Rosulip, 20 mg 28 pcs.

Indications

Primary hypercholesterolemia (Fredrickson type IIa) or mixed hypercholesterolemia (type IIb) as an adjunct to diet when diet and other non-drug treatments (eg, exercise, weight loss) are insufficient.

Pharmacological effect

Pharmacotherapeutic group:

lipid-lowering agent – HMG-CoA reductase inhibitor.

ATX code: C10AA07

PHARMACOLOGICAL PROPERTIES

Mechanism of action

Rosuvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol (C). The main target of action of rosuvastatin is the liver, where cholesterol synthesis and catabolism of low-density lipoproteins (LDL) take place.

Rosuvastatin increases the number of “liver” LDL receptors on the surface of liver cells, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of very low-density lipoprotein (VLDL) synthesis, thereby reducing the total amount of LDL and VLDL.

Pharmacodynamics

Rosuvastatin reduces elevated concentrations of LDL-C, total cholesterol and triglycerides (TG), increases the concentration of high-density lipoprotein-C (HDL-C), and also reduces the concentration of apolipoprotein B (Apo B), low-density lipoprotein cholesterol (non-HDL-C), VLDL-C, VLDL-TG and increases the concentration of apolipoprotein A-I (Apo A-I) (see tables 1 and 2), reduces the ratio of LDL-C/HDL-C, total cholesterol/HDL-C and non-HDL-C/HDL-C and the Apo B/Apo A-I ratio.

The therapeutic effect develops within one week after the start of treatment. Within 2 weeks of therapy, the effectiveness reaches a level that is 90% of the maximum possible. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular use of the drug.

Table 1. Dose response in patients with primary hypercholesterolemia (Fredrickson type ΙΙa and ΙΙb) (mean adjusted percentage change from baseline).

Dose

Number of patients

LDL-C

General HS

HDL-C

TG

Non-HDL cholesterol

Apo B

Apo A-Ι

Placebo

13

-7

-5

3

-3

-7

-3

0

10 mg

17

-52

-36

14

-10

-48

-42

4

20 mg

17

-55

-40

8

-23

-51

-46

5

40 mg

18

-63

-46

10

-28

-60

-54

0

Special instructions

Renal effects

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

From the musculoskeletal system

The following effects on the musculoskeletal system have been reported with the use of rosuvastatin in all dosages and, in particular, when taking doses of the drug exceeding 20 mg: myalgia, myopathy, and in rare cases, rhabdomyolysis.

Determination of CPK activity

Determination of CPK activity should not be carried out after intense physical activity or in the presence of other possible reasons for increased CPK activity, which may lead to incorrect interpretation of the results obtained. If the initial CPK activity is significantly increased (>5x ULN), a repeat measurement should be performed after 5–7 days. Therapy should not be started if a repeat test confirms initial CPK activity (>5x ULN).

Before starting therapy

When prescribing Rozulip®, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see section “With caution”), the balance of risk and possible benefit of therapy should be considered and clinical observation should be carried out.

During therapy

The patient should be informed to immediately report to the doctor the unexpected onset of muscle pain, muscle weakness or cramps, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (>5x ULN) or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is not increased >5x ULN). If symptoms disappear and CPK activity returns to normal, re-prescribing Rozulip® or other HMG-CoA reductase inhibitors in lower doses should be considered with careful monitoring of the patient.

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

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

There were no signs of increased effects on skeletal muscles when taking rosuvastatin and concomitant therapy. However, an increased incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g/day), azole antifungals, HIV protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, simultaneous administration of Rozulip® and gemfibrozil is not recommended. The risk/benefit ratio should be carefully weighed when using Rozulip® together with fibrates or lipid-lowering doses of nicotinic acid. Taking Rozulip® at a dose of 40 mg together with fibrates is contraindicated (see sections “Interaction with other drugs”, “Contraindications”).

2-4 weeks after the start of treatment and/or when increasing the dose of the drug Rozulip®, monitoring of lipid metabolism parameters is necessary (if necessary, dose adjustment is required).

Liver

It is recommended to determine liver function indicators before starting therapy and 3 months after starting therapy. Taking Rozulip® should be stopped or the dose reduced if the activity of “liver” transaminases in the blood serum is > 3x ULN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of underlying diseases should be carried out before starting treatment with Rozulip®.

Special populations. Ethnic groups

During pharmacokinetic studies among Chinese and Japanese patients, an increase in systemic concentrations of rosuvastatin was noted compared with values ​​​​obtained among European patients (see sections “Dosage and Administration” and “Pharmacokinetics”).

HIV protease inhibitors

Concomitant use of the drug with HIV protease inhibitors is not recommended (see section “Interaction with other drugs”).

Lactose

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

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with some statins, especially over long periods of use. Manifestations of the disease may include shortness of breath, nonproductive cough and deterioration in general health (weakness, weight loss and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus type 2

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

Application in pediatric practice

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

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND MECHANISMS

There have been no studies examining the effect of rosuvastatin on the ability to drive and use machinery. However, based on pharmacodynamic properties, rosuvastatin should not have such an effect. Caution should be exercised when driving a vehicle or doing work that requires increased concentration and psychomotor reaction (dizziness may occur during therapy).

Active ingredient

Rosuvastatin

Composition

Active ingredient:

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

Excipients:

ludipress 65.16 / 130.32 / 260.64 / 521.28 mg [(lactose monohydrate (93%), povidone (3.5%), crospovidone (3.5%)], crospovidone 3.75/ 7.50/ 15.00/ 30.00 mg, magnesium stearate 0.75/ 1.50 / 3.00 / 6.00 mg; shell: opadry 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, engraved with E and the number 593 on one side of the tablet, odorless or almost odorless.

Pregnancy

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

Women of reproductive age should use adequate methods of contraception. Since cholesterol and its biosynthesis products are important for fetal development, the potential risk of inhibiting HMG-CoA reductase outweighs the benefits of using the drug.

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

Contraindications

hypersensitivity to rosuvastatin and any of the excipients of the drug;
active liver disease, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity (> 3 x upper limit of normal (ULN);
severe renal dysfunction (creatinine clearance <30 ml/min); myopathy; simultaneous use of cyclosporine; in women: pregnancy, breastfeeding, as well as the lack of adequate methods of contraception in women with preserved reproductive function; patients predisposed to the development of myotoxic complications; children under 18 years of age (due to the lack of sufficient clinical data, efficacy and safety have not been established, see section “Special Instructions”); lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose).

With caution

There is a risk of developing myopathy/rhabdomyolysis – renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions in which an increase in plasma concentration of rosuvastatin is noted; race (Asian race); simultaneous use with fibrates (see section “Pharmacokinetics”); history of liver disease, sepsis; arterial hypotension; major surgery, trauma, severe metabolic, endocrine or electrolyte disturbances, or uncontrolled seizures.

Side Effects

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

The frequency of occurrence of undesirable effects is presented as follows:

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

Immune system

Rare: hypersensitivity reactions, including angioedema

Endocrine system

Common: type 2 diabetes mellitus

From the central nervous system (CNS)

Common: headache, dizziness

From the digestive tract

Common: constipation, nausea, abdominal pain

Rare: pancreatitis

From the skin

Uncommon: pruritus, skin rash, urticaria

From the musculoskeletal system

Common: myalgia

Rare: myopathy (including myositis), rhabdomyolysis

Others

Common: asthenic syndrome

From the urinary system

Proteinuria may be detected in patients receiving rosuvastatin. Changes in the amount of protein in the urine (from none or trace amounts to ++ or more) are observed in less than 1% of patients receiving 10 – 20 mg of the drug. A slight change in the amount of protein in the urine was noted when taking a dose of 20 mg. In most cases, proteinuria decreases or disappears during therapy and does not indicate the onset of acute or progression of existing kidney disease.

From the musculoskeletal system

The following effects on the musculoskeletal system have been reported with the use of rosuvastatin at all doses and, in particular, when taking doses of the drug exceeding 20 mg: myalgia, myopathy (including myositis), in rare cases, rhabdomyolysis with or without acute renal failure.

A dose-dependent increase in creatine phosphokinase (CPK) activity is observed in a small number of patients taking rosuvastatin. In most cases it was minor, asymptomatic and temporary. In case of increased CPK activity (>5x ULN), therapy should be suspended (see section “Special Instructions”).

From the liver

When using rosuvastatin, a dose-dependent increase in the activity of “liver” transaminases is observed in a small number of patients. In most cases it is minor, asymptomatic and temporary.

Laboratory indicators

When using rosuvastatin, the following changes in laboratory parameters were also observed: increased concentrations of glucose, bilirubin, gamma-glutamyl transpeptidase activity, alkaline phosphatase, thyroid dysfunction.

Post-marketing use

The following side effects have been reported during post-marketing use of rosuvastatin:

From the hematopoietic system

Frequency unknown: thrombocytopenia

From the digestive tract

Very rare: jaundice, hepatitis

Rarely: increased activity of liver transaminases

Frequency unknown: diarrhea

From the musculoskeletal system

Very rare: arthralgia

Not known: immune-mediated necrotizing myopathy

From the side of the central nervous system

Very rare: memory loss or decline

Not known: peripheral neuropathy

From the respiratory system:

Frequency unknown: cough, shortness of breath

From the urinary system

Very rare: hematuria

From the skin and subcutaneous fat

Frequency unknown: Stevens-Johnson syndrome

From the reproductive system and mammary gland

Frequency unknown: gynecomastia

Others

Frequency unknown: peripheral edema

The following side effects have been reported with some statins:

depression, sleep disorders, including insomnia and nightmares, sexual dysfunction. Isolated cases of interstitial lung disease have been reported, especially with long-term use of drugs (see section “Special instructions”).

Interaction

The effect of the use of other drugs on rosuvastatin

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

Cyclosporine: with simultaneous 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). Does not affect plasma concentrations of cyclosporine. Rozulip® is contraindicated in patients taking cyclosporine (see section “Contraindications”).

HIV protease inhibitors: Although the exact mechanism of interaction is unknown, coadministration of HIV protease inhibitors may result in a significant increase in exposure to rosuvastatin (see Table 3). A pharmacokinetic study of co-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 two-fold and five-fold increases in AUC (0-24)
and Cmax of rosuvastatin, respectively. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Method of administration and dosage”, “Special instructions”, table 3).

Gemfibrozil and other lipid-lowering drugs: combined use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax
and AUC of rosuvastatin (see section “Special instructions”). Based on specific interaction data, a pharmacokinetically significant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible.

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section “Special Instructions”). When taking the drug simultaneously with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day), an initial dose of the drug of 5 mg is recommended for patients; taking a dose of 40 mg is contraindicated when co-administered with fibrates (see sections “Contraindications”, “Dosage and Administration”, “Special Instructions”).

Ezetimibe: Concomitant use of rosuvastatin 10 mg and ezetimibe 10 mg was associated with an increase in rosuvastatin AUC in patients with hypercholesterolemia (see Table 3). An increased risk of side effects due to the pharmacodynamic interaction between Rozulip® and ezetimibe cannot be excluded.

Antacids: simultaneous use of rosuvastatin and antacid suspensions containing magnesium and aluminum hydroxide leads to a decrease in plasma concentrations of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are used 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin: simultaneous use of rosuvastatin and erythromycin leads to a decrease in AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by erythromycin.

Cytochrome P450 isoenzymes: results from 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, interaction of rosuvastatin with other drugs at the metabolic level involving cytochrome P450 isoenzymes is not expected. There was no clinically significant interaction of rosuvastatin with fluconazole (an inhibitor of the CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of the CYP2A6 and CYP3A4 isoenzymes).

Fusidic acid: No studies have been conducted to study the interaction of rosuvastatin and fusidic acid. As with other statins, there have been post-marketing reports of rhabdomyolysis with co-administration of rosuvastatin and fusidic acid. Patients must be closely monitored. If necessary, it is possible to temporarily stop taking rosuvastatin.

Interactions with drugs that require dose adjustment of rosuvastatin (see Table 3)

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

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

Companion mode

therapy

Reception mode

rosuvastatin

Change in AUC

rosuvastatin

Cyclosporine 75-200 mg 2 times a day,

6 months

10 mg 1 time per day, 10 days

7.1x magnification

Atazanavir 300 mg/ritonavir 100 mg once a day, 8 days

10 mg once

3.1x magnification

Simeprevir 152 mg once a day, 7 days

10 mg once

2.8x magnification

Lopinavir 400 mg/ritonavir 100 mg 2 times a day, 17 days

20 mg 1 time per day, 7 days

2.1x magnification

Clopidogrel 300 mg (loading dose), then 75 mg after 24 hours

20 mg once

2x magnification

Gemfibrozil 600 mg 2 times a day, 7 days

80 mg once

1.9x magnification

Eltrombopag 75 mg once daily, 10 days

10 mg once

1.6x magnification

Darunavir 600 mg/ritonavir 100 mg 2 times a day, 7 days

10 mg 1 time per day, 7 days

1.5 times magnification

Tipranavir 500 mg/ritonavir 200 mg 2 times a day, 11 days

10 mg once

1.4x magnification

Dronedarone 400 mg 2 times a day.

No data

1.4x magnification

Itraconazole 200 mg once a day, 5 days

10 mg or 80 mg once

1.4x magnification

Ezetimibe 10 mg once a day, 14 days

10 mg once a day, 14 days

1.2 times magnification

Fosamprenavir 700 mg/ritonavir 100 mg 2 times a day, 8 days

10 mg once

No changes

Aleglitazar 0.3 mg, 7 days

40 mg, 7 days

No changes

Silymarin 140 mg 3 times a day, 5 days

10 mg once

No changes

Fenofibrate 67 mg 3 times a day, 7 days

10 mg, 7 days

No changes

Rifampin 450 mg once a day, 7 days

20 mg once

No changes

Ketoconazole 200 mg 2 times a day, 7 days

80 mg once

No changes

Fluconazole 200 mg once a day, 11 days

80 mg once

No changes

Erythromycin 500 mg 4 times a day, 7 days

80 mg once

28% reduction

Baikalin 50 mg 3 times a day, 14 days

20 mg once

47% reduction

Effect of rosuvastatin on other drugs

Vitamin K antagonists: Initiating rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (eg, warfarin) may lead to 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, INR monitoring is recommended.

Oral contraceptives/hormone replacement therapy: Concomitant use of rosuvastatin and oral contraceptives increases ethinyl estradiol AUC and norgestrel AUC by 26% and 34%, respectively. This increase in plasma concentration should be taken into account when selecting the dose of oral contraceptives. There are no pharmacokinetic data on the simultaneous use of Rozulip® and hormone replacement therapy; therefore, a similar effect cannot be excluded 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 between rosuvastatin and digoxin is expected.

Overdose

When taking several daily doses simultaneously, the pharmacokinetic parameters of rosuvastatin do not change.

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 maintaining the functions of vital organs and systems. Monitoring of liver function and CPK activity is necessary. The effectiveness of hemodialysis is unlikely.

Storage conditions

Store at a temperature not exceeding 30 oC. Keep the drug out of the reach of children!

Shelf life

3 years

Manufacturer

EGIS, Hungary