Storvas

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STORVAS (STORVAS)

Composition:

Active substance: atorvastatin;

1 tablet contains atorvastatin calcium salt equivalent to atorvastatin 10 mg, 20 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; colloidal anhydrous silicon dioxide; sodium croscarmellose; sodium hydroxycarbonate; anhydrous sodium carbonate; hydroxypropylcellulose; butylhydroxyanisole; butylhydroxytoluene; magnesium stearate; Opadry YS-1-7040 white (hypromellose, polyethylene glycol 8000, titanium dioxide (E171), talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

10 mg: white or almost white, oval-shaped, film-coated tablets with "A30" embossed on one side and flat on the other;

20 mg: white or almost white, oval-shaped, film-coated tablets with "A31" embossed on one side and flat on the other.

Pharmacotherapeutic group.

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

Pharmacological Properties.

Pharmacodynamics.

Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme responsible for regulating the conversion of HMG-CoA to mevalonate—a precursor of sterols (including cholesterol). In patients with homozygous and heterozygous familial hypercholesterolemia (FH), non-familial hypercholesterolemia, and mixed dyslipidemias, atorvastatin reduces concentrations of total cholesterol, LDL-C (low-density lipoprotein cholesterol), and apolipoprotein B (apo B). Atorvastatin also reduces levels of very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TG), and slightly increases HDL-C (high-density lipoprotein cholesterol).

Atorvastatin reduces cholesterol and lipoprotein levels in plasma by inhibiting HMG-CoA reductase and hepatic cholesterol synthesis, and by increasing the number of hepatic LDL (low-density lipoprotein) receptors on cell surfaces, thereby enhancing the uptake and catabolism of LDL.

Atorvastatin reduces the synthesis of LDL and the number of LDL particles. It induces a pronounced and sustained increase in LDL receptor activity in combination with favorable changes in the quality of circulating LDL particles. Atorvastatin reduces LDL levels in patients with homozygous familial hypercholesterolemia, in whom therapy with conventional lipid-lowering agents is often ineffective.

In humans, both atorvastatin and some of its metabolites exhibit pharmacological activity. The primary site of action of atorvastatin is the liver, which plays a central role in cholesterol synthesis and LDL clearance. Reduction in LDL-C levels correlates well with drug dose and its concentration in the body. Individual dosing is based on therapeutic response.

In dose-effect studies, atorvastatin (10–80 mg) reduced total cholesterol by 30–46%, LDL-C by 41–61%, apo B by 34–50%, and TG by 14–33%. This effect was consistent in patients with heterozygous familial hypercholesterolemia, non-familial hypercholesterolemia, and mixed hyperlipidemia, including those with non-insulin-dependent diabetes mellitus.

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

In patients with Fredrickson type IIa and IIb hyperlipoproteinemia, the mean percentage increase in HDL-C with atorvastatin 10–80 mg was 5.1–8.7%, regardless of dose. Furthermore, significant dose-dependent reductions in the ratios of TC/HDL-C and LDL-C/HDL-C were observed.

The effect of atorvastatin 80 mg once daily for 16 weeks on the incidence of ischemia and overall mortality in patients with unstable angina or non-Q-wave myocardial infarction showed a significant reduction in the risk of myocardial ischemia and mortality, as well as a reduced risk of rehospitalization due to angina and confirmed myocardial ischemia. The risk reduction for ischemia and mortality was inversely proportional to LDL-C concentration. Atorvastatin reduced the risk of ischemia and fatal outcomes in patients with non-Q-wave myocardial infarction and unstable angina equally in both men and women, both under and over 65 years of age.

Prevention of Cardiovascular Complications.

Atorvastatin significantly reduced the incidence of fatal cardiovascular diseases and fatal myocardial infarction, overall cardiovascular events, and the frequency of fatal and non-fatal strokes, and decreased the need for myocardial revascularization procedures. With atorvastatin use, overall mortality and cardiovascular mortality were slightly reduced, although favorable trends were observed. The therapeutic effect was independent of sex, age, or baseline LDL-C levels.

Heterozygous Familial Hypercholesterolemia in Pediatric Practice.

In boys and postmenarcheal girls (10–17 years) with heterozygous familial hypercholesterolemia or severe hypercholesterolemia, atorvastatin at doses of 10–20 mg once daily significantly reduced plasma levels of total cholesterol, LDL-C, triglycerides, and apo B. No significant effects on growth or sexual maturation in boys or on menstrual cycle length in girls were observed. Safety and efficacy of doses above 20 mg in children have not been studied. The long-term impact of atorvastatin therapy in childhood on reducing morbidity and mortality in adulthood has not been established.

Recurrent Strokes.

In patients without pre-existing cardiovascular disease who had experienced a stroke or transient ischemic attack within 6 months prior to treatment initiation, atorvastatin 80 mg reduced the risk of fatal and non-fatal strokes by 15%, significantly reduced the incidence of cardiovascular events, risk of serious coronary complications, and revascularization procedures.

At the same dose, atorvastatin reduced the number of ischemic strokes but increased the number of hemorrhagic strokes. Atorvastatin did not affect mortality from hemorrhagic strokes. A reduction in cardiovascular complications with atorvastatin 80 mg was demonstrated across all patient groups, except in those who had already experienced a hemorrhagic stroke or recurrent hemorrhagic stroke at the start of therapy. Atorvastatin 80 mg reduces the number of strokes and the number of coronary complications.

Pharmacokinetics.

Absorption. Atorvastatin is rapidly absorbed after oral administration; plasma concentrations reach peak levels within 1–2 hours. Both the extent and rate of absorption increase proportionally with dose. Atorvastatin tablets have a bioavailability of 95–99% compared to a solution. The absolute bioavailability of atorvastatin is approximately 12%, and systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is attributed to presystemic clearance in the gastrointestinal mucosa and/or first-pass metabolism in the liver. Although absorption and plasma levels are reduced by approximately 25% and 9%, respectively, when administered with food—as measured by maximum concentration (Cmax) and area under the concentration-time curve (AUC)—the reduction in LDL-C levels is independent of whether atorvastatin is taken with or without food. Evening administration results in lower plasma concentrations (approximately 30% lower for Cmax and AUC) compared to morning dosing. However, the reduction in LDL-C levels is independent of the time of administration.

Distribution. The mean volume of distribution of atorvastatin is approximately 381 L. Over 98% of the drug is bound to plasma proteins. The erythrocyte/plasma ratio is approximately 0.25, indicating limited penetration into red blood cells.

Metabolism. Atorvastatin is metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro, the inhibitory effect of ortho- and parahydroxylated metabolites on HMG-CoA reductase is nearly equivalent to that of atorvastatin. Approximately 70% of the drug's inhibitory effect on HMG-CoA reductase is attributed to the activity of circulating metabolites. In vitro studies indicate a significant role of hepatic cytochrome P450 3A4 in atorvastatin metabolism, which may result in increased plasma concentrations of atorvastatin when coadministered with inhibitors of this enzyme, such as erythromycin. In vitro studies also show that atorvastatin is a weak inhibitor of cytochrome P450 3A4. Concomitant administration of atorvastatin and terfenadine—a compound primarily metabolized by cytochrome P450 3A4—did not result in a significant increase in terfenadine plasma concentrations. Therefore, atorvastatin is unlikely to significantly alter the pharmacokinetics of other cytochrome P450 3A4 substrates. In animals, ortho-hydroxylated metabolites undergo further glucuronidation.

Elimination. Atorvastatin and its metabolites are primarily excreted in bile following hepatic and/or extrahepatic metabolism. However, the drug does not undergo significant enterohepatic recirculation. The mean elimination half-life of atorvastatin in humans is approximately 14 hours, while the half-life of HMG-CoA reductase inhibitory activity, due to circulating active metabolites, ranges from 20 to 30 hours. Less than 2% of an orally administered dose is excreted in urine.

Elderly Patients. Plasma concentrations of atorvastatin in healthy elderly patients (aged 65 years and older) are higher (approximately 40% for Cmax and 30% for AUC) than in younger individuals. No differences in treatment efficacy between elderly patients and other age groups have been observed.

Children. Pharmacokinetic data in pediatric patients are not available.

Sex. Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC). However, no clinically significant differences in lipid-modifying effects between men and women have been observed.

Renal Impairment. Renal disease does not affect plasma concentrations of atorvastatin or its lipid-lowering effects. Therefore, dose adjustment is not necessary in patients with renal impairment.

Hemodialysis. Studies have not included patients with end-stage renal disease; hemodialysis is unlikely to significantly alter atorvastatin clearance, as the drug is almost entirely bound to plasma proteins.

Hepatic Impairment. Plasma concentrations of atorvastatin are markedly increased (Cmax approximately 16-fold, AUC 11-fold) in patients with alcoholic cirrhosis.

Carcinogenesis, Mutagenesis, Impairment of Fertility. In animal studies, atorvastatin showed no evidence of carcinogenic effects.

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases.

For adult patients without clinically evident ischemic heart disease but with multiple risk factors for the development of ischemic heart disease, such as age, smoking, arterial hypertension, low HDL-C (high-density lipoprotein cholesterol) levels, 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 risk of revascularization procedures and angina.

For patients with type 2 diabetes mellitus and without clinically evident ischemic heart disease, but with multiple risk factors for the development of ischemic heart disease, such as retinopathy, albuminuria, smoking, or arterial hypertension, the drug 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 risk of revascularization procedures;
• reducing the risk of hospitalization due to congestive heart failure;
• reducing the risk of angina development.

Hyperlipidemia.

• As an adjunct to diet to reduce elevated total cholesterol, LDL-C (low-density lipoprotein cholesterol), apolipoprotein B, and triglyceride levels, and to increase HDL-C (high-density lipoprotein cholesterol) levels in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification).
• As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (type IV according to Fredrickson classification).
• For the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrickson classification), when dietary measures are 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 menarche, aged 10 to 17 years, with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy laboratory results are as follows:

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 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 medicinal product Storvas is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Plasma levels of Storvas may be significantly increased when co-administered with inhibitors of CYP3A4 and transporters. Table 3 lists medicinal products that may increase exposure to Storvas and the risk of myopathy and rhabdomyolysis when used concomitantly, along with recommendations for prevention and management (see sections "Special precautions for use" and "Pharmacological properties").

Table 1

Interaction with other medicinal products that increases the risk of myopathy and rhabdomyolysis during treatment with the medicinal product Storvas

Table 2

Interaction with medicinal products that may reduce exposure to the medicinal product Storvas

Table 3

Effect of the medicinal product Storvas on other medicinal products

Diltiazem hydrochloride.

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

Cimetidine.

No evidence of interaction between atorvastatin and cimetidine has been observed in clinical studies.

Antacids.

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

Colestipol.

Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when co-administered with colestipol. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeds 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 inhibitors.

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

Ezetimibe.

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

Fusidic acid.

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

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

Other medicinal products.

Clinical studies have shown that concomitant use of atorvastatin with antihypertensive agents or during estrogen replacement therapy is not associated with clinically significant adverse effects. Studies on interactions with other drugs have not been conducted.

Effect of other medicinal products on Storvas.

Colchicine: Although formal interaction studies between atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with concomitant use of atorvastatin and colchicine. Therefore, caution should be exercised when prescribing atorvastatin 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").

Special precautions for use.

Myopathy and rhabdomyolysis

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

Myopathy risk factors

Risk factors for developing myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other medications, and higher doses of Storvas (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant therapy with other medicinal products

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

Measures to prevent or reduce the risk of myopathy and rhabdomyolysis

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

Concomitant consumption of large quantities of grapefruit juice (more than 1.2 liters per day) is not recommended in patients taking Storvas (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Immune-mediated necrotizing myopathy

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

Myasthenia gravis, ocular myasthenia. Rare cases have been reported in which statins induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, the medicinal product should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Liver function abnormalities

Statins, like some other hypolipidemic therapeutic agents, have been associated with abnormalities in liver function biochemical parameters. Persistent elevation (more than 3 times the upper limit of normal range, occurring on two or more occasions) of serum transaminases was observed in 0.7% of patients receiving Storvas 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, respectively.

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

Prior to initiating therapy with Storvas, 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 statin medications, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Storvas, treatment should be discontinued immediately. Unless an alternative etiology is identified, re-initiation of therapy with the drug should not be undertaken.

Storvas should be prescribed with caution in patients who consume alcohol excessively and/or have a history of liver disease. Storvas 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 concentrations have been reported with HMG-CoA reductase inhibitors, including Storvas.

Statins inhibit cholesterol synthesis and may theoretically impair adrenal and/or gonadal steroid hormone secretion. Clinical studies have shown that Storvas 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 has any effect on the "gonadal-pituitary-hypothalamus" system in premenopausal women. Caution should be exercised when co-administering statin-class drugs with medicinal products that may reduce levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Use in patients with recent stroke or transient ischemic attack

In a retrospective analysis of the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, in which 4731 patients without ischemic heart disease and with a history of stroke or transient ischemic attack within the previous 6 months received Storvas 80 mg versus placebo, a higher incidence of hemorrhagic stroke was observed in the group receiving Storvas 80 mg compared to the placebo group (55 cases, 2.3% in the atorvastatin group versus 33 cases, 1.4% in the placebo group; RR: 1.68, 95% confidence interval (CI): 1.09, 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 and 18 in the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the group receiving atorvastatin (38, 1.6%) compared to the placebo group (16, 0.7%). Certain baseline characteristics, including a history of hemorrhagic and lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group (see section "Adverse reactions").

Among 39,828 patients who received Storvas in clinical trials, 15,813 (40%) were aged 65 years or older, and 2,800 (7%) were aged 75 years or older. No overall differences in safety and efficacy were observed between these patients and younger patients, nor were there differences in treatment response between elderly and younger patients according to other clinical experience; however, increased sensitivity in some elderly patients cannot be excluded. Since advanced age (over 65 years) is a predisposing factor for myopathy, Storvas should be prescribed with caution in elderly patients.

Hepatic insufficiency

Storvas is contraindicated in patients with active liver disease, including persistent elevations of liver transaminases of unknown etiology (see sections "Contraindications" and "Pharmacological properties").

Before starting treatment

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

• renal impairment;
• hypothyroidism;
• family or personal history of inherited muscle disorders;
• previous history of statin or fibrate myotoxicity;
• previous history of liver disease and/or alcohol abuse.

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

Increased plasma levels of the drug are possible, particularly due to interactions (see section "Interaction with other medicinal products and other forms of interaction") and in specific patient populations (see section "Pharmacokinetics"), including patients with inherited disorders.

In such cases, it is recommended to evaluate the risk-benefit ratio of treatment and conduct clinical monitoring of patients. If CK levels are markedly elevated (exceeding the upper limit of normal [ULN] by more than 5 times) prior to treatment initiation, therapy should not be started.

Measurement of creatine kinase levels

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

During treatment

Patients should be aware of the need to immediately report the development of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.

If these symptoms occur during atorvastatin treatment, CK levels should be determined. If CK levels are markedly elevated (exceeding ULN by more than 5 times), treatment should be discontinued.

Discontinuation of therapy should also be considered if CK elevation does not reach fivefold ULN but muscle symptoms are severe and cause daily discomfort.

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

Atorvastatin treatment must be discontinued if clinically significant elevation of CK levels (exceeding ULN by more than 10 times) is observed or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use with other medicinal products

The risk of rhabdomyolysis increases when atorvastatin is used concomitantly with certain medicinal products that may increase atorvastatin plasma concentrations. Examples include potent inhibitors of CYP3A4 or transport proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, and darunavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibric acid derivatives, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or the combination telaprevir/ritonavir. If possible, alternative medicinal products (that do not interact with atorvastatin) should be used instead of the above-mentioned agents.

If concomitant therapy with atorvastatin and the mentioned drugs is necessary, the benefit and risks 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.

Atorvastatin must not be co-administered with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients requiring systemic fusidic acid, statin therapy should be suspended for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if symptoms of muscle weakness, pain, or tenderness occur.

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

In exceptional circumstances where long-term systemic fusidic acid treatment is required, e.g., for the treatment of severe infections, the need for concomitant use of Storvas and fusidic acid should be considered on an individual basis and conducted under close physician supervision.

Interstitial lung disease

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

Excipients

The medicinal product Storvas contains lactose. This product should not be taken by patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

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

Limitations of use

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

Use during pregnancy or breastfeeding.

Pregnancy. Storvas is contraindicated in pregnant women, as its safety in pregnancy has not been established and there is no clear benefit of lipid-lowering drugs during pregnancy. Since HMG-CoA reductase inhibitors reduce cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Storvas may have harmful effects on the fetus. Storvas should be discontinued as soon as pregnancy is confirmed (see section "Contraindications").

The background risk of major congenital malformations and miscarriages in the specified population is unknown. In the general US population, the estimated background risk of major congenital malformations and miscarriages in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Contraception. Storvas may harm the fetus if used during pregnancy. Women of childbearing potential should be informed of the need for effective contraception during treatment with this medicinal product.

Limited published data from observational studies, meta-analyses, and clinical cases on the use of calcium atorvastatin have not shown an increased risk of major congenital malformations or miscarriages.

Rare reports of congenital anomalies following in utero exposure to other HMG-CoA reductase inhibitors have been received. 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

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

Ability to influence reaction speed when driving or operating machinery.

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

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 the medicinal product is 10 or 20 mg once daily. For patients requiring substantial LDL-C reduction (more than 45%), therapy may be initiated at a dose of 40 mg once daily. The dosage range of the drug is from 10 to 80 mg once daily. The drug can be administered as a single dose at any time of day, independent of food intake. Initial and maintenance doses should be individually adjusted depending on the treatment goal and patient response. After initiation of treatment 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 initial dose 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 dosage of the drug for patients with homozygous familial hypercholesterolemia ranges from 10 to 80 mg per day. Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis), or when such lipid-lowering therapies are unavailable.

Concomitant lipid-lowering therapy.

Atorvastatin may be coadministered with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Special instructions", "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 the use of the drug; therefore, dose adjustment in patients with renal impairment is not required (see sections "Special instructions", "Pharmacokinetics").

Dosing in patients taking cyclosporine, clarithromycin, itraconazole, or certain protease inhibitors.

Treatment with the drug should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitors (telaprevir). Atorvastatin should be used with caution in HIV patients taking lopinavir + ritonavir and should be administered at the lowest necessary dose. In patients taking clarithromycin, itraconazole, or HIV patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the therapeutic dose of atorvastatin should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, atorvastatin treatment should be limited to a dose of 40 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose (see sections "Special instructions" and "Interaction with other medicinal products and other forms of interaction").

Children.

The safety and efficacy of the drug in patients aged 10–17 years with heterozygous familial hypercholesterolemia have been evaluated in a 6-month controlled clinical study in adolescent boys and girls after onset of menstruation. Patients receiving the drug had an overall adverse reaction profile similar to those receiving placebo. No significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls was observed (see sections "Adverse reactions", "Method of administration and dosage"). Adolescent girls should be advised about acceptable contraceptive methods during treatment with atorvastatin (see section "Use during pregnancy or lactation").

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, which included 8 pediatric patients (see subsection "Homozygous familial hypercholesterolemia").

Overdose.

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

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed during clinical trials of a medicinal product cannot be directly compared with those of another drug, and may not reflect the rates observed in clinical practice.

In the database of placebo-controlled clinical trials of atorvastatin, among 16,066 patients (8,755 receiving atorvastatin and 7,311 receiving placebo; age range 10–93 years, 39% women; 91% Caucasian, 3% Black, 2% Asian, 4% other), with a median treatment duration of 53 weeks, 9.7% of patients receiving atorvastatin and 9.5% of patients receiving placebo discontinued treatment due to adverse reactions, regardless of causal relationship to the drug. Five most common adverse reactions in patients treated with atorvastatin leading to treatment discontinuation and occurring at a higher frequency than in the placebo group were recorded: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and increased liver enzymes (0.4%).

In patients treated with atorvastatin in placebo-controlled trials (n=8,755), the most commonly observed adverse reactions (incidence >2% and higher than in the placebo group), regardless of causal relationship, were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), limb pain (6.0%), and urinary tract infections (5.7%).

Table 4 summarizes the incidence of clinical adverse reactions, regardless of causal relationship, reported in >2% of patients and at a higher frequency than in the placebo group, among patients treated with atorvastatin (n=8,755) from 17 placebo-controlled trials.

Table 4

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

* In > 2% of patients treated with atorvastatin at any dose, the incidence of adverse reactions was higher than in the placebo group.

Other adverse reactions reported during placebo-controlled studies include:

General disorders: malaise, pyrexia.

Gastrointestinal disorders: gastrointestinal discomfort, belching, 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, increased alkaline phosphatase in blood, increased creatine kinase (CK) activity, hyperglycemia.

Nervous system disorders: nightmares, unknown - myasthenia gravis.

Respiratory system disorders: epistaxis.

Skin and appendages disorders: urticaria.

Eye disorders: blurred vision, visual disturbance, unknown - ocular myasthenia.

Ear and labyrinth disorders: tinnitus.

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 (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000).

Nervous system disorders: common: headache; uncommon: dizziness, paraesthesia, hypoaesthesia, dysgeusia, amnesia; rare: peripheral neuropathy, frequency unknown - myasthenia gravis.

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

Musculoskeletal and connective tissue disorders: common: arthralgia, back pain; rare: myopathy, myositis, rhabdomyolysis, muscle rupture; very rare: lupus-like syndrome.

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

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

Hepatobiliary disorders: very rare: liver failure.

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

Respiratory, thoracic and mediastinal disorders: common: throat and larynx pain.

Blood and lymphatic system disorders: rare: thrombocytopenia.

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

Eye disorders: uncommon: blurred vision, frequency unknown - ocular myasthenia.

Vascular disorders: rare: vasculitis.

Laboratory test abnormalities: common: abnormal liver function tests, increased blood CK activity; uncommon: positive urine leukocyte test.

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

Elevations in serum CK activity exceeding ULN by more than 3 times were observed in 2.5% of patients treated with atorvastatin. This is consistent with observations during clinical trials with other HMG-CoA reductase inhibitors. In 0.4% of patients receiving atorvastatin, levels exceeding ULN by more than 10 times were observed.

Adverse reactions observed during clinical trials:

urinary tract infections, diabetes mellitus, stroke.

In a study including 10,305 participants (age range 40–80 years, 19% women; 94.6% Caucasian, 2.6% Black, 1.5% South Asian, and 1.3% mixed/other), who received atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile in patients receiving atorvastatin was comparable to that in the placebo group over a median follow-up period of 3.3 years.

In a study including 2,838 patients (age range 39–77 years, 32% women; 94.3% Caucasian, 2.4% South Asian, 2.3% Afro-Caribbean, and 1% other) with type 2 diabetes mellitus, who received atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall incidence of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 3.9 years. No cases of rhabdomyolysis were reported.

In a study including 10,001 patients (age range 29–78 years, 19% women; 94.1% Caucasian, 2.9% Black, 1.0% Asian, and 2.0% other) with clinically evident ischemic heart disease, who received atorvastatin 10 mg daily (n=5,006) or atorvastatin 80 mg daily (n=4,995), more serious adverse reactions and cases of treatment discontinuation due to adverse reactions were observed in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) over a median follow-up period of 4.9 years. Persistent transaminase elevations (≥3 times ULN, confirmed twice within 4–10 days) occurred in 62 (1.3%) patients receiving atorvastatin 80 mg and in 9 (0.2%) patients receiving atorvastatin 10 mg. CK elevations (≥10 times ULN) were generally low but higher in the high-dose atorvastatin group (13, 0.3%) compared to the low-dose group (6, 0.1%).

In a study including 8,888 patients (age range 26–80 years, 19% women; 99.3% Caucasian, 0.4% Asian, 0.3% Black, and 0.04% other), who received atorvastatin 80 mg daily (n=4,439) or simvastatin 20–40 mg daily (n=4,449), there was no difference in the overall incidence of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 4.8 years.

In a study including 4,731 patients (age range 21–92 years, 40% women; 93.3% Caucasian, 3.0% Black, 0.6% Asian, and 3.1% other) without clinically evident ischemic heart disease but with a history of stroke or transient ischemic attack (TIA) within the previous 6 months, who received atorvastatin 80 mg daily (n=2,365) or placebo (n=2,366), over a median follow-up period of 4.9 years, a higher incidence of persistent elevations in liver transaminases (≥3 times ULN, confirmed twice within 4–10 days) was observed in the atorvastatin group (0.9%) compared to the placebo group (0.1%). Cases of creatine kinase elevation (≥10 times ULN) were rare but occurred more frequently in the atorvastatin group (0.1%) than in the placebo group (0.0%). Diabetes mellitus was reported as an adverse reaction in 144 patients (6.1%) in the atorvastatin group and in 89 patients (3.8%) in the placebo group (see section "Special precautions for use").

A post-hoc analysis showed that atorvastatin 80 mg reduced the incidence of ischemic stroke (218 of 2,365, 9.2% vs. 274 of 2,366, 11.6%) but increased the incidence of hemorrhagic stroke (55 of 2,365, 2.3% vs. 33 of 2,366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 cases in the atorvastatin group vs. 18 in the placebo group). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38 cases) compared to the placebo group (16 cases). Patients who entered the study with a history of hemorrhagic stroke had an increased risk of hemorrhagic stroke (7 (16%) in the atorvastatin group vs. 2 (4%) in the placebo group).

No significant differences in all-cause mortality were observed between treatment groups: 216 (9.1%) in the atorvastatin 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportion of patients who died from cardiovascular causes was numerically lower in the atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The proportion of patients who died from non-cardiovascular causes was numerically higher in the atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%).

Adverse reactions during clinical trials of atorvastatin in children:

In a 26-week controlled study in boys and girls after onset of menstruation with heterozygous familial hypercholesterolemia (aged 10 to 17 years) (n=140, 31% female; 92% Caucasian, 1.6% Black, 1.6% Asian, and 4.8% other ethnic groups), the safety and tolerability profile of atorvastatin 10–20 mg daily as an adjunct to diet for lowering total cholesterol, LDL-C, and apolipoprotein B levels was generally similar to that of placebo.

Post-marketing experience.

The following adverse reactions have been identified during post-marketing use of atorvastatin. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with atorvastatin treatment reported after marketing authorization, regardless of causal assessment, include: anaphylaxis, angioedema, bullous eruptions (including exudative multiform erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis), rhabdomyolysis, myositis, increased fatigue, tendon rupture, fatal and non-fatal liver failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.

Rare cases of immune-mediated necrotizing myopathy associated with statin use have been reported (see section "Special precautions for use").

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

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

Adverse reactions reported during post-marketing surveillance:

Blood and lymphatic system disorders: thrombocytopenia.

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

Metabolism and nutrition disorders: weight gain.

Nervous system disorders: headache, hypoaesthesia, dysgeusia.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain; rare: muscle rupture; very rare: lupus-like syndrome.

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

Laboratory test abnormalities: increased ALT activity, increased blood CK activity.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Packaging.

10 tablets in a blister, 3 or 9 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Manufacturer's address.

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.