Aspiroza®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AspiRosa®

Composition:

Active substances: rosuvastatin, acetylsalicylic acid;

1 capsule of 5 mg/100 mg contains two tablets:

− 1 tablet of rosuvastatin 5 mg (as calcium rosuvastatin 5.2 mg) and 1 tablet of acetylsalicylic acid 100 mg;

1 capsule of 10 mg/100 mg contains two tablets:

− 1 tablet of rosuvastatin 10 mg (as calcium rosuvastatin 10.4 mg) and 1 tablet of acetylsalicylic acid 100 mg;

1 capsule of 20 mg/100 mg contains three tablets:

− 2 tablets of rosuvastatin 10 mg each (as calcium rosuvastatin 10.4 mg each, together containing 20 mg of rosuvastatin as calcium rosuvastatin 20.8 mg) and 1 tablet of acetylsalicylic acid 100 mg;

Excipients:

for film-coated rosuvastatin tablet: lactose monohydrate (type 100), microcrystalline cellulose (type 102), microcrystalline cellulose (type 112), magnesium oxide heavy, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate (type 50);

film coating: partially hydrolyzed polyvinyl alcohol, titanium dioxide, talc, yellow iron oxide, lecithin (soy), red iron oxide, xanthan gum, black iron oxide;

for acetylsalicylic acid tablet: microcrystalline cellulose (type 102), corn starch, colloidal anhydrous silicon dioxide, stearic acid;

hard capsule: gelatin, titanium dioxide, indigotine-FD&C Blue 2, yellow iron oxide.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

Capsules 5 mg/100 mg:

hard gelatin capsules, size № 2; cap: opaque, dark green; body: opaque, white.

Each capsule contains two tablets:

• rosuvastatin 5 mg tablet: round, biconvex tablet, coated with a brown film coating;
• acetylsalicylic acid 100 mg tablet: oval, biconvex tablet, white or almost white.

Capsules 10 mg/100 mg:

hard gelatin capsules, size № 1; cap: opaque, light green, with black print «RSV 10»; body: opaque, white, with black print «ASA 100».

Each capsule contains two tablets:

• rosuvastatin 10 mg tablet: round, biconvex tablet, coated with a brown film coating;
• acetylsalicylic acid 100 mg tablet: oval, biconvex tablet, white or almost white.

Capsules 20 mg/100 mg:

hard gelatin capsules, size № 0; cap: opaque, green, with black print «RSV 20»; body: opaque, white, with black print «ASA 100».

Each capsule contains three tablets:

• two rosuvastatin 20 mg tablets together (10 mg each): round, biconvex tablets, coated with a brown film coating;
• acetylsalicylic acid 100 mg tablet: oval, biconvex tablet, white or almost white.

Pharmacotherapeutic group. HMG-CoA reductase inhibitors, other combinations. Rosuvastatin and acetylsalicylic acid. ATC code C10BX05

Pharmacological properties.

Pharmacodynamics.

Rosuvastatin.

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme responsible for the rate-limiting step that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a cholesterol precursor. The primary site of action of rosuvastatin is the liver—the target organ for cholesterol reduction.

Rosuvastatin increases the number of low-density lipoprotein (LDL) receptors on the surface of liver cells, enhancing LDL uptake and catabolism, and inhibits hepatic synthesis of very low-density lipoproteins (VLDL), thereby reducing the total number of VLDL and LDL particles.

The medicinal product reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C) levels. It also reduces levels of apolipoprotein B (apoB), non-HDL-C, very low-density lipoprotein cholesterol (VLDL-C), triglyceride-rich VLDL (TG-VLDL), and increases apolipoprotein A-I (apoA-I) levels—corresponding data are presented in Table 1.

The medicinal product also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Table 1

Dose-response in patients with primary hypercholesterolemia type IIa and IIb

(adjusted mean percentage change from baseline)

Dose	N	LDL-C	Total Cholesterol	HDL-C	TG	non-HDL-C	apoB	apoA-I
Placebo	13	7	5	3	3	7	3	0
5	17	45	33	13	35	44	38	4
10	17	52	36	14	10	48	42	4
20	17	55	40	8	23	51	46	5
40	18	63	46	10	28	60	54	0

The therapeutic effect is achieved within 1 week after starting the drug, and 90% of the maximum effect is reached within 2 weeks. The maximum effect is usually achieved within 4 weeks and persists thereafter.

Acetylsalicylic acid.

The antithrombotic effect of acetylsalicylic acid (ASA) is due to inhibition of thromboxane A2 synthesis in platelets (a prostaglandin that stimulates platelet aggregation and causes vasoconstriction). Since even small doses of ASA are absorbed, all circulating platelets are irreversibly inhibited along the pathway from the gastrointestinal tract to the liver in the prehepatic mesenteric blood vessels.

The effect is sustained and typically lasts throughout the entire 8-day lifespan of platelets.

Meanwhile, ASA concentrations during posthepatic circulation only slightly inhibit cyclooxygenase in the endothelium responsible for prostacyclin synthesis (a prostaglandin that inhibits platelet aggregation but has vasodilatory effects). This effect is temporary. Platelet function related to hemostasis remains largely unchanged.

After ASA is eliminated from the blood, progenitor endothelial cells resynthesize prostacyclin. As a result, a single low daily dose of ASA (< 100 mg/day) inhibits thromboxane A2 in platelets without significantly affecting prostacyclin synthesis.

Pharmacokinetics.

Rosuvastatin.

Absorption. Maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution. Rosuvastatin is significantly taken up by the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. About 90% of rosuvastatin is bound to plasma proteins, predominantly to albumin.

Metabolism. Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The primary isoenzyme involved is CYP2C9, with minor contributions from 2C19, 3A4, and 2D6. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitor activity.

Elimination. Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (including both absorbed and unabsorbed drug), with the remainder excreted in urine. About 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours and does not increase with dose escalation. The geometric mean value of plasma drug clearance is approximately 50 L/h (coefficient of variation – 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity. Systemic exposure to rosuvastatin increases proportionally with dose. With repeated daily administration, pharmacokinetic parameters remain unchanged.

Special patient groups.

Age and sex. No clinically significant effect of age or sex on rosuvastatin pharmacokinetics has been observed in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers.

Race. Pharmacokinetic studies have shown that median AUC and Cmax values in Mongoloid race patients (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) are approximately twice as high as in Caucasians; in Indians, median AUC and Cmax values are increased by approximately 1.3-fold. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and Negroid race patients.

Renal impairment. In a study involving patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in individuals with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin were 3 times higher and levels of the N-desmethyl metabolite were 9 times higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

Hepatic impairment. In a study of patients with varying degrees of hepatic dysfunction, no evidence of increased rosuvastatin exposure was observed in patients with Child-Pugh scores of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin use in patients with Child-Pugh scores greater than 9 is lacking.

Genetic polymorphism. The disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. With specific polymorphic forms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Routine genotyping is not required in clinical practice, but patients with such polymorphisms are recommended to receive a lower daily dose of the drug.

Acetylsalicylic acid.

Absorption. After oral administration, ASA is rapidly absorbed from the proximal part of the small intestine; however, during the absorption process, a significant portion of the dose is hydrolyzed in the gastric wall. Peak plasma concentration occurs within 0.5–2 hours. Food intake reduces the rate but not the extent of ASA absorption. During and after absorption, it is converted into its main active metabolite—salicylic acid.

Distribution. The volume of distribution of ASA is approximately 0.20 L/kg body weight. Salicylic acid is 90% bound to plasma proteins (primarily to albumin).

Salicylic acid slowly penetrates synovial and joint fluid, crosses the placenta, and is excreted into breast milk.

Metabolism. Salicylic acid formed by hydrolysis of ASA has a short elimination half-life of approximately 15–20 minutes.

Salicylic acid is further converted into glycine and glucuronic acid conjugates, and a small portion is oxidized to gentisic acid.

At higher therapeutic doses, the metabolic capacity for salicylic acid is increased, and pharmacokinetics become nonlinear. This increases the apparent elimination half-life of salicylic acid from several hours to approximately 24 hours.

Elimination. ASA is almost completely excreted by the kidneys as salicylic acid (about 10%), salicyluric acid (about 75%), and conjugates of salicyluric acid (about 10%). Tubular reabsorption of salicylic acid is pH-dependent. If urine is alkaline, the percentage of unchanged salicylic acid in excreted urine may increase from approximately 10% to 80%.

Preclinical data.

The preclinical safety profile of ASA is well documented. In animal studies, salicylates caused kidney damage without any other organ involvement. ASA has been extensively studied for mutagenicity and carcinogenicity; no relevant evidence of mutagenic or carcinogenic properties has been found. Salicylates showed embryotoxic and teratogenic effects in studies on various animal species (e.g., cardiac and skeletal malformations, gastroschisis).

Cases of implantation disorders, embryotoxic and fetotoxic effects, and effects on a child's learning ability after prenatal exposure to salicylates have been reported.

Clinical characteristics.

Indications.

The medicinal product is intended for secondary prevention of cardiovascular complications in adult patients whose condition is adequately controlled with rosuvastatin and acetylsalicylic acid at doses equivalent to those in this combination.

Contraindications.

Related to the combination of active substances:

• Hypersensitivity to rosuvastatin, salicylates, other non-steroidal anti-inflammatory drugs (NSAIDs), or to any of the excipients of the medicinal product.
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Pregnancy and breastfeeding. It is also contraindicated in women of childbearing potential who are not using appropriate contraceptive measures.

Related to rosuvastatin:

• Active liver disease, including unexplained persistent elevations of serum transaminases and any increase in serum transaminase levels exceeding three times the upper limit of normal.
• Myopathy. The 40 mg dose is contraindicated in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:
  • moderate renal impairment (creatinine clearance (CrCl) < 60 mL/min);
  • hypothyroidism;
  • personal or family history of hereditary muscular disorders;
  • history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
  • alcohol abuse;
  • conditions that may lead to increased plasma concentration of the drug;
  • Mongoloid race. The 40 mg dose of rosuvastatin is contraindicated in patients of Mongoloid race;
  • concomitant use of fibrates.
• Concomitant therapy with sofosbuvir, velpatasvir, voxilaprevir, or cyclosporine.

Related to acetylsalicylic acid:

• History of asthma, rhinitis, nasal polyps; contraindicated in patients with a history of mastocytosis in whom severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia, and vomiting) may occur upon administration of acetylsalicylic acid.
• Active or recurrent peptic ulcer and/or gastrointestinal bleeding, other types of bleeding, including cerebral hemorrhage.
• Hemorrhagic diathesis, coagulation disorders such as hemophilia and thrombocytopenia.
• Severe hepatic insufficiency.
• Severe congestive heart failure.
• Gout.
• Combination with methotrexate at doses of 15 mg/week or higher (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Rosuvastatin.

Effect of concomitant drugs on rosuvastatin.

Inhibitors of transporter proteins. Rosuvastatin is a substrate for certain transporter proteins, particularly the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of AspiRosa® with drugs that inhibit these transporters may increase rosuvastatin plasma concentrations and increase the risk of myopathy (see sections "Dosage and administration", "Special precautions", Table 2).

Cyclosporine. During concomitant use, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). The medicinal product is contraindicated in patients receiving cyclosporine (see section "Contraindications"). Concomitant use did not affect cyclosporine plasma concentrations.

Protease inhibitors. Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin AUC (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of the medicinal product with certain protease inhibitor combinations may be considered after careful evaluation of dose adjustment, considering the expected increase in rosuvastatin AUC (see sections "Special precautions", "Dosage and administration", Table 2).

Gemfibrozil and other lipid-lowering agents. Concomitant use of rosuvastatin and gemfibrozil leads to a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special precautions").

Based on data from specific studies, a pharmacokinetically significant interaction with fenofibrate is not expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, lipid-lowering agents (≥ 1 g/day), and niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used individually. The 40 mg dose of rosuvastatin is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special precautions"). Such patients should initiate therapy with a 5 mg dose.

Ezetimibe. Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse effects (see section "Special precautions").

Antacid medicinal products. Concomitant use of rosuvastatin with suspensions of antacids containing aluminum and magnesium hydroxides reduced rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin. Concomitant use of rosuvastatin and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Cytochrome P450 enzymes. Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. Furthermore, rosuvastatin is a weak substrate of these isoenzymes. Therefore, interactions via P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring dose adjustment of rosuvastatin (see also Table 2).

When co-administration of AspiRosa® with other medicinal products capable of increasing rosuvastatin exposure is necessary, the dose of the medicinal product should be adjusted. If an approximately 2-fold or greater increase in drug exposure (AUC) is expected, treatment with AspiRosa® should be initiated at a dose of 5 mg/100 mg once daily. The maximum daily dose of AspiRosa® should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting drugs; for example, when used with gemfibrozil, the rosuvastatin dose should be 20 mg (1.9-fold increase in exposure), and when used with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

(AUC; in descending order of magnitude)

Dosing regimen of the interacting medicinal product	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg – 100 mg – 100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg single dose	↑ 7.4-fold
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Paritaprevir 150 mg/ombitasvir 25 mg/ritonavir 100 mg once daily + dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3-fold
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2-fold
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Elvitegravir 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5-fold
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4-fold
Dronedarone 400 mg twice daily	Unknown	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4-fold **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold **
Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days	10 mg, single dose	↔
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	↔
Silymarin 140 mg three times daily, 5 days	10 mg, single dose	↔
Fenofibrate 67 mg three times daily, 7 days	10 mg, 7 days	↔
Rifampicin 450 mg once daily, 7 days	20 mg, single dose	↔
Ketoconazole 200 mg twice daily, 7 days	80 mg, single dose	↔
Fluconazole 200 mg once daily, 11 days	80 mg, single dose	↔
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baicalein 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%
* Data presented as fold change represent the ratio between rosuvastatin used in combination versus alone. Data presented as percentage change represent the percent difference compared to rosuvastatin used alone. Increases are indicated by ↑, no change by ↔, decreases by ↓. ** Multiple interaction studies were conducted at different rosuvastatin doses; the most significant ratio is reported in the table.

Effect of rosuvastatin on concomitant medicinal products.

Vitamin K antagonists. As with other HMG-CoA reductase inhibitors, initiation of treatment with the medicinal product AspiRosa® or increasing its dose in patients concurrently receiving vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation of the medicinal product or reduction of its dose may lead to a decrease in INR. In such cases, appropriate monitoring of INR values is recommended both at the beginning of rosuvastatin therapy and after discontinuation or subsequent dose adjustments.

Oral contraceptives/hormone replacement therapy (HRT). Concomitant use of rosuvastatin and oral contraceptives resulted in 26% and 34% increases in AUC of ethinylestradiol and norethisterone, respectively. This increase in plasma levels should be considered when selecting doses of oral contraceptives. There are no pharmacokinetic data available in patients who concurrently received rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, this combination has been widely used by women in clinical trials and was well tolerated.

Other medicinal products.

Digoxin. According to data from specific studies, clinically significant interaction with digoxin is not expected.

Fusidic acid. Studies on the interaction between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) has not yet been established. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination. In patients for whom systemic fusidic acid is considered necessary, treatment with AspiRosa® should be discontinued for the entire duration of fusidic acid therapy (see also section "Special precautions for use").

Acetylsalicylic acid.

The use of several platelet aggregation inhibitors, such as ASA, NSAIDs, ticlopidine, clopidogrel, tirofiban, eptifibatide, increases the risk of bleeding, as does their combination with heparin and its derivatives (hirudin, fondaparinux), oral anticoagulants, and thrombolytic agents. Clinical and biological parameters of hemostasis should be monitored regularly in patients scheduled for thrombolytic therapy.

Contraindicated combinations.

When ASA is used concomitantly with methotrexate in doses of 15 mg/week or higher, hematological toxicity of methotrexate increases (due to decreased renal clearance of methotrexate caused by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates) (see section "Contraindications").

Combinations not recommended.

• Uricosuric agents (e.g., benzbromarone, probenecid, sulfinpyrazone): Concomitant use of ASA with uricosuric agents is not recommended due to reduced efficacy resulting from competitive effects on renal tubular excretion of uric acid.
• Concomitant use with ASA increases plasma levels of phenytoin and valproate. When used concomitantly with valproic acid, ASA displaces it from plasma protein binding, reducing its metabolism. As a result, plasma levels of valproate increase, leading to a higher frequency of adverse reactions with signs of intoxication such as tremor, nystagmus, ataxia, and personality changes.
• Pharmacodynamic interactions may occur between selective serotonin reuptake inhibitors (SSRIs) and ASA, increasing the risk of bleeding due to synergistic effects.
• Concomitant use with ASA increases plasma concentrations of digoxin due to reduced renal excretion.
• Concomitant use of ASA with antidiabetic agents (e.g., insulin, sulfonylureas) may lead to decreased blood glucose levels.

Combinations requiring caution.

• Diuretics in combination with high doses of ASA: reduced diuretic effect. There is a risk of acute renal failure due to decreased glomerular filtration rate as a result of reduced renal prostaglandin synthesis. Reduced efficacy may also be caused by aldosterone antagonists (spironolactone and potassium canrenoate) or loop diuretics (e.g., furosemide). At the beginning of treatment, patients should consume sufficient fluids; renal function should be monitored.
• Systemic glucocorticoids: increased risk of gastrointestinal ulcers and bleeding. Decreased salicylate blood levels during corticosteroid therapy; risk of salicylate overdose after discontinuation of glucocorticoid therapy.
• Metotrexate at doses less than 15 mg/week: concomitant use of methotrexate and ASA increases hematological toxicity of methotrexate due to reduced renal clearance of methotrexate by acetylsalicylic acid. Weekly blood counts should be monitored during the first weeks of combined therapy. Careful monitoring is required even in cases of mild renal dysfunction and in elderly patients.
• Heparin: in patients receiving ASA and heparin concomitantly at therapeutic doses, as well as in elderly patients, the risk of bleeding is increased. When used together, international normalized ratio (INR), activated partial thromboplastin time (aPTT), and/or bleeding time should be carefully monitored.

Combinations with warnings.

• Other anticoagulants (coumarin derivatives, prophylactic doses of heparin), other antiplatelet agents, and other thrombolytic agents: increased risk of bleeding.
• NSAIDs: increased risk of gastrointestinal mucosal damage, bleeding, and prolonged bleeding time.
• Concomitant use with NSAIDs such as ibuprofen or naproxen may attenuate the irreversible inhibition of platelets by acetylsalicylic acid. The clinical significance of this interaction is unknown. Treatment with ibuprofen or naproxen in patients at risk of cardiovascular disease may limit the cardioprotective effect of ASA (see section "Special precautions for use").
• Metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation when taken concomitantly. Therefore, metamizole should be used with caution in patients taking low-dose acetylsalicylic acid for cardioprotection.
• Antacids may increase renal excretion of ASA, making the urine more alkaline.
• Alcohol: increased risk of gastrointestinal ulcers and bleeding, prolonged bleeding time.
• Antihypertensive agents (ACE inhibitors and β-blockers): when AspiRosa® is used concomitantly with these medicinal products, careful monitoring of the patient's blood pressure and dose adjustment if necessary are recommended.
• Enhanced effects of barbiturates, lithium, sulfonamides, and triiodothyronine.
• Prolonged plasma elimination half-life of penicillin.

Special precautions for use.

Rosuvastatin.

Renal effects.

Proteinuria, predominantly of tubular origin, detected by dipstick testing, has been observed in patients treated with high doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent. Proteinuria was not a predictor of acute or progressive kidney disease (see section "Adverse reactions"). The incidence of serious renal adverse events in post-marketing studies was higher with the 40 mg dose of rosuvastatin. In such cases, renal function should be monitored regularly in patients.

Myasthenia gravis.

Rare cases of statins inducing "de novo" or exacerbating pre-existing myasthenia gravis or ocular myasthenia have been reported (see section "Adverse reactions"). If symptoms worsen, treatment with the medicinal product AspiRosa®** should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.**

Musculoskeletal effects.

Adverse events related to the musculoskeletal system, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin, particularly at doses exceeding 20 mg. Rhabdomyolysis has very rarely been reported with ezetimibe used in combination with HMG-CoA reductase inhibitors. Since a pharmacodynamic interaction is possible, such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis associated with rosuvastatin is higher with the 40 mg dose.

Measurement of creatine kinase (CK) levels.

CK levels should not be measured following significant physical exertion or in the presence of other potential causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 times the upper limit of normal [ULN]), repeat testing should be performed within 5–7 days. If repeat testing confirms that baseline CK levels exceed 5 times ULN, treatment should not be initiated.

Before initiating treatment.

AspiRosa®, like other agents containing HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:

• renal dysfunction;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma concentrations of the drug (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• concomitant use of fibrates.

In such patients, the treatment-related risk should be weighed against the expected benefit; clinical monitoring is also recommended. If baseline CK levels are markedly elevated (> 5 × ULN), treatment should not be initiated.

During treatment.

Patients should be advised to promptly report any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The medicinal product should be discontinued if CK levels are markedly elevated (> 5 × UL0N) or if muscle symptoms are severe and cause daily discomfort (even if CK ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, therapy with AspiRosa® or an alternative HMG-CoA reductase inhibitor may be resumed at the lowest effective dose and under close monitoring. Routine monitoring of CK levels in patients without such symptoms is not necessary. Very rare cases of immune-mediated necrotizing myopathy have been reported during or after statin therapy, including rosuvastatin. Clinical features of immune-mediated necrotizing myopathy include proximal muscle weakness and elevated serum CK levels, which persist even after discontinuation of statins.

There is no evidence of increased musculoskeletal effects with the combination of rosuvastatin and concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors together with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, concomitant use of AspiRosa® with gemfibrozil is not recommended. The benefit of further lipid-lowering with AspiRosa® in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose of rosuvastatin is contraindicated with concomitant use of fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

AspiRosa® should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. For patients for whom systemic fusidic acid is considered life-saving, statin therapy should be discontinued 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 they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be resumed seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic action of fusidic acid is required, e.g., for treatment of severe infections, concomitant use of AspiRosa® and fusidic acid may be considered only under close medical supervision.

AspiRosa® should not be administered to patients with acute, serious conditions indicating myopathy or potential for renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Hepatic effects.

Like other products containing HMG-CoA reductase inhibitors, AspiRosa® should be used with caution in patients who abuse alcohol and/or have a history of liver disease. It is recommended to assess liver biochemical parameters before starting treatment and again after 3 months. Treatment should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The incidence of serious hepatic events (mainly elevated liver transaminases) is higher with the 40 mg dose of rosuvastatin. In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating therapy with AspiRosa®.

Rare cases of fatal and non-fatal liver failure have been reported in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice develops during treatment with rosuvastatin, the drug should be discontinued immediately. If no other cause is identified, re-initiation of AspiRosa® is not recommended.

Race.

Pharmacokinetic studies indicate approximately twofold higher exposure in patients of Mongoloid race compared to Caucasians (see sections "Dosage and administration", "Contraindications", and "Pharmacokinetics").

Protease inhibitors.

Increased systemic exposure to rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with AspiRosa® in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the start of therapy and with dose escalation in patients receiving protease inhibitors should be considered. Concomitant use of the medicinal product with certain protease inhibitors is not recommended unless the dose of AspiRosa® is adjusted (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Interstitial lung disease.

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

Diabetes mellitus.

Available data suggest that statins, as a class, may increase blood glucose levels and may cause hyperglycemia requiring treatment in some patients at high risk of developing diabetes mellitus in the future. However, this risk is outweighed by the reduction in vascular risk with statin therapy, and therefore should not be a reason to discontinue statin treatment. Patients at risk (fasting glucose 5.6–6.0 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglycerides, arterial hypertension) should be monitored clinically and biochemically according to current guidelines. In the JUPITER study, the overall incidence of diabetes mellitus was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

Children. Assessment of linear growth (height), body weight, BMI, and secondary sexual characteristics according to Tanner in children aged 6 to 17 years taking rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed. In studies in children and adolescents taking rosuvastatin for 52 weeks, CK levels > 10 times ULN and muscle symptoms following physical exertion or increased physical activity were observed more frequently compared to adults (see section "Adverse reactions").

The medicinal product should not be used in children (under 18 years of age) (see section "Children").

Acetylsalicylic acid.

Concomitant use of the medicinal product AspiRosa® with anticoagulants or other agents affecting hemostasis (e.g., warfarin, thrombolytics, antiplatelet agents, anti-inflammatory agents, and selective serotonin reuptake inhibitors) is not recommended unless absolutely necessary, as they increase the risk of bleeding. If concomitant use cannot be avoided, frequent monitoring of INR is indicated. Patients should be warned to watch for signs of bleeding, especially gastrointestinal bleeding.

Hypersensitivity to analgesics, anti-inflammatory, or anti-rheumatic agents, as well as allergy to other substances. Patients with allergic reactions (e.g., rash, pruritus, or urticaria), asthma, pollinosis, nasal mucosal edema (nasal polyps), or chronic respiratory diseases in their history should be closely monitored.

Patients with hypertension, history of peptic ulcers, chronic or recurrent peptic ulcer disease or gastrointestinal bleeding, symptoms of chronic gastric or duodenal dyspepsia or their recurrence, or concomitant use of drugs that increase the risk of ulcer development (such as oral corticosteroids, selective serotonin reuptake inhibitors, and deferasirox) should avoid acetylsalicylic acid (which may cause gastric mucosal irritation and bleeding).

Patients should report any unusual bleeding symptoms to their physician. If gastrointestinal bleeding or ulcers occur, treatment should be discontinued.

Elderly patients are at increased risk of adverse effects of NSAIDs, including acetylsalicylic acid, particularly gastrointestinal bleeding and perforation, which may be fatal. If long-term therapy is required, patients should be regularly reviewed.

Use with caution in patients with impaired liver function (contraindicated in severe cases), as acetylsalicylic acid is primarily metabolized in the liver. Liver function tests should be performed regularly in patients with mild to moderate hepatic impairment.

Caution is required in patients with impaired renal function or cardiovascular circulation (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or significant blood loss), as acetylsalicylic acid may increase the risk of renal dysfunction and acute renal failure.

Concomitant use of acetylsalicylic acid with uricosuric agents such as benzbromarone, probenecid, or sulfinpyrazone is not recommended.

The medicinal product is not recommended during menorrhagia, as it may exacerbate menstrual bleeding.

In surgical procedures (including dental), use of acetylsalicylic acid-containing products increases the likelihood of bleeding or increased bleeding due to inhibition of platelet aggregation. Temporary discontinuation of treatment should be considered on a case-by-case basis, usually one week prior to surgery.

Acetylsalicylic acid may contribute to Reye's syndrome in children. Reye's syndrome is a very rare condition affecting the brain and liver and may lead to fatal outcomes. The medicinal product should not be used in children (under 18 years of age).

In patients with glucose-6-phosphate dehydrogenase deficiency, acetylsalicylic acid may cause hemolysis or hemolytic anemia. Risk factors for hemolysis include high drug doses, fever, and acute infectious processes.

Alcohol consumption together with acetylsalicylic acid increases the risk of gastrointestinal tract injury. Patients should be aware of the risk of gastrointestinal tract damage and bleeding when taking rosuvastatin with acetylsalicylic acid and alcohol, especially with prolonged or heavy alcohol use.

Caution is required when concomitantly using NSAIDs such as ibuprofen or naproxen, as NSAIDs may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation.

Serious skin adverse reactions, including Stevens-Johnson syndrome, have been rarely reported in association with acetylsalicylic acid use. The medicinal product should be discontinued if any clinical signs of hypersensitivity reactions occur, including skin rash and mucosal lesions.

In low doses, acetylsalicylic acid may reduce uric acid excretion. This may trigger gout attacks in susceptible patients.

The risk of hypoglycemic effect with sulfonylureas and insulin may be increased with high-dose acetylsalicylic acid.

Important information on excipients.

Patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive measures.

If a patient becomes pregnant while taking this medicinal product, treatment should be discontinued immediately.

Pregnancy.

Rosuvastatin.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any benefit from using the medicinal product during pregnancy. Data from animal studies on reproductive toxicity are limited.

Acetylsalicylic acid.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage, cardiac malformations, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy.

Animal studies have shown that prostaglandin inhibitors increase pre- and post-implantation losses and embryo/fetal death. In addition, a higher frequency of severe developmental abnormalities, including cardiovascular malformations, has been observed in animals treated with prostaglandin inhibitors during organogenesis.

All prostaglandin synthesis inhibitors may:

affect the fetus through:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function with potential progression to renal failure and oligohydramnios;

affect the woman and fetus through:

• prolonged bleeding time, anti-aggregatory effect, which may occur even with very low doses;
• inhibition of uterine contractions and bleeding in the pregnant woman, and prolonged duration of labor.

Due to the above, acetylsalicylic acid is contraindicated during pregnancy.

Breastfeeding.

There are no data on the passage of rosuvastatin into human breast milk.

Salicylates are excreted into breast milk. Concentrations in breast milk are equivalent to or even higher than plasma concentrations in the mother.

Ability to influence reaction speed when driving or operating machinery.

Acetylsalicylic acid does not affect the ability to drive or operate machinery.

Studies on the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted. However, given the pharmacodynamic properties of the medicinal product, it is unlikely that AspiRosa® will affect this ability. Dizziness during treatment should be considered when driving or operating machinery.

Method of Administration and Dosage.

The recommended dose of the medicinal product AspiRosa® is 1 capsule per day. The medicinal product can be taken at any time of the day with food. Capsules should be swallowed with plenty of fluid and must not be crushed, broken, or chewed.

The fixed-dose combination is not suitable for initial therapy.

Prior to switching to the fixed combination, the patient's condition should be stabilized on individual doses of the respective monocomponent agents taken concomitantly.

The dosage of AspiRosa® should be identical to the doses of rosuvastatin and ASA previously administered as monocomponent agents at the time of transition.

If dose adjustment of either active component of the combination is required for any reason (e.g., newly diagnosed condition related to treatment, change in patient status, or drug interactions), the individual components should be reintroduced to establish appropriate dosing.

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

Elderly Patients.

Dose adjustment based on age is not required.

Patients with Renal Impairment.

Dose adjustment is not required in patients with mild to moderate renal impairment.

AspiRosa® is contraindicated in patients with severe renal impairment.

Patients with Hepatic Impairment.

Dose adjustment is not required in patients with mild to moderate hepatic impairment.

AspiRosa® is contraindicated in patients with severe hepatic impairment or active liver disease.

No increase in systemic exposure of rosuvastatin was observed in patients with a Child–Pugh score of 7 or lower. However, systemic exposure increased in individuals with a Child–Pugh score of 8–9 (see section "Pharmacokinetics"). In such patients, renal function should be assessed (see section "Special Warnings and Precautions for Use"). Experience with the medicinal product in patients with a Child–Pugh score greater than 9 is lacking.

Race.

Increased systemic exposure of rosuvastatin has been observed in Asian patients.

Genetic Polymorphism.

Certain types of genetic polymorphism may lead to increased exposure to rosuvastatin (see section "Pharmacokinetics"). Patients with such polymorphism types are recommended to receive a lower daily dose of AspiRosa®.

Concomitant Use.

Rosuvastatin is a substrate of various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products that may increase rosuvastatin plasma concentrations due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir-boosted atazanavir, lopinavir, and/or tipranavir; see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Where possible, alternative medicinal products should be considered, and temporary interruption of therapy may be necessary. If concomitant use of these medicinal products with AspiRosa® cannot be avoided, the benefit and risk of concomitant use should be carefully weighed, and the dose of AspiRosa® should be adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Higher doses of ASA may reduce the beneficial effect of rosuvastatin; therefore, additional doses of ASA should be avoided.

Children.

The safety and efficacy of the rosuvastatin/ASA combination in children (under 18 years of age) have not been established.

The medicinal product must not be used in children (under 18 years of age).

Overdose.

Rosuvastatin.

Experience in treating rosuvastatin overdose is limited to date; there is no specific antidote, and treatment is symptomatic.

Liver function and creatine kinase (CK) levels should be monitored. Hemodialysis is ineffective.

Acetylsalicylic Acid (ASA).

Overdose is unlikely due to the low ASA content in AspiRosa®. However, intoxication (accidental overdose) in very young children or therapeutic overdose in elderly individuals may manifest with symptoms such as dizziness, headache, tinnitus, hearing disturbances, confusion, and gastrointestinal disturbances (nausea, vomiting, and stomach pain).

Severe ASA intoxication may be life-threatening and may present with serious acid-base disturbances and hyperventilation, leading to respiratory alkalosis. Respiratory acidosis may occur due to respiratory center depression, and metabolic acidosis may develop due to the presence of salicylates in the blood.

Other possible manifestations include hyperthermia, increased sweating, possible dehydration, restlessness, seizures, hallucinations, and hypoglycemia. Central nervous system depression may lead to coma, cardiovascular collapse, and respiratory arrest.

Symptoms of chronic salicylate poisoning are nonspecific (e.g., tinnitus, headache, irritability, increased sweating, hyperventilation) and may therefore go unnoticed.

Symptoms of severe intoxication may develop acutely or gradually, for example, within 12–24 hours after ingestion. After oral administration of ASA doses up to 150 mg/kg body weight, moderate intoxication is possible, while doses > 300 mg/kg body weight may lead to severe intoxication.

ASA absorption may be delayed due to delayed gastric emptying or formation of gastric concretions.

The severity of the condition cannot be assessed based solely on plasma salicylate concentrations. Arterial blood gas analysis (ABGA) must be performed, as therapy is based not on blood salicylate levels but on clinical symptoms and ABGA findings.

Treatment.

Due to the life-threatening nature of severe intoxication, all necessary preventive measures should be taken immediately: immediate hospitalization, prevention or reduction of absorption by administering appropriate doses of activated charcoal within the first 4 hours (10-fold amount of activated charcoal relative to the ingested ASA mass); in cases of severe intoxication, gastric lavage or endoscopic tablet removal may be required.

Appropriate monitoring and correction of electrolytes are necessary. Administration of glucose and sodium bicarbonate in the early stages is indicated to correct acidosis and enhance elimination (urine pH > 8), improve diuresis, cooling in case of hyperthermia, and benzodiazepines for seizures.

Hemodialysis may be considered in cases of severe intoxication (to remove ASA).

Cases of decompensation leading to fatal outcomes after intubation have been reported. Therefore, if possible, intubation should be performed after initiation of alkalization, apnea time should be minimized, and maintenance of hyperventilation should be ensured.

Adverse Reactions

All adverse reactions are listed by organ systems and frequency: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1,000 – < 1/100), rare (≥ 1/10,000 – < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Adverse reactions associated with rosuvastatin:

Adverse events observed during rosuvastatin use are generally mild and transient.

Eye disorders: frequency not known: ocular myasthenia.

Blood and lymphatic system disorders: rare: thrombocytopenia.

Immune system disorders: rare: hypersensitivity reactions, including angioedema.

Endocrine disorders: common: diabetes mellitus^1.

Psychiatric disorders: frequency not known: depression.

Nervous system disorders: common: headache, dizziness; very rare: polyneuropathy, memory loss; frequency not known: peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis.

Respiratory, thoracic and mediastinal disorders: frequency not known: cough, dyspnea.

Gastrointestinal disorders: common: constipation, nausea, abdominal pain; rare: pancreatitis; frequency not known: diarrhea.

Hepatobiliary disorders: rare: increased levels of liver transaminases; very rare: jaundice, hepatitis^4,5.

Skin and subcutaneous tissue disorders: uncommon: pruritus, rash, urticaria; frequency not known: Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders: common: myalgia; rare: myopathy (including myositis), rhabdomyolysis^5, lupus-like syndrome, muscle rupture; very rare: arthralgia; frequency not known: tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy^3.

Renal and urinary disorders: very rare: hematuria^2,5.

Reproductive system and breast disorders: very rare: gynecomastia.

General disorders: common: asthenia; frequency not known: edema.

Adverse reactions associated with acetylsalicylic acid (ASA):

In patients with severe glucose-6-phosphate dehydrogenase deficiency, hemolysis and hemolytic anemia have been observed during ASA use.

Due to the antiplatelet effect of ASA, the risk of bleeding is increased. Bleeding events such as perioperative bleeding, hematoma, epistaxis, urogenital bleeding, and gingival bleeding have been reported.

Serious bleeding events, such as gastrointestinal bleeding and hemorrhagic stroke, have been observed rarely or very rarely, especially in patients with uncontrolled arterial hypertension and/or concomitant use of anticoagulants, which may be life-threatening in some cases.

Blood and lymphatic system disorders: common: prolonged bleeding time; rare: thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, iron-deficiency anemia^6.

Immune system disorders: uncommon: asthma; rare: hypersensitivity reactions such as erythematous/eczematous skin reactions, urticaria, rhinitis, nasal congestion, bronchospasm, angioedema, hypotension progressing to shock; very rare: severe skin reactions, including exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis^8.

Metabolism and nutritional disorders: very rare: hypoglycemia, acid-base imbalance; frequency not known: gout attacks.

Ear and labyrinth disorders: rare: tinnitus, hearing disturbances.

Respiratory, thoracic and mediastinal disorders: uncommon: rhinitis, dyspnea; rare: bronchospasm, asthma attacks.

Nervous system disorders: rare: headache, dizziness, confusion.

Gastrointestinal disorders: common: microbleeding^6 (70%), gastrointestinal symptoms (heartburn, nausea, vomiting, abdominal pain), diarrhea; uncommon: dyspepsia, gastrointestinal inflammation, gastrointestinal bleeding^6, gastrointestinal ulcers, which in very rare cases may lead to perforation^7.

Hepatobiliary disorders: rare: hepatic dysfunction; very rare: increased transaminase levels, Reye's syndrome.

Renal and urinary disorders: rare: renal impairment; acute renal failure has been reported.

Eye disorders: rare: visual disturbances.

^1 Frequency depends on the presence or absence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglycerides, history of arterial hypertension).

As with other HMG-CoA reductase inhibitors, the incidence of adverse reactions tends to be dose-dependent.

^2 Proteinuria detected by urine dipstick testing is predominantly of tubular origin and has been observed in patients taking rosuvastatin. Changes in urinary protein content from negative or trace to ++ or higher were observed in < 1% of patients intermittently during treatment with rosuvastatin at doses of 10 and 20 mg, and in approximately 3% at the 40 mg dose. A slight increase in the frequency of changes from negative or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued therapy. Based on clinical studies and post-marketing surveillance, no causal relationship has been established between proteinuria and acute or progressive kidney disease to date.

Cases of hematuria have been reported during rosuvastatin use; clinical studies indicate a low frequency.

^3 Skeletal muscle disorders such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure have been reported with all doses of rosuvastatin, but more frequently at doses > 20 mg.

Dose-dependent increases in creatine kinase (CK) levels have been observed in patients taking rosuvastatin; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 × ULN), treatment should be discontinued (see section "Special Warnings and Precautions for Use").

^4 As with other HMG-CoA reductase inhibitors, dose-dependent increases in transaminase levels have been observed in a small number of patients taking rosuvastatin; in most cases, this was mild, asymptomatic, and transient.

The following adverse events have been reported with some statins:

• Sexual dysfunction;
• Isolated cases of interstitial lung disease, particularly with long-term use (see section "Special Warnings and Precautions for Use").

^5 The frequency of reports of rhabdomyolysis, serious renal and hepatic disorders (mainly elevated hepatic transaminase activity) is higher with the 40 mg dose of rosuvastatin.

^6 Bleeding may lead to acute and chronic post-hemorrhagic anemia/iron-deficiency anemia (due to so-called occult microbleeding) with corresponding laboratory findings and clinical symptoms such as asthenia, pallor of the skin, and hypoperfusion.

Iron-deficiency anemia due to occult gastrointestinal blood loss may occur after prolonged use of 100 mg ASA.

^7 Gastrointestinal disorders such as general symptoms and signs of dyspepsia, epigastric pain, and abdominal pain; in individual cases, gastrointestinal inflammation, erosive-ulcerative lesions of the gastrointestinal tract, which may rarely cause gastrointestinal hemorrhage and perforation, with corresponding laboratory and clinical manifestations.

^8 Hypersensitivity reactions with corresponding laboratory and clinical manifestations include asthmatic episodes, mild to moderate skin reactions, and reactions involving the respiratory tract, gastrointestinal tract, and cardiovascular system, including symptoms such as rash, swelling, pruritus, cardiorespiratory failure, and very rarely severe reactions including anaphylactic shock.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging. 10 capsules per blister; 3 blisters per carton.

Prescription status. Prescription only.

Marketing Authorization Holder. JSC "Pharmaceutical Company "Darnitsya".

Address of the Marketing Authorization Holder and location of its business activities.

13 Borispilska Street, Kyiv, 02093, Ukraine.

Manufacturer. Adamed Pharma S.A.

Address of the Manufacturer and location of its business activities.

5 Marshal Józef Piłsudski Street, Pabianice, 95–200, Poland.