duzce, Turkey.