Torzax

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORSAX® (TORZAX®)

Composition:

Active substance: atorvastatin;

1 tablet contains atorvastatin calcium equivalent to atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg;

Excipients: lactose monohydrate/microcrystalline cellulose; calcium carbonate; copovidone; crospovidone; sodium croscarmellose; sodium lauryl sulfate; colloidal anhydrous silicon dioxide; talc; magnesium stearate; Opadry White Y-1-7000 (hypromellose; polyethylene glycol 400; titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

10 mg tablets: round, biconvex, film-coated tablets of white color, with a score line on one side and engraved "10" on the other.

20 mg tablets: round, biconvex, film-coated tablets of white color, with a score line on one side and engraved "20" on the other.

40 mg tablets: round, biconvex, film-coated tablets of white color, with a score line on one side and engraved "40" on the other.

80 mg tablets: oval, biconvex, film-coated tablets of white color, with a score line on one side and engraved "80" on the other.

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

Pharmacological properties.

Pharmacodynamics.

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, the enzyme responsible for catalyzing the conversion of HMG-CoA to mevalonate, a precursor of sterols (including cholesterol). In the liver, triglycerides (TG) and cholesterol are incorporated into very-low-density lipoproteins (VLDL), which enter the bloodstream and are transported to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL and are primarily catabolized via interaction with receptors exhibiting high affinity for LDL (LDL receptors).

Atorvastatin reduces plasma concentrations of cholesterol and lipoproteins by inhibiting HMG-CoA reductase, decreasing cholesterol synthesis in the liver, and increasing the number of LDL receptors on the surface of hepatocytes, thereby enhancing the uptake and catabolism of LDL.

Pharmacokinetics.

Absorption. The drug is rapidly absorbed after oral administration. Maximum plasma concentration (Cmax) is reached within 1–2 hours. Absorption and plasma concentration increase proportionally with dose. The bioavailability of atorvastatin in tablet form is 95% and 99% compared to solution, respectively. Absolute bioavailability of atorvastatin is approximately 12%, while systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance in the intestinal mucosa and extensive first-pass metabolism in the liver.

Distribution. The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is ≥ 98%.

Metabolism. Atorvastatin is extensively metabolized by cytochrome P450 3A4, forming ortho- and para-hydroxylated derivatives and various β-oxidation products, which are further metabolized via glucuronidation. In vitro, the ortho- and para-hydroxylated metabolites exhibit HMG-CoA reductase inhibitory activity equivalent to that of atorvastatin. Circulating metabolites account for approximately 70% of the drug's inhibitory effect on HMG-CoA reductase.

Elimination. Atorvastatin is primarily eliminated via bile after hepatic and/or extrahepatic biotransformation and undergoes negligible enterohepatic recirculation. The elimination half-life (T1/2) of atorvastatin in plasma is approximately 14 hours. The inhibitory effect on HMG-CoA reductase persists for 20–30 hours due to the presence of active metabolites.

Atorvastatin is a substrate for hepatic enzyme transporters OATP1B1 and OATP1B3. The metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of efflux transporters MRP2 (multidrug resistance-associated protein 2) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.

Special patient groups

Elderly patients. Plasma concentrations of atorvastatin and its metabolites are higher in healthy elderly volunteers compared to younger patients, although the hypolipidemic effects are comparable to those observed in younger age groups.

Gender. Plasma concentrations of atorvastatin and its active metabolites differ between women and men (Cmax is approximately 20% higher in women, while AUC is 10% lower). However, these differences are not clinically significant, and the hypolipidemic effect of the drug is nearly identical in men and women.

Renal impairment. Renal disease does not affect plasma concentrations of atorvastatin or the lipid effects of atorvastatin and its active metabolites.

Hepatic impairment. In patients with alcoholic cirrhosis, plasma concentrations of atorvastatin and its metabolites are markedly increased (Cmax approximately 16-fold higher, AUC 11-fold higher).

SLCO1B1 polymorphism. Patients with SLCO1B1 polymorphism are at increased risk of elevated atorvastatin exposure, which may increase the risk of developing rhabdomyolysis.

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases.

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

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

For patients with type 2 diabetes mellitus without clinically evident ischemic heart disease but with the presence of several risk factors for ischemic heart disease, such as retinopathy, albuminuria, tobacco smoking, or arterial hypertension, atorvastatin is indicated for:

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

For patients with clinically evident ischemic heart disease, atorvastatin is indicated for:

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

Hyperlipidemia.

• As an adjunct to diet to reduce elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglycerides (TG), 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 levels in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are unavailable.
• As an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B levels in boys and girls (after onset of menstruation) aged 10 to 17 years with heterozygous familial hypercholesterolemia, if, after appropriate dietary therapy, the following laboratory results are observed:

a) LDL-C remains ≥ 190 mg/dL, or

b) LDL-C ≥ 160 mg/dL and

• a family history of premature cardiovascular disease, or
• two or more other cardiovascular risk factors in the child.

Contraindications.

Hypersensitivity to atorvastatin or to any of the excipients;

active liver disease or persistent elevations of serum transaminases (more than 3 times the upper limit of normal);

pregnancy and breastfeeding, or the likelihood of pregnancy due to inadequate contraceptive measures;

patients taking antiviral agents for hepatitis C (glecaprevir/pibrentasvir).

Interaction with other medicinal products and other forms of interaction.

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

Potent CYP3A4 inhibitors. Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate for hepatic enzyme transporters such as OATP1B1 and OATP1B3. The metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of efflux transporters and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin (see section "Pharmacodynamics"). Concomitant use of atorvastatin with potent CYP3A4 inhibitors may increase plasma concentrations of atorvastatin. The extent of interaction and increased effect depends on the variability of the impact on CYP3A4. Concomitant use of atorvastatin with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents used for HCV treatment (e.g., elbasvir/grazoprevir), and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use cannot be avoided, consider using a lower initial and maximum dose of atorvastatin. Appropriate clinical monitoring of the patient is also recommended.

Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase plasma concentrations of atorvastatin. An increased risk of myopathy has been observed when erythromycin is used concomitantly with statins. Amiodarone and verapamil inhibit CYP3A4 activity; their concomitant use with atorvastatin may lead to increased atorvastatin exposure.

When used concomitantly with moderate CYP3A4 inhibitors, consideration should be given to prescribing atorvastatin at a lower maximum dose and appropriate clinical monitoring of the patient should be conducted. Clinical monitoring is also recommended after initiation of therapy or dose adjustment of the inhibitor.

Grapefruit juice. Grapefruit juice contains one or more components that inhibit CYP3A4 and therefore may increase plasma concentrations of drugs metabolized by CYP3A4. Consumption of 240 mL (1 glass) of grapefruit juice reduces the area under the plasma concentration-time curve (AUC) of the active ortho-hydroxymetabolite by 20.4%. A larger amount of grapefruit juice (more than 1.2 L per day for 5 days) increases the AUC of atorvastatin by 2.5-fold, as well as the AUC of active atorvastatin and its metabolites.

Glecaprevir/pibrentasvir. Concomitant administration of atorvastatin (10 mg once daily for 7 days) with glecaprevir (400 mg once daily) or pibrentasvir (120 mg once daily for 7 days) results in an AUC ratio of 8.3. Concomitant use of atorvastatin with products containing glecaprevir or pibrentasvir is contraindicated (see section "Contraindications").

Clarithromycin. The AUC of atorvastatin was significantly increased when atorvastatin (80 mg) was coadministered with clarithromycin (500 mg twice daily) compared to atorvastatin alone. Therefore, patients taking clarithromycin should use atorvastatin with caution at doses exceeding 20 mg (see sections "Special precautions for use", "Dosage and administration").

Combination of protease inhibitors. The AUC of atorvastatin was significantly increased when atorvastatin was coadministered with several combinations of HIV protease inhibitors, as well as with the hepatitis C virus protease inhibitor telaprevir, compared to atorvastatin alone. Therefore, concomitant use of atorvastatin with telaprevir (hepatitis C protease inhibitor) or with the HIV protease inhibitor combination tipranavir + ritonavir should be avoided. Atorvastatin should be used with caution in patients taking the HIV protease inhibitor combination lopinavir + ritonavir, and the lowest necessary dose should be used. In patients taking HIV protease inhibitors such as saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the atorvastatin dose should not exceed 20 mg and should be used with caution (see sections "Special precautions for use", "Dosage and administration"). For patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, the atorvastatin dose should not exceed 40 mg, and careful clinical monitoring is recommended.

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

Cyclosporine. Atorvastatin and its metabolites are substrates of the OATP1B1 transporter. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin was 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").

Medical recommendations for the use of interacting medicinal products are provided in the table (see also sections "Dosage and administration", "Special precautions for use").

Elbasvir/grazoprevir. When atorvastatin (10 mg single dose) was coadministered with elbasvir (50 mg once daily) or grazoprevir (200 mg once daily for 13 days), the AUC ratio was 1.95. The dose of atorvastatin should not exceed 20 mg per day when used concomitantly with products containing elbasvir or grazoprevir.

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis

*Use with caution and at the lowest necessary dose.

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

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

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

Rifampicin or other CYP3A4 inducers. Concomitant use of atorvastatin and inducers of P450 3A4 (rifampicin, efavirenz, St. John's wort) may cause varying degrees of decreased plasma concentration of atorvastatin.

Due to the dual mechanism of action of rifampicin (inducer of cytochrome P450 3A4 and inhibitor of the hepatic transporter OATP1B1), simultaneous administration with atorvastatin is recommended, as delayed administration of atorvastatin after rifampicin therapy has been associated with a significant reduction in atorvastatin plasma concentration. When concomitant use is necessary, the efficacy of the drug should be monitored.

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

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

Antacids. Concomitant use of atorvastatin and an oral antacid suspension containing aluminum and magnesium hydroxides reduces the plasma concentration of atorvastatin by approximately 35%, although this did not affect the reduction in LDL-C levels.

Colestipol. When atorvastatin and colestipol are used concomitantly, plasma concentrations of atorvastatin and its active metabolites are reduced by approximately 25%. However, the hypolipidemic effect of the combination is greater than that achieved with either agent alone.

Azithromycin. Concomitant use of atorvastatin (10 mg daily) and azithromycin (500 mg daily) does not alter the plasma concentration of atorvastatin.

Transport inhibitors. Inhibitors of transport proteins (e.g., cyclosporine, letermovir) may increase the bioavailability of atorvastatin. If concomitant use is necessary, dose reduction and clinical monitoring of efficacy are recommended. The use of atorvastatin is not recommended in patients receiving letermovir concomitantly with cyclosporine (see section "Special precautions").

Ezetimibe. The risk of muscle-related events increases with concomitant use of ezetimibe and atorvastatin. Clinical monitoring of patients is recommended.

Fusidic acid. Muscle events, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and fusidic acid. Patients should be closely monitored, and atorvastatin treatment should be temporarily discontinued if necessary.

Digoxin. Repeated concomitant administration of digoxin and 10 mg atorvastatin slightly increases steady-state plasma digoxin concentrations. Patients taking digoxin should be under continuous monitoring.

Oral contraceptives. Concomitant use of atorvastatin and oral contraceptives increases plasma concentrations of norethindrone and ethinylestradiol, which should be taken into account when selecting an oral contraceptive for women taking the drug.

Warfarin. Concomitant use of atorvastatin and warfarin leads to a slight reduction in prothrombin time during the first days of such treatment, but this parameter normalizes after 15 days of atorvastatin use. However, continuous monitoring of patients receiving warfarin is required when atorvastatin is added to their treatment regimen.

Antipyrine. Since atorvastatin does not alter the pharmacokinetics of antipyrine, interactions with other drugs metabolized by this cytochrome (such as terfenadine, tolbutamide, triazolam, oral contraceptives) are unlikely.

Amlodipine. In drug interaction studies, concomitant use of 80 mg atorvastatin with 10 mg amlodipine in healthy volunteers was associated with increased atorvastatin exposure, although without clinically significant effects.

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").

The above interactions and warnings should be considered when treating children.

Special precautions.

Effect on skeletal muscles.

Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been reported during the use of atorvastatin and other drugs of this class. A history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients require closer monitoring for skeletal muscle disorders.

Atorvastatin, like other drugs in the statin class, occasionally causes myopathy, characterized by muscle pain or weakness in combination with elevated creatine phosphokinase (CPK) levels more than 10 times above the upper limit of normal (ULN). Concomitant use of higher doses of atorvastatin with certain medicinal products, such as cyclosporine and potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors), increases the risk of myopathy/rhabdomyolysis.

Rare cases of immune-mediated necrotizing myopathy (IMNM)—an autoimmune myopathy associated with statin use—have been reported. IMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; muscle biopsy reveals necrotizing myopathy without significant inflammation; improvement is observed with immunosuppressive therapy.

The possibility of myopathy should be considered in any patient with diffuse myalgia, muscle tenderness, or weakness and/or significantly 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 muscle symptoms persist after discontinuation of Torvax®. Treatment should be discontinued in cases of significant elevation of CPK levels, diagnosis of myopathy, or suspicion thereof.

The risk of myopathy during treatment with drugs of this class increases with concomitant use of cyclosporine, fibrates, erythromycin, clarithromycin, hepatitis C virus (HCV) protease inhibitors telaprevir, combinations of HIV protease inhibitors including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir, and fosamprenavir + ritonavir, as well as niacin or antifungal azole agents. Physicians considering combination therapy with Torvax® and fibrates, erythromycin, clarithromycin, saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, antifungal azoles, or lipid-modifying doses of niacin should carefully weigh the potential benefits against 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 period. Consideration should be given to using lower initial and maintenance doses of atorvastatin when co-administered with the aforementioned medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). In such situations, periodic monitoring of CPK activity is advisable, although there is no guarantee that such monitoring will prevent the development of severe myopathy.

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

Treatment with Torvax® should be temporarily or permanently discontinued in patients with an acute, serious condition indicating the development of myopathy, or in the presence of risk factors for renal failure due to rhabdomyolysis (e.g., severe acute infection, arterial hypotension, surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, and uncontrolled seizures).

Liver function disorders.

Statins, like some other hypolipidemic therapeutic agents, have been associated with abnormalities in liver function biochemical parameters. Persistent elevations (more than 3 times above ULN, 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 doses of 10, 20, 40, and 80 mg, respectively.

During clinical trials of atorvastatin, jaundice developed in one patient. Elevations in liver function tests in other patients were not associated with the development of jaundice or other clinical signs and symptoms. With dose reduction, temporary interruption, or discontinuation of atorvastatin, transaminase levels returned to pre-treatment levels or approximately to those levels without permanent sequelae. Eighteen out of 30 patients with persistent elevations in liver function tests continued treatment with atorvastatin at reduced doses.

Prior to initiating therapy, liver enzyme test results should be obtained and repeated as clinically necessary. Cases of fatal and non-fatal liver failure have been reported in patients taking statins, including atorvastatin. In the event of serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice during treatment with Torvax®, therapy must be immediately discontinued. If no other cause for serious liver injury is identified, statin therapy should not be restarted.

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

Endocrine function.

Elevations in HbA1c and fasting serum glucose concentrations have been reported with the use of HMG-CoA reductase inhibitors, including atorvastatin.

Statins inhibit cholesterol synthesis and theoretically may impair adrenal and/or gonadal steroid secretion. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied in a sufficient number of patients. It is unknown whether the drug affects the hypothalamic-pituitary-gonadal system in premenopausal women. Caution should be exercised when co-administering statin-class drugs with medicinal products that may reduce the level or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Hemorrhagic stroke.

Atorvastatin therapy at a dose of 80 mg in patients without cardiovascular disease who experienced stroke or transient ischemic attack within 6 months or less before starting treatment increases the frequency of hemorrhagic strokes. In patients who experienced hemorrhagic stroke at the beginning of therapy, the risk of recurrent hemorrhagic stroke increased. Atorvastatin at a dose of 80 mg reduces the overall incidence of strokes and cardiovascular events.

Before starting treatment.

Atorvastatin should be prescribed with caution in patients with risk factors predisposing to rhabdomyolysis. Determination of CPK levels before initiating statin therapy is necessary in the following cases: renal impairment; hypothyroidism; personal or family history of inherited muscle disorders; previous muscle toxicity during treatment with statins or fibrates; previous liver disease and/or alcohol consumption; in elderly patients (aged 70 years or older), the need for this test is determined based on the presence of other risk factors for rhabdomyolysis; in cases of potential increased atorvastatin plasma concentration, e.g., due to drug interactions or in special patient groups, including genetic subpopulations (see section "Pharmacokinetics").

In such situations, the benefit-risk ratio of treatment must be carefully evaluated. Careful clinical monitoring is recommended. Treatment with this drug should not be initiated if baseline CPK levels are significantly elevated (more than 5 times above ULN).

Determination of CPK levels.

CPK levels should not be measured after intense physical exertion or in the presence of any other factors that may elevate CPK levels, as this may lead to inaccurate results. If baseline CPK levels are significantly elevated (more than 5 times above ULN), repeat testing after 5–7 days is recommended to confirm the results.

During treatment:

• patients should immediately inform their physician of any occurrence of muscle pain, cramps, or weakness, especially if accompanied by malaise and elevated body temperature;
• if such symptoms occur during atorvastatin therapy, CPK levels should be determined. If this parameter is significantly elevated (more than 5 times above ULN), the drug should be discontinued;
• in cases of severe muscle symptoms causing significant discomfort, even if CPK levels are less than 5 times above ULN, treatment should be discontinued;
• if symptoms resolve completely and CPK levels return to normal, atorvastatin or another statin may be reintroduced at a lower dose; the patient should remain under continuous medical supervision;
• atorvastatin treatment must be discontinued in cases of clinically significant elevation of CPK levels (more than 10 times above ULN) or in cases of diagnosed or suspected rhabdomyolysis.

Concomitant use with other medicinal products.

The risk of developing rhabdomyolysis increases with concomitant use of atorvastatin and certain medicinal products, such as potent CYP3A4 inhibitors or transporter proteins (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir).

The risk of myopathy and/or rhabdomyolysis may increase 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 discontinuing Torvax® in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, CPK levels should be monitored 2–3 times per week, and patients should be closely observed for any signs or symptoms suggestive of myopathy.

The risk of developing myopathy also increases with concomitant use of gemfibrozil and other fibrates, antiviral agents for hepatitis C (HCV) treatment (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin, or ezetimibe. If possible, alternative medicinal products that do not interact with atorvastatin should be used instead of the aforementioned agents.

If concomitant treatment with atorvastatin and the above-mentioned agents is necessary, the benefit and risk of concomitant use should be carefully evaluated. If patients are taking medicinal products that increase atorvastatin plasma concentration, 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; atorvastatin therapy should be temporarily discontinued during treatment with fusidic acid.

Interstitial lung disease.

Rare cases of interstitial lung disease have been reported during treatment with some statins (particularly during long-term therapy). Symptoms may include dyspnea, non-productive cough, and general deterioration in health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Limitations of use.

The drug has not been studied under conditions where the primary lipoprotein abnormality was elevated chylomicron levels (types I and V according to Fredrickson classification).

Myasthenia.

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

The product contains lactose; therefore, it should not be administered to patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

1 tablet of 10 mg contains 45.82 mg of lactose;
1 tablet of 20 mg contains 91.63 mg of lactose;
1 tablet of 40 mg contains 183.26 mg of lactose;
1 tablet of 80 mg contains 366.53 mg of lactose.

Use during pregnancy or breastfeeding.

Atorvastatin is contraindicated in pregnant women and women who may become pregnant. Statins may cause fetal harm when administered during pregnancy. Atorvastatin may be used in women of childbearing potential only if pregnancy is highly unlikely; such patients must be informed about potential risk factors. If a woman becomes pregnant during treatment with Torvax®, drug administration should be immediately discontinued, and the patient should be re-counseled regarding potential risks to the fetus and the lack of known clinical benefit from continuing the drug during pregnancy.

During normal pregnancy, serum cholesterol and triglyceride levels increase. The use of hypolipidemic drugs during pregnancy provides no benefit, as cholesterol and its derivatives are necessary for normal fetal development. Atherosclerosis is a chronic process; therefore, interruption of hypolipidemic therapy during pregnancy has no significant impact on the long-term outcomes of treatment for primary hypercholesterolemia.

Adequate and well-controlled studies on the use of atorvastatin during pregnancy have not been conducted. Rare reports of congenital anomalies following intrauterine exposure to statins have been received. In a prospective observational study of approximately 100 pregnancies in women treated with other statins, the frequency of fetal congenital anomalies, spontaneous abortions, and intrauterine deaths/stillbirths did not exceed the frequency expected in the general population. However, this study could only exclude a 3- to 4-fold increase in the risk of congenital anomalies compared to the background rate. In 89% of these cases, treatment was initiated before pregnancy and discontinued during the first trimester (after pregnancy was detected).

Breastfeeding period.

It is not known whether atorvastatin passes into human breast milk, although small amounts of another drug in this class are known to pass into milk. Because statins have the potential to cause serious adverse reactions in breastfed infants, women requiring treatment with Torvax® should not breastfeed their infants (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery.

Atorvastatin has a negligible effect on the ability to drive or operate machinery; however, caution is recommended when performing these activities.

Method of administration and dosage.

Hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification).

The recommended initial dose of Torzax® is 10 or 20 mg once daily. For patients requiring a substantial reduction in LDL-C levels (more than 45%), therapy may be initiated with 40 mg once daily. The dosage range of Torzax® is 10 to 80 mg once daily. The drug can be administered as a single daily dose at any time and independently of food intake. Initial and maintenance doses of Torzax® should be individually adjusted based on treatment goals and clinical response. After initiation of treatment and/or dose titration, lipid levels should be analyzed within 2–4 weeks and the dose adjusted accordingly.

Heterozygous familial hypercholesterolemia in children (aged 10–17 years).

The recommended initial dose of Torzax® is 10 mg/day; the maximum recommended dose is 20 mg/day (doses exceeding 20 mg have not been studied in this patient group). Doses should be individually adjusted according to the recommended treatment goal. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous familial hypercholesterolemia.

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

Concomitant lipid-lowering therapy.

Torzax® may be coadministered with bile acid sequestrants. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should be used with caution (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction").

Dosing in patients with renal impairment.

Renal disease does not affect plasma concentrations or LDL-C reduction with Torzax®. Therefore, dose adjustment in patients with renal impairment is not required (see section "Special precautions").

Dosing in patients taking atorvastatin in combination with other medicinal products.

Torzax® should not be used in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitors (telaprevir). The drug should be prescribed with caution in HIV patients taking lopinavir + ritonavir and should be used at the lowest necessary dose. For patients taking clarithromycin, itraconazole, or HIV patients receiving combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the therapeutic dose of Torzax® should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose of Torzax®. For patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, atorvastatin therapy should be limited to a dose of 40 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose of atorvastatin (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction").

In patients taking antiviral agents for hepatitis C (elbasvir/grazoprevir) or letermovir for prevention of cytomegalovirus infection concomitantly with atorvastatin, the atorvastatin dose should not exceed 20 mg daily (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

The use of atorvastatin is not recommended in patients taking letermovir concomitantly with cyclosporine (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

Children.

The safety and efficacy of the drug in patients aged 10–17 years with heterozygous familial hypercholesterolemia were evaluated in a 6-month controlled clinical study in adolescent boys and girls (after onset of menstruation). Patients receiving atorvastatin had an overall adverse reaction profile similar to those receiving placebo. Infectious diseases were the most commonly observed adverse events in both groups, regardless of causal relationship assessment. Doses higher than 20 mg were not studied in this patient group. In this controlled study, no significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle duration in girls was observed (see sections "Method of administration and dosage", "Adverse reactions"). Adolescent girls should be counseled regarding acceptable contraceptive methods during atorvastatin treatment (see section "Use during pregnancy or breastfeeding").

Atorvastatin has not been studied in controlled clinical trials involving prepubertal patients or patients under 10 years of age.

The clinical efficacy of the drug at doses up to 80 mg/day over 1 year was evaluated in an uncontrolled study in patients with homozygous familial hypercholesterolemia, including 8 children.

Overdose.

There is no specific antidote; symptomatic and supportive therapy should be administered. Liver function tests should be performed and serum CK levels measured. Since atorvastatin is highly bound to plasma proteins, hemodialysis is not effective.

Side effects

Classification of frequency of adverse reactions:

very common (< 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Rare: thrombocytopenia.

Vascular disorders

Rare: vasculitis.

Immune system disorders

Common: allergic reactions;

very rare: anaphylactic reaction.

Metabolism and nutrition disorders

Common: hyperglycemia;

uncommon: hypoglycemia, weight gain, loss of appetite.

Psychiatric disorders

Uncommon: insomnia, nightmares.

Nervous system disorders

Common: headache;

uncommon: dizziness, paresthesia, hypesthesia, taste alteration, amnesia;

rare: peripheral neuropathy;

frequency not known: myasthenia gravis.

Eye disorders

Uncommon: blurred vision;

rare: visual disturbances;

frequency not known: ocular myasthenia.

Ear and labyrinth disorders

Uncommon: tinnitus;

very rare: hearing loss.

Renal and urinary disorders

leukocyturia, urinary tract infections.

Respiratory, thoracic and mediastinal disorders

Common: pharyngolaryngeal pain, nasal hemorrhage.

Gastrointestinal disorders

Common: constipation, flatulence, dyspepsia, nausea, diarrhea;

uncommon: vomiting, upper and lower abdominal pain, belching, pancreatitis.

Hepatobiliary disorders

Uncommon: hepatitis;

rare: cholestasis, cholestatic jaundice;

very rare: hepatic failure.

Skin and subcutaneous tissue disorders

Uncommon: urticaria, skin rash, pruritus, alopecia;

rare: angioneurotic edema, bullous dermatitis, including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, drug-induced lichenoid reaction.

Musculoskeletal and connective tissue disorders

Common: myalgia, arthralgia, limb pain, muscle spasm, joint swelling, back pain;

uncommon: neck pain, muscle fatigue;

rare: myopathy, myositis, rhabdomyolysis, muscle rupture, tendinopathy, which sometimes complicated by tendon rupture;

very rare: lupus-like syndrome;

frequency not known: ONJ (see section "Special precautions and warnings").

Reproductive system and breast disorders

Very rare: gynecomastia, impotence.

General disorders and administration site conditions

Uncommon: discomfort, asthenia, chest pain, peripheral edema, fatigue, increased temperature.

Investigations

In patients treated with atorvastatin, mild and transient increases in serum transaminases have been observed, which do not require discontinuation of treatment.

Common: changes in liver function tests, increased creatine kinase in blood;

uncommon: presence of leukocytes in urine.

Children

Nervous system disorders

Common: headache.

Gastrointestinal disorders

Common: abdominal pain.

Investigations

Common: increased alanine aminotransferase, increased CK in blood.

Based on available data, the frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.

With the use of some statins, the following adverse events have been reported: sexual dysfunction; depression; very rare cases of interstitial lung disease, particularly with long-term therapy.

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua.

Shelf life

10 mg tablets

2 years. Do not use after the expiry date stated on the packaging.

20 mg, 40 mg and 80 mg tablets

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions

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

Keep out of reach and sight of children.

Packaging

10 mg, 20 mg and 80 mg tablets

Primary packaging: 10 tablets in a blister made of PVC/PVdC film and aluminum foil;

Secondary packaging: 3 blisters in a cardboard box.

40 mg tablets

Primary packaging: 15 tablets in a blister made of PVC/PVdC film and aluminum foil;

Secondary packaging: 2 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and location of operations

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.