Rovamed film-coated tablets 20 mg blister No. 30

Instructions for Rovamed film-coated tablets 20 mg blister No. 30

Composition

active ingredient: rosuvastatin;

1 film-coated tablet contains rosuvastatin calcium 5.21 mg equivalent to rosuvastatin 5 mg or rosuvastatin calcium 10.419 mg equivalent to rosuvastatin 10 mg, or rosuvastatin calcium 20.838 mg equivalent to rosuvastatin 20 mg, or rosuvastatin calcium 41.676 mg equivalent to rosuvastatin 40 mg;

Excipients: microcrystalline cellulose, type 101; colloidal anhydrous silica; crospovidone, type A; microcrystalline cellulose, type 102; lactose, monohydrate; magnesium stearate;

film coating: Opadry II Yellow 33K12488 (HPMC 2910/hypromellose 6 cP; titanium dioxide (E 171); lactose monohydrate; triacetin; iron oxide yellow) (5 mg tablets);

Opadry II Pink 33K94423 (HPMC 2910/hypromellose 6 cP; titanium dioxide (E 171); lactose monohydrate; triacetin; iron oxide red) (10 mg tablets);

Opadry II Pink 33K94423 (HPMC 2910/hypromellose 6 cP; titanium dioxide (E 171); lactose monohydrate; triacetin; iron oxide red) (20 mg tablets);

Opadry II Pink 33K94424 (HPMC 2910/hypromellose 6 cP; titanium dioxide (E 171); lactose monohydrate; triacetin; iron oxide red) (40 mg tablets).

Dosage form

Film-coated tablets.

Main physicochemical properties:

5 mg tablets – yellow, round, biconvex, film-coated tablets, with the inscription “ROS” over “5” on one side, without inscriptions on the other side;

10 mg tablets – pink, round, biconvex, film-coated tablets, with the inscription “ROS” over “10” on one side, without inscriptions on the other side;

20 mg tablets – pink, round, biconvex, film-coated tablets, with the inscription “ROS” over “20” on one side, without inscriptions on the other side;

40 mg tablets – pink oval, biconvex, film-coated tablets, debossed with “ROS” on one side and “40” on the other side.

Pharmacotherapeutic group

Lipid-lowering agents. HMG-CoA reductase inhibitors.

ATX code C10A A07.

Pharmacological properties

Pharmacodynamics.

Mechanism of action: 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, the 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.

Pharmacodynamic effects: Rosuvastatin reduces elevated LDL-cholesterol (LDL-C), total cholesterol, and triglycerides and increases HDL-cholesterol (HDL-C). It also reduces apolipoprotein B (apoB), non-LDL-C, VLDL-C, VLDL-triglycerides (VLDL-TG), and increases apoA-I (see Table 1). Rosuvastatin also reduces the LDL-C/HDL-C, total-C/HDL-C, non-LDL-C/HDL-C, and apoB/apoA-I ratios.

Table 1

Dose response in patients with primary hypercholesterolemia types IIa and IIb (adjusted mean percent change from baseline)

The therapeutic effect is achieved within 1 week after the start of the drug, 90% of the maximum effect is achieved after 2 weeks. The maximum effect is usually achieved after 4 weeks and continues thereafter.

Clinical efficacy: Rovamed® is effective in the treatment of adults with hypercholesterolemia – with or without hypertriglyceridemia – regardless of race, gender or age, as well as in special patient groups such as diabetics or patients with familial hypercholesterolemia.

In pooled phase III studies, rosuvastatin was effective in lowering cholesterol levels in most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C level approximately 4.8 mmol/L) to the target values established by the recognized European Atherosclerosis Society (EAS; 1998); approximately 80% of patients taking the 10 mg dose achieved the EAS target LDL-C levels (<3 mmol/L).

In an open-label, up-titration study, the response to rosuvastatin 20–40 mg was studied in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels were reduced by an average of 22%.

In clinical studies involving a limited number of patients, an additive effect of rosuvastatin on lowering triglyceride levels when used in combination with fenofibrate and on increasing HDL-C levels when used in combination with niacin was observed (see section "Special warnings and precautions for use").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of coronary heart disease (defined as Framingham risk <10% over 10 years), a mean LDL-C of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined as increased carotid intima-media thickness (CIMT)) were randomized to receive either 40 mg rosuvastatin or placebo once daily for 2 years. Compared with placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid sites by -0.0145 mm/year [95% confidence interval (CI) -0.0196, -0.0093; p<0.0001]. The change from baseline was -0.0014 mm/year (-0.12%/year (not statistically significant)) in the rosuvastatin group compared with a progression of +0.0131 mm/year (1.12%/year (p<0.0001)) in the placebo group. No direct correlation between the reduction in TCIMSA and the reduction in the risk of cardiovascular events was demonstrated. The METEOR study enrolled patients at low risk of coronary heart disease, who are not representative of the target population for the 40 mg dose. The 40 mg dose should only be administered to patients with severe hypercholesterolemia and high risk of cardiovascular events (see section 4.2).

In the Rosuvastatin Intervention Trial to Support the Use of Statins as Primary Prevention (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular disease was evaluated in 17,802 men (≥50 years) and women (≥60 years).

Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and followed for an average of 2 years.

LDL-C concentration decreased by 45% (p<0.001) in the rosuvastatin group compared to the placebo group.

In a post-hoc analysis of the high-risk subgroup of patients with a baseline Framingham score >20% (1558 participants), there was a significant reduction in the incidence of the composite endpoint of cardiovascular death, stroke, and myocardial infarction (p=0.028) in the rosuvastatin group compared with placebo. The absolute risk reduction for events was 8.8 events per 1000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p=0.193). In a post-hoc analysis of the high-risk subgroup (9302 participants in total) with a baseline SCORE score ≥5% (extrapolated to include participants aged 65 years and older), there was a significant reduction in the composite endpoint of cardiovascular death, stroke, and myocardial infarction (p=0.0003) in the rosuvastatin group compared with placebo. The absolute risk reduction, expressed as an event rate, was 5.1 events per 1000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p=0.076).

In the JUPITER study, 6.6% of rosuvastatin-treated patients and 6.2% of placebo-treated patients discontinued study drug due to adverse events. The most common adverse events leading to discontinuation were myalgia (0.3% rosuvastatin-treated patients, 0.2% placebo-treated patients), abdominal pain (0.03% rosuvastatin-treated patients, 0.02% placebo-treated patients), and rash (0.02% rosuvastatin-treated patients, 0.03% placebo-treated patients). The most common adverse events observed in the rosuvastatin group at a frequency greater than or equal to that observed in the placebo group were urinary tract infections (8.7% in the rosuvastatin group, 8.6% in the placebo group), nasopharyngitis (7.6% in the rosuvastatin group, 7.2% in the placebo group), back pain (7.6% in the rosuvastatin group, 6.9% in the placebo group), and myalgia (7.6% in the rosuvastatin group, 6.6% in the placebo group).

Children: In a double-blind, randomized, multicenter, placebo-controlled, 12-week study (n=176, 97 male and 79 female) followed by a 40-week open-label rosuvastatin titration period (n=173, 96 male and 77 female), patients aged 10–17 years (Tanner stages II–IV, girls who had started menstruating at least 1 year previously) with heterozygous familial hypercholesterolemia received rosuvastatin 5, 10, or 20 mg daily or placebo for 12 weeks, after which all participants received daily rosuvastatin for 40 weeks. At the beginning of the study, approximately 30% of patients were aged 10–13 years and approximately 17%, 18%, 40% and 25% of them were in Tanner stages II, III, IV and V, respectively.

At the end of the 40-week open-label dose titration period to target (maximum dose was 20 mg once daily), 70 of 173 patients (40.5%) achieved a target LDL-C level of less than 2.8 mmol/L.

After 52 weeks of study treatment, no effect on growth, weight, body mass index (BMI), or puberty was observed (see section 4.4).

This study (n=176) is not suitable for comparing rare adverse events.

Rosuvastatin was also studied in a 2-year, open-label, target-titration study in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female, Tanner stage

After 24 months of treatment with rosuvastatin, the least squares mean reduction from baseline in LDL-C was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the least squares mean reduction from baseline in LDL-C was -43% (baseline: 234 mg/dL, month 24: 124 mg/dL), -45% (baseline: 234 mg/dL, month 24: 124 mg/dL), and -35% (baseline: 241 mg/dL, month 24: 153 mg/dL) in the age groups 6 to <10, 10 to <14, and 14 to <18 years, respectively.

Rosuvastatin 5 mg, 10 mg and 20 mg also resulted in statistically significant mean changes from baseline in the following secondary lipid and lipoprotein variables: HDL-C, total-C, non-HDL-C, LDL-C/HDL-C, total-C/HDL-C, TG/HDL-C, non-HDL-C/HDL-C, apoB, apoB/apoA-1. Each of these changes demonstrated improvements in lipid responses and were maintained over 2 years. After 24 months of treatment, no effects on growth, weight, BMI or puberty were observed (see section 4.4).

A randomized, double-blind, placebo-controlled, multicenter, crossover study evaluated rosuvastatin 20 mg once daily versus placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included an active 4-week dietary lead-in phase during which patients were treated with rosuvastatin 10 mg, a crossover phase consisting of a 6-week period of rosuvastatin 20 mg with or without a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received rosuvastatin 20 mg. Patients receiving ezetimibe or apheresis continued to receive this treatment throughout the study. A statistically significant (p = 0.005) reduction in LDL-C (22.3%; 85.4 mg/dL, or 2.2 mmol/L) was observed after 6 weeks of treatment with rosuvastatin 20 mg compared with placebo. There were also statistically significant reductions in total-C (20.1%, p = 0.003), non-HDL-C (22.9%, p = 0.003), and apoB (17.1%, p = 0.024). Reductions in TG, LDL-C/HDL-C, total-C/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of treatment with rosuvastatin 20 mg compared with placebo. The reduction in LDL-C after 6 weeks of treatment with rosuvastatin 20 mg followed by 6 weeks of placebo was maintained through 12 weeks of continuous therapy. One patient had further reductions in LDL-C (8.0%), total-C (6.7%), and non-HDL-C (7.4%) after 6 weeks of treatment with dose titration to 40 mg.

During continuation of open-label treatment with rosuvastatin 20 mg, 9 of these patients maintained LDL-C reductions ranging from -12.1% to -21.3% for up to 90 weeks.

In an open-label, up-titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction from baseline in LDL-C (21.0%), total-C (19.2%), and non-HDL-C (21.0%) after 6 weeks of treatment with rosuvastatin 20 mg was consistent with that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

The European Medicines Agency has waived the obligation to submit the results of studies with rosuvastatin in all subsets of the paediatric population in homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia and for the prevention of cardiovascular events (see section 4.2 for information on paediatric use).

Pharmacokinetics.

Absorption: Peak plasma concentrations of rosuvastatin are reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Metabolism. Rosuvastatin undergoes minor metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for metabolism by cytochrome P450 enzymes. The main isoenzyme involved is CYP2C9, with 2C19, 3A4 and 2D6 playing a somewhat smaller role. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitory activity.

Excretion. Approximately 90% of the rosuvastatin dose is excreted unchanged in the feces (absorbed and unabsorbed active substance together), the rest is excreted in the urine. Approximately 5% of rosuvastatin is excreted in the urine in unchanged form. The half-life from blood plasma is approximately 19 hours and does not increase with increasing dose. The geometric mean value of the drug clearance from blood plasma is approximately 50 l/hour (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 populations

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").

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

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

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

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

Children: Two studies of the pharmacokinetics of rosuvastatin (tablets) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (total of 214 patients) showed that the drug exposure in children was lower than or similar to that in adult patients. The exposure of rosuvastatin was predictable according to the dose and duration of administration over 2 years of observation.

Indication

Treatment of hypercholesterolemia

Adults, adolescents and children aged 6 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.

Adults, adolescents and children aged 6 years and over with homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or when such treatments are inappropriate.

Prevention of cardiovascular disorders

Prevention of major cardiovascular events in patients estimated to be at high risk of a first cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors.

Contraindication

Rovamed® is contraindicated

patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology and any elevation of serum transaminases greater than three times the upper limit of normal (ULN);

patients with severe renal impairment (creatinine clearance <30 ml/min);

patients with myopathy;

patients who were simultaneously receiving the combination of sofosbuvir/velpatasvir/voxilaprevir (see section “Interaction with other medicinal products and other types of interactions”);

patients who are simultaneously receiving cyclosporine;

during pregnancy and breastfeeding, as well as women of reproductive age who do not use adequate contraception.

The 40 mg dose is contraindicated in patients with a predisposition to myopathy/rhabdomyolysis.

Such risk factors include:

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

hypothyroidism;

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

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

alcohol abuse;

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

belonging to the Mongoloid race;

concomitant use of fibrates.

(See sections “Special instructions for use”, “Interaction with other medicinal products and other types of interactions” and “Pharmacokinetics”).

Interaction with other medicinal products and other types of interactions

Effect of concomitant medications on rosuvastatin

Transporter protein inhibitors. Rosuvastatin is a substrate for some transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of Rovamed® with medicinal products that inhibit these transporters may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections 4.2, 4.4, and 4.5).

Cyclosporine. During concomitant use of Rovamed® and cyclosporine, 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 cyclosporine concomitantly (see section "Contraindications"). Concomitant use did not affect the concentration of cyclosporine in the blood plasma.

Protease inhibitors. Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (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 rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Co-administration of Rovamed® and some combinations of protease inhibitors is possible after careful consideration of dose adjustment of Rovamed®, taking into account the expected increase in rosuvastatin exposure (see sections “Interaction with other medicinal products and other forms of interaction”, “Special instructions for use”, “Method of administration and dosage”, Table 2).

Gemfibrozil and other lipid-lowering agents. Concomitant use of Rovamed® and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax (see section 4.4). Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA inhibitors, probably due to the fact that they can cause myopathy when used separately. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections 4.4 and 4.4). These patients should also be started on the 5 mg dose.

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

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

Cytochrome P450 enzymes. In vitro and in vivo studies have shown that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, drug interactions resulting from P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring dose adjustment of rosuvastatin (see also Table 2). If it is necessary to use Rovamed® with other drugs that can increase the exposure of rosuvastatin, the dose of Rovamed® should be adjusted. If the AUC of the drug is expected to increase by approximately 2 or more times, the use of Rovamed® should be started with a dose of 5 mg 1 time per day. The maximum daily dose of Rovamed® should be adjusted so that the expected exposure of rosuvastatin does not exceed the exposure observed when taking a dose of 40 mg per day without the use of drugs that interact with the drug; for example, when used with gemfibrozil, the dose of Rovamed® will be 20 mg (1.9-fold increase in exposure), when used with the combination of ritonavir/atazanavir – 10 mg (3.1-fold increase in exposure), when used simultaneously with cyclosporine – 5 mg (7.1-fold increase).

If the drug increases the AUC of rosuvastatin by less than 2 times, the initial dose does not need to be reduced, but caution should be exercised when increasing the dose of rosuvastatin to more than 20 mg.

Table 2

Effect of concomitant medications on rosuvastatin exposure

(AUC; in descending order of magnitude) from published clinical trial data

*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 the ↑ icon, no change –, decrease – ↓.

**Several interaction studies have been conducted at different doses of rosuvastatin, the most significant relationship is presented in Table 2.

Drugs/combinations that did not have a clinically significant effect on the AUC ratio of rosuvastatin when used concomitantly: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg for 7 days 3 times a day; fluconazole 200 mg for 11 days 1 time a day; fosamprenavir 700 mg / ritonavir 100 mg for 8 days 2 times a day; ketoconazole 200 mg for 7 days 2 times a day; rifampin 450 mg for 7 days 1 time a day; silymarin 140 mg for 5 days 3 times a day.

Vitamin K antagonists. As with other HMG-CoA reductase inhibitors, when initiating or increasing the dose of Rovamed® in patients concomitantly receiving vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant), an increase in the international normalized ratio (INR) may occur. Discontinuation of Rovamed® or dose reduction may result in a decrease in the INR. In such cases, appropriate monitoring of INR is advisable.

Oral contraceptives/hormone replacement therapy (HRT). Concomitant use of Rovamed® 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 pharmacokinetic data in patients taking Rovamed® 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 specific studies, no clinically significant interaction with digoxin is expected.

Fusidic acid. Interaction studies with rosuvastatin and 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. Rhabdomyolysis (including some fatal cases) has been reported in patients receiving this combination.

In patients in whom systemic fusidic acid is considered necessary, rosuvastatin should be discontinued for the duration of fusidic acid treatment. See also section 4.4.

Children: Interaction studies have only been conducted in adults. The extent of interaction in children is unknown.

Application features

Renal Effects: Dipstick proteinuria, predominantly of tubular origin, has been reported in patients treated with higher doses of rosuvastatin, including 40 mg, and in most cases has been transient or intermittent. Proteinuria has not been a predictor of acute or progressive renal disease (see Adverse Reactions). The frequency of serious renal events reported in post-marketing studies is higher with the 40 mg dose. Patients receiving the 40 mg dose should have their renal function monitored regularly during follow-up.

Skeletal muscle effects: Skeletal muscle disorders, such as myalgia, myopathy and, rarely, rhabdomyolysis, have been reported in patients taking rosuvastatin at all doses, particularly doses above 20 mg. Very rare cases of rhabdomyolysis have been reported when ezetimibe was used in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded (see section 4.5), and this combination should therefore be used with caution.

As with other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis associated with rosuvastatin in the post-marketing period was higher with the 40 mg dose.

Creatine kinase (CK) levels. CK levels should not be measured after significant exercise or in the presence of possible alternative causes of CK elevation that may complicate interpretation of results. If baseline CK levels are significantly elevated (>5 times ULN), repeat testing should be performed within 5-7 days to confirm the results. If repeat testing confirms baseline CK levels greater than 5 times ULN, treatment should not be initiated.

Before starting treatment. Rovamed®, like other HMG-CoA reductase inhibitors, should be prescribed with caution to patients with a predisposition to myopathy/rhabdomyolysis.

Such risk factors include:

kidney dysfunction;

hypothyroidism;

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

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

alcohol abuse;

age > 70