Instructions for use of Klivas Duo 20 mg/100 mg capsules No. 28
Composition
active ingredients: rosuvastatin, acetylsalicylic acid;
1 capsule of 5 mg/100 mg contains 5.20 mg of rosuvastatin calcium, which is equivalent to 5.00 mg of rosuvastatin and 100.00 mg of acetylsalicylic acid;
1 capsule of 10 mg/100 mg contains 10.40 mg of rosuvastatin calcium, which is equivalent to 10.00 mg of rosuvastatin and 100.00 mg of acetylsalicylic acid;
1 capsule of 20 mg/100 mg contains 20.80 mg of rosuvastatin calcium, which is 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); heavy magnesium oxide; crospovidone (type A); colloidal anhydrous silica; 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), iron oxide yellow (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.
Dosage form
The capsules are hard.
Basic physicochemical properties.
Capsules 5 mg/100 mg: hard gelatin capsules size No. 2, cap: opaque dark green, body: opaque white. Capsule contents: one oval, biconvex, white or almost white acetylsalicylic acid tablet and one round, biconvex, brown, film-coated rosuvastatin tablet.
Capsules 10 mg/100 mg: hard gelatin capsules size No. 1, cap: opaque light green, with black inscription "RSV 10", body: opaque white, with black inscription "ASA 100". Capsule contents: one oval, biconvex, white or almost white acetylsalicylic acid tablet and one round, biconvex, brown film-coated rosuvastatin tablet.
Capsules 20 mg/100 mg: hard gelatin capsules size No. 0, cap: opaque green, with black inscription "RSV 20", body: opaque white, with black inscription "ASA 100". Capsule contents: one oval, biconvex, white or almost white tablet of acetylsalicylic acid and two round, biconvex, brown-coated tablets of rosuvastatin.
Pharmacotherapeutic group
HMG-CoA reductase inhibitors, other combinations. Rosuvastatin and acetylsalicylic acid.
ATX code C10BX05.
Pharmacological properties
Pharmacodynamics.
Rosuvastatin
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, a target organ for lowering 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 the hepatic synthesis of very low-density lipoprotein (VLDL), thereby reducing the total number of VLDL and LDL particles.
Rosuvastatin reduces elevated LDL-cholesterol (LDL-C), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C). It also reduces apoprotein B (ApoB), non-HDL-cholesterol (non-HDL-C), VLDL-cholesterol (LDL-C), VLDL-triglycerides, and increases apoprotein A-I (ApoA-I). Rosuvastatin also reduces the LDL-C/HDL-C, total-C/HDL-C, and non-HDL-C/HDL-C ratios, and ApoB/ApoA-I.
The therapeutic effect is achieved within 1 week after the start of the drug, 90% of the maximum effect is achieved after 2 weeks. The maximum effect is usually achieved after 4 weeks and continues thereafter.
Acetylsalicylic acid
Acetylsalicylic acid irreversibly inhibits platelet aggregation. This effect on platelets is due to the acetylation of cyclooxygenase. This irreversibly inhibits the synthesis of thromboxane A2 (a prostaglandin that stimulates platelet aggregation and has a vasoconstrictor effect) in platelets. This effect is permanent and usually lasts throughout the entire 8-day life span of platelets.
Surprisingly, acetylsalicylic acid also inhibits the synthesis of prostacyclin (a prostaglandin that inhibits platelet aggregation but has a vasodilating effect) in endothelial cells of blood vessels. This effect is temporary.
After acetylsalicylic acid is removed from the blood, nucleated endothelial cells begin to synthesize prostacyclin again.
As a result, a single low daily dose of acetylsalicylic acid (< 100 mg/day) causes inhibition of thromboxane A2 in platelets without a significant effect on prostacyclin synthesis.
The European Medicines Agency has waived the obligation to submit the results of studies with the combination of rosuvastatin/acetylsalicylic acid in all subsets of the paediatric population for the approved indication (for use in children, see section 4.2).
Pharmacokinetics.
Rosuvastatin
Absorption: Peak plasma concentrations of rosuvastatin are reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.
Distribution: Rosuvastatin is extensively taken up by the liver, which is the main 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.
Genetic polymorphisms: The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves the transporter proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased exposure to rosuvastatin. The specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher exposure (AUC) to rosuvastatin compared to the genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. This specific genotyping is not routinely used in clinical practice, but a lower daily dose of rosuvastatin is recommended for patients with these types of polymorphisms.
Biotransformation. Rosuvastatin undergoes minor metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for metabolism by cytochrome P450 enzymes. The main isoenzyme involved is CYP2C9, with 2C19, 3A4 and 2D6 playing a somewhat smaller role. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitory activity.
Excretion. Approximately 90% of the rosuvastatin dose is excreted unchanged in the feces (absorbed and unabsorbed active substance together), the remainder is excreted in the urine. Approximately 5% is excreted in the urine in unchanged form. The plasma half-life is approximately 19 hours and does not increase with increasing dose. The geometric mean plasma clearance of the drug is approximately 50 l/h (coefficient of variation - 21.7%). Hepatic uptake of rosuvastatin, as well as other HMG-CoA reductase inhibitors, occurs with the participation of the membrane transporter OATP-C, which plays an important role in the hepatic elimination of rosuvastatin.
Acetylsalicylic acid
Absorption. After oral administration, acetylsalicylic acid (ASA) is rapidly absorbed in the proximal small intestine. Peak plasma concentrations are reached after 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: The volume of distribution of ASA is approximately 0.20 l/kg body weight. The level of binding of the first product of ASA transformation, the anti-inflammatory salicylic acid, to plasma proteins, primarily albumin, is 90%.
Salicylic acid slowly penetrates the synovial membrane and synovial fluid. It crosses the placenta and enters breast milk.
Biotransformation: ASA is converted primarily to salicylic acid by hydrolysis. The half-life of ASA is short, approximately 15–20 minutes.
Salicylic acid is then converted to glycinic acid and glucuronic acid conjugates and trace amounts of gentisic acid. At higher therapeutic doses, the conversion capacity of salicylic acid is exhausted and the pharmacokinetics are non-linear. This results in an increase in the apparent half-life of salicylic acid from a few hours to approximately 24 hours.
Excretion: Excreted mainly by the kidneys.
Tubular resorption of salicylic acid is pH dependent. By alkalinizing the urine, the proportion of unchanged salicylic acid excreted increases from approximately 10% to 80%.
Linearity/nonlinearity
Systemic exposure to rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with repeated daily administration.
Special populations
Age and gender: Age and gender had no clinically significant effect on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers.
Renal impairment. In a study in patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in subjects with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 ml/min), plasma concentrations of rosuvastatin were 3-fold and those of the N-desmethyl metabolite were 9-fold 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, there was no evidence of increased exposure to rosuvastatin in patients with Child-Pugh scores of 7 or less. However, two patients with Child-Pugh scores of 8 and 9 had systemic exposures at least twice that of patients with lower scores. There is no experience with rosuvastatin in patients with Child-Pugh scores greater than 9.
Indication
The drug Klivas® Duo is intended for secondary prevention of cardiovascular diseases as replacement therapy in adult patients whose condition is adequately controlled with the simultaneous use of monocomponents of the drug in equivalent therapeutic doses.
Contraindication
Regarding the use of rosuvastatin:
active liver disease, including persistent elevations of serum transaminases of unknown etiology or any elevation of serum transaminases to at least three times the upper limit of normal (ULN);
severe renal impairment (creatinine clearance <30 ml/min);
myopathy;
concomitant therapy with cyclosporine;
concomitant use of the combination of sofosbuvir/velpatasvir/voxilaprevir (see section “Interaction with other medicinal products and other types of interactions”).
Regarding the use of acetylsalicylic acid:
Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs); bronchial asthma, rhinitis and nasal polyps. Contraindicated in patients with mastocytosis, in whom the use of acetylsalicylic acid may cause severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia and vomiting);
history of active or recurrent gastric and duodenal ulcers and/or gastrointestinal bleeding or other types of bleeding such as cerebrovascular hemorrhage;
hemorrhagic diathesis, blood clotting disorders such as hemophilia and thrombocytopenia;
severe liver or kidney dysfunction;
severe uncompensated heart failure;
combination with methotrexate used in doses > 15 mg/week (see section "Interaction with other medicinal products and other types of interactions").
Regarding the use of the medicinal product Klivas® Duo:
Pregnancy and breastfeeding. Contraindicated for women of reproductive age who are not using contraception;
hypersensitivity to any of the components of the drug.
Interaction with other medicinal products and other types of interactions
Interactions with rosuvastatin
Effect of concomitant medications on rosuvastatin
Transport protein inhibitors
Rosuvastatin is a substrate for several transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections 4.2 and 4.4, Table 1).
Cyclosporine
During concomitant use of rosuvastatin and ciclosporin, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 1). Rosuvastatin is contraindicated in patients receiving concomitant ciclosporin (see section "Contraindications").
Concomitant use did not affect the 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 1). For example, in a pharmacokinetic study, co-administration of 10 mg of rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was accompanied by an increase in rosuvastatin AUC and Cmax by approximately 3- and 7-fold, respectively. Concomitant use of rosuvastatin and some combinations of protease inhibitors is possible after careful consideration of the dose adjustment of rosuvastatin, taking into account the expected increase in rosuvastatin exposure (see sections “Method of administration and dosage”, “Special instructions for use”, “Interaction with other medicinal products and other forms of interaction”, Table 1).
Gemfibrozil and other lipid-lowering agents
Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected, but 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, probably because they can cause myopathy when used alone. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections 4.3 and 4.4). These patients should also be started on the 5 mg dose.
Ezetimibe
Concomitant administration of rosuvastatin 10 mg and ezetimibe 10 mg to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 1). A pharmacodynamic interaction between rosuvastatin and ezetimibe, which could lead to adverse events, cannot be excluded (see section 4.4).
Antacid medications
Concomitant administration of rosuvastatin with antacid suspensions containing aluminum or magnesium hydroxide reduced rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when the antacid was administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.
Erythromycin
Concomitant use of rosuvastatin and erythromycin decreased rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to increased intestinal motility due to erythromycin.
Cytochrome P450 enzymes
In vitro and in vivo studies have shown that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, drug interactions resulting from P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Interactions requiring dose adjustment of rosuvastatin (see also Table 1)
If it is necessary to use rosuvastatin with other drugs that can increase the exposure of rosuvastatin, the dose of rosuvastatin should be adjusted. If the exposure of the drug (AUC) is expected to increase by approximately 2 or more times, the use of rosuvastatin should be started at a dose of 5 mg once a day. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure of rosuvastatin does not exceed the exposure observed when taking a dose of 40 mg / day without the use of drugs that interact with the drug; for example, when used with gemfibrozil, the dose of rosuvastatin will be 20 mg (an increase in exposure of 1.9 times), when used with the combination of ritonavir / atazanavir - 10 mg (an increase of 3.1 times).
If the drug increases the AUC of rosuvastatin by less than 2 times, the initial dose does not need to be reduced, but caution should be exercised when increasing the dose of rosuvastatin above 20 mg.
Table 1
Effect of concomitant medications on rosuvastatin exposure (AUC; in descending order of magnitude) based on published clinical trial data
| Increase in rosuvastatin AUC by 2 times or more | | |
| Dosing regimen of the interacting drug | Rosuvastatin dosage 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 times |
| Cyclosporine 75 mg twice daily to 200 mg twice daily, 6 months | 10 mg once daily, 10 days | ↑ 7.1 times |
| Darolutamide 600 mg twice daily, 5 days | 5 mg, single dose | ↑ 5.2 times |
| Regorafenib 160 mg once daily, 14 days | 5 mg, single dose | ↑ 3.8 times |
| Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days | 10 mg, single dose | ↑ 3.1 times |
| Velpatasvir 100 mg once daily | 10 mg, single dose | ↑ 2.7 times |
| Ombitasvir 25 mg / paritaprevir 150 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days | 5 mg, single dose | ↑ 2.6 times |
| Grazoprevir 200 mg/elbasvir 50 mg once daily, 11 days | 10 mg, single dose | ↑ 2.3 times |
| Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days | 5 mg once daily, 7 days | ↑ 2.2 times |
| Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days | 20 mg once daily, 7 days | ↑ 2.1 times |
| Clopidogrel 300 mg, then 75 mg 24 hours later | 20 mg, single dose | ↑ 2 times |
| Gemfibrozil 600 mg twice daily, 7 days | 80 mg, single dose | ↑ 1.9 times |
| Increase in rosuvastatin AUC less than 2-fold | | |
| Dosing regimen of the interacting drug | Rosuvastatin dosage regimen | Changes in rosuvastatin AUC* |
| Eltrombopag 75 mg once daily, 5 days | 10 mg, single dose | ↑ 1.6 times |
| Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days | 10 mg once daily, 7 days | ↑ 1.5 times |
| Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days | 10 mg, single dose | ↑ 1.4 times |
Dronedarone 400 mg twice daily | Not known | ↑ 1.4 times | | Itraconazole 200 mg once daily, 5 days | 10 mg, single dose | ↑ 1.4 times** |
| Ezetimibe 10 mg once daily, 14 days | 10 mg once daily, 14 days | ↑ 1.2 times** |
| Decreased rosuvastatin AUC | | |
| Dosing regimen of the interacting drug | Rosuvastatin dosage regimen | Changes in rosuvastatin AUC* |
| Erythromycin 500 mg four times a day, 7 days | 80 mg, single dose | ↓ 20% |
| Baicalin 50 mg three times a day, 14 days | 20 mg, single dose | ↓ 47% |
* Data presented as x-fold change represent the ratio between rosuvastatin in combination and rosuvastatin alone. Data presented as % change represent the % difference relative to rosuvastatin alone. Increase is indicated by the ↑ icon, decrease by the ↓ icon. ** Several interaction studies have been conducted at different doses of rosuvastatin, the most significant relationship is presented in Table 1. | | |
Drugs/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 3 times a day; fluconazole 200 mg for 11 days 1 time a day; fosamprenavir 700 mg / ritonavir 100 mg for 8 days 2 times a day; ketoconazole 200 mg for 7 days 2 times a day; rifampin 450 mg for 7 days 1 time a day; silymarin 140 mg for 5 days 3 times a day.
Effect of rosuvastatin on concomitant medications
Vitamin K antagonists
As with other HMG-CoA reductase inhibitors, when initiating or increasing the dose of rosuvastatin in patients receiving concomitant vitamin K antagonists (e.g. warfarin or other coumarin anticoagulants), an increase in the international normalized ratio (INR) may occur. Discontinuation of rosuvastatin or dose reduction may decrease the INR. In such cases, appropriate monitoring of INR is advisable.
Oral contraceptives/hormone replacement therapy (HRT)
Concomitant use of rosuvastatin and oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, 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 taking rosuvastatin and HRT simultaneously, so a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.
Digoxin
According to special studies, no clinically significant interaction with digoxin is expected.
Fusidic acid
Interaction studies of rosuvastatin with fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased by concomitant use of systemic fusidic acid with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) is not yet clear. Rhabdomyolysis (including some fatal cases) has been reported in patients receiving this combination.
In patients for whom systemic fusidic acid is considered necessary, rosuvastatin treatment should be discontinued for the duration of fusidic acid treatment. See also section 4.4.
Interactions with acetylsalicylic acid
The use of multiple platelet aggregation inhibitors, such as ASA, NSAIDs, ticlopidine, clopidogrel, tirofiban, eptifibatide, increases the risk of bleeding, as does their combination with heparin and its derivatives (hirudin, fondaparinux), oral anticoagulants and thrombolytics. Clinical and biological parameters of hemostasis should be regularly measured in patients planning to start thrombolytic therapy.
Contraindicated combinations
When used with methotrexate at doses of 15 mg/week or more, the hematological toxicity of methotrexate increases (due to a decrease in the renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates) (see section "Contraindications").
Combinations that are not recommended.
Uricosuric agents (e.g. benzbromarone, probenecid, sulfinpyrazone): due to reduced efficacy due to competitive action on the excretion of uric acid through the renal tubules, the simultaneous use of ASA with uricosuric agents is not recommended.
In the case of simultaneous use with ASA, there is an increase in the levels of phenytoin and valproate in the blood plasma. When used simultaneously with valproic acid, ASA displaces it from its connection with plasma proteins, reducing the metabolism of the latter. As a result, plasma levels of valproate increase, which increases the frequency of adverse reactions with the appearance of signs of intoxication, such as tremor, nystagmus, ataxia and personality changes.
Pharmacodynamic interactions may develop between selective serotonin reuptake inhibitors and ASA, which increases the risk of bleeding due to a synergistic effect.
In the case of simultaneous use of antidiabetic agents (e.g. insulin, sulfonylurea) with ASA, a decrease in blood sugar levels is possible.
Combinations that should be used with caution.
Diuretics in combination with high doses of ASA: reduced diuretic effect. There is a risk of acute renal failure due to a decrease in glomerular filtration rate as a result of reduced prostaglandin synthesis in the kidneys. Reduced efficacy may be caused by aldosterone antagonists (spironolactone and potassium canrenoate) or loop diuretics (e.g. furosemide). At the beginning of treatment, patients should consume sufficient fluids; renal function should be monitored.
Systemic glucocorticosteroids: increased risk of gastrointestinal ulcers and bleeding. Decreased blood salicylate levels during corticosteroid therapy, risk of salicylate overdose after discontinuation of glucocorticosteroid therapy.
Methotrexate at doses less than 15 mg/week: Concomitant use of methotrexate and ASA increases the hematological toxicity of methotrexate due to a decrease in the renal clearance of methotrexate by acetylsalicylic acid. Weekly blood counts should be monitored during the first weeks of combination therapy. Close monitoring is necessary in cases of even mild renal dysfunction, as well as in elderly patients.
Heparin: Patients receiving ASA and heparin at therapeutic doses, as well as elderly patients, are at increased risk of bleeding. When used together, the international normalized ratio, activated partial thromboplastin time (APTT) and/or bleeding time should be carefully monitored.
Combinations for which there are caveats.
Other anticoagulants (coumarin derivatives, prophylactic doses of heparin), other antiplatelet agents and other thrombolytic agents: increased risk of bleeding.
NSAIDs: increased risk of damage to the gastrointestinal mucosa, bleeding, and prolongation of bleeding time.
Concomitant use with NSAIDs such as ibuprofen or naproxen may attenuate the irreversible inhibition of platelets by acetylsalicylic acid. The clinical significance of this interaction is unknown. Treatment with ibuprofen or naproxen in patients at risk of cardiovascular disease may limit the cardioprotective effect of ASA (see section "Special warnings and precautions for use").
Metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation when taken simultaneously. Therefore, metamizole should be used with caution in patients taking low doses of acetylsalicylic acid for cardioprotection.
Antacids can increase the excretion of ASA by the kidneys, making the urine alkaline.
Alcohol: increased risk of gastrointestinal ulcers and bleeding, prolongation of bleeding time.
Antihypertensive agents (angiotensin-converting enzyme inhibitors and β-blockers): in case of simultaneous use of the drug Klivas®Duo and these drugs, it is recommended to carefully monitor the patient's blood pressure and adjust the dose if necessary.
Enhancement of the effects of barbiturates, lithium, sulfonamides and triiodothyronine.
Prolongation of the half-life of penicillin from blood plasma.
Application features
Rosuvastatin
Effects on the kidneys
Proteinuria, detected by dipstick analysis, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, including 40 mg, and in most cases was transient or intermittent. Proteinuria was not a harbinger of acute or progressive renal disease (see section 4.8). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. Patients taking the drug at a dose of 40 mg should have their renal function checked regularly.
Effects on skeletal muscles
Skeletal muscle disorders, such as myalgia, myopathy and, rarely, rhabdomyolysis, have been reported in patients taking rosuvastatin at all doses, particularly above 20 mg. Very rare cases of rhabdomyolysis have been reported when ezetimibe was used in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded (see section 4.5), and therefore this combination should be used with caution.
Creatine kinase level
Creatine kinase (CK) levels should not be measured after significant exercise or in the presence of possible alternative causes of CK elevation that may complicate interpretation of results. If baseline CK levels are significantly elevated (> 5 × ULN), a repeat test should be performed within 5–7 days to confirm the results. If the repeat test results confirm that baseline CK levels are greater than 5 times ULN, the drug should not be initiated.
Before starting treatment
Rosuvastatin, like other HMG-CoA reductase inhibitors, should be administered with caution to patients with a predisposition to myopathy/rhabdomyolysis. Risk factors for this include:
– kidney dysfunction;
– hypothyroidism;
– personal or family history of hereditary muscle diseases;
– history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
– age > 70 years;
– situations that may lead to increased plasma levels of the drug (see sections “Method of administration and dosage”, “Interaction with other medicinal products and other types of interactions” and “Pharmacokinetics”);
– concomitant use of fibrates.
In such patients, the risk of treatment should be weighed against the expected benefit; clinical monitoring is also recommended. If baseline CK levels are significantly elevated (> 5 × ULN), treatment should not be initiated.
During treatment
Patients should be asked to report unexplained muscle pain, weakness or cramps immediately, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The drug should be discontinued if CK levels are significantly elevated (> 5 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels are ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, rosuvastatin or an alternative HMG-CoA reductase inhibitor can be restarted at the lowest dose and under close supervision. There is no need to regularly monitor CK levels in asymptomatic patients. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with statins, including rosuvastatin. Clinical manifestations of IONM include proximal muscle weakness and elevated serum creatine kinase levels, which persist even after discontinuation of statins.
In clinical studies, there was no evidence of increased effects on skeletal muscle in a small number of patients taking rosuvastatin and concomitant medications. However, an increased incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors 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 some HMG-CoA inhibitors. Therefore, the use of rosuvastatin in combination with gemfibrozil is not recommended. The benefits of further lipid changes when using rosuvastatin in combination with fibrates or niacin should be carefully weighed against the potential risks associated with the use of such combinations. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections “Interaction with other medicinal products and other types of interactions” and “Adverse reactions”).
Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days of stopping fusidic acid. In patients for whom systemic fusidic acid is considered essential, statin treatment should be discontinued for the duration of fusidic acid treatment. Rhabdomyolysis (including some fatalities) has been reported in patients receiving the combination of fusidic acid and statins (see section 4.5). Patients should be advised to seek medical advice immediately 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 where prolonged systemic exposure to fusidic acid is required, e.g. for the treatment of severe infections,
