Roxera, 15 mg 30 pcs.

Primary hypercholesterolemia according to Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) – as an addition to diet when diet and other non-medicamental methods of treatment (for example, physical exercises, weight reduction) are insufficient.

– familial homozygous hypercholesterolemia – as an adjunct to diet and other lipid-lowering therapy (e.g., LDL-apheresis) or in cases when such therapy is not sufficiently effective.

– Hypertriglyceridemia (type IV by Fredrickson classification) – as a dietary supplement.

– To slow the progression of atherosclerosis – as a supplement to diet in patients who are indicated for therapy to reduce plasma concentration of total CHD and LDL-C.

– Primary prevention of major cardiovascular complications (stroke, myocardial infarction, arterial revascularization) in adult patients without clinical signs of CHD, but with an increased risk of its development (age over 50 years for men and over 60 years for women, increased plasma concentration of C-reactive protein [≥ 2 mg/L] in the presence of at least one additional risk factor, such as arterial hypertension, low plasma concentration of HDL-C, smoking, family history of early-onset CHD).

Active ingredient

Composition

1 film-coated tablet, 5 mg/10 mg/15 mg/20 mg/30 mg/40 mg contains:

Core:

Active substance:

Rosuvastatin calcium 5.21 mg/10.42 mg/15.62 mg/20.83 mg/31.25 mg/41.66 mg, equivalent to rosuvastatin 5.00 mg/10.00 mg/15.00 mg/20.00 mg/30.00 mg/40.00 mg

Supplements:

Microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, magnesium stearate

Shell film:

Butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer [1:2:1], macrogol-6000, titanium dioxide, lactose monohydrate

How to take, the dosage

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

Before starting therapy with Roxera®, the patient should start a standard hypocholesterolemic diet and continue it during treatment. The drug dose should be chosen individually depending on the therapy goals and the therapeutic response to treatment, taking into account the national recommendations for target plasma lipid concentrations.

The recommended starting dose of Roxera® for patients starting to take the drug or for patients switched from other HMG-CoA reductase inhibitors should be 5 or 10 mg once daily.

When concomitant use of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day), the initial dose of 5 mg/day is recommended for patients.

When choosing the initial dose, the individual plasma concentrations of cholesterol should be taken into account and the possible risk of cardiovascular complications should be taken into account; the potential risk of adverse reactions (ADRs) should also be considered. If necessary, the dose can be increased in 4 weeks.

Due to the possible development of NIs with the 40 mg/day dose compared to lower doses of the drug, increasing the dose to the maximum 40 mg/day should only be considered in patients with severe hypercholesterolemia and with a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) who have not achieved the desired therapy with the 20 mg/day dose and who will be monitored by a physician. We recommend especially close monitoring of patients receiving the drug at a dose of 40 mg/day.

The 40 mg/day dose is not recommended in patients who have not previously seen a physician. After 2-4 weeks of therapy and/or if the dose of Roxera® is increased, the lipid metabolism parameters should be monitored (dose adjustment is required if necessary).

Patients with renal failure

In patients with mild to moderate renal failure, no dose adjustment is required. In patients with severe renal failure (CKD

Interaction

Influence of other drugs on rosuvastatin

Transport protein inhibitors

Rosuvastatin is a substrate for some transport proteins, particularly OATP1B1 and BCRP. Concomitant use of the drugs that are inhibitors of these transport proteins may be accompanied by an increase in plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections “Dosage and administration” and “Precautions” and Table 3).

Cyclosporine

When rosuvastatin and cyclosporine are used concomitantly, the AUC of rosuvastatin is, on average, 7 times higher than the value seen in healthy volunteers (see Table 3). Concomitant use with rosuvastatin does not affect the plasma concentration of cyclosporine. The use of rosuvastatin is contraindicated in patients taking cyclosporine (see section “Contraindications”).

HIV protease inhibitors

Concurrent use of HIV protease inhibitors may significantly increase rosuvastatin exposure (see Table 3). Concomitant use of 20 mg rosuvastatin and a combination of two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) is associated with increases in equilibrium AUC(0-24 h) and Cmax rosuvastatin by 2 and 5 times, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see section “Dosage and administration” and table 3).

Gemfibrozil and other hypolipidemic agents

The concomitant use of rosuvastatin and gemfibrozil results in a 2-fold increase in Cmax and AUC of rosuvastatin in plasma (see See section “Special Precautions”). Based on the data on specific interactions, no pharmacokinetic interaction with fenofibrate is expected, pharmacodynamic interaction is possible. Hemphibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (more than 1 g/day) 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”). Simultaneous use of fibrates and rosuvastatin at a daily dose of 30 mg is contraindicated. In these patients the therapy should be started with 5 mg/day (see sections “Contraindications”, “Dosage and administration” and “Cautions”).

Ezetimibe

The concomitant use of rosuvastatin at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increased AUC of rosuvastatin in patients with hypercholesterolemia (see Table 3). Pharmacodynamic interaction between rosuvastatin and ezetimibe with increased risk of adverse reactions cannot be excluded.

Antacids

Concomitant use of rosuvastatin and antacids containing aluminum and/or magnesium hydroxide decreases plasma concentration of rosuvastatin by approximately 50%. This effect is weaker if antacids are used 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Eritromycin

Concomitant use of rosuvastatin and erythromycin results in a 20% decrease in the AUC(0-t) of rosuvastatin and its Cmax by 30%. Such interaction may occur as a result of intestinal motility enhancement caused by erythromycin use.

Iso-enzymes of the cytochrome P450 system

The results of in vivo and in vitro studies showed that rosuvastatin was neither an inhibitor nor an inducer of cytochrome P450 system isoenzymes. In addition, rosuvastatin is a weak substrate for this isoenzyme system. Therefore, no interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 isoenzymes is expected.

No clinically significant interaction between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor) was noted.

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

The dose of Roxera® should be adjusted if its concomitant use with drugs that increase rosuvastatin exposure is necessary. If an increase in exposure of 2 or more times is expected, the starting dose of Roxera® should be 5 mg once daily.

The maximum daily dose of Roxera® should also be adjusted to ensure that the expected exposure to rosuvastatin does not exceed that of a 40 mg dose taken without concomitant administration of drugs that interact with rosuvastatin. For example, the maximum daily dose of Roxera® when concomitantly used with gemfibrozil is 20 mg (1.9-fold increase in exposure) and with ritonavir/atazanavir is 10 mg (3.1-fold increase in exposure).

Table 3

The effect of concomitant therapy on rosuvastatin exposure (AUC, data shown in descending order) – results of published clinical trials

Regime of concomitant therapy

Regime of taking rosuvastatin

Change in AUC of rosuvastatin*

Cyclosporine 75-200 mg 2 times daily, 6 months

10 mg once daily, 10 days

Increase by 7.1 times

Regorafenib 160 mg once daily, 14 days

5 mg once

Increase by 3.8 times

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

10 mg once

Increase by 3.1 times

Simeprevir 150 mg once daily, 7 days

10 mg once

Increase by 2.8 times

Velpatasvir 100 mg once daily

10 mg once

Increase by 2.7 times

Ombitasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days

5 mg once

Increase by 2.6 times

Grazoprevir 200 mg/elbasvir 50 mg once daily, 11 days

10 mg once

Increase by 2.3 times

Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days

5 mg once daily, 7 days

Increase by 2.2 times

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

20 mg once a day, 7 days

Increase by 2.1 times

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

20 mg once

Magnification by 2 times

Gemfibrozil 600 mg 2 times daily, 7 days

80 mg once

Increase by 1.9 times

Eltrombopag 75 mg once daily, 5 days

10 mg once

Increase by 1.6 times

Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days

10 mg once daily, 7 days

Increase by 1.5 times

Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days

10 mg once

Increase by 1.4 times

Dronedarone 400 mg 2 times daily

No data

Increase by 1.4 times

Itraconazole 200 mg once daily, 5 days

10 mg once

**increase 1.4 times

Ezetimibe 10 mg once daily, 14 days

10 mg once daily, 14 days

**Multiplying 1.2 times

Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days

10 mg once

No change

Aleglitazar 0.3 mg, 7 days

40 mg, 7 days

No change

Silymarin 140 mg 3 times daily, 5 days

10 mg once

No change

Fenofibrate 67 mg 3 times daily, 7 days

10 mg, 7 days

No change

Rifampicin 450 mg once daily, 7 days

20 mg once

No change

Ketoconazole 200 mg 2 times daily, 7 days

80 mg once

No change

Special Instructions

For daily dose up to 30 mg

Risk for myopathy/rhabdomyolysis – renal failure, hypothyroidism, hereditary muscle disease history (including family history) and previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions in which increased plasma concentration of rosuvastatin was noted; race (mongoloid race – Japanese and Chinese); concomitant use with fibrates; history of liver disease; sepsis; arterial hypotension; major surgical interventions; trauma; severe metabolic, endocrine or electrolyte disorders; uncontrolled seizures; concomitant use with ezetimibe.

At a daily dose of 30 mg or more

Mild renal impairment (CK more than 60 ml/min); age over 65 years; history of liver disease; sepsis; arterial hypotension; extensive surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures; concomitant use with ezetimibe.

It is contraindicated in persons under 18 years of age.

Patients with renal failure

In patients with mild to moderate renal failure, no dose adjustment is required. In patients with severe renal failure (CKD less than 30 ml/min) the use of Roxera® is contraindicated. The use of Roxera® in dose more than 30 mg/day is contraindicated in patients with renal insufficiency of moderate and severe degree of severity (CKD less than 60 ml/min). For patients with moderate renal insufficiency, the recommended starting dose of Roxera®® is 5 mg/day.

Patients with hepatic insufficiency

The drug Roxera® is contraindicated in patients with liver disease in the active phase.

Use in elderly patients

No dose adjustment is required.

Kidney function impairment

Canal tubular proteinuria was observed in patients receiving high doses of rosuvastatin (particularly 40 mg/day), which was detected with test strips and in most cases was intermittent or transient. Such proteinuria is not indicative of acute disease or progression of concomitant renal disease. The incidence of serious renal dysfunction observed in a post-marketing study of rosuvastatin is higher with a dose of 40 mg/day. In patients taking Roxera® at a dose of 30 or 40 mg/day it is recommended to monitor renal function parameters during treatment (at least once every 3 months).

Effects on the musculoskeletal system

The following musculoskeletal effects have been reported with rosuvastatin at all doses, but particularly at doses greater than 20 mg/day: myalgia, myopathy, and, rarely, rhabdomyolysis. Very rare cases of rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors and ezetimibe. This combination should be used with caution as pharmacodynamic interaction cannot be excluded.

As with other HMG-CoA-reductase inhibitors, the incidence of rhabdomyolysis in post-marketing use of rosuvastatin is higher when using 40 mg/day dose.

Determination of serum CPK activity

Serum CPK activity should not be determined after intense physical activity and in the presence of other possible causes of increased CPK activity, it may lead to misinterpretation of the results obtained. If the initial serum CPK activity is significantly elevated (5 times the upper limit of normal), a repeat analysis should be performed after 5-7 days. The therapy should not be started if the results of the repeated analysis confirm the initial high serum activity of CPK (more than 5 times higher than the upper limit of the norm).

Before starting therapy

Depending on the daily dose, Roxera® should be administered with caution in patients with existing risk factors for myopathy/rhabdomyolysis.

Such factors include:

In such patients, the risks and possible benefits of therapy should be evaluated. Clinical monitoring is also recommended. If baseline serum CPK activity is more than 5 times the upper limit of normal, therapy with Roxera® should not be initiated.

While therapy with the drug

The patient should be informed to report immediately to a physician if muscle pain, muscle weakness, or cramps occur unexpectedly, especially when combined with malaise and fever. Serum CPK activity should be determined in such patients. Therapy should be discontinued if serum CPK activity is significantly increased (more than 5 times the upper limit of normal), or if muscle symptoms are severe and cause daily discomfort (even if serum CPK activity is no more than 5 times the upper limit of normal). If symptoms disappear and serum CPK activity returns to normal, consideration should be given to resuming use of Roxer® or other HMG-CoA reductase inhibitors at lower doses with close medical supervision. Monitoring of serum CPK activity in the absence of symptoms is unnecessary.

Very rare cases of immune-mediated necrotizing myopathy with clinical manifestations as persistent proximal muscle weakness and increased serum CPK activity during therapy or upon discontinuation of HMG-CoA reductase inhibitors, including rosuvastatin, have been reported. Additional muscular and nervous system studies, serological studies, as well as therapy with immunosuppressive agents may be required.

No evidence of increased skeletal muscle effects with rosuvastatin and concomitant therapy has been noted. However, an increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives (e.g. gemfibrozil), cyclosporine, nicotinic acid in lipid-lowering doses (over 1 g/day), antifungal agents – azole derivatives, HIV protease inhibitors and macrolide antibiotics.

When used concomitantly with some HMG-CoA reductase inhibitors, gemfibrozil increases the risk of myopathy. Thus, concomitant use of Roxera® and gemfibrozil is not recommended. The benefits of further changes in plasma lipid concentrations when combining Roxera® with fibrates or nicotinic acid at lipid-lowering doses should be carefully weighed against the possible risks. Roxera® at a dose of 30 mg/day is contraindicated for combination therapy with fibrates.

The drug Roxera® should not be used simultaneously or within 7 days after discontinuation of therapy with systemic fusidic acid. In patients in whom the use of fusidic acid is considered necessary, statin therapy should be discontinued for the duration of fusidic acid therapy. Rhabdomyolysis (including death in some cases) has been reported in patients receiving fusidic acid concomitantly with statins. The patient should seek medical attention immediately if any symptoms of muscle weakness, pain or soreness occur.

Therapy with Roxera® may be resumed 7 days after the last dose of fusidic acid.

In exceptional cases where prolonged use of systemic fusidic acid is required, such as in the treatment of severe infections, the need for simultaneous use of Roxera® and fusidic acid should be considered individually and under close medical supervision.

Due to the increased risk of rhabdomyolysis, Roxera® should not be used in patients with acute conditions that may lead to myopathy or conditions that predispose to renal failure (e.g., sepsis, arterial hypotension, extensive surgery, trauma, severe metabolic, endocrine or electrolyte disorders, uncontrolled convulsions).

2-4 weeks after the treatment start and/or if the dose of Roxera® is increased, the lipid metabolism parameters should be controlled (dose adjustment is necessary if needed).

Liver

Depending on the daily dose, Roxera® should be used with caution in patients with excessive alcohol consumption and/or in patients with a history of liver disease, or its use is contraindicated (see

The use is contraindicated (see Sections “Contraindications” and “With Caution”).

It is recommended that liver function tests be determined before therapy and 3 months after initiation. The use of Roxera® should be discontinued or the dose of the drug should be reduced if serum hepatic transaminase activity exceeds 3 times the upper limit of normal.

Patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome should be treated with therapy for underlying disease before starting treatment with Roxera®.

Ethnic characteristics

In pharmacokinetic studies, increased plasma concentrations of rosuvastatin were observed in members of the Mongoloid race compared to members of the Caucasoid race.

Interstitial lung disease

Single cases of interstitial lung disease have been reported when using some HMG-CoA reductase inhibitors, especially for a long time. Manifestations of the disease may include dyspnea, non-productive cough, and deterioration of general well-being (weakness, weight loss, and fever).

Treatment with HMG-CoA reductase inhibitors should be stopped if interstitial lung disease is suspected.

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.

HIV protease inhibitors

Contemporary use of the drug with HIV protease inhibitors is not recommended (see “Interaction with Other Drugs”).

Special information on excipients

The drug Roxera® contains lactose, so it is contraindicated in patients with lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.

Studies to study the effect of rosuvastatin on the ability to drive vehicles and operate mechanisms have not been conducted. Nevertheless, taking into account the possibility of dizziness and other NJ, caution should be exercised when driving vehicles and operating other mechanisms requiring high concentration and quick psychomotor reactions.

Synopsis

Tablets 5 mg:

Round, biconvex, film-coated white tablets, beveled and engraved “5” on one side.

Break appearance: white rugged mass with white film coating.

Tablets 10 mg:

Round, biconvex, white film-coated tablets, beveled and engraved “10” on one side.

Break appearance: white rugged mass with white film coating.

Tablets 15 mg:

Round, biconvex, white film-coated tablets, beveled and engraved “15” on one side.

Breakage appearance: white rough mass with white film coating.

Tablets 20 mg:

Round, biconvex, white film-coated, beveled tablets.

Breakage appearance: white rough mass with white film coating.

Tablets 30 mg:

Oblong with rounded ends, biconvex, film-coated white tablets, with a rib on both sides.

Breakage appearance: white rough mass with white film coating.

Tablets 40 mg:

Oblong with rounded ends, biconvex, film-coated white tablets.

Breakage appearance: white rough mass with white film coating.

Contraindications

Side effects

Non-malignant NPOs observed with rosuvastatin are usually mild and resolve independently. As with other HMG-CoA reductase inhibitors, the incidence of NIH is mainly dose-dependent.

World Health Organization (WHO) recommended frequency classification for NNI:

very common ≥ 1/10

often ≥ 1/100 to < 1/10

infrequently from ≥ 1/1000 to < 1/100

rarely from ≥ 1/10000 to < 1/1000

very rarely < 1/10000

frequency is unknown cannot be estimated from available data.

Disorders on the part of the blood and lymphatic system

frequency unknown: thrombocytopenia.

immune system disorders

rare: hypersensitivity reactions, including angioedema.

Endocrine system disorders

often: type 2 diabetes.

Nervous system disorders

often: headache, dizziness;

very rare: loss or reduction of memory;

frequency unknown: peripheral neuropathy.

Respiratory system, chest and mediastinal organs disorders

incidence unknown: cough, dyspnea.

Gastrointestinal tract disorders

often: constipation, nausea, abdominal pain;

rarely: pancreatitis;

very rare: jaundice, hepatitis;

frequency unknown: diarrhea.

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

Skin and subcutaneous tissue disorders

Overdose

No clinical picture of overdose has been described. Pharmacokinetic parameters of rosuvastatin do not change when taking several daily doses simultaneously.

Treatment of overdose is symptomatic; control of liver function and serum CPK activity is necessary. There is no specific antidote. Hemodialysis is ineffective.

Pregnancy use

The drug Roxera® is contraindicated in pregnancy and during breastfeeding.

Women of reproductive age should use adequate contraceptive methods.

Since cholesterol and substances synthesized from cholesterol are important for fetal development, the potential risk of fetal HMG-CoA reductase inhibition exceeds the benefits of using the drug during pregnancy for the mother.

If pregnancy occurs during therapy, the drug should be immediately discontinued.

There are no data regarding penetration of rosuvastatin into breast milk (it is known that other HMG-CoA reductase inhibitors can penetrate into breast milk), therefore, during breastfeeding the drug should be stopped.

Similarities