Rosulip, 20 mg 28 pcs.

Indications

Active ingredient

Composition

Active ingredient:

Each tablet contains 5 mg, 10 mg, 20 mg or 40 mg rosuvastatin (in the form of, respectively: 5.34 / 10.68 / 21.36 / 42.72 mg rosuvastatin zinc).

Auxiliary Ingredients:

ludipress 65.16 / 130.32 / 260.64 / 521.28 mg [(lactose monohydrate (93%), povidone (3.5%), crosspovidone (3.5%)], crosspovidone 3.75/ 7.50/ 15.00/ 30.00 mg, magnesium stearate 0.75/ 1.50/ 3.00/ 6.00 mg; shell: Opadray II White 85F 18422 1.90 / 3.80 / 7.50 / 15.00 mg [polyvinyl alcohol (40%), titanium dioxide (25%), macrogol 3350 (20.2%), talc (14.8%)].

Round biconvex film-coated tablets, white or almost white, with E and number 593 engraved on one side of the tablet, odorless or almost odorless.

How to take, the dosage

To the mouth, do not chew or crush the tablet, swallow it whole with water. The drug can be taken at any time of the day regardless of meals.

People should start a standard hypocholesterolemic diet prior to initiating therapy with the drug Rosulip® and continue this diet during therapy. The dose of the drug should be adjusted individually depending on the goals of therapy and the therapeutic response to treatment, taking into account current recommendations for target lipid concentrations.

The recommended starting dose for patients starting the drug or switching from other HMG-CoA reductase inhibitors should be 5 or 10 mg of Rosulip® once daily. When choosing the initial dose, the individual concentration of cholesterol should be guided and the possible risk of cardiovascular complications should be taken into account, as well as the potential risk of side effects should be assessed. If necessary, the dose can be increased to a larger one in 4 weeks (see section “Pharmacodynamics”).

With regard to the possible development of side effects at a dose of 40 mg compared to lower doses of the drug (see section “Side effects”).

See side effects) dose increase to 40 mg after an additional dose above the recommended initial dose for 4 weeks of therapy may only be undertaken in patients with severe hypercholesterolemia and with a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), in whom the desired therapy result was not achieved with the 20 mg dose and who will be under specialist supervision (see section “Special indications”). We recommend especially close monitoring of patients receiving the drug at a dose of 40 mg.

The 40 mg dose is not recommended for patients who have not previously seen a physician.

After 2-4 weeks of therapy and/or when the dose of Rosulip® is increased, lipid metabolism parameters should be monitored (dose adjustment is required if necessary).

Elderly patients

Dose adjustment is not required.

Patients with renal impairment

Dose adjustment is not required in patients with mild to moderate renal impairment. In patients with severe renal insufficiency (CKD < 30 ml/min) the use of Rosulip® is contraindicated. The use of the drug in dose 40 mg is contraindicated in patients with moderate renal impairment (CKD < 30-60 ml/min) (see section “Cautionary Note” and “Pharmacodynamics”). In patients with moderate renal dysfunction, a starting dose of 5 mg is recommended.

Patients with hepatic impairment

Rosulip® is contraindicated in patients with active liver disease (see “Contraindications” sections).

Particular populations

Ethnic groups

In studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increased systemic concentration of rosuvastatin was noted among Japanese and Chinese (see section “Special indications”).

This fact should be considered when prescribing Rosulip® to these groups of patients. When prescribing doses of 10 and 20 mg, the recommended starting dose for mongoloid patients is 5 mg. A dose of 40 mg is contraindicated in mongoloid patients (see Contraindications).

Genetic polymorphisms

Carriers of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes showed increased exposure (AUC) to rosuvastatin compared to carriers of SLCO1B1 c.521TT and ABCG2 c.421CC genotypes. For c.521CC or c.421AA genotype carriers the recommended maximum dose of Rosulip® is 20 mg once daily (see sections “Pharmacokinetics”, “Precautions” and “Interaction with other medicinal products”).

Patients with predisposition to myopathy

The drug is contraindicated in a dose of 40 mg in patients with factors that may indicate a predisposition to myopathy (see Contraindications). When prescribing doses of 10 and 20 mg, the recommended starting dose for this group of patients is 5 mg (see Contraindications).

Companion therapy

Rosuvastatin binds to various transport proteins (in particular to OATP1B1 and BCRP). When co-administration of Rosulip® with drugs (such as cyclosporine, certain human immunodeficiency virus (HIV) protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase plasma concentrations of rosuvastatin through interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may be increased (see sect. See sections “Cautions” and “Interaction with other medicinal products”). You should read the instructions for use for these drugs before prescribing them with Rosulip® , assess the possibility of alternative therapy or temporary discontinuation of Rosulip®. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Rosulip® should be assessed and the possibility of reducing its dose should be considered (see section “Interaction with other medicinal products”).

Interaction

Influence of other drugs on rosuvastatin

Transport protein inhibitors: Rosuvastatin binds to some transport proteins, in particular OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see Table 3 and sections “Administration and Doses” and “Precautions”).

Cyclosporine: When concomitant use of rosuvastatin and cyclosporine the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see Table 3). No effect on the plasma concentration of cyclosporine. Rosulip® is contraindicated in patients taking cyclosporine (see section “Contraindications”).

HIV protease inhibitors: although the exact mechanism of interaction is unknown, co-administration of HIV protease inhibitors may result in a significant increase in exposure to rosuvastatin (see Table 3). A pharmacokinetic study of concomitant administration of 20 mg rosuvastatin with a combination drug containing two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers resulted in approximately twofold and fivefold increases in AUC(0-24) and Cmax rosuvastatin, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Dosage and administration”, “Special indications”, Table 3).

Gemfibrozil and other hypolipidemic agents: co-administration of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax and AUC of rosuvastatin (see section “Special Precautions”). Based on specific interaction data, no pharmacokinetic interaction with fenofibrate is expected; pharmacodynamic interaction is possible.

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when concomitantly used with HMG-CoA reductase inhibitors, possibly due to the fact that they may cause myopathy when used in monotherapy (see section “Special Indications”). In concomitant use of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day) patients are recommended the initial dose of the drug is 5 mg, taking a dose of 40 mg is contraindicated in concomitant administration with fibrates (see sections “Contraindications”, “Dosage and administration”, “Cautions”).

Ezetimibe: concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe was associated with increased AUC of rosuvastatin in patients with hypercholesterolemia (see Table 3). An increased risk of side effects due to pharmacodynamic interaction between Rosulip® and ezetimibe cannot be excluded.

Antacids: concomitant use of rosuvastatin and suspensions of antacids containing magnesium and aluminum hydroxide leads to decrease of plasma concentration of rosuvastatin by approximately 50%. This effect is weaker if antacids are used 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Erythromycin: Concomitant use of rosuvastatin and erythromycin decreases AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by taking erythromycin.

Cytochrome P450 isoenzymes: In vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, no interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 isoenzymes is expected. No clinically significant interaction of rosuvastatin with fluconazole (CYP2C9 and CYP3A4 isoenzymes inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzymes inhibitor) was observed.

Fusidic acid: There have been no studies on interaction between rosuvastatin and fusidic acid. As with other statins, there have been post-marketing reports of cases of rhabdomyolysis when co-administering rosuvastatin and fusidic acid. Patients should be closely monitored. If necessary, temporary discontinuation of rosuvastatin is possible.

Drug interactions that require rosuvastatin dose adjustment (see Table 3)

The dose of Rosulip® should be adjusted if it is necessary to combine it with drugs that increase exposure to rosuvastatin. Read the instructions for use of these drugs before prescribing them together with rosuvastatin. If an increase in exposure by 2-fold or more is expected, the initial dose of Rosulip® should be 5 mg once daily. The maximum daily dose of Rosulip® should also be adjusted so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without concomitant administration of drugs that interact with rosuvastatin. For example, maximum daily dose of Rosulip® in concomitant use with gemfibrozil is 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir – 10 mg (3.1-fold increase in exposure).

Table 3. Effect of concomitant therapy on exposure to rosuvastatin (AUC, data are given in descending order) – results of published clinical trials

Mode of concomitant

therapy

Regimen

rosuvastatin

Change in AUC

rosuvastatin

Cyclosporine 75-200 mg 2 times per day.,

6 months.

10 mg once daily, 10 days

7.1-fold increase

Atazanavir 300 mg/ritonavir 100 mg once daily., 8 days

10 mg once

A 3.1-fold increase

Simeprevir 152 mg once daily., 7 days

10 mg once

2.8-fold increase

Lopinavir 400 mg/ritonavir 100 mg twice daily., 17 days

20 mg once daily, 7 days

2.1-fold increase

Aleglitazar 0.3 mg, 7 days

40 mg, 7 days

No change

Silymarin 140 mg 3 times a day., 5 days

10 mg once

No change

/p>

Fenofibrate 67 mg 3 times daily., 7 days

10 mg, 7 days

No change

Rifampin 450 mg once daily., 7 days

20 mg once

No change

/p>

Ketoconazole 200 mg 2 times daily., 7 days

80 mg once

No change

/p>

Fluconazole 200 mg once daily., 11 days

80 mg once

No change

/p>

Erythromycin 500 mg 4 times a day., 7 days

80 mg once

28% reduction

Baicalin 50 mg 3 times daily., 14 days

20 mg once

474% reduction

Effect of rosuvastatin use on other drugs

Vitamin K antagonists: Starting rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (e.g., warfarin) may result in an increase in the International Normalized Ratio (INR). Discontinuation of rosuvastatin or reduction of the drug dose may lead to a decrease in INR. In such cases it is recommended to control INR.

Oral contraceptives/hormone replacement therapy: Concomitant use of rosuvastatin and oral contraceptives increases AUC of ethinylestradiol and AUC of nogestrel by 26% and 34%, respectively. This increase in plasma concentration should be considered when selecting a dose of oral contraceptives. Pharmacokinetic data on concomitant use of Rosulip® and hormone replacement therapy are not available, therefore, one cannot rule out a similar effect when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Other medicinal products: No clinically significant interaction of rosuvastatin with digoxin is expected.

Special Instructions

Renal effects

In patients receiving high doses of rosuvastatin (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria was not indicative of acute kidney disease or progression of renal disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function parameters during treatment.

Musculoskeletal disorders

The following musculoskeletal effects have been reported with rosuvastatin at all doses and especially with doses higher than 20 mg: myalgia, myopathy and, rarely, rhabdomyolysis.

The determination of CPK activity

The determination of CPK activity should not be performed after vigorous physical activity or in the presence of other possible reasons for the increase of CPK activity, which may lead to misinterpretation of the results. If the baseline CPK activity is significantly elevated (>5x VGN), a repeat measurement should be performed after 5-7 days. Do not initiate therapy if the repeat test confirms baseline CPK activity (>5x BHN).

Pending therapy

When prescribing Rosulip®, as with other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see “Caution” section), the risk/benefit ratio of therapy should be considered and clinical monitoring should be conducted.

At the time of therapy

The patient should be informed of the need to immediately inform the physician if muscle pain, muscle weakness, or cramps occur unexpectedly, especially in conjunction with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (>5x VGN) or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is increased not >5x VGN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing Rosulip® or other HMG-CoA reductase inhibitors at lower doses with close monitoring of the patient.

Routine monitoring of CPK activity in the absence of symptoms is unnecessary.

There have been very rare cases of immune-mediated necrotizing myopathy with clinical manifestations of persistent proximal muscle weakness and increased serum CPK activity during treatment or upon discontinuation of statins, including rosuvastatin. Additional muscular and nervous system studies, serologic studies, and therapy with immunosuppressive agents may be required.

There have been no indications of increased skeletal muscle effects with rosuvastatin and concomitant therapy. However, an increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (over 1 g/day), azole antifungals, HIV protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when concomitantly prescribed with some HMG-CoA reductase inhibitors. Thus, concomitant administration of Rosulip® and gemfibrozil is not recommended. It should be carefully weighed the ratio of risk to possible benefit when concomitant use of Rosulip® and fibrates or lipid-lowering doses of nicotinic acid. Rosulip® at a dose of 40 mg together with fibrates is contraindicated (see sections “Interaction with other medicinal products” and “Contraindications”).

Lipid metabolic parameters should be monitored 2-4 weeks after the start of treatment and/or when increasing the dose of Rosulip® (if necessary, a dose adjustment is required).

The liver

Liver function tests are recommended before the start of therapy and 3 months after the start of therapy. Rosulip® should be discontinued or the dose of the drug should be reduced if serum hepatic transaminase activity > 3x VGN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for the underlying disease should be given before starting treatment with Rosulip®.

Particular populations. Ethnic groups

Pharmacokinetic studies in Chinese and Japanese patients have shown increased systemic rosuvastatin concentrations compared to those in European patients (see sections “Administration and Doses” and “Pharmacokinetics”).

HIV protease inhibitors

The co-administration of the drug with HIV protease inhibitors is not recommended (see section “Interaction with other medicinal products”).

Lactose

The drug should not be used in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Interstitial lung disease

Single cases of interstitial lung disease have been reported with some statins, especially for long periods of time. Manifestations of the disease may include dyspnea, non-productive cough, and worsening of general well-being (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Type 2 diabetes mellitus

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, rosuvastatin therapy has been associated with an increased risk of developing type 2 diabetes mellitus.

Pediatric use

The efficacy and safety of Rosulip® in children under 18 years of age has not yet been established; therefore, the use of this drug is contraindicated in patients in this age group.

The effect of rosuvastatin on the ability to drive vehicles and operate machinery

There have been no studies on the effect of rosuvastatin on the ability to drive vehicles and operate machinery. However, based on the pharmacodynamic properties, rosuvastatin should have no such effect. Caution should be exercised when driving motor transport or working with high concentration and psychomotor reactions (dizziness may occur during therapy).

Contraindications

With caution

Risk for myopathy/rhabdomyolysis – renal failure, hypothyroidism, personal or family history of hereditary muscle disease and prior history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions with increased plasma concentrations of rosuvastatin; race (Asian race); concomitant use with fibrates (see section “Pharmacokinetics”); history of liver disease, sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders or uncontrolled convulsive seizures.

Side effects

Side effects observed when taking Rosulip® are usually mild and go away on their own. As with other HMG-CoA reductase inhibitors, the incidence of side effects is mostly dose-dependent.

The incidence of adverse effects is as follows:

Frequent (> 1/100, < 1/10); infrequent (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000), unspecified frequency (cannot be calculated from available data).

Immune system

Rare: hypersensitivity reactions, including angioedema

Endocrine system

Often: Diabetes mellitus type 2

Central nervous system (CNS) disorders

Often: headache, dizziness

Digestive tract disorders

Often: constipation, nausea, abdominal pain

Rarely: pancreatitis

Skin side

Infrequently: skin itching, skin rash, urticaria

Musculoskeletal disorders

Often: myalgia

Rarely: Myopathy (including myositis), rhabdomyolysis

Other

Often: asthenic syndrome

Urinary system disorders

In patients receiving rosuvastatin, proteinuria may be detected. Changes in the amount of protein in the urine (from no or trace amounts to ++ or greater) are seen in less than 1% of patients receiving 10 to 20 mg of the drug. Slight changes in urine protein have been observed with the 20 mg dose. In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progression of existing renal disease.

Musculoskeletal disorders

The following musculoskeletal effects have been reported with rosuvastatin at all doses and especially with doses greater than 20 mg: Myalgia, myopathy (including myositis), in rare cases, rhabdomyolysis with or without acute renal failure.

Dose-dependent increase in creatine phosphokinase (CPK) activity has been observed in a small number of patients taking rosuvastatin. In most cases it was insignificant, asymptomatic and temporary. In case of increased CPK activity (>5x VGN), therapy should be suspended (see section “Special Precautions”).

Hepatic disorders

When using rosuvastatin, a dose-dependent increase in hepatic transaminase activity has been observed in a small number of patients. In most cases it is mild, asymptomatic and temporary.

Laboratory parameters

The following changes in laboratory parameters have also been observed with rosuvastatin: increase in glucose concentration, bilirubin, gamma-glutamyl transpeptidase activity, alkaline phosphatase, thyroid function disorders.

Postmarketing use

The following side effects have been reported in the postmarketing use of rosuvastatin:

Hematopoietic system disorders

The frequency is unknown: Thrombocytopenia

Digestive tract disorders

Very rare: jaundice, hepatitis

Rare: increased activity of “hepatic” transaminases

Frequency unknown: diarrhea

Musculoskeletal side

Very rare: arthralgia

Frequency unknown: Immune-mediated necrotizing myopathy

CNS side

Very rare: loss or impairment of memory

Prevalence unknown: peripheral neuropathy

Respiratory system disorders:

Prevalence unknown: cough, shortness of breath

Urinary system disorders

Very rare: Hematuria

Skin and subcutaneous fatty tissue disorders

Frequency unknown: Stevens-Johnson syndrome

Reproductive and mammary system disorders

Prevalence unknown: Gynecomastia

Other

Prevalence unknown: peripheral edema

The following side effects have been reported with some statins:

Depression, sleep disturbances, including insomnia and “nightmares,” sexual dysfunction. Single cases of interstitial lung disease have been reported, especially with long-term use of the drugs (see “Special Precautions”).

Overdose

The pharmacokinetic parameters of rosuvastatin do not change when several daily doses are taken simultaneously.

There is no specific treatment for rosuvastatin overdose. In case of overdose it is recommended to carry out symptomatic and supportive therapy, measures aimed at maintenance of functions of vital organs and systems. Control of liver function and CPK activity is necessary. Hemodialysis is unlikely to be effective.

Pregnancy use

Rosulip is contraindicated in pregnancy and during lactation (breastfeeding). If pregnancy is diagnosed during therapy, the drug should be discontinued immediately.

Women of reproductive age should use adequate methods of contraception. Because chs and products of its biosynthesis are important for fetal development, the potential risk of HMG-CoA reductase inhibition exceeds the benefits of the drug.

There are no data on excretion of rosuvastatin with breast milk, therefore breastfeeding should be discontinued if it is necessary to use the drug during lactation.

Similarities