Atorvastatin krka

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATORVASTATIN KRKA (Atorvastatin KRKA)

Composition:

Active substance: atorvastatin;

One film-coated tablet contains 10 mg, or 20 mg, or 40 mg of atorvastatin as atorvastatin calcium;

Excipients:

Tablets of 10 mg, 20 mg: povidone, sodium lauryl sulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate;

Coating: talc, polyvinyl alcohol, macrogol 3000, titanium dioxide (E 171);

Tablets of 40 mg: povidone, sodium lauryl sulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, crospovidone, magnesium stearate;

Coating: hypromellose, macrogol 400, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, slightly convex, film-coated tablets.

Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors. Atorvastatin. ATC code C10AA05.

Pharmacological properties

Pharmacodynamics

The medicinal product contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoprotein (VLDL) particles, which enter plasma and are transported to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolized primarily via interaction with high-affinity LDL receptors (LDL receptors).

Atorvastatin reduces plasma concentrations of cholesterol and lipoproteins in serum by inhibiting HMG-CoA reductase, thereby suppressing cholesterol biosynthesis in the liver, and by increasing the number of hepatic LDL receptors on the cell surface, resulting in enhanced uptake and catabolism of LDL.

Atorvastatin reduces the formation of LDL and the number of LDL particles. Atorvastatin induces a pronounced and sustained increase in LDL receptor activity in combination with favorable changes in the quality of circulating LDL particles. Atorvastatin effectively reduces LDL cholesterol (LDL-C) levels in patients with homozygous familial hypercholesterolemia, a group that has not always responded to therapy with lipid-lowering agents.

In addition to its effects on plasma lipids, atorvastatin exerts other effects that enhance its antiatherosclerotic action. It inhibits the synthesis of isoprenoids—substances that act as growth factors for vascular smooth muscle cell proliferation—reduces plasma viscosity and the activity of certain coagulation and aggregation factors. Due to these actions, it improves hemodynamics and promotes normalization of blood coagulation processes. Furthermore, HMG-CoA reductase inhibitors affect macrophage metabolism and thereby suppress their activation, reducing the risk of rupture of atherosclerotic plaques.

It has been demonstrated that atorvastatin reduces total cholesterol (30–46%), LDL-C (41–61%), apolipoprotein B (34–50%), and triglycerides (14–33%), while causing variable increases in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A levels in dose-response studies. These results are consistent with data from patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with insulin-independent diabetes mellitus.

It has been proven that lowering levels of total cholesterol, LDL-C, and apolipoprotein B reduces the risk of cardiovascular complications and cardiovascular mortality.

Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after oral administration and reaches peak plasma concentration within 1–2 hours. The extent of absorption and plasma concentration of atorvastatin are dose-dependent. The bioavailability of atorvastatin in tablet form and as a solution is 95% and 99%, respectively. The absolute bioavailability of atorvastatin is approximately 12%, and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance in the gastrointestinal mucosa and biotransformation during first-pass metabolism through the liver.

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 (CYP3A4), forming ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro, ortho- and para-hydroxylated metabolites exhibit HMG-CoA reductase inhibitory activity equivalent to that of atorvastatin. Approximately 70% of the inhibitory effect of the drug on HMG-CoA reductase is attributed to the activity of circulating metabolites. In vitro studies confirm the importance of atorvastatin biotransformation.

Excretion

Atorvastatin and its metabolites are primarily eliminated in bile following hepatic and/or extrahepatic biotransformation, but do not undergo enterohepatic recirculation. The mean elimination half-life of atorvastatin in humans is approximately 14 hours. The inhibitory activity against HMG-CoA reductase persists for 20–30 hours due to the presence of active metabolites.

Atorvastatin is a substrate for hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and transporter 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.

Use in specific patient populations

Elderly patients

Plasma concentrations of atorvastatin in healthy elderly volunteers (aged ≥ 65 years) are higher than in younger individuals, whereas the lipid-lowering effects are comparable to those observed in younger patients.

Children

Apparent oral clearance of atorvastatin in children was found to be similar to that in adults when scaled allometrically by body weight, as body weight was the only significant covariate in the population pharmacokinetic model of atorvastatin using data from children with heterozygous familial hypercholesterolemia (aged 6 to 17 years, n = 39) in an open 8-week study. Consistent reductions in LDL cholesterol and total cholesterol were observed over the exposure to atorvastatin and o-hydroxyatorvastatin.

Gender

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

Renal impairment

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

Hepatic impairment

Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease (Child-Pugh class B) (approximately 16-fold for Cmax and 11-fold for AUC).

SLCO1B1 polymorphism

Hepatic metabolism of all HMG-CoA reductase inhibitors, including atorvastatin, involves the transporter protein OATP1B1. Patients with SLCO1B1 polymorphism are at risk of increased atorvastatin exposure, which may lead to an increased risk of rhabdomyolysis (see section "Special warnings and precautions for use"). Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher atorvastatin exposure (AUC) compared to individuals without this genotype variant (c.521TT). Impaired hepatic uptake of atorvastatin is also possible in these patients. The effect on efficacy is unknown.

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases

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

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

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

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

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

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

Hyperlipidemia

• Primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification). As an adjunct to diet to reduce elevated levels of total cholesterol (TC), LDL-C, apolipoprotein B, and triglycerides, as well as to increase HDL-C levels.
• Hypertriglyceridemia (type IV according to Fredrickson classification). As an adjunct to diet for treatment of patients with elevated serum triglyceride levels.
• Primary dysbetalipoproteinemia (type III according to Fredrickson classification). For treatment of patients when dietary measures are insufficient.
• Homozygous familial hypercholesterolemia. To reduce TC and LDL-C as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are unavailable.
• Heterozygous familial hypercholesterolemia in pediatric patients (aged 10–17 years). As an adjunct to diet to reduce levels of TC, LDL-C, and apolipoprotein B in adolescent boys and girls after onset of menstruation aged 10 to 17 years, if after appropriate dietary therapy laboratory results are:
  • a) LDL-C remains ≥ 4.91 mmol/L (≥ 190 mg/dL), or
  • b) LDL-C ≥ 4.14 mmol/L (≥ 160 mg/dL) and:
    • premature cardiovascular disease is present in family history, or
    • two or more other cardiovascular risk factors are present in the pediatric patient.

Contraindications.

• Hypersensitivity to any component of the medicinal product.
• Acute liver disease or persistent elevations (of unknown etiology) in serum transaminase levels three times or more above the upper limit of normal.
• Pregnancy, breastfeeding, and women of childbearing potential who are not using appropriate contraceptive methods.
• Concomitant use with antiviral hepatitis C agents – glecaprevir/pibrentasvir.

Interaction with other medicinal products and other forms of interaction.

Effect of concomitantly administered drugs on atorvastatin

Atorvastatin is metabolized by CYP3A4 and is a substrate of hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin (see section "Pharmacokinetics").

Concomitant use of medicinal products that are inhibitors of CYP3A4 or transporter proteins may lead to increased plasma concentrations of atorvastatin and increased risk of myopathy. This risk may also increase with concomitant use of atorvastatin and other medicinal products that may cause myopathy, such as fibric acid derivatives and ezetimibe (see sections "Contraindications" and "Special precautions for use").

Inhibitors of CYP3A4

Strong inhibitors of CYP3A4 are known to significantly increase atorvastatin concentrations (see Table 1 and detailed information below). Concomitant use with strong CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for hepatitis C treatment (e.g., elbasvir/grazoprevir), azole antifungals, and HIV protease inhibitors including ritonavir, lopinavir, cobicistat, atazanavir, indinavir, darunavir) should be avoided if possible. If concomitant use cannot be avoided, consideration should be given to using lower initial and maximum doses of atorvastatin. Appropriate clinical monitoring of the patient is recommended (see Table 1).

Moderate inhibitors of CYP3A4 (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase atorvastatin plasma concentrations (see Table 1). Concomitant use of erythromycin and statins is associated with increased risk of myopathy. Drug interaction studies assessing the effect of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to inhibit CYP3A4 activity; therefore, concomitant administration of these agents with atorvastatin may lead to increased atorvastatin effects. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to reducing the maximum atorvastatin doses. Clinical monitoring of the patient after initiation or dose adjustment of the inhibitor is also recommended (see sections "Special precautions for use" and "Dosage and administration").

Inducers of CYP3A4

Concomitant use of atorvastatin with inducers of cytochrome P450 3A (e.g., efavirenz, rifampicin, St. John's wort) may lead to variable reduction in atorvastatin plasma concentrations. Due to the dual mechanism of interaction of rifampicin (induction of cytochrome P450 3A and inhibition of hepatic OATP1B1 transporter), concomitant use of atorvastatin and rifampicin is recommended, as administration of atorvastatin with a large time interval after rifampicin is associated with significant reduction in atorvastatin plasma concentrations. However, the effect of rifampicin on atorvastatin concentrations in liver cells is unknown, and if concomitant use cannot be avoided, careful monitoring of treatment efficacy in the patient is advised.

Inhibitors of transporter proteins

Inhibitors of transporter proteins (e.g., cyclosporine, letermovir) can increase systemic exposure to atorvastatin. Cyclosporine and letermovir are inhibitors of transporters involved in atorvastatin disposition, including OATP1B1/1B3, P-gp, and BCRP, leading to increased exposure (see Table 1). The effect of inhibition of uptake transporters on atorvastatin exposure in liver cells is unknown. If concomitant use of these agents cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).

The use of atorvastatin is not recommended in patients receiving letermovir concomitantly with cyclosporine (see section "Special precautions for use").

Gemfibrozil/fibric acid derivatives

The use of fibrates as monotherapy has been associated with muscle-related adverse events, including rhabdomyolysis. The risk of such events may be increased with concomitant use of fibric acid derivatives and atorvastatin. If concomitant use cannot be avoided, the lowest dose of atorvastatin should be used to achieve therapeutic goals, and patients should be appropriately monitored (see section "Special precautions for use").

Ezetimibe

The use of ezetimibe as monotherapy has been associated with muscle-related adverse events, including rhabdomyolysis. Therefore, concomitant use of ezetimibe and atorvastatin increases the risk of such events. Appropriate clinical monitoring of these patients is recommended.

Cholestyramine

Plasma concentrations of atorvastatin and its metabolites were lower (atorvastatin concentration ratio: 0.74) when atorvastatin was coadministered with cholestyramine. However, the hypolipidemic effect of the combination of atorvastatin and cholestyramine exceeded the effect of each agent used alone.

Fusidic acid

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

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

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, atorvastatin should be used with caution when coadministered 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 for use").

Effect of atorvastatin on concomitantly administered medicinal products

Digoxin

Steady-state digoxin concentrations were slightly increased when multiple doses of digoxin were coadministered with 10 mg atorvastatin. Patients receiving digoxin should be appropriately monitored.

Oral contraceptives

Concomitant use of atorvastatin with oral contraceptives resulted in increased plasma concentrations of norethisterone and ethinylestradiol.

Warfarin

In a clinical study in patients on long-term warfarin therapy, concomitant use of 80 mg atorvastatin daily with warfarin led to a small reduction (approximately 1.7 seconds) in prothrombin time during the first 4 days of therapy, but this parameter returned to normal within the next 15 days of atorvastatin treatment. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before initiating atorvastatin therapy and frequently during the initial phase in patients receiving coumarin anticoagulants to confirm absence of significant changes. Once a stable prothrombin time has been established, monitoring can continue at intervals normally recommended for patients on coumarin anticoagulants. This procedure should be repeated if atorvastatin therapy is discontinued or the dose changed. In patients not receiving anticoagulants, atorvastatin therapy was not associated with bleeding or changes in prothrombin time.

Effect of concomitantly administered medicinal products on the pharmacokinetics of atorvastatin Table 1

Concomitantly administered drugs and dosing regimen	Atorvastatin
	Dose (mg)	Ratio AUC1	Clinical recommendations2
Glecaprevir 400 mg once daily/pibrentasvir 120 mg once daily, 7 days	10 mg once daily for 7 days	8.3	Co-administration with products containing glecaprevir or pibrentasvir is contraindicated (see section "Contraindications")
Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 8 days (from day 14 to day 21)	40 mg once daily, 10 mg single dose on day 20	9.4	If co-administration of atorvastatin is necessary, the dose should not exceed 10 mg daily. Clinical monitoring of patients is recommended.
Telaprevir 750 mg every 8 hours, 10 days	20 mg single dose	7.9
Cyclosporine 5.2 mg/kg/day, stable dose	10 mg once daily for 28 days	8.7
Lopinavir 400 mg twice daily/ritonavir 100 mg twice daily, 14 days	20 mg once daily for 4 days	5.9	If co-administration of atorvastatin is necessary, dose reduction of atorvastatin is recommended. Clinical monitoring of patients is recommended when dosing exceeds 20 mg.
Clarithromycin 500 mg twice daily, 9 days	80 mg once daily for 8 days	4.5
Saquinavir 400 mg twice daily/ritonavir (300 mg twice daily for 5–7 days, increased to 400 mg on day 8), 4–18 days, taken 30 minutes after atorvastatin	40 mg once daily for 4 days	3.9	If co-administration of atorvastatin is necessary, dose reduction of atorvastatin is recommended. Clinical monitoring of patients is recommended when dosing exceeds 40 mg.
Darunavir 300 mg twice daily/ritonavir 100 mg twice daily, 9 days	10 mg once daily for 4 days	3.4
Itraconazole 200 mg once daily, 4 days	40 mg single dose	3.3
Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days	10 mg once daily for 4 days	2.5
Fosamprenavir 1400 mg twice daily, 14 days	10 mg once daily for 4 days	2.3
Elbasvir 50 mg once daily/grazoprevir 200 mg once daily, 13 days	10 mg single dose	1.95	The atorvastatin dose should not exceed 20 mg daily when co-administered with products containing elbasvir or grazoprevir.
Simeprevir 150 mg once daily, 10 days	40 mg single dose	2.12	The atorvastatin dose should not exceed 20 mg daily when co-administered with products containing simeprevir.
Ledipasvir 480 mg once daily, 10 days	20 mg single dose	3.29	The atorvastatin dose should not exceed 20 mg daily when co-administered with products containing ledipasvir.
Nelfinavir 1250 mg twice daily, 14 days	10 mg once daily for 28 days	1.74	No specific recommendations.
Grapefruit juice3 240 ml once daily	40 mg single dose	1.37	Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended.
Diltiazem 240 mg once daily, 28 days	40 mg single dose	1.51	Clinical monitoring of patients is recommended following initiation or dose adjustment of diltiazem.
Erythromycin 500 mg four times daily, 7 days	10 mg single dose	1.33	Dose reduction and clinical monitoring of patients are recommended.
Amlodipine 10 mg, single dose	80 mg single dose	1.18	No specific recommendations.
Cimetidine 300 mg four times daily, 2 weeks	10 mg once daily for 2 weeks	1	No specific recommendations.
Colestipol 10 g twice daily, 24 weeks	40 mg once daily for 8 weeks	0.744	No specific recommendations.
Antacid suspension5 containing magnesium and aluminum hydroxide 30 ml four times daily, 17 days	10 mg once daily for 15 days	0.66	No specific recommendations.
Efavirenz 600 mg once daily, 14 days	10 mg for 3 days	0.59	No specific recommendations.
Rifampicin 600 mg once daily, 7 days (administered concomitantly)	40 mg single dose	1.12	If concomitant administration cannot be avoided, clinical monitoring of patients is recommended.
Rifampicin 600 mg once daily, 5 days (administered separately)	40 mg single dose	0.20
Gemfibrozil 600 mg twice daily, 7 days	40 mg single dose	1.35	The lowest starting dose is recommended, along with clinical monitoring of patients.
Fenofibrate 160 mg once daily, 7 days	40 mg single dose	1.03	The lowest starting dose is recommended, along with clinical monitoring of patients.
Boceprevir 800 mg three times daily, 7 days	40 mg single dose	2.3	The lowest starting dose is recommended, along with clinical monitoring of patients. The atorvastatin dose should not exceed 20 mg daily during co-administration with boceprevir.

1 Ratio of combination therapy with atorvastatin to atorvastatin monotherapy use.

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

3 Contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of medicinal products metabolized by CYP3A4. Consumption of one 240 mL glass of grapefruit juice also resulted in a 20.4% reduction in AUC of the active ortho-hydroxy metabolite. Large quantities of grapefruit juice (over 1.2 L per day for 5 days) increased atorvastatin AUC by 2.5-fold and AUC of active HMG-CoA reductase inhibitors (atorvastatin and metabolites) by 1.3-fold.

4 Single sample taken 8–16 hours after dose administration.

5 Accompanied by approximately 35% reduction in plasma concentration of atorvastatin, but the hypolipidemic effect of atorvastatin remained unchanged.

Effect of atorvastatin on the pharmacokinetics of concurrently administered medicinal products. Table 2

Atorvastatin	Concomitant Medication and Dosing Regimen
	Drug/Dose (mg)	Ratio of AUC1	Clinical Recommendations
80 mg once daily for 10 days	Digoxin 0.25 mg once daily, 20 days	1.15	Clinical monitoring of patients is recommended.
40 mg once daily for 22 days	Oral contraceptives once daily, 2 months norethisterone 1 mg ethinylestradiol 35 mcg	1.28 1.19	No specific recommendations.
80 mg once daily for 15 days	Phenazone 600 mg single dose2	1.03	No specific recommendations.
10 mg once daily	Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 7 days	1.08	No specific recommendations.
10 mg once daily for 4 days	Fosamprenavir 1400 mg twice daily, 14 days	0.73	No specific recommendations.
10 mg once daily for 4 days	Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days	0.99	No specific recommendations.

1 The ratio of combination therapy with atorvastatin to atorvastatin monotherapy.

2 When multiple doses of atorvastatin and phenazone are administered simultaneously, changes in phenazone clearance are negligible or not observed.

Special precautions for use.

Myopathy and rhabdomyolysis

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

Factors increasing the risk of myopathy

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

Measures to avoid or reduce the risk of myopathy and rhabdomyolysis

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

Treatment with Atorvastatin KRKA 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 atorvastatin. Atorvastatin KRKA 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 beginning of treatment or when the dose of Atorvastatin KRKA is increased. Patients should be advised to immediately report 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) have been reported during or after treatment with some statins. Clinically, IMNM is characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels, which persist despite discontinuation of statin therapy; positive antibodies to HMG-CoA reductase; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive therapy. Additional neuromuscular and serological investigations may be required. Immunosuppressive therapy may be needed. The risk of IMNM should be carefully considered before initiating another statin. If another statin is initiated, monitoring for signs and symptoms of IMNM is necessary.

Liver effects

Before initiating therapy, liver enzyme tests should be obtained and periodically repeated thereafter. Liver function tests should be performed in patients who develop symptoms suggestive of liver dysfunction. Patients with elevated transaminase levels should have liver function monitored until abnormalities resolve. Persistent increases in serum transaminase levels to 3 or more times the upper limit of normal (ULN) warrant discontinuation of the medicinal product (see section "Undesirable effects").

Atorvastatin should be used with caution in patients who consume alcohol excessively and/or have a history of liver disease.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

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

Skeletal muscle

Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare cases affect skeletal muscle and cause myalgia, myositis, and myopathy, which may progress to rhabdomyolysis—a potentially life-threatening condition characterized by markedly elevated creatine kinase (CK) (>10 times above normal), myoglobinemia, and myoglobinuria, which may lead to renal failure.

There are very rare reports of immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins; positive antibodies to HMG-CoA reductase and improvement with immunosuppressive therapy. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels, which persist despite discontinuation of statin therapy.

Myasthenia gravis

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

Before initiating treatment

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

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• prior history of statin- or fibrate-induced myotoxicity;
• prior liver disease and/or alcohol abuse.

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

Increased plasma levels of the drug may occur, particularly due to drug interactions or in specific patient groups, including patients with inherited disorders (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").

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

Measurement of creatine kinase levels

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

During treatment

• Patients should be informed to immediately report muscle pain, cramps or weakness, especially if accompanied by malaise or fever.
• If these symptoms occur during treatment with atorvastatin, CK levels should be measured. If CK levels are markedly elevated (more than 5 times above ULN), treatment should be discontinued.
• Discontinuation should also be considered if CK elevation does not exceed 5 times ULN but muscle symptoms are severe and cause persistent discomfort.
• After symptom resolution and normalization of CK levels, reinitiation of atorvastatin therapy or initiation of an alternative statin may be considered, using the lowest possible dose of atorvastatin and with close monitoring.
• Atorvastatin treatment must be discontinued if clinically significant elevation of CK (more than 10 times above ULN) occurs or if rhabdomyolysis is diagnosed or suspected.

Concomitant use with other medicinal products

The risk of rhabdomyolysis increases with concomitant use of atorvastatin and certain medicinal products that may increase plasma concentrations of atorvastatin. Examples include strong inhibitors of CYP3A4 or transporter proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, lopinavir, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc. The risk of myopathy may also increase with concomitant use of gemfibrozil and other fibric acid derivatives, antiviral agents for hepatitis C (e.g., boceprevir, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin, or ezetimibe. If possible, alternative medicinal products (not interacting with atorvastatin) should be used instead.

If concomitant treatment with atorvastatin and these agents is necessary, a careful assessment of benefits and risks should be performed. In patients taking drugs that increase atorvastatin plasma concentrations, a reduction of atorvastatin dose to the lowest possible level is recommended. Additionally, when using strong CYP3A4 inhibitors, consideration should be given to using a lower initial dose of atorvastatin and appropriate clinical monitoring (see section "Interaction with other medicinal products and other forms of interaction").

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

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

In exceptional cases where prolonged fusidic acid therapy is required, e.g., for treatment of severe infections, the possibility of concomitant use of atorvastatin and fusidic acid should be evaluated on a case-by-case basis and under continuous medical supervision.

The risk of developing 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 Atorvastatin KRKA in patients receiving daptomycin unless the benefit outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times weekly, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

Interstitial lung disease

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

Children

Data from three-year studies assessing overall child development indicate no clinically significant effect of atorvastatin on growth, body weight, or sexual maturation (Tanner scale) (see section "Undesirable effects").

Diabetes

Some data suggest that statins as a class may increase HbA1c and serum glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, this risk is outweighed by the reduction in cardiovascular risk associated with statin use and therefore should not be a reason to discontinue statin therapy. According to national guidelines, clinical and biochemical monitoring should be performed in at-risk patients (fasting glucose 5.6–6.9 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension).

Excipients

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

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

Limitations of use

The product 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.

Women of reproductive potential should use appropriate contraceptive methods during treatment (see section "Contraindications"). If a patient intends to become pregnant while taking atorvastatin, she should discontinue the medicinal product at least one month before planned conception.

Pregnancy

Atorvastatin is contraindicated during pregnancy, as safety has not been established and there are no controlled studies of atorvastatin use in pregnant women. Rare cases of congenital anomalies have been reported following in utero exposure to HMG-CoA reductase inhibitors. Animal studies have shown toxic effects on reproductive function.

Atorvastatin treatment may reduce intrauterine levels of mevalonate, necessary for cholesterol biosynthesis. Atherosclerosis is a chronic process; therefore, interruption of lipid-lowering therapy during pregnancy is not expected to significantly affect the long-term outcomes of primary hypercholesterolemia treatment.

Therefore, atorvastatin should not be used in pregnant women or in women who are planning or suspect pregnancy. Atorvastatin treatment should be discontinued during pregnancy or if pregnancy is confirmed (see section "Contraindications").

Breastfeeding period

It is unknown whether atorvastatin and its metabolites pass into human breast milk; however, it is known that a small amount of atorvastatin or its metabolites passes into the milk of rats. Due to the potential risk of serious adverse effects, women taking atorvastatin should discontinue breastfeeding (see section "Contraindications").

Atorvastatin is contraindicated during breastfeeding (see section "Contraindications").

Fertility

In animal studies, atorvastatin did not affect fertility in males or females.

Ability to drive and use machines

Atorvastatin has negligible influence on the ability to drive and use machines.

Method of Administration and Dosage.

Dosage

Before initiating treatment with the drug, the degree of hypercholesterolemia should be determined, and adherence to an appropriate diet, physical activity, weight reduction in obese patients, and management of other underlying medical conditions should be ensured. While taking the drug, the patient should follow a standard cholesterol-lowering diet.

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

The recommended initial dose of atorvastatin is 10 mg or 20 mg once daily. For patients requiring a significant reduction in LDL-C levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily. The dosage range of the drug is from 10 to 80 mg once daily. The drug can be administered as a single dose at any time of day, regardless of food intake. Initial and maintenance doses should be individually adjusted based on treatment goals and patient response. Lipid levels should be analyzed 2 to 4 weeks after initiating treatment and/or dose titration, and the dose should be adjusted accordingly.

Heterozygous familial hypercholesterolemia in pediatric patients (aged 10–17 years)

The recommended initial dose of atorvastatin 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. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous familial hypercholesterolemia

The atorvastatin dose for patients with homozygous familial hypercholesterolemia ranges from 10 to 80 mg per day. Atorvastatin KRKA 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

The drug may be used with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").

Dosage in patients with renal impairment

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

Dosage in patients taking cyclosporine, clarithromycin, itraconazole, or certain protease inhibitors

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

Children

Heterozygous familial hypercholesterolemia

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

• a) LDL-C remains ≥ 4.91 mmol/L (≥ 190 mg/dL), or
• b) LDL-C ≥ 4.14 mmol/L (≥ 160 mg/dL) and:

o familial hypercholesterolemia or early cardiovascular disease in first- or second-degree relatives is present in the family history, or

o two or more other cardiovascular risk factors are present.

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

• A 6-month placebo-controlled clinical trial involving 187 boys and girls after onset of menstruation, aged 10 to 17 years. Patients receiving atorvastatin at doses of 10 mg or 20 mg daily had an overall adverse reaction profile similar to that of patients receiving placebo. In this limited controlled study, atorvastatin did not show a significant effect on growth or sexual maturation in boys, or on menstrual cycle length in girls.
• A 3-year open-label uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, in whom dose was titrated to achieve a target LDL-C level < 130 mg/dL (3.36 mmol/L). The safety and efficacy of atorvastatin in lowering LDL-C were generally consistent with those observed in adult patients, despite limitations of the uncontrolled study design.

Girls after onset of menstruation should be counseled regarding contraception, if appropriate for the patient.

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

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

Homozygous familial hypercholesterolemia

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

Overdose.

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

Adverse Reactions

Since clinical trials are conducted under varying conditions, the frequency of adverse reactions observed during clinical trials of a drug cannot be directly compared to frequencies reported in clinical trials of other drugs and may not reflect the frequencies observed in clinical practice.

According to data from clinical trials in patients receiving atorvastatin, the most common adverse reactions leading to discontinuation of atorvastatin and occurring at a higher frequency than in the placebo group (> 2%) were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and increased liver enzymes (0.4%).

The most frequently reported adverse reactions (≥ 2% compared to placebo), regardless of causality, in patients treated with atorvastatin (n = 8755), were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremities (6.0%), and urinary tract infection (5.7%).

Other adverse reactions reported during placebo-controlled trials include:

General disorders: malaise, pyrexia.

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

Musculoskeletal and connective tissue 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 phosphokinase activity, hyperglycemia.

Nervous system disorders: frequency unknown: nightmares.

Respiratory system disorders: epistaxis.

Skin and subcutaneous tissue disorders: urticaria.

Eye disorders: frequency unknown: blurred vision, visual disturbances; frequency unknown: ocular myasthenia.

Ear and labyrinth disorders: tinnitus.

Vascular disorders: vasculitis.

Renal and urinary 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), frequency not known (≤ 1/100000).

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

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

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

Blood and lymphatic system disorders: rare: thrombocytopenia.

Ear and labyrinth disorders: uncommon: tinnitus.

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

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

Hepatobiliary disorders: very rare: liver failure.

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

Musculoskeletal disorders: common: myalgia, arthralgia, pain in extremities, muscle spasms, joint swelling; uncommon: back pain, neck pain, muscle weakness; rare: myopathy, myositis, rhabdomyolysis, muscle rupture, tendinopathy (sometimes complicated by tendon rupture), and red-brown discoloration of urine; very rare: lupus-like syndrome; frequency not known: immune-mediated necrotizing myopathy (see section "Special precautions for use").

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

Laboratory findings: common: abnormal liver function tests, increased creatine kinase in blood; uncommon: presence of leukocytes in urine.

As with other HMG-CoA reductase inhibitors, increases 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 increases in serum transaminase activity (exceeding the upper limit of normal [ULN] by more than 3 times) were observed in 0.8% of patients receiving atorvastatin. This increase was dose-dependent and reversible in all patients.

In 2.5% of patients receiving atorvastatin, creatine kinase (CK) serum activity increased to more than 3 times above the ULN. This is consistent with observations from clinical trials of other HMG-CoA reductase inhibitors.

Elevations exceeding 10 times the ULN were observed in 0.4% of patients receiving atorvastatin (see section "Special precautions for use").

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

Children (10–17 years)

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

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

Post-marketing experience with atorvastatin

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

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

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

Blood and lymphatic system disorders: thrombocytopenia.

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

Metabolism and nutrition disorders: weight gain.

Nervous system disorders: headache, hypesthesia, dysgeusia.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain.

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

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

If serious adverse reactions occur, treatment with the drug should be discontinued.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug approval is important. 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 to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister; 3 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.