Rozzor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROZOR (ROZZOR)

Composition:

Active substances: acetylsalicylic acid, rosuvastatin;

1 hard capsule contains:

1 tablet of acetylsalicylic acid 75 mg and 2 tablets of rosuvastatin 2.5 mg each (as rosuvastatin calcium 2.60 mg each),

or 1 tablet of acetylsalicylic acid 75 mg and 2 tablets of rosuvastatin 5 mg each (as rosuvastatin calcium 5.20 mg each),

or 1 tablet of acetylsalicylic acid 75 mg and 2 tablets of rosuvastatin 10 mg each (as rosuvastatin calcium 10.40 mg each);

Excipients:

for acetylsalicylic acid tablets: microcrystalline cellulose, anhydrous citric acid, talc, colloidal anhydrous silicon dioxide, sodium croscarmellose, hypromellose, polyethylene glycol 6000 (macrogol 6000), titanium dioxide (E 171);

for rosuvastatin tablets: lactose monohydrate; microcrystalline cellulose; calcium hydrogen phosphate; sodium croscarmellose; magnesium stearate; talc; colloidal anhydrous silicon dioxide; hypromellose; titanium dioxide (E 171); polyethylene glycol 6000 (macrogol 6000); iron oxide (E 172);

capsule (body and cap): gelatin, titanium dioxide (E 171), water.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: opaque, hard, white or almost white gelatin capsules containing one film-coated acetylsalicylic acid tablet, white or almost white, and two film-coated rosuvastatin tablets, yellow-brown in color.

Pharmacotherapeutic group.

Lipid-lowering agents. Lipid-lowering agents, combinations. HMG-CoA reductase inhibitors, other combinations. Rosuvastatin and acetylsalicylic acid.

ATC code C10BX05.

Pharmacological properties.

Pharmacodynamics.

Acetylsalicylic acid

Acetylsalicylic acid inhibits platelet aggregation. Although its mechanism of action is not completely understood, the effect is probably mainly due to acetylation and irreversible inactivation of the enzyme cyclooxygenase (COX-1), which is involved in the formation of thromboxane A2 in platelets and prostacyclin in vascular endothelium. This significantly affects platelet aggregation and vasodilation. The anti-aggregatory effect is particularly pronounced for platelets, since they are unable to resynthesize cyclooxygenase. Thus, the effect persists throughout the entire platelet life cycle, which lasts 7–10 days. Prophylactic and therapeutic use in arterial thromboembolism is based on the aforementioned effect.

Acetylsalicylic acid inhibits prostacyclin synthesis in the kidneys. In patients with normal renal function, this effect is not significant. In patients with chronic renal failure, heart failure or hepatic failure, as well as those with reduced plasma volume, inhibited prostacyclin synthesis may lead to the development of acute renal failure, fluid retention, and severe heart failure (see section "Contraindications").

Experimental data indicate that ibuprofen may reduce the inhibitory effect of low-dose acetylsalicylic acid on platelet aggregation when both drugs are administered concomitantly. In a study, patients received ibuprofen 400 mg either 8 hours before or 30 minutes after acetylsalicylic acid 81 mg. Under these conditions, a reduction in the effect of acetylsalicylic acid on thromboxane formation and platelet aggregation was observed. Due to the limited and uncertain extrapolation of in vitro data, conclusions regarding the possibility of regular ibuprofen use cannot be made, and during short-term ibuprofen use, the impact on efficacy and clinical significance is unlikely to be relevant.

Rosuvastatin

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that determines the rate-limiting step in the conversion of 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 reducing cholesterol levels.

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

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of LDL cholesterol, total cholesterol, and triglycerides, and increases HDL cholesterol levels. It also reduces levels of apolipoprotein B (apoB), cholesterol not associated with high-density lipoproteins (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), very-low-density lipoprotein triglycerides (VLDL-TG), and increases apolipoprotein A-I (apoA-I) levels (see Table 1). Rosuvastatin 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	Triglycerides	Non-HDL-C	apoB	apoA-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5 mg	17	-45	-33	13	-35	-44	-38	4
10 mg	17	-52	-36	14	-10	-48	-42	4
20 mg	17	-55	-40	8	-23	-51	-46	5
40 mg	18	-63	-46	10	-28	-60	-54	0

Therapeutic effect is achieved within 1 week after starting the medication, with 90% of the maximum effect reached within 2 weeks. Maximum effect is usually achieved within 4 weeks and persists thereafter.

Pharmacokinetics.

Acetylsalicylic acid

Absorption

Absorption of acetylsalicylic acid occurs primarily in the small intestine and partially in the stomach. Maximum plasma concentration of acetylsalicylic acid is reached within 40 minutes.

Distribution

Acetylsalicylic acid is hydrolyzed with a half-life of 30 minutes to salicylic acid, which in therapeutic doses is approximately 80% bound to albumin.

Elimination

Elimination of salicylic acid is dose-dependent. With daily doses < 3 g, the elimination half-life is 2–4 hours. Salicylic acid and its metabolites are primarily excreted by the kidneys.

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. Approximately 90% of rosuvastatin is bound to plasma proteins, primarily albumin.

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main 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 (both absorbed and unabsorbed active substance), with the remainder excreted in urine. Approximately 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 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. Pharmacokinetic parameters do not change with repeated daily administration.

Special patient groups

Age and sex

No clinically significant effect of age or sex on the pharmacokinetics of rosuvastatin in adults has been observed.

Race

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

Renal impairment

In a study involving patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite were observed in patients with mild or moderate renal insufficiency. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin were 3 times higher and levels of 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 involving patients with varying degrees of hepatic dysfunction, no evidence of increased rosuvastatin exposure was observed in patients scoring 7 or less on the Child-Pugh scale. However, in two patients scoring 8 and 9 on the Child-Pugh scale, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin use in patients scoring more than 9 on the Child-Pugh scale is lacking.

Genetic polymorphism

The distribution 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 polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Special genotyping is not required in clinical practice, but patients with such polymorphisms should be prescribed a lower daily dose of rosuvastatin.

Clinical characteristics.

Indications.

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

Contraindications.

Related to the combination of active substances

• Hypersensitivity to rosuvastatin, salicylates, other nonsteroidal anti-inflammatory drugs (NSAIDs), or any of the excipients of the medicinal product;
• severe renal impairment (creatinine clearance < 30 mL/min);
• pregnancy and breastfeeding; the drug is also contraindicated in women of childbearing potential who are not using appropriate contraceptive methods.

Related to acetylsalicylic acid

• asthma, rhinitis, angioedema, or urticaria induced by acetylsalicylic acid or NSAIDs;
• hemophilia;
• thrombocytopenia;
• active peptic ulcer of the stomach or duodenum;
• liver cirrhosis;
• hemorrhagic diathesis;
• 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 forms of interaction").

Related to rosuvastatin

• active liver disease, including persistent elevations of serum transaminases of unknown etiology and any increases in serum transaminases exceeding the upper limit of normal (ULN) by 3 times;
• myopathy. The 40 mg dose of rosuvastatin is contraindicated in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:
  • moderate renal impairment (creatinine clearance < 60 mL/min);
  • hypothyroidism;
  • personal or family history of hereditary muscle disorders;
  • history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
  • alcohol abuse;
  • situations that may lead to increased plasma concentration of the drug;
  • Mongoloid race;
  • concomitant use of fibrates (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Special precautions");
• concomitant use with the combination sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
• concomitant use with cyclosporine.

Interaction with other medicinal products and other forms of interaction.

Interaction studies of the combination acetylsalicylic acid/rosuvastatin with other medicinal products have not been conducted. The information below refers only to interactions known for each individual component of the medicinal product.

Acetylsalicylic acid

Anticoagulants, thrombolytics/other platelet aggregation inhibitors, selective serotonin reuptake inhibitors (SSRIs)

Salicylates inhibit platelet function and thus enhance the effect of anticoagulants/thrombolytics, barbiturates, lithium, sulfonamides, and triiodothyronine. Due to increased risk of bleeding, caution should be exercised when combining acetylsalicylic acid with anticoagulants, thrombolytics, or other platelet aggregation inhibitors. Monitoring of coagulation is recommended. Pharmacodynamic interactions may occur between SSRIs and acetylsalicylic acid: increased risk of bleeding due to synergistic effect.

Cyclosporine, tacrolimus

Concomitant use of NSAIDs with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Renal function should be monitored when NSAIDs are used concomitantly with either of these drugs.

Diuretics and antihypertensive agents

NSAIDs may reduce the efficacy of diuretics and antihypertensive drugs. As with other NSAIDs, concomitant use of ACE inhibitors with acetylsalicylic acid may increase the risk of acute renal failure.

Corticosteroids and other NSAIDs

Concomitant use with NSAIDs such as ibuprofen or naproxen may reduce the irreversible platelet inhibition by acetylsalicylic acid. The clinical significance of this interaction is unknown. Treatment with NSAIDs such as ibuprofen or naproxen in patients at risk of cardiovascular disease may limit the cardioprotective effect of acetylsalicylic acid (see section "Special precautions").

Systemic glucocorticoids may increase the risk of gastrointestinal ulcers and bleeding. Glucocorticoid therapy reduces salicylate blood levels, and after discontinuation of glucocorticoids, there is a risk of salicylate overdose.

Medicinal products increasing uric acid excretion (probenecid)

Salicylates neutralize the effect of probenecid; therefore, their concomitant use should be avoided.

Ibuprofen

Experimental data indicate that ibuprofen may reduce the inhibitory effect of low-dose acetylsalicylic acid on platelet aggregation when used concomitantly. Due to limited and uncertain extrapolation of in vitro data, conclusions about the possibility of regular ibuprofen use cannot be made; however, for temporary use, the effect and clinical significance are unlikely to be relevant.

Metamizole

Concomitant use of metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation. This combination should be prescribed with caution to patients taking low-dose acetylsalicylic acid as a cardioprotector.

Metotrexate

Concomitant use of methotrexate and acetylsalicylic acid increases hematological toxicity of methotrexate due to reduced renal clearance of methotrexate by acetylsalicylic acid (see section "Contraindications"). Weekly blood counts should be monitored during the first weeks of combined therapy. Careful monitoring is required even in patients with mild renal dysfunction and in elderly patients.

Digoxin

Acetylsalicylic acid inhibits renal excretion of digoxin, leading to increased plasma concentration of the drug. Monitoring of digoxin plasma concentration is recommended. Dose adjustment may be necessary.

Valproic acid

It has been reported that acetylsalicylic acid reduces valproate binding to serum albumin, thereby increasing its free plasma concentration at steady state. This leads to an increased frequency of adverse reactions with signs of intoxication such as tremor, nystagmus, ataxia, and personality changes.

Phenytoin

Salicylates reduce phenytoin binding to plasma albumin. This may lead to decreased total phenytoin plasma levels and increased free fraction of phenytoin. However, the increased concentration of unbound phenytoin in plasma does not significantly affect therapeutic efficacy.

Sulfonylurea preparations

Salicylic acid is believed to enhance the hypoglycemic effect of sulfonylurea drugs. Several reports confirm this effect. The mechanism is unclear but may involve reduced binding of sulfonylurea to serum albumin. Concomitant use of acetylsalicylic acid reduces total serum concentration of glyburide and increases its clearance.

Nicotinic acid

In a study, administration of acetylsalicylic acid (1 g) resulted in a sharp increase in plasma concentration of nicotinic acid. The mechanism likely involves competitive inhibition of glycine conjugation of nicotinic acid.

Alcohol

Alcohol increases the risk of gastrointestinal ulcers and bleeding, prolongs bleeding time.

Penicillins

The plasma half-life of penicillin is prolonged.

Rosuvastatin

Effect of concomitant drugs on rosuvastatin

Inhibitors of transport proteins

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

Cyclosporine

In patients concomitantly using rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients receiving cyclosporine concomitantly (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 exposure (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing 2 protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of rosuvastatin with certain combinations of protease inhibitors may be possible after careful dose adjustment of rosuvastatin due to expected increased exposure (see Table 2 and sections "Special precautions", "Dosage and administration").

Gemfibrozil and other lipid-lowering agents

Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special precautions").

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses (≥ 1 g/day) of 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 is contraindicated when used concomitantly with fibrates (see sections "Contraindications" and "Special precautions"). Such patients should also start therapy with a 5 mg dose.

Ezetimibe

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

Antacid preparations

Concomitant use of rosuvastatin with suspensions of antacids containing aluminum hydroxide or magnesium hydroxide 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 peristalsis caused by erythromycin.

Cytochrome P450 enzymes

Results of in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. Additionally, rosuvastatin is a weak substrate of these isoenzymes. Thus, interactions with medicinal products due to P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (inhibitor of CYP2C9 and CYP3A4) or ketoconazole (inhibitor of CYP2A6 and CYP3A4).

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

If rosuvastatin must be used concomitantly with other drugs capable of increasing rosuvastatin exposure, the dose of the drug should be adjusted. If exposure (AUC) is expected to increase by approximately 2 times or more, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that its expected exposure does not exceed the exposure observed with a 40 mg/day dose without interacting drugs: for example, when used with gemfibrozil, the rosuvastatin dose would be 20 mg (exposure increase 1.9 times), when used with ritonavir/atazanavir combination – 10 mg (exposure increase 3.1 times).

If rosuvastatin AUC increases by less than 2 times, initial dose reduction is not required, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 2 – Effect of concomitant medicinal products on rosuvastatin exposure (AUC; in descending order of magnitude) based on published data from clinical studies

Increased AUC of rosuvastatin by 2 times or more
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	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 up to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-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
Obritasvir 25 mg/paritaprevir 150 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
Increased AUC of rosuvastatin less than 2-fold
Eltrombopag 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**
Decreased AUC of rosuvastatin
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baykaline 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 rosuvastatin used alone. Data presented as % change represent the % difference relative to values when rosuvastatin is used alone.

Increases are indicated by ↑, decreases by ↓.

**Several interaction studies were conducted at different doses of rosuvastatin; the most significant ratio is presented in Table 2.

Medicinal products/combinations that had no clinically significant effect on rosuvastatin AUC when co-administered: aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg three times daily, 7 days; fluconazole 200 mg once daily, 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days; ketoconazole 200 mg twice daily, 7 days; rifampicin 450 mg once daily, 7 days; silymarin 140 mg three times daily, 5 days.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation of rosuvastatin or reduction of its dose may lead to a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of these agents in patients receiving rosuvastatin and HRT concurrently; therefore, a similar effect cannot be excluded. However, the combination has been widely used by women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on specific interaction studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Interaction studies 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 fully elucidated. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination.

In patients for whom systemic fusidic acid treatment is considered necessary, rosuvastatin therapy should be discontinued for the entire duration of fusidic acid treatment. See also section "Special precautions".

Special precautions for use.

Acetylsalicylic acid

Acetylsalicylic acid should be used with caution in the following situations:

• Impaired renal function or cardiovascular circulation disorders (e.g., renal vascular disease, congestive heart failure, hypovolemia, extensive surgery, sepsis, or severe bleeding), as acetylsalicylic acid may increase the risk of renal dysfunction and acute renal failure;
• Impaired liver function;
• Concomitant use of NSAIDs such as ibuprofen or naproxen, as NSAIDs may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If acetylsalicylic acid is used for cardioprotection, patients should consult their physician before initiating NSAID therapy for pain relief (see section "Interaction with other medicinal products and other forms of interaction");
• Symptoms of chronic gastric or duodenal dyspepsia or their recurrence;
• Bronchial asthma or general tendency to hypersensitivity, as acetylsalicylic acid may induce bronchospasm or an asthma attack or other hypersensitivity reactions. Risk factors include a history of asthma, hay fever, nasal polyps, or chronic respiratory disease: allergic reactions (e.g., rash, pruritus, or urticaria) to other substances in the past;
• Nasal polyps;
• Glucose-6-phosphate dehydrogenase deficiency, as acetylsalicylic acid may cause hemolysis or hemolytic anemia. Factors that may increase the risk of hemolysis include high drug doses, fever, or acute infectious illness;
• Concomitant use of anticoagulants;
• Due to the inhibitory effect of acetylsalicylic acid on platelet aggregation, which persists for several days after administration, the use of products containing acetylsalicylic acid may increase the likelihood or severity of bleeding during surgical procedures (including minor surgeries, such as tooth extraction).

When used in low doses, acetylsalicylic acid reduces the excretion of uric acid. In patients who normally have reduced uric acid excretion, this may lead to the development of gout.

Although the medicinal product is not intended for use in children, one of the components of the medicinal product ROZSOR, namely acetylsalicylic acid, when used in children and adolescents with fever and/or viral infections, may increase the risk of Reye's syndrome, a life-threatening encephalopathy characterized primarily by severe vomiting, loss of consciousness, and hepatic dysfunction. Reye's syndrome requires immediate medical intervention. The risk may be increased if acetylsalicylic acid is used as a concomitant medicinal product, although a causal relationship has not been established. If these conditions are accompanied by persistent vomiting, this may be a manifestation of Reye's syndrome.

Treatment should be discontinued at the first signs of gastrointestinal bleeding or ulceration (see section "Contraindications").

Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as allergy to other substances, requires careful monitoring of patients with a history of allergic reactions.

Rare cases of serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with the use of acetylsalicylic acid (see section "Adverse reactions"). Treatment should be discontinued at the first signs of rash, mucosal lesions, or other signs of hypersensitivity.

Rosuvastatin

Renal effects

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

Musculoskeletal effects

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, particularly above 20 mg. Very rarely, cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be ruled out (see section "Interaction with other medicinal products and other forms of interaction"), and therefore such a combination should be used with caution.

As with other HMG-CoA reductase inhibitors, the frequency of post-marketing reports of rhabdomyolysis associated with rosuvastatin use was higher with the 40 mg dose.

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

Creatine kinase levels

Creatine kinase (CK) levels should not be measured after significant physical exertion or in the presence of possible alternative 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]), a repeat test should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK values exceed 5 times the ULN, treatment should not be initiated.

Before starting treatment

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

• Impaired renal function;
• 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;
• Situations that may lead to increased plasma levels of the drug (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Method of administration and dosage");
• 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 times ULN), treatment should not be initiated.

During treatment

Patients should be advised to report immediately any unexplained muscle pain, weakness, or tenderness, 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 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be resumed at the lowest dose and under close supervision. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin. Clinical manifestations of IMNM include proximal muscle weakness and elevated serum creatine kinase levels, which persist even after discontinuation of statins.

Clinical trials have not provided evidence of increased musculoskeletal effects in a small number of patients taking rosuvastatin and concomitant medications. However, an increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, the use of rosuvastatin in combination with gemfibrozil is not recommended. The benefit of further lipid-lowering with rosuvastatin 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 when used concomitantly with fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is considered essential, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving a combination of fusidic acid and statins (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 restarted seven days after the last dose of fusidic acid. In exceptional cases, when prolonged systemic fusidic acid is required, e.g., for the treatment of severe infections, the need for concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and such therapy should be conducted under close medical supervision.

Rosuvastatin should not be used in 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).

Severe skin reactions

Severe skin reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported during rosuvastatin use (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and monitored closely. If signs or symptoms indicating such severe skin reactions occur, use of the medicinal product ROZSOR should be discontinued immediately and alternative therapy considered.

If a patient develops a severe skin reaction such as Stevens-Johnson syndrome or DRESS syndrome while taking the medicinal product ROZSOR, this product must not be used in the future.

Hepatic effects

Like other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease.

It is recommended to check liver function biochemistry before starting treatment and again after 3 months. Rosuvastatin use should be discontinued or the dose reduced if serum transaminase levels exceed three times the ULN. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose.

In the post-marketing period, 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 causes are identified, treatment with rosuvastatin should not be resumed.

Race

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

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 rosuvastatin 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 drug with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").

Lactose intolerance

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

Interstitial lung disease

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

Diabetes mellitus

Some evidence suggests that statins increase blood glucose levels and may cause hyperglycemia in some patients at high risk of developing diabetes mellitus, to a level requiring appropriate diabetes treatment. However, this risk is outweighed by the reduction in vascular risk with statin use, and therefore should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, BMI > 30 kg/m², elevated triglycerides, arterial hypertension) should be monitored both clinically and biochemically according to national 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, primarily in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

Excipients

Sodium content

The medicinal product ROZSOR contains less than 1 mmol sodium (23 mg) per capsule, i.e., it is almost sodium-free.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated in women during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive measures.

If a patient becomes pregnant during treatment with this medicinal product, treatment should be discontinued immediately.

Acetylsalicylic acid

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy. Epidemiological data indicate an increased risk of miscarriage and of congenital heart defects and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy.

The risk is considered to increase with increasing dose of acetylsalicylic acid and duration of treatment. In animals, administration of prostaglandin synthesis inhibitors has been shown to increase pre- and post-implantation losses and embryo/fetal death. Increased frequency of multiple malformations, including cardiovascular, has also been reported in animals exposed to prostaglandin synthesis inhibitors during organogenesis.

All prostaglandin synthesis inhibitors may:

• Affect the fetus:
  • Cardio-pulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
  • Impaired renal function, which may lead to renal failure and thus reduced amniotic fluid volume;
• Affect the mother and fetus:
  • Prolonged bleeding time, antiplatelet aggregation effect, which may occur even at very low doses;
  • Inhibition of uterine contractions, which may lead to delayed/prolonged labor.

Breastfeeding

Low amounts of salicylates and their metabolites pass into breast milk. Concentrations in breast milk are equivalent to or even higher than plasma concentrations in the mother.

Rosuvastatin

Pregnancy

Since cholesterol and other products of cholesterol biosynthesis play a crucial role in fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefit of using the drug during pregnancy. Data from animal studies on toxic effects on reproductive function are limited.

Breastfeeding

Rosuvastatin passes into the milk of rats. Data on the passage of the drug into human breast milk are not available (see section "Contraindications").

Ability to influence reaction speed when driving or operating machinery.

Acetylsalicylic acid

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

Rosuvastatin

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 drug, it is unlikely that rosuvastatin will affect this ability. When driving or operating machinery, the possibility of dizziness during treatment should be taken into account.

Method of Administration and Dosage

The dose should be individually adjusted depending on the therapeutic goal and the patient's response to treatment, following recommendations of current accepted guidelines.

The medicinal product can be taken at any time of day, regardless of food intake.

Dosage

Prior to switching to this medicinal product, the patient's condition should be adequately controlled with unchanged doses of the individual monotherapy agents currently being taken concurrently. The dose of the medicinal product should correspond to the doses of the individual components of the combination being used at the time of the switch.

The recommended initial dose of the medicinal product is 75 mg/5 mg or 75 mg/10 mg orally once daily, both for patients who have not previously used statins and for those switching from another HMG-CoA reductase inhibitor. When selecting the initial dose, the individual patient's cholesterol levels and future cardiovascular risk, as well as the likelihood of adverse reactions, should be taken into account. If necessary, the dose may be increased to 75 mg/20 mg, but only after 4 weeks.

The maximum recommended dose of the medicinal product is 75 mg/20 mg.

Specific Patient Groups

Elderly Patients

The recommended initial dose for patients aged >70 years is 75 mg/5 mg (see section "Special Warnings and Precautions for Use"). No other dose adjustment based on age is required.

Patients with Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment.

The recommended initial dose for patients with moderate renal impairment (creatinine clearance < 60 mL/min) is 75 mg/5 mg.

The use of the medicinal product is contraindicated in patients with severe renal impairment at any dose (see sections "Pharmacokinetics" and "Contraindications").

Patients with Hepatic Impairment

In patients with hepatic impairment scoring 7 or less on the Child–Pugh scale, no increase in systemic exposure to rosuvastatin was observed. However, in individuals scoring 8 or 9 on the Child–Pugh scale, systemic exposure increased (see section "Pharmacokinetics"). Renal function assessment is advisable in such patients (see section "Special Warnings and Precautions for Use"). Experience with the medicinal product in patients scoring more than 9 points on the Child–Pugh scale is lacking. The medicinal product is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to the medicinal product has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use"). The recommended initial dose for patients of Asian origin is 75 mg/5 mg.

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased rosuvastatin exposure (see section "Pharmacokinetics"). Patients known to have such polymorphism types are recommended to receive a lower daily dose (75 mg/5 mg) of the medicinal product.

Patients with Predisposition to Myopathy

The recommended initial dose for patients with risk factors for myopathy is 75 mg/5 mg (see section "Special Warnings and Precautions for Use").

Concomitant Use

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

Children

The medicinal product is not intended for use in children.

Overdose

Acetylsalicylic Acid

Symptoms

Dizziness, tinnitus, hearing loss, restlessness, irritability, hallucinations, tremor, ringing in the ears, hyperventilation, thirst sensation, skin flushing, sweating. In severe cases – loss of consciousness, seizures, hyperthermia, nausea, vomiting, abdominal pain, respiratory alkalosis in adults. Hypokalemia, dehydration, increased ammonia levels, oliguria, coagulation disorders, renal function impairment. In severe cases, there is a risk of non-cardiogenic pulmonary edema, rhabdomyolysis, and renal failure. Acute respiratory distress syndrome (ARDS), arrhythmias, and heart failure may develop.

Treatment

Administration of gastric emptying agents. Activated charcoal significantly shortens elimination time. Rehydration, correction of metabolic acidosis and possibly electrolyte imbalances. Omeprazole for gastric mucosal protection. Use of antiemetics, urinary alkalinization with sodium bicarbonate to enhance salicylate elimination, glucose administration. Coagulation parameters should be monitored. Vitamin K is administered in cases of severe poisoning or coagulation disorders. In cases of bleeding disorders, platelet concentrate and/or fresh frozen plasma should be administered. If insufficient response, antifibrinolytic agents may be used. Supportive care for unconsciousness. In cases of severe poisoning (moderate or high salicylate concentration combined with pronounced acidosis and CNS disturbances) and in renal failure, hemodialysis should also be considered. Symptomatic therapy (e.g., for hyperthermia, cerebral edema, pulmonary edema).

Rosuvastatin

There is no specific treatment for overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be implemented as needed. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions

Below are the adverse reactions listed separately for each component of the medicinal product ROZZOR.

Acetylsalicylic acid

Within each group, adverse reactions are listed in order of decreasing severity: 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).

Additional adverse reactions have been reported in spontaneous reports for all dosage forms of acetylsalicylic acid, including oral short-term and long-term therapy; therefore, classification by frequency cannot be established.

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

Due to its antiplatelet effect, acetylsalicylic acid may increase the risk of bleeding. Bleeding events such as perioperative bleeding, hematomas, epistaxis, urogenital bleeding, and gingival bleeding have been observed.

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

Blood and lymphatic system disorders: prolonged bleeding time; rarely – thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, iron-deficiency anemia.

Immune system disorders: uncommon – asthma; rare – hypersensitivity reactions such as erythematous/eczematous skin reactions, urticaria, rhinitis, nasal congestion, bronchospasm, angioedema, hypotension progressing to shock.

Skin and subcutaneous tissue disorders: rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); very rare – exudative polymorphic erythema.

Metabolism and nutrition disorders: very rare – hypoglycemia, acid-base imbalance.

Nervous system disorders: rare – headache, dizziness, tinnitus, visual disturbances, hearing disturbances, confusion.

Gastrointestinal disorders: very common – microbleeding (70%); common – gastric symptoms; uncommon – dyspepsia, nausea, vomiting, diarrhea; rare – gastrointestinal bleeding, gastrointestinal ulcers, which in very rare cases may lead to perforation.

Hepatobiliary disorders: rare – hepatic dysfunction; very rare – increased transaminase levels.

Renal and urinary disorders: rare – renal function impairment; cases of acute renal failure have been reported.

Other: very rare – Reye's syndrome (see section "Special precautions").

Rosuvastatin

Adverse events observed during rosuvastatin use are generally mild and transient. In controlled clinical trials, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

The adverse reaction profile observed with rosuvastatin, based on clinical trials and extensive post-marketing experience, is presented below. Adverse reactions are classified according to MedDRA organ system class and frequency: common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: rare – thrombocytopenia.

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

Endocrine disorders: common – diabetes mellitus*.

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.

Eye disorders: frequency not known – ocular myasthenia.

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 liver transaminase levels; very rare – jaundice, hepatitis.

Skin and subcutaneous tissue disorders: uncommon – pruritus, rash, urticaria; frequency not known – Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

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

Renal and urinary disorders: very rare – hematuria.

Reproductive system and breast disorders: very rare – gynecomastia.

General disorders and administration site conditions: common – asthenia; frequency not known – edema.

*Frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of arterial hypertension).

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

Renal effects

Proteinuria, detected by urine dipstick testing and predominantly of tubular origin, has been observed in patients taking rosuvastatin. Changes in urinary protein content from 0 or trace to "++" or higher were observed in < 1% of patients at certain time points during treatment with 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of change from 0 or trace to "+" was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued therapy. To date, based on clinical trials and post-marketing surveillance, no causal relationship has been established between this adverse reaction and acute or progressive kidney disease.

Cases of hematuria have been reported during rosuvastatin treatment; clinical trial data indicate a low frequency.

Musculoskeletal effects

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, particularly at doses > 20 mg.

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

Hepatic effects

As with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin have experienced dose-dependent increases in transaminase levels; in most cases, this was mild, asymptomatic, and transient. Increases in HbA1c levels have also been observed with rosuvastatin use.

Sexual dysfunction

With the use of some statins, adverse events such as sexual dysfunction have been reported; isolated cases of interstitial lung disease, particularly with long-term use, have also been observed (see section "Special precautions").

The frequency of reports of rhabdomyolysis and serious renal and hepatic disorders (mainly increased hepatic transaminase activity) is higher with the 40 mg dose.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions during the post-marketing phase of the medicinal product. This enables continuous 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.

You can report an adverse event related to the use of this medicinal product by calling +38 (050) 309-83-54 (available 24/7).

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

7 capsules in a blister, 4 blisters in a cardboard box.

Or 28 capsules in a bottle, 1 bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

TOV NVF "MIKROKHEM" (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of operations.

Ukraine, 01013, Kyiv, Budynsturiyi St., 5.

INSTRUCTION

for medical use of the medicinal product

ROZZOR

(ROZZOR)

Composition:

Active substances: acetylsalicylic acid, rosuvastatin;

1 hard capsule contains:

1 tablet of acetylsalicylic acid 75 mg and 2 tablets of rosuvastatin 2.5 mg each (as rosuvastatin calcium 2.60 mg each)

or 1 tablet of acetylsalicylic acid 75 mg and 2 tablets of rosuvastatin 5 mg each (as rosuvastatin calcium 5.20 mg each)

or 1 tablet of acetylsalicylic acid 75 mg and 2 tablets of rosuvastatin 10 mg each (as rosuvastatin calcium 10.40 mg each);

Excipients:

for acetylsalicylic acid tablets: microcrystalline cellulose, anhydrous citric acid, talc, anhydrous colloidal silicon dioxide, sodium croscarmellose, hypromellose, polyethylene glycol 6000 (macrogol 6000), titanium dioxide (E 171);

for rosuvastatin tablets: lactose monohydrate; microcrystalline cellulose; calcium hydrogen phosphate; sodium croscarmellose; magnesium stearate; talc; anhydrous colloidal silicon dioxide; hypromellose; titanium dioxide (E 171); polyethylene glycol 6000 (macrogol 6000); iron oxide (E 172);

Capsule (body and cap): gelatin, titanium dioxide (E 171), water.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: opaque, hard gelatin capsules, white or almost white, containing one film-coated tablet of acetylsalicylic acid, white or almost white, and two film-coated tablets of rosuvastatin, yellowish-brown in color.

Pharmacotherapeutic group.

Lipid-lowering agents. Lipid-lowering agents, combinations. HMG-CoA reductase inhibitors, other combinations. Rosuvastatin and acetylsalicylic acid.

ATC code C10BX05.

Pharmacological properties.

Pharmacodynamics.

Acetylsalicylic acid

Acetylsalicylic acid inhibits platelet aggregation. Although its mechanism of action is not fully understood, the effect is probably mainly due to acetylation and irreversible inactivation of the enzyme cyclooxygenase (COX-1), which is involved in the formation of thromboxane A2 in platelets and prostacyclin in vascular endothelium. This significantly affects platelet aggregation and vasodilation. The anti-aggregatory effect is particularly pronounced for platelets, since they are unable to resynthesize cyclooxygenase. Thus, the effect persists throughout the entire platelet life cycle, which lasts 7–10 days. Prophylactic and therapeutic use in arterial thromboembolism is based on the above-mentioned effect.

Acetylsalicylic acid inhibits prostacyclin synthesis in the kidneys. In patients with normal renal function, this effect is not significant. In patients with chronic renal failure, heart failure or hepatic failure, as well as in those with reduced plasma volume, inhibited prostacyclin synthesis may lead to the development of acute renal failure, fluid retention, and severe heart failure (see section "Contraindications").

Experimental data indicate that ibuprofen may reduce the inhibitory effect of low-dose acetylsalicylic acid on platelet aggregation when both drugs are administered concomitantly. In a study, patients received ibuprofen 400 mg either 8 hours before or 30 minutes after administration of acetylsalicylic acid 81 mg. A reduction in the effect of acetylsalicylic acid on thromboxane formation and platelet aggregation was observed. Due to the limited and uncertain extrapolation of in vitro data, conclusions regarding the possibility of regular ibuprofen use cannot be made; however, with short-term ibuprofen use, the impact on efficacy and clinical significance is unlikely to be relevant.

Rosuvastatin

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the conversion of 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 reducing cholesterol levels.

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

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of LDL cholesterol, total cholesterol, and triglycerides, and increases HDL cholesterol levels. It also reduces levels of apolipoprotein B (apoB), cholesterol not associated with high-density lipoproteins (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), very-low-density lipoprotein triglycerides (VLDL-TG), and increases apolipoprotein A-I (apoA-I) levels (see Table 1). Rosuvastatin 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 C	HDL-C	TG	non-HDL-C	apoB	apoA-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5 mg	17	-45	-33	13	-35	-44	-38	4
10 mg	17	-52	-36	14	-10	-48	-42	4
20 mg	17	-55	-40	8	-23	-51	-46	5
40 mg	18	-63	-46	10	-28	-60	-54	0

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

Pharmacokinetics.

Acetylsalicylic acid

Absorption

Absorption of acetylsalicylic acid occurs primarily in the small intestine and partially in the stomach. Maximum plasma concentration of acetylsalicylic acid is reached within 40 minutes.

Distribution

Acetylsalicylic acid is hydrolyzed with a half-life of 30 minutes to salicylic acid, which, at therapeutic doses, is approximately 80% bound to albumin.

Elimination

Elimination of salicylic acid is dose-dependent. At daily doses < 3 g, the elimination half-life is 2–4 hours. Salicylic acid and its metabolites are primarily excreted by the kidneys.

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. Approximately 90% of rosuvastatin is bound to plasma proteins, predominantly to albumin.

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from CYP2C19, CYP3A4, and CYP2D6. The main identified metabolites are the 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 activity of circulating HMG-CoA reductase inhibitors.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (both absorbed and unabsorbed active substance), with the remainder excreted in urine. Approximately 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 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 hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with repeated daily administration.

Special patient populations

Age and gender

No clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults has been observed.

Race

Pharmacokinetic studies have shown that median AUC and Cmax values in patients of Mongoloid race (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 times. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and African patients.

Renal impairment

In a study involving patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite were observed in individuals with mild or moderate renal insufficiency. 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 involving patients with varying degrees of hepatic dysfunction, no evidence of increased rosuvastatin exposure was observed in individuals scoring 7 or less on the Child–Pugh scale. However, in two patients scoring 8 and 9 on the Child–Pugh scale, systemic exposure was at least twice as high as in patients with lower scores. There is no experience with the use of rosuvastatin in patients scoring more than 9 on the Child–Pugh scale.

Genetic polymorphism

The distribution 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 forms of polymorphism SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Special genotyping is not required in clinical practice, but patients with such polymorphisms are recommended to receive a lower daily dose of rosuvastatin.

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 of this combination.

Contraindications.

Related to the combination of active substances

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

Related to acetylsalicylic acid

• Asthma, rhinitis, angioedema, or urticaria induced by acetylsalicylic acid or NSAIDs;
• Hemophilia;
• Thrombocytopenia;
• Active peptic ulcer of the stomach or duodenum;
• Liver cirrhosis;
• Hemorrhagic diathesis;
• 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").

Related to rosuvastatin

• Active liver disease, including persistent elevations of serum transaminases of unknown etiology and any increases in serum transaminases exceeding three times the upper limit of normal (ULN);
• Myopathy. The 40 mg dose of rosuvastatin is contraindicated in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:
  • Moderate renal impairment (creatinine clearance < 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;
  • Concomitant use of fibrates (see sections "Pharmacokinetics", "Interaction with other medicinal products and other types of interactions", and "Special precautions for use");
• Concomitant use with the combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions");
• Concomitant use with cyclosporine.

Interaction with other medicinal products and other types of interactions.

Interaction studies of the combination of acetylsalicylic acid/rosuvastatin with other medicinal products have not been conducted. The information below refers only to interactions known for each individual component of the medicinal product.

Acetylsalicylic acid

Anticoagulants, thrombolytics/other platelet aggregation inhibitors, selective serotonin reuptake inhibitors (SSRIs)

Salicylates inhibit platelet function and thus enhance the effects of anticoagulants/thrombolytic agents, barbiturates, lithium, sulfonamides, and triiodothyronine. Due to the increased risk of bleeding, caution should be exercised when combining acetylsalicylic acid with anticoagulants, thrombolytics, or other platelet aggregation inhibitors. Coagulation monitoring is recommended. Pharmacodynamic interactions may occur between SSRIs and acetylsalicylic acid: increased risk of bleeding due to synergistic effects.

Cyclosporine, tacrolimus

Concomitant use of NSAIDs with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Renal function should be monitored when NSAIDs are used concomitantly with either of these drugs.

Diuretics and antihypertensive agents

NSAIDs may reduce the efficacy of diuretics and antihypertensive drugs. As with other NSAIDs, concomitant use of angiotensin-converting enzyme (ACE) inhibitors with acetylsalicylic acid may increase the risk of acute renal failure.

Corticosteroids and other NSAIDs

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 NSAIDs such as ibuprofen or naproxen in patients at risk of cardiovascular disease may limit the cardioprotective effect of acetylsalicylic acid (see section "Special precautions for use").

Systemic glucocorticosteroids may increase the risk of gastrointestinal ulcers and bleeding. Corticosteroid therapy reduces salicylate blood levels, and after discontinuation of glucocorticosteroids, there is a risk of salicylate overdose.

Medicinal products that increase uric acid excretion (probenecid)

Salicylates neutralize the effect of probenecid; therefore, their concomitant use should be avoided.

Ibuprofen

Experimental data indicate that ibuprofen may reduce the inhibitory effect of low-dose acetylsalicylic acid on platelet aggregation when used concomitantly. Due to the limited and uncertain extrapolation of in vitro data, conclusions regarding the possibility of regular ibuprofen use cannot be made, and the clinical relevance of occasional ibuprofen use is unlikely to be significant.

Metamizole

Concomitant use of metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation. This combination should be prescribed with caution to patients taking low-dose acetylsalicylic acid as a cardioprotector.

Metotrexate

Concomitant use of methotrexate and acetylsalicylic acid increases the hematological toxicity of methotrexate due to reduced renal clearance of methotrexate by acetylsalicylic acid (see section "Contraindications"). Weekly blood counts should be monitored during the first weeks of combination therapy. Careful monitoring is required even in patients with mild renal dysfunction and in elderly patients.

Digoxin

Acetylsalicylic acid inhibits renal excretion of digoxin, leading to increased plasma concentrations of the drug. Monitoring of digoxin plasma levels is recommended. Dose adjustment may be necessary.

Valproic acid

Acetylsalicylic acid has been reported to reduce valproate binding to serum albumin, thereby increasing free plasma concentrations at steady state. This may lead to an increased frequency of adverse reactions suggestive of intoxication, such as tremor, nystagmus, ataxia, and personality changes.

Phenytoin

Salicylates reduce phenytoin binding to plasma albumin. This may lead to decreased total plasma phenytoin levels and increased free fraction of phenytoin. However, the increased concentration of unbound phenytoin in plasma does not significantly affect therapeutic efficacy.

Sulfonylurea preparations

Salicylic acid is believed to potentiate the hypoglycemic effect of sulfonylurea drugs. Several reports support this effect. The mechanism is unclear but may involve reduced binding of sulfonylureas to serum albumin. When acetylsalicylic acid is used concomitantly, total serum concentrations of glyburide decrease and its clearance increases.

Nicotinic acid

In a study, administration of acetylsalicylic acid (1 g) resulted in a sharp increase in plasma concentrations of nicotinic acid. The mechanism likely involves competitive inhibition of glycine conjugation of nicotinic acid.

Alcohol

Alcohol increases the risk of gastrointestinal ulcers and bleeding, and prolongs bleeding time.

Penicillins

The plasma half-life of penicillin is prolonged.

Rosuvastatin

Effect of concomitant medications on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with drugs that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see Table 2 and sections "Special precautions for use", "Dosage and administration").

Cyclosporine

In patients receiving concomitant rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients receiving cyclosporine concomitantly (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 exposure (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 approximately 3- and 7-fold increases in AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin with certain combinations of protease inhibitors may be possible after careful dose adjustment of rosuvastatin due to the expected increase in exposure (see Table 2 and sections "Special precautions for use", "Dosage and administration").

Gemfibrozil and other lipid-lowering agents

Concomitant use of rosuvastatin and gemfibrozil led to a 2-fold increase in AUC and Cmax of rosuvastatin (see section "Special precautions for use").

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses (≥ 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions for use"). Such patients should also start therapy with a 5 mg dose.

Ezetimibe

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

Antacids

Concomitant use of rosuvastatin with suspensions of antacids containing aluminum or magnesium hydroxide 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 of in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. Additionally, rosuvastatin is a weak substrate of these isoenzymes. Therefore, interactions with medicinal products due to P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (inhibitor of CYP2C9 and CYP3A4) or ketoconazole (inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustment (see also Table 2)

When rosuvastatin must be used concomitantly with other drugs that may increase rosuvastatin exposure, the dose of the medicinal product should be adjusted. If an increase in drug exposure (AUC) of approximately 2-fold or more is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that its expected exposure does not exceed that observed with a 40 mg/day dose without interacting drugs: for example, when used with gemfibrozil, the rosuvastatin dose would be 20 mg (exposure increased 1.9-fold), when used with ritonavir/atazanavir combination, 10 mg (exposure increased 3.1-fold).

If the increase in rosuvastatin AUC is less than 2-fold, the initial dose need not be reduced, but caution is required when increasing the rosuvastatin dose above 20 mg.

Table 2 – Effect of concomitant medicinal products on rosuvastatin exposure (AUC; in descending order) based on published data from clinical studies

Increased AUC of rosuvastatin by 2 times or more
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	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
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-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
Ortho-silasvir 25 mg/paritaprevir 150 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
Increased AUC of rosuvastatin less than 2-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**
Decreased AUC of rosuvastatin
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baykaline 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

*Data presented as fold-change represent the ratio between co-administration of rosuvastatin and rosuvastatin alone. Data presented as % change represent the percentage difference relative to values observed with rosuvastatin alone.

Increases are indicated by ↑, decreases by ↓.

**Several interaction studies were conducted at different doses of rosuvastatin; the most significant ratio is presented in Table 2.

Medicinal products/combinations that had no clinically significant effect on rosuvastatin AUC when administered concomitantly: aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg three times daily, 7 days; fluconazole 200 mg once daily, 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days; ketoconazole 200 mg twice daily, 7 days; rifampicin 450 mg once daily, 7 days; silymarin 140 mg three times daily, 5 days.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). Discontinuation of rosuvastatin or reduction of its dose may result in a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients receiving rosuvastatin and HRT simultaneously; therefore, a similar effect cannot be excluded. However, the combination has been widely used by women in clinical trials and was generally well tolerated.

Other medicinal products

Digoxin

Based on specific interaction studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Interaction studies 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 therapy is considered necessary, rosuvastatin treatment should be discontinued for the entire duration of fusidic acid treatment. See also section "Special warnings and precautions for use".

Special precautions.

Acetylsalicylic acid

Acetylsalicylic acid should be used with caution in the following situations:

• renal function impairment or cardiovascular circulatory disorders (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), since acetylsalicylic acid may further increase the risk of renal function impairment and acute renal failure;
• hepatic function impairment;
• concomitant use of NSAIDs such as ibuprofen or naproxen, since NSAIDs may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If acetylsalicylic acid is used for cardioprotection, patients should consult their physician before starting NSAIDs for pain relief (see section "Interaction with other medicinal products and other forms of interaction");
• symptoms of chronic gastric or duodenal dyspepsia or their recurrence;
• bronchial asthma or general tendency to hypersensitivity, since acetylsalicylic acid may induce bronchospasm, asthma attacks, or other hypersensitivity reactions. Risk factors include history of asthma, hay fever, nasal polyps, or chronic respiratory disease; allergic reactions (e.g., rash, pruritus, or urticaria) to other substances in the past;
• nasal polyps;
• glucose-6-phosphate dehydrogenase deficiency, since acetylsalicylic acid may cause hemolysis or hemolytic anemia. Factors that may increase the risk of hemolysis include high drug doses, fever, or acute infectious conditions;
• concomitant use of anticoagulants;
• due to the inhibitory effect of acetylsalicylic acid on platelet aggregation, which persists for several days after administration, the use of products containing acetylsalicylic acid may increase the likelihood or severity of bleeding during surgical procedures (including minor surgeries such as tooth extraction).

When used in low doses, acetylsalicylic acid reduces the excretion of uric acid. In patients who normally have reduced uric acid excretion, this may lead to the development of gout.

Although the medicinal product is not intended for use in children, one of the components of the medicinal product ROSZOR, namely acetylsalicylic acid, when used in children and adolescents with fever and/or viral infections, may increase the risk of Reye's syndrome, a life-threatening encephalopathy characterized by severe vomiting, loss of consciousness, and hepatic dysfunction. Reye's syndrome requires urgent medical intervention. The risk may be increased if acetylsalicylic acid is used concomitantly, but a causal relationship has not been established. If the mentioned conditions are accompanied by persistent vomiting, this may be a manifestation of Reye's syndrome.

Treatment with the medicinal product should be discontinued at the first signs of gastrointestinal bleeding or ulceration (see section "Contraindications").

Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as allergy to other substances, requires careful monitoring of patients with a history of allergic reactions.

Rarely, serious skin reactions such as Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with the use of acetylsalicylic acid (see section "Adverse reactions"). Treatment should be discontinued at the first signs of rash, mucosal lesions, or other signs of hypersensitivity.

Rosuvastatin

Renal effects

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

Musculoskeletal effects

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, particularly above 20 mg. Very rarely, cases of rhabdomyolysis have been reported with ezetimibe used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction"), and therefore such combinations should be used with caution.

As with other HMG-CoA reductase inhibitors, the frequency of post-marketing reports of rhabdomyolysis associated with rosuvastatin use was higher with the 40 mg dose.

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

Creatine kinase levels

Creatine kinase (CK) levels should not be measured after significant physical exertion or in the presence of possible alternative 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 to confirm results. If repeat testing confirms baseline CK levels > 5 times ULN, treatment should not be initiated.

Before starting treatment

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

• renal function impairment;
• 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 levels of the drug (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Dosage and administration");
• concomitant use of fibrates.

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

During treatment

Patients should be advised to immediately report unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be measured in such patients. The medicinal product should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose under close monitoring. Routine monitoring of CK levels in asymptomatic patients is not required. Very rarely, immune-mediated necrotizing myopathy (IMNM) has been reported during or after statin therapy, including rosuvastatin. Clinical manifestations of IMNM include proximal muscle weakness and elevated serum creatine kinase levels, which persist even after discontinuation of statins.

Clinical trials did not provide evidence of increased musculoskeletal effects in a small number of patients taking rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, the concomitant use of rosuvastatin with gemfibrozil is not recommended. The benefit of further lipid-lowering with rosuvastatin 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").

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered essential, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving a combination of fusidic acid and statins (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 restarted seven days after the last dose of fusidic acid. In exceptional cases, when prolonged systemic fusidic acid is required, e.g., for the treatment of severe infections, the need for concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and such therapy should be conducted under close medical supervision.

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

Severe skin reactions

Severe skin reactions, including Stevens–Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported during rosuvastatin use, which may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored by a physician. If signs or symptoms suggestive of such severe skin reactions occur, use of ROSZOR should be immediately discontinued and alternative therapy considered.

If a patient develops a severe skin reaction such as Stevens–Johnson syndrome or DRESS syndrome while taking ROSZOR, this product must not be used in the future.

Hepatic effects

Like other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease.

It is recommended to check liver function biochemistry before starting treatment and again after 3 months. Rosuvastatin use should be discontinued or the dose reduced if serum transaminase levels exceed three times the ULN. The frequency of reports of serious hepatic events (mainly elevated liver transaminases) in the post-marketing period was higher with the 40 mg dose.

In the post-marketing period, rare cases of fatal or 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 causes are identified, rosuvastatin therapy should not be resumed.

Race

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

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 rosuvastatin 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 product with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Lactose intolerance

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

Interstitial lung disease

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

Diabetes mellitus

Evidence suggests that statins may increase blood glucose levels and, in some patients at high risk of developing type 2 diabetes, may lead to hyperglycemia requiring treatment for diabetes. However, the benefit of reduced vascular risk with statin use outweighs this risk, and therefore it should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, BMI > 30 kg/m², elevated triglycerides, arterial hypertension) should be monitored clinically and biochemically according to national guidelines.

In the JUPITER study, the overall incidence of diabetes was 2.8% in the rosuvastatin group and 2.3% in the placebo group, primarily in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

Excipients

Sodium content

The medicinal product ROSZOR contains less than 1 mmol of sodium (23 mg) per capsule, i.e., it is almost sodium-free.

Use during pregnancy or breastfeeding

The medicinal product is contraindicated in women during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive methods.

If a patient becomes pregnant during treatment with this medicinal product, treatment should be discontinued immediately.

Acetylsalicylic acid

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy. Epidemiological data indicate an increased risk of miscarriage and risk of congenital heart defects and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy.

The risk is believed to increase with higher doses of acetylsalicylic acid and longer duration of treatment. In animal studies, administration of prostaglandin synthesis inhibitors has been shown to increase pre- and post-implantation losses and embryo/fetal death. Increased incidence of multiple malformations, including cardiovascular defects, has also been reported in animals exposed to prostaglandin synthesis inhibitors during organogenesis.

All prostaglandin synthesis inhibitors may:

• affect the fetus:
  • cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction, which may lead to renal failure and, consequently, oligohydramnios;
• affect the mother and fetus:
  • prolonged bleeding time, anti-aggregatory effect on platelets, which may occur at very low doses;
  • inhibition of uterine contractions, which may lead to delayed/prolonged labor.

Breastfeeding

Low amounts of salicylates and their metabolites pass into breast milk. Concentrations in breast milk are equivalent to or even higher than plasma concentrations in the mother.

Rosuvastatin

Pregnancy

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

Breastfeeding

Rosuvastatin passes into the milk of rats. Data on penetration of the drug into human breast milk are lacking (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery.

Acetylsalicylic acid

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

Rosuvastatin

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

Method of Administration and Dosage

The dose should be individually adjusted according to the therapeutic goal and the patient's response to treatment, following recommendations of current accepted guidelines.

The medicinal product can be taken at any time of day, regardless of food intake.

Dosage

Prior to switching to this medicinal product, the patient's condition should be stable on unchanged doses of the individual monotherapy components currently being taken. The dose of the medicinal product should be based on the doses of the individual components of the combination being used at the time of switching.

The recommended initial dose of the medicinal product is 75 mg/5 mg or 75 mg/10 mg orally once daily, both for patients who have not previously used statins and for those switching from another HMG-CoA reductase inhibitor. When selecting the initial dose, the individual patient's cholesterol levels and future cardiovascular risk, as well as the likelihood of developing adverse reactions, should be considered. If necessary, the dose may be increased to 75 mg/20 mg, but only after 4 weeks.

The maximum recommended dose of the medicinal product is 75 mg/20 mg.

Specific Patient Groups

Elderly Patients

The recommended initial dose for patients aged >70 years is 75 mg/5 mg (see section "Special Warnings and Precautions for Use"). No other dose adjustment based on age is required.

Patients with Renal Impairment

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

The recommended initial dose for patients with moderate renal impairment (creatinine clearance < 60 mL/min) is 75 mg/5 mg.

The use of the medicinal product in patients with severe renal impairment is contraindicated at any dose (see sections "Pharmacokinetics" and "Contraindications").

Patients with Hepatic Impairment

In patients with hepatic impairment scoring 7 or less on the Child-Pugh scale, no increase in systemic exposure to rosuvastatin has been observed. However, in patients scoring 8 or 9 points on the Child-Pugh scale, systemic exposure increases (see section "Pharmacokinetics"). Renal function assessment is advisable in such patients (see section "Special Warnings and Precautions for Use"). Experience with the medicinal product in patients scoring more than 9 points on the Child-Pugh scale is lacking. The medicinal product is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to the medicinal product has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use"). The recommended initial dose for patients of Asian origin is 75 mg/5 mg.

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased rosuvastatin exposure (see section "Pharmacokinetics"). Patients known to have such polymorphism types are recommended to receive a lower daily dose (75 mg/5 mg) of the medicinal product.

Patients Predisposed to Myopathy

The recommended initial dose for patients with risk factors for developing myopathy is 75 mg/5 mg (see section "Special Warnings and Precautions for Use").

Concomitant Use

One component of the medicinal product ROSZOR, namely 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 its plasma concentration due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir in combination with atazanavir, lopinavir and/or tipranavir; see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"). If possible, alternative medicinal products should be considered, and temporary interruption of therapy with ROSZOR may be necessary. If concomitant use of these medicinal products with ROSZOR cannot be avoided, the benefit and risk of concomitant use should be carefully weighed, and the dose of ROSZOR should be adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

The medicinal product is not intended for use in children.

Overdose.

Acetylsalicylic Acid

Symptoms

Dizziness, tinnitus, hearing loss, restlessness, irritability, hallucinations, tremor, ringing in the ears, hyperventilation, thirst, skin flushing, sweating. In severe cases – loss of consciousness, seizures, hyperthermia, nausea, vomiting, abdominal pain, respiratory alkalosis in adults. Hypokalemia, dehydration, elevated ammonia levels, oliguria, coagulation disorders, impaired renal function. In severe cases, there is a risk of non-cardiogenic pulmonary edema, as well as rhabdomyolysis and renal failure. Acute respiratory distress syndrome (ARDS) may develop, as well as arrhythmias and heart failure.

Treatment

Measures to empty the stomach. Activated charcoal significantly reduces elimination time. Rehydration, correction of metabolic acidosis and, possibly, electrolyte imbalances. Omeprazole for protection of gastric mucosa. Use of antiemetics, urinary alkalinization with sodium bicarbonate to enhance salicylate elimination, glucose administration. Coagulation parameters should be monitored. Vitamin K is administered in cases of severe poisoning or coagulation disorders. In cases of bleeding disorders, platelet concentrate and/or fresh frozen plasma are administered. If insufficient effect is achieved, antifibrinolytic agents are prescribed. Supportive care in case of unconsciousness. In cases of severe poisoning (moderate or high salicylate concentration combined with pronounced acidosis and CNS disturbances) and in renal failure, hemodialysis should also be considered. Symptomatic therapy (e.g., in case of hyperthermia, cerebral edema, pulmonary edema).

Rosuvastatin

There is no specific antidote for overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be implemented as necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Side effects

Below are the side effects listed separately for each component of the medicinal product ROZZOR.

Acetylsalicylic acid

Within each group, adverse reactions are listed in order of decreasing severity: 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 the available data).

Information on other adverse reactions has been reported spontaneously for all dosage forms of acetylsalicylic acid, including oral short-term and long-term therapy, therefore classification by frequency categories is not possible.

In patients with severe forms of glucose-6-phosphate dehydrogenase deficiency, hemolysis and hemolytic anemia have been observed.

Due to the antiplatelet effect, use of acetylsalicylic acid may increase the risk of bleeding. Bleeding events such as perioperative bleeding, hematoma, epistaxis, urogenital bleeding, and gingival bleeding have been observed.

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

Blood and lymphatic system disorders: prolonged bleeding time; rarely – thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, iron-deficiency anemia.

Immune system disorders: uncommon – asthma; rare – hypersensitivity reactions such as erythematous/eczematous skin reactions, urticaria, rhinitis, nasal congestion, bronchospasm, angioedema, hypotension progressing to shock.

Skin and subcutaneous tissue disorders: rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); very rare – exudative polymorphic erythema.

Metabolism and nutrition disorders: very rare – hypoglycemia, acid-base imbalance.

Nervous system disorders: rare – headache, dizziness, tinnitus, visual disturbances, hearing disturbances, confusion.

Gastrointestinal disorders: very common – microbleeding (70%); common – gastric symptoms; uncommon – dyspepsia, nausea, vomiting, diarrhea; rare – gastrointestinal bleeding, gastrointestinal ulcers, which in very rare cases may lead to perforation.

Hepatobiliary disorders: rare – hepatic dysfunction; very rare – increased transaminase levels.

Renal and urinary disorders: rare – renal function impairment; cases of acute renal failure have been reported.

Other: very rare – Reye's syndrome (see section "Special precautions for use").

Rosuvastatin

Adverse events observed during treatment with rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

Below is the profile of adverse reactions observed with rosuvastatin based on clinical trial data and extensive post-marketing experience. Adverse reactions are classified according to the MedDRA standardized medical terminology system organ classes with the following frequency categories: common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: rare – thrombocytopenia.

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

Endocrine disorders: common – diabetes*.

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.

Eye disorders: frequency not known – ocular myasthenia.

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 liver transaminase levels; very rare – jaundice, hepatitis.

Skin and subcutaneous tissue disorders: uncommon – pruritus, rash, urticaria; frequency not known – Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

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

Renal and urinary disorders: very rare – hematuria.

Reproductive system and breast disorders: very rare – gynecomastia.

General disorders and administration site conditions: common – asthenia; frequency not known – edema.

*Frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of arterial hypertension).

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

Renal effects

Proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients treated with rosuvastatin. Changes in urinary protein content from 0 or trace to "++" or higher were observed in < 1% of patients at certain time points during treatment with 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of change from 0 or trace to "+" was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued treatment. To date, based on clinical trial data and post-marketing surveillance, no causal relationship has been established between this adverse reaction and acute or progressive kidney disease.

Cases of hematuria have been reported during treatment with rosuvastatin; according to clinical trial data, the frequency is low.

Musculoskeletal effects

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, particularly 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 precautions for use").

Hepatic effects

As with other HMG-CoA reductase inhibitors, dose-dependent increases in transaminase levels have been observed in a small number of patients treated with rosuvastatin; in most cases, this was mild, asymptomatic, and transient. Increases in HbA1c levels have also been observed during treatment with rosuvastatin.

Sexual dysfunction

Adverse events such as sexual dysfunction have been reported with some statins; isolated cases of interstitial lung disease, particularly with long-term use, have also been reported (see section "Special precautions for use").

The frequency of reports of rhabdomyolysis and serious renal and hepatic disorders (mainly increased hepatic transaminase activity) is higher when the drug is administered at a dose of 40 mg.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions during the post-marketing period of the medicinal product. This 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.

You can report an adverse event associated with the use of this medicinal product by calling +38 (050) 309-83-54 (24/7).

Shelf life

2 years.

Storage conditions

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

Keep out of reach of children.

Packaging

7 capsules in a blister, 4 blisters in a cardboard pack.

Or 28 capsules in a bottle, 1 bottle in a cardboard pack.

Prescription status

Prescription only.

Manufacturer

LLC "MIKROKHIM" (production unit (all stages of the manufacturing process)).

Manufacturer's address and location of operations

24-v Promyslova Street, Sievierodonetsk, Luhansk Oblast, 93400, Ukraine