Roxera

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Roxera® (Roxera®)

Composition:

Active substance: One film-coated tablet contains 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, or 40 mg of rosuvastatin (as rosuvastatin calcium);

Excipients: microcrystalline cellulose, lactose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: methacrylic acid copolymer, polyethylene glycol 6000, titanium dioxide (E 171), lactose monohydrate.

Dosage form. Film-coated tablets.

Main physicochemical properties:

5 mg: white, round, slightly biconvex, film-coated tablets with beveled edges and engraved "5" on one side;

10 mg: white, round, slightly biconvex, film-coated tablets with beveled edges and engraved "10" on one side;

15 mg: white, round, slightly biconvex, film-coated tablets with beveled edges and engraved "15" on one side;

20 mg: white, round, film-coated tablets with beveled edge;

30 mg: white, biconvex, film-coated tablets in capsule shape with notches on both sides;

40 mg: white, biconvex, film-coated tablets in capsule shape.

Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors.

ATC code C10A A07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the conversion of 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 reducing cholesterol levels.

Rosuvastatin increases the number of LDL receptor particles on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of LDL, thereby reducing the total number of LDL and non-HDL lipoprotein particles.

Pharmacodynamic effects

Roxera® reduces elevated levels of LDL-cholesterol, total cholesterol, and triglycerides, and increases HDL-cholesterol levels. It also reduces levels of apolipoprotein B, non-HDL-cholesterol, LDL-cholesterol, LDL-triglycerides, and increases apolipoprotein A-I levels (Table 1). Roxera® also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Table 1

Dose-response in patients with primary hypercholesterolemia type IIa and IIb

(adjusted mean percentage change from baseline)

The therapeutic effect is achieved within 1 week after starting the medication, with 90% of the maximum effect reached within 2 weeks. Maximum effect is usually achieved within 4 weeks and persists thereafter.

Clinical efficacy and safety

Roxera® is effective in the treatment of adults with hypercholesterolemia—with or without hypertriglyceridemia—regardless of race, gender, or age, as well as in patients from special groups such as those with diabetes mellitus or familial hypercholesterolemia.

Based on pooled Phase III trial data, Roxera® effectively reduced cholesterol levels in most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C approximately 4.8 mmol/L) to target values established by the European Atherosclerosis Society (EAS; 1998) guidelines; approximately 80% of patients receiving the 10 mg dose achieved EAS target LDL-C levels (<3 mmol/L).

In a large study involving 435 patients with heterozygous familial hypercholesterolemia, patients received Roxera® at doses ranging from 20 to 80 mg using an intensive dose-titration regimen. A favorable effect of the drug on lipid parameters and achievement of target levels was observed at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53%. Target EAS LDL-C levels (<3 mmol/L) were achieved in 33% of patients.

In an open-label dose-titration study, the response to Roxera® at doses of 20–40 mg was evaluated in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased on average by 22%.

In clinical studies involving a limited number of patients, an additive effect of Roxera® was observed on triglyceride reduction when used in combination with fenofibrate, and on HDL-C elevation when used in combination with niacin (see section "Special precautions").

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

In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular events was evaluated in 17,802 men (≥50 years) and women (≥60 years).

Study participants were randomly assigned to receive either placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901), with a mean follow-up of 2 years.

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

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

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

Children

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

LDL-C levels decreased by 38.3%, 44.6%, and 50.0% in the rosuvastatin 5 mg, 10 mg, and 20 mg groups, respectively, compared to 0.7% in the placebo group.

At the end of the 40-week open-label dose-titration period aimed at achieving target levels (maximum dose 20 mg once daily), target LDL-C levels (<2.8 mmol/L) were achieved in 70 of 173 patients (40.5%).

After 52 weeks of investigational treatment, no effect on growth, weight, BMI, or sexual maturation was observed (see section "Special precautions"). This study (n=176) is not suitable for comparison of rare adverse events.

Rosuvastatin was also studied in a 2-year open-label study with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage <II-V). The initial dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n=64) were titrated up to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n=134) were titrated up to a maximum dose of 20 mg once daily.

After 24 months of rosuvastatin treatment, the least squares mean reduction in LDL-C from baseline was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the least squares mean reduction in LDL-C from baseline 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.

Treatment with rosuvastatin at doses of 5 mg, 10 mg, and 20 mg also resulted in statistically significant mean changes from baseline in secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C, total cholesterol/HDL-C, TG/HDL-C, non-HDL-C/HDL-C, apoB, and apoB/apoA-1. Each of these changes demonstrated improved lipid responses and was maintained over 2 years.

After 24 months of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special precautions").

In a randomized, double-blind, placebo-controlled, multicenter, crossover study, rosuvastatin 20 mg once daily was compared with placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active run-in phase with diet adherence during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients on ezetimibe or apheresis continued these treatments 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 rosuvastatin 20 mg treatment compared to placebo. Statistically significant reductions were also observed in total cholesterol (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 cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of rosuvastatin 20 mg compared to placebo. The reduction in LDL-C after 6 weeks of rosuvastatin 20 mg followed by 6 weeks of placebo was maintained over 12 weeks of continuous therapy. One patient showed further reductions in LDL-C (8.0%), total cholesterol (6.7%), and non-HDL-C (7.4%) after 6 weeks of treatment with dose titration to 40 mg.

During continued open-label treatment with rosuvastatin 20 mg in 9 of these patients up to 90 weeks, LDL-C reduction was maintained between -12.1% and -21.3%.

In an open-label dose-titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction in LDL-C (21.0%), total cholesterol (19.2%), and non-HDL-C (21.0%) from baseline after 6 weeks of rosuvastatin 20 mg treatment 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 results of rosuvastatin studies in all pediatric subgroups with homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia, and for prevention of cardiovascular disorders (see section "Dosage and administration" for information on pediatric use).

Pharmacokinetics

Absorption

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

Distribution

Rosuvastatin is extensively metabolized in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, primarily albumin.

Metabolism

Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin undergoes only minimal CYP450-mediated metabolism, which is not clinically significant. CYP2C9 is the main isoenzyme involved, with lesser contributions from CYP2C19, 3A4, and 2D6. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone form is considered clinically inactive. Rosuvastatin retains more than 90% of its HMG-CoA reductase inhibitory activity in the systemic circulation.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (comprising both absorbed and unabsorbed active substance), with the remainder excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The half-life does not increase with higher doses. The geometric mean plasma clearance is approximately 50 L/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves the membrane transporter OATP-C, which is important for the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. There are no changes in pharmacokinetic parameters after multiple daily administrations.

Patient groups

Age and gender

No clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults has been observed. 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 show approximately a 2-fold increase in AUC and Cmax of rosuvastatin in Asian patients (Japanese, Chinese, Filipino, Vietnamese, and Korean) compared to Caucasian patients; in Indian patients, AUC and Cmax are increased by approximately 1.3-fold. Pharmacokinetic analysis of patient groups did not reveal any clinically significant differences in pharmacokinetics between Caucasian and Black patients.

Renal impairment

In a study involving patients with varying degrees of renal dysfunction, mild or moderate kidney disease did not affect plasma concentrations of rosuvastatin or the N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations increased 3-fold and N-desmethyl metabolite concentrations increased 9-fold compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis sessions were approximately 50% higher than in healthy volunteers.

Hepatic impairment

In a study involving patients with varying degrees of hepatic dysfunction, there was no evidence of increased rosuvastatin exposure in patients with Child-Pugh scores of 7 or less. However, at least a 2-fold increase in systemic exposure was observed in two patients with Child-Pugh scores of 8 and 9.

Genetic polymorphism

Distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves the transporter proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. With specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Routine genotyping is not required in clinical practice, but patients with these polymorphisms are recommended to receive a lower daily dose of Roxera®.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10–17 years or 6–17 years (total of 214 patients) showed that drug exposure in children was lower or similar to that in adult patients. Rosuvastatin exposure was predictable according to dose and duration of administration over more than 2 years of observation.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

For adults, adolescents, and children aged 6 years and older with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb), as an adjunct to diet, when dietary measures and other non-pharmacological interventions (e.g., physical exercise, weight reduction) are insufficient.

For adults, adolescents, and children aged 6 years and older with 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 estimated to be at high risk of a first cardiovascular event, as an adjunct to correction of other risk factors.

Contraindications.

Doses of 5 mg, 10 mg, 15 mg, and 20 mg are contraindicated:

• in patients with hypersensitivity to rosuvastatin or any inactive ingredient;
• in patients with active liver disease, including disease of unknown etiology, persistent elevations in serum transaminases, or elevations in any serum transaminase greater than 3 times the upper limit of normal;
• in patients with severe renal impairment (creatinine clearance < 30 mL/min);
• in patients with myopathy;
• in patients concurrently taking cyclosporine;
• in patients concurrently taking sofosbuvir/velpatasvir/voxilaprevir (see "Interaction with other medicinal products and other forms of interaction");
• in patients with existing risk factors for myotoxic complications;
• during pregnancy or breastfeeding, and in women of childbearing potential who are not using appropriate contraceptive measures;
• in children under 6 years of age.

Doses of 30 mg and 40 mg are contraindicated:

• in patients with hypersensitivity to rosuvastatin or any inactive ingredient;
• in patients with active liver disease, including unexplained, persistent elevations in serum transaminases and any elevation in serum transaminases greater than 3 times the upper limit of normal;
• in patients concurrently taking cyclosporine;
• during pregnancy or breastfeeding, and in women of childbearing potential who are not using appropriate contraceptive measures;
• in children;
• in patients with myopathy or existing risk factors for myopathy/rhabdomyolysis; such risk factors include: moderate renal impairment (creatinine clearance < 60 mL/min); hypothyroidism; personal or family history of inherited muscular disorders; history of muscle toxicity associated with another HMG-CoA reductase inhibitor or fibrate; alcohol abuse; conditions that may increase plasma levels (e.g., severe hepatic insufficiency); Asian ancestry; concomitant use of fibrates; age over 70 years.

Interaction with other medicinal products and other forms of interaction.

Rosuvastatin is a substrate for certain transporter proteins, including OATP1B1, which mediates hepatic uptake, and the efflux transporter BCRP. Concomitant administration of Rosuva® with medicinal products that inhibit these transporter proteins may increase rosuvastatin plasma concentrations and increase the risk of myopathy.

When Rosuva® must be used concomitantly with other medicinal products that increase rosuvastatin exposure, the dose of Rosuva® should be adjusted. Treatment should be initiated at a dose of 5 mg once daily if an increase in exposure (AUC) of approximately 2-fold or more is expected. The maximum daily dose of Rosuva® should be adjusted so that the expected rosuvastatin exposure does not exceed the concentration observed when a 40 mg daily dose of Rosuva® is taken in the absence of drug interactions. For example, a 5 mg dose of Rosuva® when co-administered with cyclosporine (7.1-fold increase in exposure), a 10 mg dose of Rosuva® when co-administered with ritonavir/atazanavir combination (3.1-fold increase), and a 20 mg dose of Rosuva® when co-administered with gemfibrozil (1.9-fold increase).

Antacids

Concomitant administration of rosuvastatin with an antacid suspension containing aluminum and magnesium hydroxide results in approximately a 50% reduction in rosuvastatin plasma concentration. This effect was reduced when the antacid was taken 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Fenofibrate, fibric acid derivatives

Although no pharmacokinetic interaction between rosuvastatin and fenofibrate has been observed, a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, and other fibric acid derivatives, including nicotinic acid, may increase the risk of myopathy when administered concomitantly with HMG-CoA reductase inhibitors.

Cyclosporine

During concomitant use of Rosuva® and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Rosuva® is contraindicated in patients receiving cyclosporine concurrently (see section "Contraindications").

Concomitant use did not affect cyclosporine plasma concentrations.

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of Rosuva® treatment or dose escalation in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the International Normalized Ratio (INR). After discontinuation or dose reduction of Rosuva®, the INR may decrease. In such cases, appropriate monitoring of INR is advisable. In patients taking vitamin K antagonists, INR should be monitored both at the start of Rosuva® treatment and after discontinuation or further dose adjustments.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may substantially increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combination medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in approximately 3-fold and 7-fold increases in AUC and Cmax of rosuvastatin, respectively. Concomitant use of Rosuva® with certain combinations of protease inhibitors may be possible after careful consideration of dose adjustment of Rosuva®, based on the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction", Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant use of Rosuva® and gemfibrozil resulted in a 2-fold increase in AUC and Cmax of rosuvastatin (see section "Special warnings and precautions for use").

Based on data from specific interaction studies, no significant pharmacokinetic interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and niacin (nicotinic acid) at lipid-lowering doses (> or equal to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they may cause myopathy even when used alone. The 40 mg dose of Rosuva® is contraindicated when fibrates are used concomitantly.

In such cases, treatment with Rosuva® should also be initiated at a dose of 5 mg.

Ezetimibe

Concomitant administration of Rosuva® 10 mg and ezetimibe 10 mg to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). A pharmacodynamic interaction between Rosuva® and ezetimibe cannot be excluded, which may lead to adverse effects (see section "Special warnings and precautions for use").

Erythromycin

Concomitant use of Rosuva® and erythromycin reduced rosuvastatin AUC(0-t) by 20% and Cmax by 30%. This interaction may be due to increased intestinal motility caused by erythromycin.

Cytochrome P450 enzymes

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

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

(AUC; in descending order of magnitude) based on published data from clinical studies

* Data presented as a change by a factor of x represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as % change represent the % difference relative to values observed with rosuvastatin administered alone.

Increases are indicated by ↑, no change by ↔, and decreases by ↓.

** Several interaction studies were conducted at different doses of rosuvastatin; the most significant ratio is presented in the table.

Medicinal products/combinations that had no clinically significant effect on the AUC ratio of rosuvastatin upon concomitant administration: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg for 7 days three times daily; fluconazole 200 mg for 11 days once daily; fosamprenavir 700 mg/ritonavir 100 mg for 8 days twice daily; ketoconazole 200 mg for 7 days twice daily; rifampicin 450 mg for 7 days once daily; silymarin 140 mg for 5 days three times daily.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of Rosuva® and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients concurrently receiving Rosuva® and HRT; therefore, the possibility of interaction cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Based on data from specific interaction studies, no clinically significant interaction with digoxin is expected.

In clinical trials, Rosuva® was co-administered with antihypertensive agents, antidiabetic drugs, and hormone replacement therapy. These studies did not show evidence of any clinically significant adverse interactions.

Fusidic acid

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when fusidic acid is systemically co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic) is currently unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination.
If systemic treatment with fusidic acid is necessary, rosuvastatin therapy should be discontinued for the entire duration of fusidic acid treatment.

Lopinavir/ritonavir

In a pharmacological study, concomitant administration of Rosuva® and a combined preparation containing two protease inhibitors (lopinavir 400 mg/ritonavir 100 mg) in healthy volunteers was associated with approximately a two-fold and five-fold increase in steady-state AUC(0-24) and Cmax of rosuvastatin, respectively. Interactions between Rosuva® and other protease inhibitors have not been studied.

Tickagrelor

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant administration of ticagrelor and rosuvastatin has led to decreased renal function, elevated creatine phosphokinase levels, and rhabdomyolysis.

Children

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

Special precautions for use.

Renal effects

In patients treated with ROXERA® at high doses, particularly 40 mg, cases of proteinuria (detected by dipstick testing) were observed, predominantly of tubular origin and mostly transient or short-lived. Proteinuria did not indicate acute or progressive kidney disease. Renal adverse events were reported more frequently in the post-marketing period with the 40 mg dose. In patients receiving ROXERA® at doses of 30 or 40 mg, renal function should be monitored regularly.

Musculoskeletal effects

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients treated with all doses of ROXERA®, particularly at doses exceeding 20 mg. Cases of rhabdomyolysis have very rarely been reported when ezetimibe is used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded; therefore, such combinations should be used with caution.

As with other HMG-CoA reductase inhibitors, rhabdomyolysis associated with ROXERA® has been reported more frequently in the post-marketing period at the 40 mg dose. Rare cases of immune-mediated necrotizing myopathy have been reported during or after statin treatment, including rosuvastatin, clinically presenting with persistent proximal muscle weakness and elevated serum creatine kinase levels. In such cases, additional neuromuscular and serological investigations, as well as immunosuppressive therapy, may be required.

There have been reports that statins may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, treatment with ROXERA® should be discontinued. Recurrences have been reported upon initial or repeated administration of the same or another statin.

Creatine phosphokinase (CPK) measurement

CPK levels should not be measured following significant physical exertion or in the presence of other potential causes of elevated CPK, as these may interfere with result interpretation. If initial CPK levels are markedly elevated (>5x upper limit of normal [ULN]), a confirmatory test should be performed within 5–7 days. If the repeat test confirms levels >5x ULN, treatment should not be initiated.

Before treatment

ROXERA®, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with risk factors predisposing to myopathy/rhabdomyolysis. These risk factors include:

• Renal impairment;
• Hypothyroidism;
• Personal or family history of hereditary muscular disorders;
• History of myotoxicity associated with other HMG-CoA reductase inhibitors or fibrates;
• Alcohol abuse;
• Age >70 years;
• Situations that may lead to increased plasma concentrations of the drug;
• Concomitant use of fibrates.

In such patients, the risk versus potential benefit of treatment should be carefully evaluated, and clinical monitoring is recommended. Treatment should not be initiated if baseline CPK levels are significantly elevated (>5x ULN).

During treatment

Patients should be advised to promptly report any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CPK levels should be measured. Treatment should be discontinued if CPK levels are markedly elevated (>5x ULN) or if muscle symptoms are severe and impair daily activities (even if CPK ≤ 5x ULN). If symptoms resolve and CPK levels return to normal, ROXERA® or an alternative HMG-CoA reductase inhibitor may be cautiously reintroduced at the lowest dose and under close supervision. Routine monitoring of CPK levels in patients without the aforementioned symptoms is not necessary.

In clinical trials, no increased musculoskeletal effects were observed in a small number of patients receiving ROXERA® with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors; therefore, ROXERA® is not recommended to be used in combination with gemfibrozil. The potential benefits of further lipid-lowering effects with concomitant use of ROXERA® and fibrates or niacin should be weighed against the potential risks of such combinations. Concomitant use of ROXERA® at doses of 30 or 40 mg with fibrates is contraindicated.

ROXERA® should not be co-administered with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. For patients requiring systemic fusidic acid, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving fusidic acid and statins concomitantly. Patients should seek immediate medical attention if they experience symptoms such as muscle weakness, pain, or fatigue.
Statin therapy may be resumed 7 days after the last dose of fusidic acid.
In exceptional cases where prolonged systemic fusidic acid treatment is necessary (e.g., for severe infections), concomitant use of ROXERA® and fusidic acid should be considered only on a case-by-case basis and under close medical supervision.

ROXERA® should be used with caution in patients with risk factors for myopathy, such as renal impairment, advanced age, hypothyroidism, or situations that may increase plasma concentrations of the drug.

ROXERA® should not be used in patients with acute, serious conditions predisposing to myopathy or increasing the risk of renal failure secondary to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances; uncontrolled seizures).

Hepatic effects

As with other HMG-CoA reductase inhibitors, ROXERA® should be used with caution in patients who abuse alcohol and/or have a history of liver disease.

Liver function should be assessed before initiating treatment and again after 3 months of therapy. If serum transaminase levels exceed three times the upper limit of normal, ROXERA® should be discontinued. Serious hepatic events (predominantly elevated liver transaminases) have been reported more frequently in the post-marketing period with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying condition should be initiated before starting ROXERA®.

In the post-marketing period, rare cases of fatal and non-fatal hepatic failure have been reported in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice develops during treatment with ROXERA®, the drug should be discontinued immediately. Reinitiation of ROXERA® therapy is not recommended if no other cause is identified.

Race

Pharmacokinetic studies have shown increased systemic exposure in Mongoloid race patients compared to Caucasians.

Dosage adjustment of ROXERA® is required for these patients (see sections "Dosage and administration" and "Pharmacokinetics"). The initial dose of ROXERA® for Mongoloid race patients should be 5 mg. Higher plasma concentrations of rosuvastatin have been observed in Asian patients (see section "Pharmacokinetics"). Increased systemic exposure should be considered when treating Mongoloid race patients whose hypercholesterolemia is not adequately controlled with doses up to 20 mg.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with ROXERA® in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the initiation of therapy and with dose escalation should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the ROXERA® dose is adjusted (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Lactose intolerance

This product should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with the use of some statins, particularly with long-term therapy. Symptoms include dyspnea, non-productive cough, and deterioration in general health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Some evidence suggests that statins increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, the reduction in vascular risk with statin therapy outweighs this risk, and therefore should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, BMI >30 kg/m², elevated triglycerides, arterial hypertension) should be monitored clinically and biochemically according to national guidelines.

In clinical trials, the overall incidence of diabetes 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.

As with other HMG-CoA reductase inhibitors, increases in HbA1c and serum glucose levels have been observed with rosuvastatin. In some cases, these parameters may exceed diagnostic thresholds for diabetes, particularly in patients at high risk.

In clinical studies, ROXERA® as monotherapy did not reduce baseline plasma cortisol concentration or affect adrenal reserve. Caution is required when ROXERA® is used concomitantly with other medicinal products that may reduce levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with rosuvastatin use, which may be life-threatening or fatal. Patients should be informed of the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of such reactions occur, ROXERA® should be discontinued immediately and alternative therapy considered.

If a patient develops a serious reaction such as SJS or DRESS while taking ROXERA®, reinitiation of treatment with this drug is contraindicated.

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics according to Tanner staging in children aged 6 to 17 years treated with rosuvastatin is limited to a 2-year period. After 2 years of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). In a clinical study in children and adolescents treated with rosuvastatin for 52 weeks, CPK levels >10 times ULN and muscle-related symptoms following physical exertion or increased physical activity were reported more frequently than in adults (see section "Adverse reactions").

Use during pregnancy or breastfeeding

The safety of ROXERA® during pregnancy or breastfeeding has not been studied.

ROXERA® is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive measures during treatment with ROXERA®.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any potential benefit of drug use during pregnancy. If a patient becomes pregnant while taking the drug, treatment should be discontinued immediately.

Limited published data suggest that rosuvastatin may pass into human breast milk. Rosuvastatin is excreted in rat milk. Due to the mechanism of action of rosuvastatin, there is a potential risk of adverse reactions in infants. Rosuvastatin is contraindicated during lactation.

Fertility

There are no data on the effect of rosuvastatin on fertility.

Ability to drive and use machines

No studies have been conducted to assess the effect of rosuvastatin on the ability to drive or operate machinery. Based on the pharmacodynamic properties of rosuvastatin, the likelihood of such an effect is low. However, when driving or operating machinery, it should be considered that dizziness may occur during treatment.

Method of Administration and Dosage.

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be maintained throughout the treatment period. The dose should be individually adjusted according to therapeutic goals and treatment efficacy, following current established guidelines.

Roxera® can be taken at any time of day, regardless of food intake.

The tablet should not be chewed or crushed. It should be swallowed whole with water.

Treatment of Hypercholesterolemia

The recommended initial dose is 5 or 10 mg orally once daily, both for patients who have not previously used statins and for those who have previously used other HMG-CoA reductase inhibitors. When selecting the initial dose, the patient's individual cholesterol levels, future cardiovascular risk, and potential risk of adverse reactions should be considered (see below). If necessary, the dose may be increased after 4 weeks to the next level. Since adverse reactions occur more frequently with the 40 mg dose compared to lower doses, dose titration to 30 mg or 40 mg should only be considered in patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved the desired response with a 20 mg dose and who must be under regular monitoring. Specialist supervision is recommended when initiating treatment with 30 mg or 40 mg.

Prevention of Cardiovascular Disorders

In a clinical trial evaluating cardiovascular risk reduction, the daily dose of the drug was 20 mg. Patients with hypercholesterolemia should undergo standard lipid level monitoring and follow dosage recommendations for the treatment of hypercholesterolemia.

Use in Elderly Patients

The recommended initial dose for patients aged over 70 years is 5 mg. No other age-related dose adjustment is required.

Dosing in Patients with Renal Impairment

Dose adjustment is not necessary in patients with mild to moderate renal impairment. The recommended initial dose for patients with moderate renal impairment (creatinine clearance <60 mL/min) is 5 mg. The 30 mg and 40 mg doses are contraindicated in patients with moderate renal impairment. Roxera® is contraindicated in patients with severe renal impairment at any dose.

Dosing in Patients with Hepatic Impairment

No increase in systemic exposure to rosuvastatin was observed in patients with a Child-Pugh score of 7. However, increased systemic exposure was observed in patients with a Child-Pugh score of 8 or 9. Renal function should be assessed in these patients. Experience with the drug in patients with a Child-Pugh score of 9 is lacking. Roxera® is contraindicated in patients with active liver disease. Increased exposure to rosuvastatin has been observed in patients with severe hepatic impairment; therefore, Roxera® should be used with caution at doses exceeding 10 mg in such patients.

Race

Increased systemic exposure to the drug has been observed in patients of Mongoloid race. The recommended initial dose for patients of Asian origin is 5 mg. The 40 mg dose is contraindicated in these patients. The maximum daily dose is 20 mg.

Dosing in Patients Predisposed to Myopathy

The recommended initial dose for patients predisposed to myopathy is 5 mg.

The 40 mg dose is contraindicated in some of these patients. The maximum daily dose is 20 mg.

Genetic Polymorphism

The SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes, compared to SLCO1B1 c.521TT and ABCG2 c.421CC genotypes, are associated with increased rosuvastatin exposure (AUC). For patients with c.521CC or c.421AA genotypes, the maximum recommended daily dose of Roxera® is 20 mg.

Rosuvastatin is a substrate for several transport proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when Roxera® is co-administered with certain medicinal products that can increase plasma concentrations of rosuvastatin via interaction with these transport proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir). Alternative therapy should be considered whenever possible, and temporary discontinuation of Roxera® may be necessary. In situations where concomitant administration of these medicinal products with Roxera® cannot be avoided, the benefits and risks of combination therapy should be carefully weighed, and the dose of Roxera® should be selected with caution.

Children

Administration of the medicinal product to children should be performed only by a specialist.

Children and adolescents aged 6 to 17 years (Tanner stage ˂II-V).

Heterozygous Familial Hypercholesterolemia

The usual initial daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg once daily.

• The usual dose for children aged 6 to 9 years with heterozygous familial hypercholesterolemia is 5 to 10 mg orally once daily. Safety and efficacy of doses exceeding 10 mg in this population have not been studied.
• The usual dose for children aged 10 to 17 years with heterozygous familial hypercholesterolemia is 5 to 20 mg orally once daily. Safety and efficacy of doses exceeding 20 mg in this population have not been studied.

The dose should be increased according to the child’s individual response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). A standard cholesterol-lowering diet should be prescribed to children and adolescents before initiating rosuvastatin therapy and should be maintained throughout treatment.

Homozogous Familial Hypercholesterolemia

The recommended maximum dose for children aged 6 to 17 years with homozygous familial hypercholesterolemia is 20 mg once daily.

The recommended initial dose is 5 to 10 mg once daily, depending on age, body weight, and prior statin use. Dose escalation to the maximum dose of 20 mg once daily should be based on the child’s individual response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). A standard cholesterol-lowering diet should be prescribed to children and adolescents before initiating rosuvastatin therapy and should be maintained throughout treatment.

Experience with doses exceeding 20 mg in this population is limited.

40 mg tablets are not to be used in children.

Children under 6 years of age

Safety and efficacy of the medicinal product in children under 6 years of age have not been studied. Therefore, Roxera® is not recommended for use in children under 6 years of age.

Overdose.

There is no specific antidote in case of overdose. Treatment is symptomatic. Supportive measures should be implemented if necessary. CK levels should be monitored and liver function tests performed. Hemodialysis is unlikely to be beneficial.

Adverse Reactions

Adverse reactions observed during the use of Rosuva® are generally mild and transient.

Immune system

Hypersensitivity reactions, including angioedema.

Endocrine system

Diabetes mellitus¹².

Nervous system

Headache, dizziness.

Gastrointestinal system

Constipation, nausea, abdominal pain, pancreatitis.

Skin and subcutaneous tissue

Pruritus, rash and urticaria, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue system and bones

Myalgia, myopathy (including myositis), and rhabdomyolysis.

General disorders

Asthenia.

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions is dose-dependent.

¹Frequency depends on the presence of risk factors (fasting plasma glucose ≥ 5.6 mmol/L, body mass index >30 kg/m², elevated triglyceride levels, history of hypertension).

²According to the results of the JUPITER study (overall reporting frequency with rosuvastatin – 2.8%; placebo – 2.3%), particularly in patients who already have a high risk of developing diabetes mellitus.

Renal effects

Proteinuria, predominantly of tubular origin (detected by "dipstick test"), has been observed in patients taking Rosuva®. Changes in urinary protein content from absent or trace to ++ or higher were reported in <1% of patients receiving 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of proteinuria from absent/trace to + was observed with the 20 mg dose. In most cases, the degree of proteinuria decreased or resolved spontaneously while continuing treatment. A review of clinical trial and post-marketing data has not identified a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria has been observed in patients taking Rosuva®; clinical trial data indicate a low frequency.

Musculoskeletal effects

Skeletal muscle changes such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been observed with all doses of Rosuva®, particularly with doses >20 mg. Rare cases of rhabdomyolysis, sometimes associated with renal failure, have been reported with rosuvastatin and other statins.

In patients taking rosuvastatin, dose-dependent increases in creatine phosphokinase (CPK) levels have been observed; in most cases, this was mild, asymptomatic, and transient. If CPK levels are elevated (>5 x upper limit of normal (ULN)), treatment should be discontinued.

Hepatic effects

As with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin experienced dose-dependent increases in transaminase levels; in most cases, this was mild, asymptomatic, and transient.

Laboratory parameters

As with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin experienced dose-proportional increases in hepatic transaminases and creatine kinase. Increases in HbA1c levels have also been observed with rosuvastatin. In a small number of patients taking Rosuva® and other HMG-CoA reductase inhibitors, abnormal urine test results (dipstick indicating proteinuria) were observed. The protein detected was generally of tubular origin. In most cases, proteinuria decreased in severity or resolved spontaneously during continued therapy and did not indicate acute or progressive kidney disease.

Other effects

In long-term controlled clinical trials, Rosuva® did not demonstrate harmful effects on ocular lenses.

No adrenal cortical dysfunction has been observed in patients treated with Rosuva®.

Post-marketing experience

In addition to the above, the following events have been reported during post-marketing use of Rosuva®:

Nervous system: polyneuropathy, memory loss, peripheral neuropathy, myasthenia gravis;

Eye disorders: ocular myasthenia;

Respiratory, thoracic and mediastinal disorders: cough, dyspnea;

Gastrointestinal disorders: diarrhea;

Hepatobiliary disorders: jaundice, hepatitis, increased hepatic transaminase activity;

Skin and subcutaneous tissue: Stevens-Johnson syndrome;

Musculoskeletal system: immune-mediated necrotizing myopathy, arthralgia. Tendon disorders, sometimes complicated by ruptures; muscle rupture; lupus-like syndrome.

Renal: hematuria;

General disorders and administration site conditions: edema;

Reproductive system and breast disorders: gynecomastia;

Blood and lymphatic system: thrombocytopenia.

Adverse reactions reported with some statins:

Depression;

Sleep disorders, including insomnia and nightmares;

Sexual dysfunction;

Isolated cases of interstitial lung disease, particularly with long-term therapy;

Tendon disorders, sometimes complicated by rupture.

The incidence of rhabdomyolysis and serious renal and hepatic disorders (mainly elevated transaminase levels) was higher with the 40 mg dose.

During post-marketing use of rosuvastatin, cases of fatal and non-fatal hepatic failure have been identified. Since these reports were spontaneous from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Rarely, post-marketing reports have described cognitive impairment (e.g., memory decline, forgetfulness, amnesia, confusion) associated with statin use. Such cognitive issues have been reported with all statins. The reported events are generally mild, reversible upon statin discontinuation, and have variable onset (from 1 day to years) and resolution times (median 3 weeks).

Pediatric population

Elevated creatine kinase levels >10 times above ULN and muscle-related symptoms following physical exertion or increased physical activity were observed more frequently in a 52-week clinical study involving children and adolescents compared to adults (see section "Special warnings and precautions for use"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from light. The medicinal product does not require special storage temperature conditions.

Keep out of reach and sight of children.

Packaging.

For 5 mg, 10 mg, 15 mg, or 20 mg tablets:

10 tablets in a blister, with 1, 2, 3, 6, or 9 blisters in a cardboard box;

14 tablets in a blister, with 1, 2, 4 blisters in a cardboard box.

For 30 mg or 40 mg tablets:

10 tablets in a blister, with 1, 2, 3, 6, or 9 blisters in a cardboard box;

7 tablets in a blister, with 2, 4, or 8 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.