Aspiroza capsules 10mg/100mg No. 30

Instructions for use Aspiroza capsules 10mg/100mg No. 30

Composition

active ingredients: rosuvastatin, acetylsalicylic acid;

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

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

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

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

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

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

excipients:

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

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

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

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

Dosage form

The capsules are hard.

Main physicochemical properties:

Capsules of 5 mg/100 mg:

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

Each capsule contains two tablets:

Rosuvastatin 5 mg tablet: round tablet with a biconvex surface, coated with a brown film coating;

acetylsalicylic acid tablet 100 mg: oval biconvex tablet of white or almost white color.

Capsules of 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".

Each capsule contains two tablets:

Rosuvastatin 10 mg tablet: round tablet with a biconvex surface, coated with a brown film coating;

acetylsalicylic acid tablet 100 mg: oval biconvex tablet of white or almost white color.

Capsules of 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".

Each capsule contains three tablets:

two rosuvastatin 20 mg tablets together (10 mg each): round tablets with a biconvex surface, coated with a brown film coating;

acetylsalicylic acid tablet 100 mg: oval biconvex tablet of white or almost white color.

Pharmacotherapeutic group

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

Pharmacological properties

Pharmacodynamics.

Rosuvastatin.

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the 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 cholesterol reduction.

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.

The drug reduces elevated levels of LDL-cholesterol (LDL-C), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C). It also reduces levels of apolipoprotein B (apoB), non-HDL-C, VLDL-C, TG, and increases levels of apolipoprotein A-1 (apoA-I) – the relevant data are listed in Table 1.

The drug also reduces the LDL-C/HDL-C ratio, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I ratio.

Table 1

Dose response in patients with primary hypercholesterolemia types IIa and IIb

(adjusted average percentage change from baseline)

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.

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

The effect is persistent and usually lasts throughout the entire 8-day life of platelets.

At the same time, ASA concentrations in the posthepatic circulation only slightly inhibit endothelial cyclooxygenase, which is responsible for the synthesis of prostacyclin (a prostaglandin that inhibits platelet aggregation but has a vasodilating effect). This effect is transient. Platelet function, which is responsible for hemostasis, is not significantly altered.

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

Pharmacokinetics.

Rosuvastatin.

Absorption: 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. About 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Metabolism. 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 identified metabolites 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.

Elimination: Approximately 90% of a rosuvastatin dose is excreted unchanged in the feces (absorbed and unabsorbed active substance combined), the remainder is excreted in the urine. Approximately 5% is excreted unchanged in the urine. 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%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs with the participation of the membrane transporter OATP-C, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity. Systemic exposure to rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with repeated daily administration.

Special patient groups.

Age and gender: There was no clinically significant effect of age or gender 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.

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

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

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

Genetic polymorphism. The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, occurs with the participation of transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms of SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased exposure to rosuvastatin. With certain forms of the SLCO1B1 p.521CC and ABCG2 p.421AA polymorphisms, rosuvastatin exposure (AUC) is increased compared with the SLCO1B1 p.521TT or ABCG2 p.421CC genotypes. Specific genotyping is not provided in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of the drug.

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

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

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

Metabolism: Salicylic acid, formed during hydrolysis from ASA, has a short half-life of approximately 15–20 minutes.

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

At higher therapeutic doses, the metabolic potential of salicylic acid increases and the pharmacokinetics become nonlinear. This increases the apparent half-life of salicylic acid from a few hours to approximately 24 hours.

Excretion: ASA is excreted almost entirely by the kidneys in the form of salicylic acid (about 10%), salicylouric acid (about 75%), and salicylouric acid conjugates (about 10%). Tubular reabsorption of salicylic acid is pH-dependent. If the urine is alkaline, the percentage of unchanged salicylic acid in the excreted urine can increase from about 10% to 80%.

Preclinical data.

The preclinical safety profile of ASA is well documented. In animal studies, salicylates caused renal damage without any other organic lesions. ASA has been extensively studied for mutagenicity and carcinogenicity; no relevant evidence of mutagenic or carcinogenic properties was found. Salicylates have been shown to be embryotoxic and teratogenic in studies in various animal species (e.g., cardiac and skeletal malformations, gastroschisis).

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

Indication

The drug is intended for secondary prevention of cardiovascular complications in adult patients whose condition is adequately controlled with the use of rosuvastatin and acetylsalicylic acid in doses equal to the doses of this combination.

Contraindication

Associated with a combination of active ingredients.

Hypersensitivity to rosuvastatin, salicylates, other non-steroidal anti-inflammatory drugs (NSAIDs) or to any of the excipients of the medicinal product.

Severe renal impairment (creatinine clearance < 30 ml/min).

Pregnancy and breastfeeding. Also contraindicated for women of reproductive age who are not using adequate contraception.

Associated with rosuvastatin:

Active liver disease, including unexplained persistent elevations of serum transaminases and any elevation of serum transaminases greater than 3 times the upper limit of normal.

Myopathy: The 40 mg dose is contraindicated in patients with a predisposition to myopathy/rhabdomyolysis. Risk factors for this include:

moderate renal impairment (creatinine clearance (CC) < 60 ml/min);

hypothyroidism;

presence of a personal or family history of hereditary muscle diseases;

history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;

alcohol abuse;

situations that may lead to an increase in the concentration of the drug in the blood plasma;

belonging to the Mongoloid race. Patients of the Mongoloid race are contraindicated to use a dose of rosuvastatin 40 mg;

concomitant use of fibrates.

Concomitant treatment with sofosbuvir, velpatasvir, voxilaprevir, or cyclosporine.

Associated with acetylsalicylic acid:

History of asthma, rhinitis, nasal polyps; contraindicated in patients with a history of mastocytosis, in whom severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia, and vomiting) may occur with acetylsalicylic acid.

History of acute or recurrent peptic ulcer and/or gastrointestinal bleeding, other types of bleeding, including cerebrovascular hemorrhage.

Hemorrhagic diathesis, clotting disorders such as hemophilia and thrombocytopenia.

Severe liver failure.

Severe congestive heart failure.

Gout.

Combination with methotrexate at a dosage of 15 mg/week or more (see section “Interaction with other medicinal products and other types of interactions”).

Interaction with other medicinal products and other types of interactions

Rosuvastatin.

Transporter protein inhibitors. Rosuvastatin is a substrate for some transporter proteins, in particular the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. The simultaneous use of the drug AspiRosa® with drugs that inhibit these transporter proteins may lead to an increase in rosuvastatin plasma concentrations and an increased risk of myopathy (see sections "Method of administration and dosage", "Special instructions for use", table 2).

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

Protease inhibitors. Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase the AUC of rosuvastatin (see Table 2). 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 AUC and Cmax of rosuvastatin by approximately 3 and 7 times, respectively. The simultaneous use of the drug and some combinations of protease inhibitors is possible after careful consideration of the dose adjustment of the drug, taking into account the expected increase in AUC of rosuvastatin (see sections "Special instructions for use", "Method of administration and dosage", Table 2).

Gemfibrozil and other lipid-lowering agents: Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax (see section 4.4).

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, lipid-lowering drugs (≥ 1 g/day) and niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA inhibitors, probably because they can cause myopathy when used alone. The 40 mg dose of rosuvastatin is contraindicated with concomitant use of fibrates (see sections 4.3 and 4.4). In such patients, therapy should be initiated at a dose of 5 mg.

Ezetimibe. Co-administration of rosuvastatin 10 mg and ezetimibe 10 mg in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe, which could lead to adverse events, cannot be excluded (see section 4.4).

Antacids: Concomitant administration of rosuvastatin with antacid suspensions containing aluminum or magnesium hydroxide decreased rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin: Concomitant use of rosuvastatin and erythromycin 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 indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of 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 2).

If it is necessary to use the drug AspiRosa® with other drugs that can increase the exposure of rosuvastatin, the dose of the drug should be adjusted. If it is expected that the exposure of the drug (AUC) will increase by approximately 2 or more times, the drug AspiRosa® should be started at a dose of 5 mg/100 mg once a day. The maximum daily dose of the drug AspiRosa® 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).

Table 2

Effect of concomitant medications on rosuvastatin exposure

(AUC; in descending order of magnitude)

Effect of rosuvastatin on concomitant medications.

Vitamin K antagonists. As with other HMG-CoA reductase inhibitors, when starting or increasing the dose of Aspirin in patients concomitantly taking vitamin K antagonists (e.g. warfarin or other coumarin anticoagulants), an increase in the international normalized ratio (INR) may occur. Discontinuation of the drug or reduction in its dose may lead to a decrease in INR. In such cases, appropriate monitoring of INR is recommended both at the beginning of treatment with rosuvastatin and after discontinuation or with subsequent changes in its dosage.

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 who used rosuvastatin and HRT simultaneously, so a similar effect cannot be excluded. However, the combination was widely used in women in clinical trials and was well tolerated.

Other medicines.

Digoxin: Based on specific 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 understood. There have been reports of rhabdomyolysis (including some fatal cases) in patients receiving this combination. In patients for whom the use of systemic fusidic acid is considered necessary, treatment with AspiRosa® should be discontinued for the entire duration of fusidic acid treatment (see also section "Special instructions").

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 thrombolytic drugs. Clinical and biological parameters of hemostasis should be regularly monitored in patients for whom thrombolytic therapy is planned.

When ASA is 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 leads to an increase in 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 with ASA, there is an increase in plasma concentration of digoxin due to a decrease in renal excretion.

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 concomitantly, the international normalized ratio, activated partial thromboplastin time (APTT) and/or bleeding time should be closely 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.

Antihypertensives (ACE inhibitors and β-blockers): in case of simultaneous use of AspiRosa® 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.

Effect on the kidneys.

Proteinuria, detected by dipstick analysis, predominantly of tubular origin, has been observed in patients treated with high doses of rosuvastatin, in particular 40 mg, and in most cases was transient or intermittent. Proteinuria was not a harbinger of acute or progressive renal disease (see section "Adverse Reactions"). The incidence of serious renal adverse events in post-marketing studies was higher with the use of a dose of rosuvastatin 40 mg. In such cases, the patient's renal function should be regularly monitored.

Musculoskeletal disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been reported in patients taking rosuvastatin, especially at doses greater than 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. Since there is a possibility of a pharmacodynamic interaction, such a combination should be used with caution.

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

Determination of creatine phosphokinase (CPK) levels.

CPK levels should not be measured after significant exercise or in the presence of possible alternative causes of CPK elevation that may complicate interpretation of results. If baseline CPK levels are significantly elevated > 5 times the upper limit of normal (ULN), a repeat test should be performed within 5–7 days. If the repeat test confirms that baseline CPK is greater than 5 times the ULN, treatment should not be initiated.

Before starting treatment.

Aspira®, like other agents containing 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;

presence of a personal or family history of hereditary muscle diseases;

history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;

alcohol abuse;

age > 70 years;

situations that may lead to increased plasma levels of the drug (see sections “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 CPK levels are significantly elevated (> 5 × ULN), treatment should not be initiated.

During treatment.

Patients should be advised to report unexplained muscle pain, weakness or cramps immediately, especially if accompanied by malaise or fever. CPK levels should be measured in such patients. The drug should be discontinued if CPK levels are significantly elevated (> 5 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CPK levels are ≤ 5 × ULN). If symptoms resolve and CPK levels return to normal, therapy with AsipRosa® or an alternative HMG-CoA reductase inhibitor can be resumed at the lowest effective dose and under close supervision. Regular monitoring of CPK levels is not necessary in patients without these symptoms. Very rare cases of immune-mediated necrotizing myopathy have been reported during or after treatment with statins, including rosuvastatin. Clinical manifestations of immune-mediated necrotizing myopathy include proximal muscle weakness and elevated serum CPK levels that persist even after discontinuation of statins.

There is no evidence of increased skeletal muscle effects from the combination of 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 AspiRosa® in combination with gemfibrozil is contraindicated.