Instructions for use Rosuvastatin-Darnitsa tablets 10mg No. 30
Composition
active ingredient: rosuvastatin;
1 tablet contains rosuvastatin 10 mg in the form of rosuvastatin calcium 10.40 mg or rosuvastatin 20 mg in the form of rosuvastatin calcium 20.80 mg;
excipients: lactose monohydrate, microcrystalline cellulose, calcium hydrogen phosphate, crospovidone, povidone, magnesium stearate, Opadry II 85F pink.
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated with a pink film coating.
Pharmacotherapeutic group
Hypolipidemic agents.
HMG-CoA reductase inhibitors. Rosuvastatin. ATC code C10A A07.
Pharmacological properties
Pharmacodynamics
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 the levels of apolipoprotein B (apoB), non-HDL-C, VLDL-C, TG-VLDL and increases the levels of apolipoprotein A-1 (apoA-I), the relevant data are shown 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.
Dose response in patients with primary hypercholesterolemia types IIa and IIb
(adjusted average percentage change from baseline)
Table 1
| Dose | N | LDL-C | Total cholesterol | HDL-C | TG | Non-HDL cholesterol | apoV | apoA-I |
| Placebo | 13 | -7 | -5 | 3 | -3 | -7 | -3 | 0 |
| 5 | 17 | -45 | -33 | 13 | -35 | -44 | -38 | 4 |
| 10 | 17 | -52 | -36 | 14 | -10 | -48 | -42 | 4 |
| 20 | 17 | -55 | -40 | 8 | -23 | -51 | -46 | 5 |
| 40 | 18 | -63 | -46 | 10 | -28 | -60 | -54 | 0 |
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.
Pharmacokinetics
Absorption
The maximum concentration of rosuvastatin in blood plasma (Cmax) is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.
Distribution
Rosuvastatin is extensively bound 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 metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitory activity.
Breeding
Approximately 90% of the rosuvastatin dose is excreted unchanged in the feces (absorbed and unabsorbed active substance together), and the remainder is excreted in the urine. Approximately 5% is excreted in the urine unchanged. 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 (see section "Children").
Pharmacokinetic studies have shown that in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) the median values of the area under the concentration-time curve (AUC) and Cmax are approximately twice as high as in representatives of the Caucasian race; in Indians the median values of AUC and Cmax are increased by approximately 1.3 times. Population pharmacokinetic analysis did not reveal any clinically significant differences between patients of the Caucasian and Negroid races.
Kidney dysfunction
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 or moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 ml/min), plasma concentrations of rosuvastatin were 3-fold higher and the levels of the N-desmethyl metabolite were 9-fold higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50% higher than in healthy volunteers.
Patients with hepatic insufficiency
In patients with varying degrees of hepatic insufficiency with a Child-Pugh score of 7 and below, no increase in the half-life of rosuvastatin was observed. However, in patients with a Child-Pugh score of 8 and 9, an approximately 2-fold increase in the half-life was observed compared with the same indicator in patients with lower Child-Pugh scores. There is no experience with the use of rosuvastatin in patients with a Child-Pugh score above 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 (AUC). In some cases of polymorphisms of SLCO1B1 p.521СС and ABCG2 p.421АА, rosuvastatin exposure is increased compared with genotypes of SLCO1B1 p.521ТТ or ABCG2 p.421СС. Specific genotyping is not provided in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of the drug.
Children
Pharmacokinetic parameters in children aged 10 to 17 years with heterozygous familial hypercholesterolemia have not been fully determined. A small pharmacokinetic study of rosuvastatin (tablet form) in 18 pediatric patients showed that the AUC of the drug in children is similar to that in adults. The results also indicate that no significant dose-proportional deviations are expected.
Indication
Treatment of hypercholesterolemia
Adults and children aged 10 years and over with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to diet when diet and other non-pharmacological measures (e.g. exercise, weight loss) are inadequate.
In homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or when such treatment is inappropriate.
Prevention of cardiovascular disorders
Prevention of major cardiovascular events in patients at high risk of a first cardiovascular event, as an adjunct to correction of other risk factors.
Contraindication
– Hypersensitivity to rosuvastatin or to any other components of the drug;
– active liver disease, including persistent elevation of serum transaminases of unknown etiology and any elevation of serum transaminases greater than 3 times the upper limit of normal;
– severe renal impairment (creatinine clearance < 30 ml/min);
– myopathy;
– simultaneous use with cyclosporine;
– pregnancy or breastfeeding. The drug is contraindicated in women of reproductive age who do not use adequate contraception.
The 40 mg dose is contraindicated in patients with a predisposition to myopathy/rhabdomyolysis. Risk factors may include:
– moderate renal impairment (creatinine clearance < 60 ml/min);
– hypothyroidism;
– presence of hereditary muscle diseases in the individual or family history;
– history of myotoxicity caused by the use of other HMG-CoA reductase inhibitors or fibrates;
– alcohol abuse;
– situations that may lead to an increase in the concentration of rosuvastatin in blood plasma;
– patients belonging to the Mongoloid race;
– concomitant use of fibrates (see sections “Interaction with other medicinal products and other types of interactions”, “Special precautions for use”).
Interaction with other medicinal products and other types of interactions
Effect of concomitant medications on rosuvastatin
Rosuvastatin is a substrate for several transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of the drug with drugs that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "Interaction with other medicinal products and other forms of interaction", "Special instructions for use", "Method of administration and dosage", see 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. Co-administration of the drug with some combinations of protease inhibitors is possible after careful consideration of dose adjustment of the drug, taking into account the expected increase in AUC of rosuvastatin (see sections “Interaction with other medicinal products and other forms of interaction”, “Special instructions for use”, “Method of administration and dosage”, see 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 "Special warnings and precautions for use").
Based on specific studies, no pharmacokinetically significant interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates (≥ 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections 4.3 and 4.4). These patients should also be started on the 5 mg dose.
Ezetimibe
Concomitant administration of 10 mg of the drug and 10 mg of ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (see Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe, which could lead to adverse events, cannot be excluded (see section 4.4).
Antacids
Concomitant use of rosuvastatin with an antacid suspension containing aluminum or magnesium hydroxide reduces the concentration of rosuvastatin in the blood plasma by 50%. This effect is less pronounced when antacids are used 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.
Erythromycin
Concomitant use of the drug and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to increased intestinal peristalsis due to the action of erythromycin.
Cytochrome P450 enzymes
The results of in vitro and in vivo studies indicate that the drug does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions as a result of 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
If it is necessary to use rosuvastatin with other drugs that can increase the AUC of rosuvastatin, the dose of the drug should be adjusted. If it is expected that the AUC of rosuvastatin will increase by approximately 2 or more times, use should be started at a dose of 5 mg 1 time per day. The maximum daily dose of rosuvastatin should be adjusted so that the expected AUC of rosuvastatin does not exceed the AUC 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).
Effect of concomitant medications on rosuvastatin exposure
(AUC; in descending order of magnitude)
Table 2
| Dosage regimen of a drug that interacts with rosuvastatin | Rosuvastatin dosage regimen | Changes in rosuvastatin AUC* |
| Cyclosporine 75 mg twice daily to 200 mg twice daily, 6 months | 10 mg once daily, 10 days | ↑ 7.1 times |
| Regorafenib 160 mg once daily, 14 days | 5 mg, single dose | ↑ 3.8 times |
| Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days | 10 mg, single dose | ↑ 3.1 times |
| Velpatasvir 100 mg once daily | 10 mg, single dose | ↑ 2.7 times |
| ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days | 5 mg, single dose | ↑ 2.6 times |
| Grazoprevir 200 mg/elbasvir 50 mg once daily, 11 days | 10 mg, single dose | ↑ 2.3 times |
| Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days | 5 mg once daily, 7 days | ↑ 2.2 times |
| Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days | 20 mg once daily, 7 days | ↑ 2.1 times |
| Clopidogrel 300 mg, then 75 mg 24 hours later | 20 mg, single dose | ↑ 2 times |
| Gemfibrozil 600 mg twice daily, 7 days | 80 mg, single dose | ↑ 1.9 times |
| Eltrombopac 75 mg once daily, 5 days | 10 mg, single dose | ↑ 1.6 times |
| Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days | 10 mg once daily, 7 days | ↑ 1.5 times |
| Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days | 10 mg, single dose | ↑ 1.4 times |
| Dronedarone 400 mg twice daily | Unknown | ↑ 1.4 times |
| Itraconazole 200 mg once daily, 5 days | 10 mg, single dose | ↑ 1.4 times ** |
| Ezetimibe 10 mg once daily, 14 days | 10 mg once daily, 14 days | ↑ 1.2 times ** |
| Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days | 10 mg, single dose | ↔ |
| Aleglitazar 0.3 mg, 7 days | 40 mg, 7 days | ↔ |
| Silymarin 140 mg three times a day, 5 days | 10 mg, single dose | ↔ |
| Fenofibrate 67 mg three times a day, 7 days | 10 mg, 7 days | ↔ |
| Rifampin 450 mg once daily, 7 days | 20 mg, single dose | ↔ |
| Ketoconazole 200 mg twice daily, 7 days | 80 mg, single dose | ↔ |
| Fluconazole 200 mg once daily, 11 days | 80 mg, single dose | ↔ |
| Erythromycin 500 mg four times a day, 7 days | 80 mg, single dose | ↓ 20% |
| Baicalin 50 mg three times a day, 14 days | 20 mg, single dose | ↓ 47% |
* Data presented as x-fold change represent the ratio between rosuvastatin in combination and alone. Data presented as % change represent the % difference relative to rosuvastatin alone.
Increase is indicated by ↑, no change by ↔, decrease by ↓
** According to interaction studies at different doses of rosuvastatin, Table 2 presents the most significant ratio.
Effect of rosuvastatin on concomitant medications
Vitamin K antagonists
As with other HMG-CoA reductase inhibitors, an increase in the International Normalized Ratio (INR) may occur when initiating therapy or when the dose is increased in patients receiving concomitant vitamin K antagonists (e.g. warfarin or other coumarin anticoagulants). Discontinuation of therapy or dose reduction may result in a decrease in INR. Appropriate monitoring of INR is recommended in such cases.
Oral contraceptives/hormone replacement therapy (HRT)
Concomitant use of the drug 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 taken into account when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients taking rosuvastatin and HRT at the same time, so a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.
Other medicines
Digoxin
Based on interaction studies, no clinically significant interaction is expected.
Fusidic acid
Interaction studies of rosuvastatin with fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased by concomitant use of systemic fusidic acid with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) is not yet clear. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic fusidic acid is necessary, it is advisable to discontinue rosuvastatin treatment for the duration of fusidic acid treatment.
Children
Interaction studies have only been conducted in adults. The extent of interaction in children is unknown.
Application features
Effects on the kidneys
Proteinuria, detected by dipstick analysis and predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, including 40 mg, and in most cases was transient or intermittent. Proteinuria was not a harbinger of acute or progressive renal disease (see section 4.8).
Renal adverse events were observed more frequently with the 40 mg dose. Patients taking the 40 mg dose should have their renal function monitored regularly.
Musculoskeletal disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been reported in patients taking rosuvastatin at all doses, particularly those 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 potential for pharmacodynamic interactions, this combination should be used with caution.
As with other HMG-CoA reductase inhibitors, reports of rhabdomyolysis associated with the use of rosuvastatin occurred more frequently with the 40 mg dose.
Determination of creatine phosphokinase (CPK) levels
CPK levels should not be measured after significant exercise or when there are possible alternative causes of CPK elevation that may complicate interpretation of results. If the initial CPK level is significantly elevated (> 5 times the upper limit of normal), additional confirmatory testing should be performed within 5–7 days. If the result of the repeat test confirms the initial level > 5 times the upper limit of normal, treatment should not be initiated.
Before starting treatment
Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution to patients with factors predisposing to the development of myopathy/rhabdomyolysis.
Such factors include:
– kidney dysfunction;
– hypothyroidism;
– presence of hereditary muscle diseases in the individual or family history;
– history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
– alcohol abuse;
– age > 70 years;
– situations that may lead to an increase in the level of rosuvastatin in the blood plasma (see sections “Pharmacokinetics”, “Interaction with other medicinal products and other types of interactions” and “Method of administration and dosage”);
– simultaneous 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 times the upper limit of normal), treatment should not be initiated.
During treatment
Patients should be advised to report unexplained muscle pain, weakness or cramps to their physician immediately, especially if accompanied by malaise or fever. CPK levels should be measured in these patients. The drug should be discontinued if CPK levels are significantly elevated (> 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if CPK levels are ≤ 5 times the upper limit of normal). If symptoms resolve and CPK levels return to normal, rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close observation. Regular CPK monitoring is not necessary in patients without these symptoms. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with statins, including rosuvastatin. Clinical manifestations of IONM include proximal muscle weakness and elevated serum CPK levels, which persist even after discontinuation of statins.
In clinical studies, there was no evidence of increased effects on skeletal muscle in a small number of patients taking rosuvastatin and concomitant medications. However, an increased incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with some HMG-CoA reductase inhibitors. Therefore, the use of rosuvastatin in combination with gemfibrozil is not recommended. The beneficial effects of further changes in lipid levels when rosuvastatin is used concomitantly with fibrates or niacin should be weighed against the potential risks of such a combination. The simultaneous use of fibrates and rosuvastatin at a dose of 40 mg is contraindicated.
The drug should not be used in patients with acute, serious conditions that suggest myopathy or the possibility of developing renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders or uncontrolled seizures).
Effect on the liver
Like other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease.
It is recommended to check biochemical indicators of liver function before starting treatment and after 3 months of treatment. The drug should be discontinued or the dose reduced if the level of serum transaminases exceeds three times the upper limit of normal. The frequency of reports of serious liver events (mainly increased liver transaminases) is higher with the 40 mg dose.
In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying disease should be treated first before initiating therapy with rosuvastatin.
Fatal or non-fatal cases of hepatic failure have been reported rarely in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice develops during treatment with rosuvastatin, rosuvastatin should be discontinued immediately. Unless other causes are identified, rosuvastatin should not be restarted.
Racial affiliation
It is known that in pharmacokinetic studies, an increase in AUC in patients of the Mongoloid race was observed approximately twice as much as in representatives of the Caucasian race. For such patients, a dose adjustment of rosuvastatin is required (see sections "Pharmacokinetics", "Contraindications" and "Method of administration and dosage").
Protease inhibitors
Increased systemic exposure to rosuvastatin has been observed in subjects taking rosuvastatin with various protease inhibitors, in combination with ritonavir. The benefit of lowering lipid levels with rosuvastatin in HIV patients receiving protease inhibitors should be weighed against the possibility of increased plasma concentrations of rosuvastatin at the start of therapy and with an increase in the dose of the drug in patients receiving protease inhibitors. The simultaneous use of rosuvastatin with protease inhibitors is not recommended unless the dose of the drug is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with the use of some statins, particularly with long-term treatment (see section 4.8). Symptoms of this disease may include dyspnoea, non-productive cough and general deterioration (fatigue, weight loss and fever). If interstitial lung disease is suspected, statins should be discontinued.
Diabetes mellitus
Some evidence suggests that statins increase blood glucose levels and, in some patients at high risk of future diabetes, may cause hyperglycemia to a level requiring appropriate diabetes management. However, this risk is outweighed by the reduced risk of vascular events with statins and should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, body mass index (BMI) > 30 kg/m2, elevated triglycerides, hypertension) should be monitored clinically and biochemically.
In the JUPITER study, the overall incidence of diabetes mellitus was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.
Children
Assessment of linear growth (height), body weight, body mass index (BMI), and secondary sexual maturation characteristics according to Tanner in children aged 10 to 17 years who took rosuvastatin was limited to a period of 1 year. During this period, no effect on growth, body weight, BMI, or sexual maturation was observed. Clinical trial experience in children and adolescents is limited, and the long-term effects of rosuvastatin use (>1 year) on sexual maturation are unknown.
In children and adolescents taking rosuvastatin, increases in CPK levels > 10 times the upper limit of normal and muscle symptoms after physical exertion or increased physical activity were observed more often compared to those in adults (see section "Adverse reactions").
Important information about excipients.
Rosuvastatin-Darnitsa contains lactose monohydrate, so if the patient has been diagnosed with intolerance to some sugars, you should consult your doctor before taking this medicine. It should not be taken by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
The drug is contraindicated during pregnancy or breastfeeding.
Since cholesterol and other cholesterol biosynthesis products play an essential role in fetal development, the potential risk from inhibition of HMG-CoA reductase outweighs the benefits of using the drug during pregnancy. Animal data on reproductive toxicity are limited. If the patient becomes pregnant while taking this drug, treatment should be discontinued immediately.
Because another drug of this class is excreted in human milk, and because HMG-CoA reductase inhibitors can cause serious adverse reactions in nursing infants, women requiring treatment with rosuvastatin should be advised not to breast-feed.
Rosuvastatin is excreted in rat milk. There are no data on the excretion of the drug into human milk (see section "Contraindications").
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of rosuvastatin on the ability to drive and use machines have not been conducted. However, given the pharmacodynamic properties of the drug, it is unlikely that rosuvastatin will affect this ability. When driving or operating other mechanisms, the possibility of dizziness should be taken into account during treatment with rosuvastatin.
Method of administration and doses
Before starting treatment, the patient should be placed on a standard cholesterol-lowering diet, which should be followed throughout treatment. The dose should be individualized depending on the goal of therapy and the patient's response to treatment, taking into account current recommendations.
The medicine can be taken at any time of the day, regardless of food intake.
Treatment of hypercholesterolemia
The recommended starting dose is 5 mg* or 10 mg orally once daily for both statin-naive patients and those switching to rosuvastatin from another HMG-CoA reductase inhibitor. The starting dose should be based on the individual patient's cholesterol level and future cardiovascular risk, as well as the likelihood of adverse reactions. If necessary, the dose may be increased to the next level after 4 weeks (see section 5.2). Given that adverse reactions occur more frequently with the 40 mg dose than with lower doses (see section "Adverse reactions"), final titration to 40 mg should only be considered in patients with severe hypercholesterolemia and high risk of cardiovascular events (particularly in patients with familial hypercholesterolemia) who have not achieved their treatment goals with the 20 mg dose and who will be under regular monitoring (see section "Special warnings and precautions for use"). Specialist supervision is recommended when starting the 40 mg dose.
Prevention of cardiovascular disorders
In the study, rosuvastatin was used at a dose of 20 mg per day to reduce the risk of cardiovascular disorders.
Elderly patients
The recommended starting dose for patients > 70 years of age is 5 mg* (see section 4.4). No other dose adjustment is necessary based on age.
Patients with renal insufficiency
No dose adjustment is required for patients with mild or moderate renal impairment.
The recommended starting dose for patients with moderate renal impairment (creatinine clearance < 60 ml/min) is 5 mg*. The 40 mg dose is contraindicated in patients with moderate renal impairment. Rosuvastatin is contraindicated in patients with severe renal impairment at any dose (see sections 4.3 and 5.2).
Patients with liver dysfunction
In patients with hepatic impairment of Child-Pugh score 7 or less, no increase in systemic exposure to rosuvastatin was observed. However, in subjects with hepatic impairment of Child-Pugh score 8 and 9, systemic exposure increased (see section 4.4).
