Clivas® duo: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLYVAS® DUO (CLIVAS DUO)

Composition:

Active substances: rosuvastatin, acetylsalicylic acid;

One 5 mg/100 mg capsule contains 5.20 mg of rosuvastatin calcium equivalent to 5.00 mg of rosuvastatin and 100.00 mg of acetylsalicylic acid;

One 10 mg/100 mg capsule contains 10.40 mg of rosuvastatin calcium equivalent to 10.00 mg of rosuvastatin and 100.00 mg of acetylsalicylic acid;

One 20 mg/100 mg capsule contains 20.80 mg of rosuvastatin calcium equivalent to 20.00 mg of rosuvastatin and 100.00 mg of acetylsalicylic acid;

Excipients:

Rosuvastatin tablets: lactose monohydrate (type 100); microcrystalline cellulose (type 102); microcrystalline cellulose (type 112); magnesium oxide heavy; crospovidone (type A); colloidal anhydrous silicon dioxide; magnesium stearate; coating: polyvinyl alcohol - partially hydrolyzed, titanium dioxide (E 171), talc, yellow iron oxide (E 172), lecithin, red iron oxide (E 172), xanthan gum, black iron oxide (E 172);

Acetylsalicylic acid tablets: microcrystalline cellulose (type 102), corn starch, colloidal anhydrous silicon dioxide, stearic acid (type 50);

Capsule: body: gelatin, titanium dioxide (E 171); cap: gelatin, titanium dioxide (E 171), indigotine FD&C Blue 2 (E 132), yellow iron oxide (E 172);

Ink: (for 10 mg/100 mg and 20 mg/100 mg capsules): shellac (E 904), dehydrated alcohol, butyl alcohol, isopropyl alcohol, propylene glycol (E 1520), concentrated ammonia solution (E 527), black iron oxide (E 172), potassium hydroxide (E 525), purified water.

Pharmaceutical form: hard capsules.

Main physicochemical properties.

5 mg/100 mg capsules: hard gelatin capsules size № 2, cap: opaque dark green, body: opaque white. Capsule contents: one oval, biconvex tablet of acetylsalicylic acid, white or almost white in color, and one round, biconvex coated tablet of rosuvastatin, brown in color.

10 mg/100 mg capsules: hard gelatin capsules size № 1, cap: opaque light green with black marking "RSV 10", body: opaque white with black marking "ASA 100". Capsule contents: one oval, biconvex tablet of acetylsalicylic acid, white or almost white in color, and one round, biconvex coated tablet of rosuvastatin, brown in color.

20 mg/100 mg capsules: hard gelatin capsules size № 0, cap: opaque green with black marking "RSV 20", body: opaque white with black marking "ASA 100". Capsule contents: one oval, biconvex tablet of acetylsalicylic acid, white or almost white in color, and two round, biconvex coated tablets of rosuvastatin, brown in color.

Pharmacotherapeutic group. Lipid-modifying agents. Lipid-modifying agents, combinations. Lipid-modifying agents in combination with other medicinal products. Rosuvastatin and acetylsalicylic acid.

ATC code C10BX05.

Pharmacological properties.

Pharmacodynamics.

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 precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for reducing cholesterol levels.

Rosuvastatin increases the number of LDL receptors on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of VLDL, thereby reducing the total number of LDL and VLDL particles.

Pharmacodynamic effect

Rosuvastatin reduces elevated levels of cholesterol, LDL-C, total cholesterol, and triglycerides, and increases HDL-C levels. It also reduces levels of apoB, non-HDL-C, LDL-C, VLDL-C, and increases apoA-I levels (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 percent 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	17	-45	-33	13	-35	-44	-38	4
10	17	-52	-36	14	-10	-48	-42	4
20	17	-55	-40	8	-23	-51	-46	5
40	18	-63	-46	10	-28	-60	-54	0

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

Clinical efficacy and safety

Rosuvastatin is effective in the treatment of adults with hypercholesterolemia – with or without hypertriglyceridemia – regardless of race, gender, or age, as well as in patients from special populations such as those with diabetes mellitus or familial hypercholesterolemia.

Based on pooled data from phase III studies, rosuvastatin effectively reduced cholesterol levels to target values established by the European Atherosclerosis Society (EAS; 1998) in the majority of patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C level approximately 4.8 mmol/L); approximately 80 % of patients receiving rosuvastatin 10 mg achieved the EAS target LDL-C levels (< 3 mmol/L).

In a large study of 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses ranging from 20 to 80 mg using an intensive dose-titration regimen. The beneficial effect of the medicinal product on lipid parameters and achievement of target levels was observed at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53 %. Target EAS LDL-C levels (< 3 mmol/L) were achieved in 33 % of patients.

In an open-label dose-titration study, the response to rosuvastatin at doses of 20–40 mg was evaluated in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased on average by 22 %.

In clinical studies involving a limited number of patients, an additive effect on triglyceride reduction was observed when rosuvastatin was used in combination with fenofibrate, and an increase in HDL-C levels was observed when rosuvastatin was used in combination with niacin (see section "Special precautions for use").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of ischemic heart disease (defined as a Framingham risk score < 10 % over 10 years), a mean LDL-C level of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness (CIMT)) were randomized into two groups and received either 40 mg rosuvastatin or placebo once daily for 2 years. Compared to placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid artery sites by -0.0145 mm/year [95 % confidence interval -0.0196, -0.0093; p < 0.0001]. The change from baseline was -0.0014 mm/year (-0.12 %/year (statistically non-significant)) in the rosuvastatin group compared to progression of +0.0131 mm/year (1.12 %/year (p < 0.0001)) in the placebo group. No direct correlation between CIMT reduction and reduced risk of cardiovascular events was demonstrated. The METEOR study included patients with low risk of ischemic heart disease who are not representative of the target population for rosuvastatin 40 mg use. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high risk of cardiovascular disorders (see section "Dosage and administration").

In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular diseases was evaluated in 17,802 men (≥ 50 years) and women (≥ 60 years).

Study participants were randomly assigned to placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901) and were followed for a mean of 2 years.

LDL-C concentrations decreased by 45 % (p < 0.001) in the rosuvastatin group compared to the placebo group.

In a retrospective analysis of data obtained from high-risk patients with a baseline Framingham risk score > 20 % (1558 participants), a significant reduction in the incidence of the composite endpoint, including cardiovascular death, stroke, and myocardial infarction (p = 0.028), was observed in the rosuvastatin group compared to placebo. The absolute risk reduction was 8.8 events per 1000 patient-years. The all-cause mortality rate remained unchanged in high-risk patients (p = 0.193). In a retrospective analysis of data obtained from high-risk patients (9302 participants overall) with a baseline SCORE ≥ 5 % (extrapolated to include data from participants over 65 years of age), a significant reduction in the incidence of the composite endpoint, including cardiovascular death, stroke, and myocardial infarction (p = 0.0003), was observed in the rosuvastatin group compared to placebo. The absolute risk reduction expressed as event rate was 5.1 events per 1000 patient-years. The all-cause mortality rate in high-risk patients remained unchanged (p = 0.076).

In the JUPITER study, 6.6 % of participants in the rosuvastatin group and 6.2 % in the placebo group discontinued the investigational medicinal product due to adverse reactions. The most common adverse reactions leading to discontinuation of treatment were myalgia (0.3 % in the rosuvastatin group, 0.2 % in placebo), abdominal pain (0.03 % in the rosuvastatin group, 0.02 % in placebo), and rash (0.02 % in the rosuvastatin group, 0.03 % in placebo). The most common adverse reactions observed in the rosuvastatin group with a frequency greater than or equal to that in the placebo group were urinary tract infections (8.7 % in the rosuvastatin group, 8.6 % in placebo), nasopharyngitis (7.6 % in the rosuvastatin group, 7.2 % in placebo), back pain (7.6 % in the rosuvastatin group, 6.9 % in placebo), and myalgia (7.6 % in the rosuvastatin group, 6.6 % in placebo).

Children

In a double-blind, randomized, multicenter, placebo-controlled 12-week study (n = 176, 97 male and 79 female participants) followed by a 40-week open-label dose-titration period (n = 173, 96 male and 77 female participants), patients aged 10–17 years (Tanner stages II–IV, girls with at least 1 year since menarche) with heterozygous familial hypercholesterolemia received rosuvastatin at doses of 5, 10, or 20 mg/day or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At the start of the study, approximately 30 % of patients were aged 10–13 years, and approximately 17 %, 18 %, 40 %, and 25 % were at Tanner stages II, III, IV, and V, respectively.

LDL-C levels decreased by 38.3 %, 44.6 %, and 50.0 % in the rosuvastatin 5, 10, and 20 mg groups, respectively, compared to 0.7 % in the placebo group.

At the end of the 40-week open-label dose-titration period to achieve the target level (maximum dose 20 mg once daily), the target LDL-C level of less than 2.8 mmol/L was achieved in 70 of 173 patients (40.5 %).

After 52 weeks of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special precautions for use"). This study (n = 176) is not suitable for comparison of rare adverse reactions.

Rosuvastatin was also studied in a 2-year open-label study with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage < II–V). The initial dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) were titrated to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n = 134) were titrated to a maximum dose of 20 mg once daily.

After 24 months of rosuvastatin treatment, the mean reduction from baseline LDL-C, determined by the least squares method, was -43 % (baseline level: 236 mg/dL, month 24: 133 mg/dL). For each age group, the mean reduction from baseline LDL-C, determined by the least squares method, was -43 % (baseline level: 234 mg/dL, month 24: 124 mg/dL), -45 % (baseline level: 234 mg/dL, month 24: 124 mg/dL), and -35 % (baseline level: 241 mg/dL, month 24: 153 mg/dL) in the age groups 6 to < 10, 10 to < 14, and 14 to < 18 years, respectively.

The use of rosuvastatin at doses of 5 mg, 10 mg, and 20 mg also resulted in statistically significant mean changes compared to baseline in the following secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C, total cholesterol/HDL-C, TG/HDL-C, non-HDL-C/HDL-C, apoB, and apoB/apoA-1. Each of these changes demonstrated improvement in lipid response and was maintained over 2 years.

After 24 months of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special precautions for use").

In a randomized, double-blind, placebo-controlled, multicenter, crossover study, rosuvastatin 20 mg once daily was compared with placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included an active 4-week dietary run-in phase during which patients were treated with rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment with rosuvastatin 20 mg preceded or followed by a 6-week treatment with placebo, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients on ezetimibe or apheresis continued this treatment throughout the study.

A statistically significant (p = 0.005) reduction in LDL-C levels (22.3 %; 85.4 mg/dL, or 2.2 mmol/L) was observed after 6 weeks of treatment with rosuvastatin 20 mg compared to placebo. Statistically significant reductions in total cholesterol (20.1 %, p = 0.003), non-HDL-C (22.9 %, p = 0.003), and apoB (17.1 %, p = 0.024) were also observed. Reductions in TG, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I levels were also observed after 6 weeks of treatment with rosuvastatin 20 mg compared to placebo. The reduction in LDL-C levels after 6 weeks of treatment with rosuvastatin 20 mg followed by 6 weeks of placebo treatment was maintained over 12 weeks of continuous therapy. One patient showed a further reduction in LDL-C (8.0 %), total cholesterol (6.7 %), and non-HDL-C (7.4 %) after 6 weeks of treatment with dose titration to 40 mg.

During continued open-label treatment with rosuvastatin 20 mg in 9 of these patients up to 90 weeks, the reduction in LDL-C levels was maintained between -12.1 % and -21.3 %.

In an open-label dose-titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction in LDL-C (21.0 %), total cholesterol (19.2 %), and non-HDL-C (21.0 %) from baseline after 6 weeks of treatment with rosuvastatin 20 mg corresponded to that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

The European Medicines Agency has waived the obligation to submit results of studies on the use of rosuvastatin in all pediatric subpopulations with homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia, and for the prevention of cardiovascular disorders (see section "Dosage and administration" for information on use in children).

Acetylsalicylic acid

Mechanism of action. The antithrombotic effect of acetylsalicylic acid is due to inhibition of thromboxane A2 synthesis in platelets. Even small doses of acetylsalicylic acid (ASA) are absorbed, and all circulating platelets are irreversibly inhibited in the prehepatic mesenteric blood vessels as they pass from the gastrointestinal tract to the liver. Meanwhile, ASA concentrations during posthepatic circulation only slightly inhibit endothelial cyclooxygenase (responsible for prostacyclin synthesis), as it recovers more rapidly. Platelet function related to hemostasis is not significantly altered.

Clinical efficacy.

Primary prevention. In a meta-analysis by the U.S. Preventive Services Task Force (Ann Intern Med 2002;136:161–172) based on 5 prospective clinical trials, a reduction in the risk of myocardial infarction (relative risk 0.72 (95 % confidence interval: 0.60–0.87)) was demonstrated with prophylactic treatment with acetylsalicylic acid at doses of 75–125 mg over 5–7 years in patients without prior cardiovascular events but with various risk factors (age > 50 years, hypertension, diabetes, smoking, hypercholesterolemia, family history). This was demonstrated only for non-fatal cardiovascular events; benefits regarding stroke and all-cause mortality were not observed. The risk of severe gastrointestinal bleeding compared to control was 0.8 % versus 0.48 %, and the risk of intracranial bleeding was 0.22 % versus 0.17 %. The risk of bleeding was higher in patients aged 70 years and older.

Prevention should only be performed after adequate control of blood pressure is established and in combination with other therapeutic measures (diet, diabetes treatment and lipid metabolism correction, smoking cessation). Risk can be assessed using scales from the European Society of Cardiology (European Heart Journal, 1998,19:1434-1503).

Secondary prevention. In a meta-analysis conducted by the Antithrombotic Trialists' Collaboration (BMJ 2002; 324: 71–85), the effects of acetylsalicylic acid and placebo were compared in 287 trials involving 135,000 high-risk patients, with additional comparison of different platelet aggregation inhibitors in 77,000 patients. High-risk patients were defined as those with cardiovascular events in the acute phase or with a history of cardiovascular events (myocardial infarction, transient ischemic attack (TIA), unstable angina, arterial occlusive disease, post-surgical status such as aortocoronary bypass, percutaneous transluminal coronary angioplasty, peripheral angioplasty, and arteriovenous shunt in dialysis patients).

A reduction in the risk of serious cardiovascular events (relative reduction by 25 %; p < 0.0001) and mortality due to cardiovascular events was observed. The absolute benefit outweighed the risks of extracranial bleeding in all high-risk patient categories.

Pediatric patients

The European Medicines Agency has waived the obligation to submit results of studies on the use of the combination of rosuvastatin / acetylsalicylic acid in all pediatric subpopulations for the approved indication (see section "Dosage and administration" for information on use in children).

Pharmacokinetics.

Rosuvastatin

Absorption. The maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. The 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 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 a lesser role played by 2C19, 3A4, and 2D6. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50 % less active than rosuvastatin, and the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90 % of the circulating HMG-CoA reductase inhibitor activity.

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

Linearity/non-linearity

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

Special patient groups

Age and gender. Age and gender had no clinically significant effect on the pharmacokinetics of rosuvastatin in adults. Exposure to rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to or lower than in adult patients with dyslipidemia (see section "Children").

Race. Pharmacokinetic studies have shown that in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans), median AUC and Cmax values 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 of 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 impairment. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin were three times higher, and levels of N-desmethyl metabolite were nine times higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50 % higher than in healthy volunteers.

Hepatic impairment. In a study of patients with varying degrees of hepatic impairment, no signs of increased rosuvastatin exposure were 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 polymorphisms. The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transporter proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. Specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher exposure (AUC) to rosuvastatin compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. This specific genotyping is not routinely used in clinical practice, but patients with these polymorphism types are recommended to receive a lower daily dose of rosuvastatin.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (total of 214 patients) showed that drug exposure in children was lower or similar to that in adult patients. Rosuvastatin exposure was predictable according to dose and duration of administration over more than 2 years of observation.

Acetylsalicylic acid

Absorption. After oral administration, acetylsalicylic acid (ASA) is rapidly absorbed in the proximal part of the small intestine. During and after absorption, it is converted into the main active metabolite – salicylic acid. Maximum plasma concentration is reached within 0.5–2 hours. However, a significant portion of the dose is hydrolyzed in the intestinal wall during absorption.

After oral administration, absorption of ASA is usually rapid and complete. Food reduces the rate but not the extent of absorption of acetylsalicylic acid.

Distribution. Salicylic acid is bound to plasma proteins by 60–90 %. The bioavailability of salicylates ranges from 80 to 100 %. The volume of distribution of ASA is approximately 0.20 L/kg body weight. The binding level of the first metabolite of ASA, anti-inflammatory salicylic acid, to plasma proteins, primarily albumin, is 90 %.

Salicylic acid slowly penetrates into the synovial membrane and synovial fluid. It crosses the placenta and enters breast milk.

Metabolism. ASA is primarily converted to salicylic acid via hydrolysis. The half-life of ASA is short, approximately 15–20 minutes.

Salicylic acid is then converted into glycine and glucuronic acid conjugates and trace amounts of gentisic acid. At higher therapeutic doses, the capacity for salicylic acid conversion is exhausted, and pharmacokinetics become non-linear. This leads to a prolonged apparent half-life of salicylic acid from several hours to approximately 24 hours.

Biotransformation of salicylic acid occurs primarily in the liver. Salicylic acid metabolites are formed by conjugation of salicylic acid with glycine and subsequently by conjugation with glucuronic acid or sulfuric acid. A small portion is oxidized to gentisic acid and converted to gentisic acid.

Elimination.

Elimination is almost entirely renal in the form of salicylic acid (approximately 10 %), salicyluric acid (approximately 75 %), and conjugates of salicyluric acid (approximately 10 %). The half-life ranges from 2–3 hours after administration of low doses to 12 hours after administration of analgesic doses.

Clinical characteristics.

Indications.

The medicinal product Clivas® Duo is indicated for secondary prevention of cardiovascular diseases as a replacement therapy in adult patients whose condition is adequately controlled with concomitant use of monocomponent medicinal products at equivalent therapeutic doses.

Contraindications.

Regarding the use of rosuvastatin:

Hypersensitivity to rosuvastatin or any of the excipients of the medicinal product;
- Active liver disease, including persistent elevations of serum transaminases of unknown etiology, or any increase in serum transaminase levels at least three times above the upper limit of normal (ULN);
- Severe renal impairment (creatinine clearance < 30 mL/min);
- Myopathy;
- Concomitant therapy with cyclosporine;
- Concurrent use of the combination sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions").

Regarding the use of acetylsalicylic acid:

Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs);
Bronchospasm, urticaria, or allergic symptoms in history after intake of acetylsalicylic acid or other NSAIDs;
Active or recurrent peptic ulcer or duodenal ulcer in history and/or gastrointestinal bleeding or other types of bleeding;
Inflammatory bowel diseases (such as Crohn’s disease, ulcerative colitis);
Hemorrhagic diathesis;
Severe hepatic insufficiency (liver cirrhosis and ascites);
Severe renal insufficiency (creatinine clearance < 30 mL/min);
Severe heart failure (NYHA class III–IV);
Combination with methotrexate administered at doses ≥ 15 mg/week (see section "Interaction with other medicinal products and other types of interactions");
Treatment of postoperative pain following coronary artery bypass grafting (using cardiopulmonary bypass apparatus).

Regarding the use of the medicinal product Clivas® Duo:

Pregnancy and breastfeeding. It is contraindicated in women of reproductive potential who are not using contraceptive methods;
Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other types of interactions.

Interactions with rosuvastatin

Effect of concomitant medicinal products 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 medicinal products that inhibit these transporters may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "Dosage and administration", "Special precautions", Table 2).

Cyclosporine

During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients receiving cyclosporine concomitantly (see section "Contraindications").

Concomitant use did not affect plasma concentrations of cyclosporine.

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-fold and 7-fold increases in AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin with certain protease inhibitor combinations may be possible after careful consideration of rosuvastatin dose adjustment, given the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other types of interactions", Table 2).

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").

Based on data from specific studies, a pharmacokinetically significant interaction with fenofibrate is not expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, 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 initiate 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 (Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse effects (see section "Special precautions").

Antacid medicinal products

Concomitant use of rosuvastatin with suspensions of antacids containing aluminum or magnesium hydroxide reduced plasma concentrations of rosuvastatin 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.

Ticagrelor

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, increased creatine phosphokinase levels, and rhabdomyolysis.

Cytochrome P450 enzymes

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

Interactions requiring rosuvastatin dose adjustment (see also Table 2)

When coadministration of rosuvastatin with other medicinal products capable of increasing rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If rosuvastatin exposure (AUC) is expected to increase approximately 2-fold 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 the expected exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting medicinal products; for example, when coadministered with gemfibrozil, the rosuvastatin dose should be 20 mg (1.9-fold increase in exposure), and when coadministered with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required; however, 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 clinical study data

Increased rosuvastatin AUC by 2-fold or more
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg / 100 mg / 100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
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
Obitasvir 25 mg / paritaprevir 150 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	Data not available	↑ 2.5-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
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1-fold
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increased rosuvastatin AUC less than 2-fold
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Elotrombopag 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	Data not available	↑ 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 rosuvastatin AUC
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
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 of rosuvastatin values when co-administered versus alone. Data presented as percent change represent the percentage difference relative to rosuvastatin values when administered alone. Increases are indicated by ↑, decreases by ↓. ** Multiple interaction studies were conducted at different rosuvastatin doses; the most significant ratio is presented in Table 1.

Medicinal products/combinations that did not have a clinically significant effect on the AUC ratio of rosuvastatin when used concomitantly: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg for 7 days three times daily; fluconazole 200 mg for 11 days once daily; fosamprenavir 700 mg / ritonavir 100 mg for 8 days twice daily; ketoconazole 200 mg for 7 days twice daily; rifampicin 450 mg for 7 days once daily; silymarin 140 mg for 5 days three times daily.

Effect of rosuvastatin on medicinal products when used concomitantly

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 decrease the INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives / Hormone replacement therapy (HRT)

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

Other medicinal products

Digoxin

According to data from specific studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Studies on the interaction between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is used concomitantly with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) has not yet been clarified. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination.

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

Children

Interaction studies have been conducted only in adults. The extent of interaction in children is unknown.

Interactions with acetylsalicylic acid

Contraindicated combinations

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

Combinations requiring cautious use.

When used concomitantly with ASA, plasma levels of phenytoin and valproate increase. When used concomitantly with valproic acid, ASA displaces it from plasma protein binding, reducing its metabolism. As a result, plasma levels of valproate increase, increasing the frequency of adverse reactions with signs of intoxication such as tremor, nystagmus, ataxia, and personality changes.
Pharmacodynamic interactions may occur between selective serotonin reuptake inhibitors and ASA, increasing the risk of bleeding due to synergistic effects.
When used concomitantly with ASA, plasma concentration of digoxin increases due to reduced renal excretion.
When used concomitantly with ASA, antidiabetic agents (e.g., insulin, sulfonylureas) may lead to decreased blood glucose levels.
Reduced effect of uricosuric agents (e.g., probenecid, sulfinpyrazone).
Diuretics in combination with high doses of ASA: reduced diuretic effect.
Methotrexate at doses less than 15 mg/week: increased methotrexate toxicity (due to decreased renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).
Concomitant use with NSAIDs such as ibuprofen or naproxen may attenuate the irreversible platelet inhibition by acetylsalicylic acid. The clinical significance of this interaction is unknown. Treatment with ibuprofen or naproxen in patients at risk of cardiovascular diseases may limit the cardioprotective effect of ASA (see section "Special instructions").
Metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation when taken concomitantly. Therefore, metamizole should be used with caution in patients taking low-dose acetylsalicylic acid for cardioprotection.
Alcohol: increased risk of gastrointestinal ulcers and bleeding, prolonged bleeding time.
Antihypertensive agents (angiotensin-converting enzyme inhibitors and β-blockers): when using Clivas® Duo and these medicinal products concomitantly, careful monitoring of the patient's blood pressure is recommended, with dose adjustment if necessary.
Enhanced effects of anticoagulants/thrombolytic agents, barbiturates, lithium, sulfonamides, and triiodothyronine.
Prolonged elimination half-life of penicillin from plasma.
Enhanced effects of other nonsteroidal anti-rheumatic agents and adverse reactions to their use.
Systemic glucocorticosteroids: increased risk of gastrointestinal ulcers and bleeding. Decreased salicylate levels in blood during corticosteroid therapy, risk of salicylate overdose after discontinuation of glucocorticosteroid therapy.
Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").

Special precautions for use.

Rosuvastatin

Renal effects

Proteinuria, predominantly of tubular origin detected by urine dipstick testing, 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 receiving the medicinal product at a dose of 40 mg.

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 excluded (see section "Interaction with other medicinal products and other forms of interaction"), and therefore such combination should be used with caution.

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

Creatine kinase levels

Creatine kinase (CK) levels should not be measured immediately after significant physical exertion or in the presence of other potential causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 × ULN), repeat testing 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:

renal 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 "Method of administration and dosage", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
concomitant use of fibrates.

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

During treatment

Patients should be advised to promptly report any unexplained muscle pain, weakness, or tenderness, 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 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 features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels, which persist even after discontinuation of statins.

There have been reports that statins may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms of these conditions worsen, treatment with Clivas® Duo should be discontinued. Recurrences have been reported upon first or repeated use of the same or another statin.

Clinical studies have not provided evidence of increased musculoskeletal effects in a small number of patients taking rosuvastatin and 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, niacin, azole antifungal agents, 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 is contraindicated when fibrates are used concomitantly (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. For patients in whom systemic fusidic acid is considered life-saving, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including 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 resumed 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic action of fusidic acid is required, such as 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. Such concomitant use requires careful medical supervision.

Rosuvastatin should not be administered to patients with acute, serious conditions indicating myopathy or potential for developing 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 adverse reactions, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with rosuvastatin use, which may be life-threatening or fatal (see section "Adverse reactions"). When prescribing the medicinal product, patients should be informed about the signs and symptoms of severe skin reactions, and careful monitoring during treatment is required. If signs or symptoms indicating a skin reaction occur, rosuvastatin should be discontinued immediately, and alternative treatment considered.

If a patient develops a serious reaction such as SJS or DRESS related to rosuvastatin use, reinitiation of treatment in such a patient is not recommended.

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.

Biochemical liver function tests are recommended before starting treatment and 3 months thereafter. Rosuvastatin use should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of reports of serious hepatic events (mainly elevated liver transaminases) in the post-marketing period was higher with the 40 mg dose of rosuvastatin.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying condition should be initiated before starting rosuvastatin therapy.

Race

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

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors combined 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 medicinal product with certain protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Method of administration and dosage" and "Interaction with other medicinal products and other forms of interaction").

Interstitial lung disease

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

Diabetes mellitus

Some evidence suggests that statins, as a class, increase blood glucose levels and may induce hyperglycemia requiring appropriate diabetes treatment in some patients at high future risk of developing diabetes. 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 5.6–6.9 mmol/L, body mass index [BMI] > 30 kg/m², elevated triglycerides, arterial hypertension) should be monitored clinically and biochemically according to current guidelines.

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

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics according to Tanner in children aged 6 to 17 years taking rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics").

In a clinical study in children and adolescents taking rosuvastatin for 52 weeks, CK levels > 10 times the ULN and muscle symptoms after physical exertion or increased physical activity were observed more frequently compared to adults (see section "Adverse reactions").

Acetylsalicylic acid

Caution is required in patients with bronchial asthma or hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as acetylsalicylic acid may cause bronchospasm or an asthma attack or other hypersensitivity reactions, as well as in patients with allergies to other substances. Careful monitoring of patients with allergic reactions (e.g., rash, pruritus, or urticaria), asthma, hay fever, nasal polyps, or chronic respiratory diseases in their history is also necessary.

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

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

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

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

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

During surgical procedures (including dental procedures), the use of medicinal products containing ASA increases the likelihood of bleeding or increased bleeding due to inhibition of platelet aggregation.

The use of acetylsalicylic acid in children and adolescents with fever and/or viral infections is possible only on a physician's prescription as second-line therapy (due to the risk of Reye's syndrome, a life-threatening encephalopathy characterized by severe vomiting, loss of consciousness, and liver dysfunction).

With certain viral infections, particularly influenza A, influenza B, and varicella, there is a risk of Reye's syndrome, a very rare but life-threatening condition requiring 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 proven. If these conditions are accompanied by persistent vomiting, this may be a manifestation of Reye's syndrome.

In patients with glucose-6-phosphate dehydrogenase deficiency, ASA may cause hemolysis of erythrocytes or hemolytic anemia. Factors increasing the risk of hemolysis include: high doses of the medicinal product, fever, and acute infectious processes.

The medicinal product should be used with caution when used concomitantly with anticoagulants. It should also be used with caution in patients with gastrointestinal ulcers, including chronic and recurrent peptic ulcer disease or gastrointestinal bleeding in their history, impaired liver function, symptoms of chronic gastric or duodenal dyspepsia or their recurrence.

Gastrointestinal ulcers, bleeding, or perforation may occur at any time, including without warning symptoms or signs in the history, during treatment with COX-2 selective or non-selective non-steroidal anti-inflammatory drugs (NSAIDs). To reduce this risk, the lowest effective dose should be used for the shortest possible duration of therapy.

Placebo-controlled studies of some selective COX-2 inhibitors have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications. It is currently unknown whether this risk is directly correlated with the COX-1/COX-2 selectivity of the respective NSAID. Since comparable clinical trial data for acetylsalicylic acid at maximum doses and as long-term therapy are currently lacking, such an increased risk cannot be excluded. Until relevant data are available, acetylsalicylic acid may be used only after careful benefit/risk assessment in patients with clinically confirmed ischemic heart disease, cerebrovascular diseases, peripheral arterial occlusive diseases, or significant risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). In such cases, the lowest effective dose should also be used for the shortest possible duration of therapy.

The effects of NSAIDs on the kidneys include, in particular, fluid retention with edema and/or hypertension. Acetylsalicylic acid should be used with caution in patients with cardiac dysfunction and other conditions predisposing to fluid retention.

Caution is also required for patients receiving diuretics or ACE inhibitors concomitantly and those at increased risk of hypovolemia.

Caution is required when NSAIDs such as ibuprofen or naproxen are used concomitantly, as NSAIDs may reduce the inhibitory effect of ASA on platelet aggregation. If the medicinal product is used before starting NSAIDs as an analgesic, the patient should consult a physician (see section "Interaction with other medicinal products and other forms of interaction").

In low doses, ASA may reduce uric acid excretion. This may trigger a gout attack in susceptible patients.

Lactose intolerance

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

Use during pregnancy or breastfeeding.

The medicinal product Clivas® Duo is contraindicated during pregnancy and breastfeeding.

Pregnancy.

Rosuvastatin.

Women of childbearing potential should use appropriate contraceptive measures during treatment with rosuvastatin.

Since cholesterol and other products of cholesterol biosynthesis play a significant role in fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefit of using the medicinal product during pregnancy. Data from animal studies on toxic effects on reproductive function are limited. If a patient becomes pregnant during treatment with this medicinal product, treatment should be discontinued immediately.

Acetylsalicylic acid.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate a risk of miscarriage and cardiac malformations and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with increasing dose and duration of therapy.

Available epidemiological data do not confirm a link between the use of acetylsalicylic acid and an increased risk of miscarriage. Epidemiological data on miscarriage are inconsistent, but an increased risk of gastroschisis cannot be excluded with the use of acetylsalicylic acid. Results from a prospective study on the effect of the medicinal product in early pregnancy (1–4 months) involving approximately 14,800 mother-child pairs do not indicate any association with an increased risk of malformations.

During the first and second trimesters of pregnancy, medicinal products containing acetylsalicylic acid should not be prescribed without clear clinical necessity. For women who may potentially be pregnant and for pregnant women in the first and second trimesters, the dose of medicinal products containing acetylsalicylic acid should be as low as possible, and the duration of treatment as short as possible.

Animal studies have shown that the use of prostaglandin inhibitors leads to increased pre- and post-implantation losses and embryo/fetal death. In addition, an increased frequency of severe developmental abnormalities, including cardiovascular malformations, was observed in animals receiving prostaglandin inhibitors during organogenesis.

According to previous experience, the risk is low when the medicinal product is used at therapeutic doses. Prenatal monitoring for detection of arterial duct constriction after acetylsalicylic acid use should be considered from week 20 of pregnancy. If arterial duct constriction occurs, treatment with acetylsalicylic acid should be discontinued.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may:

affect the fetus as follows:
- cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
- impaired kidney function with possible subsequent development of renal failure with oligohydramnios;
affect the woman and fetus as follows:
- prolonged bleeding time, anti-aggregatory effect, which may occur even with very low doses;
- inhibition of uterine contractions and bleeding in the pregnant woman and prolonged duration of labor.

Therefore, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Breastfeeding

Breastfeeding is contraindicated during treatment with Clivas® Duo.

It is known that rosuvastatin penetrates into the milk of rats. There are no data on the penetration of the medicinal product into human breast milk (see section "Contraindications").

Salicylates pass into breast milk. Concentrations in breast milk are equivalent to or even higher than concentrations in maternal plasma. In case of forced use during lactation, breastfeeding should be discontinued in case of regular use of high doses (> 300 mg/day).

Fertility. The use of acetylsalicylic acid may impair female fertility; therefore, its use is not recommended for women wishing to become pregnant. For women trying to conceive or undergoing infertility evaluation, discontinuation of acetylsalicylic acid should be considered.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product may have a negligible or moderate effect on the ability to drive or operate machinery.

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

Acetylsalicylic acid has no effect on the ability to drive or operate machinery.

Method of Administration and Dosage

The medicinal product Clivas® Duo can be taken at any time of the day with food. Capsules should be swallowed whole, without chewing, and accompanied by a large amount of liquid.

Dosage

The recommended dose of the medicinal product Clivas® Duo is one capsule per day.

This fixed-dose combination is not suitable for initiating therapy.

Patients whose condition is adequately controlled on stable doses of the individual components may be switched to Clivas® Duo. The choice of dose of Clivas® Duo should be based on the doses of the individual components at the time of switching.

If a dose adjustment of either active ingredient in the fixed-dose combination is required for any reason (e.g., recently diagnosed concomitant disease, change in patient status, or drug interaction), patients should be switched back to the individual components to allow appropriate dose titration.

Elderly patients

Dose adjustment is not required.

Patients with renal impairment

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

Clivas® Duo is contraindicated in patients with severe renal impairment at any dose (see section "Contraindications" and "Pharmacokinetics").

Patients with hepatic impairment

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

Clivas® Duo is contraindicated in patients with severe hepatic impairment at any dose.

No increase in systemic exposure was observed in patients with a Child–Pugh score of 7 or lower. However, increased systemic exposure has been observed in patients with a Child–Pugh score of 8 and 9 (see section "Pharmacokinetics"). For these patients, assessment of liver function should be considered (see section "Special Warnings and Precautions for Use"). Experience with use in patients with a Child–Pugh score above 9 is lacking. Treatment with Clivas® Duo is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to rosuvastatin has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use").

Genetic polymorphisms

Certain types of genetic polymorphisms may lead to increased exposure to rosuvastatin (see section "Pharmacokinetics"). Patients with any of these specific polymorphism types should be prescribed a lower daily dose of rosuvastatin.

Concomitant therapy

Rosuvastatin is a substrate of several transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products that can increase rosuvastatin plasma concentrations via interactions with 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"). Alternative treatments should be considered whenever possible, and in certain cases, temporary discontinuation of rosuvastatin therapy may be appropriate. In situations where concomitant use of such medicinal products with rosuvastatin cannot be avoided, the benefits and risks of combination therapy should be carefully weighed, and the rosuvastatin dose should be carefully selected (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Higher doses of acetylsalicylic acid reduce the beneficial effect of rosuvastatin; therefore, additional doses of acetylsalicylic acid should be avoided (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

The safety and efficacy of rosuvastatin/acetylsalicylic acid in children (under 18 years of age) have not been established. The combination of rosuvastatin/acetylsalicylic acid is not recommended for patients under 18 years of age.

Overdose.

Symptoms

Rosuvastatin

There is no specific antidote for overdose. In case of overdose, symptomatic treatment should be administered and supportive measures taken if necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Acetylsalicylic acid

Severe intoxication may be life-threatening. Symptoms of severe poisoning may develop acutely or gradually, for example, within 12–24 hours after administration.

Following oral administration of acetylsalicylic acid (ASA) doses up to 150 mg/kg body weight, moderate intoxication may occur, and doses > 300 mg/kg body weight may lead to severe intoxication.

Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of gastric concretions, or when the drug is administered in enteric-coated tablet form.

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

Symptoms

Headache, nausea, hypoglycemia or hyperglycemia, skin rash, dizziness, tinnitus, visual and hearing disturbances, tremor, confusion, hyperthermia, increased sweating, hyperventilation, respiratory alkalosis with metabolic compensation leading to metabolic acidosis, electrolyte imbalance, dehydration, seizures, coma, respiratory distress syndrome, cardiac arrhythmias.

Symptoms of chronic salicylate intoxication are nonspecific (e.g., tinnitus, headache, irritability, increased sweating, hyperventilation) and may therefore be overlooked.

Treatment

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

Appropriate monitoring and correction of electrolyte levels. Administration of glucose and sodium bicarbonate in the early stages to correct acidosis and enhance elimination (urine pH > 8), improvement of diuresis, cooling in case of hyperthermia, benzodiazepines for seizures.

Hemodialysis may be used in cases of severe intoxication.

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

Adverse Reactions

The table below presents the profile of adverse reactions based on clinical trial data and extensive post-marketing experience. Adverse reactions are classified by frequency and organ systems.

By frequency, adverse reactions are categorized as follows:
Common (≥ 1/100 to < 1/10),
Uncommon (≥ 1/1,000 to < 1/100),
Rare (≥ 1/10,000 to < 1/1,000),
Very rare (< 1/10,000),
Not known (cannot be estimated from available data).

With rosuvastatin use:

Blood and lymphatic system disorders:
Rare – thrombocytopenia

Immune system disorders:
Rare – hypersensitivity reactions, including angioedema

Endocrine disorders:
Common – diabetes mellitus^1

Psychiatric disorders:
Not known – depression

Nervous system disorders:
Common – dizziness, headache;
Very rare – polyneuropathy, memory loss;
Not known – peripheral neuropathy, sleep disorders (insomnia, nightmares), myasthenia gravis

Eye disorders:
Not known – ocular form of myasthenia

Respiratory, thoracic and mediastinal disorders:
Not known – cough, dyspnea

Gastrointestinal disorders:
Common – abdominal pain, nausea, constipation;
Rare – pancreatitis;
Not known – diarrhea

Hepatobiliary disorders:
Rare – increased transaminase levels;
Very rare – hepatitis, jaundice

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

Musculoskeletal and connective tissue disorders:
Common – myalgia;
Rare – myopathy (including myositis) and rhabdomyolysis, lupus-like syndrome, muscle rupture;
Very rare – arthralgia;
Frequency not known – tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy

Renal and urinary disorders:
Very rare – hematuria

Reproductive system and breast disorders:
Very rare – gynecomastia

General disorders:
Common – asthenia;
Frequency not known – edema

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

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

With acetylsalicylic acid use:

Blood and lymphatic system disorders:
Prolonged bleeding time;
Rare – thrombocytopenia, agranulocytosis, pancytopenia, leukopenia, aplastic anemia, iron deficiency anemia;
Not known – hemolysis and hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Due to its antiplatelet effect, acetylsalicylic acid (ASA) 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 reported rarely or very rarely, particularly in patients with uncontrolled hypertension and/or concomitant use of anticoagulants, which in some cases may be potentially life-threatening.

Immune system disorders:
Uncommon – asthma;
Rare – hypersensitivity reactions such as erythematous/eczematous skin reactions, urticaria, rhinitis, nasal congestion, bronchospasm, angioedema, hypotension progressing to shock;
Very rare – severe skin reactions, including exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)

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

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

Gastrointestinal disorders:
Very common – minor gastrointestinal blood loss (microbleeding);
Common – gastric symptoms;
Uncommon – dyspepsia, nausea, vomiting, diarrhea;
Rare – gastrointestinal bleeding, gastrointestinal ulcers, which in very rare cases may lead to perforation. Formation of intestinal diaphragm-like strictures, especially with long-term use.

Hepatobiliary disorders:
Rare – hepatic dysfunction;
Very rare – increased transaminase levels

Renal and urinary disorders:
Rare – impaired renal function;
Not known – acute renal failure

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

Description of selected adverse reactions

Renal effects

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

Hematuria has 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 times the upper limit of normal), treatment should be discontinued (see section "Special warnings and precautions for use").

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.

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 warnings and precautions for use").

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

Shelf life.

3 years.

Storage conditions.

Store in the original packaging to protect from moisture, at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

Adamed Pharma S.A.

Manufacturer's address and place of business.

ul. marsz. J. Pilsudskiego 5, Pabianice, 95-200, Poland

Marketing Authorization Holder.

LLC "ASINO UKRAINE"

Address of the Marketing Authorization Holder.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine

If adverse effects occur or if you have any questions regarding the safety of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at:
8 Vatslava Havela Boulevard, Kyiv, 03124, Tel./Fax: +38 044 281 2333.