Rozvator

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROZAVATOR (ROSVATOR)

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains rosuvastatin 10 mg or 20 mg as rosuvastatin calcium;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium citrate, magnesium stearate, crospovidone;

Coating composition: Opadry Pink 03B 24082 (hypromellose, titanium dioxide (E 171), polyethylene glycol 400, iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg: round, film-coated tablets, light pink to pink in color, with the imprint «RT 2» on one side and flat on the other;

20 mg: round, film-coated tablets, light pink to pink in color, with the imprint «RT 3» on one side and flat on the other.

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

ATC code C10AA07.

Pharmacological properties.

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme responsible for the rate-limiting step 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 reducing cholesterol levels.

Rosuvastatin increases the number of low-density lipoprotein receptors (LDL receptors) on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamics.

Rosuvastatin reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C) levels. It also decreases levels of apolipoprotein B (apoB), non-HDL-C, VLDL-C, and VLDL-TG, while increasing apolipoprotein A-I (apoA-I) levels (Table 1). The drug 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 percent change from baseline)

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

Pharmacokinetics.

Absorption

The maximum plasma concentration (Cmax) of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is extensively taken up by 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 to albumin.

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-mediated metabolism. The main isoenzyme involved is CYP2C9, with a lesser role played by CYP2C19, CYP3A4, and CYP2D6. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitor activity.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (including both absorbed and unabsorbed rosuvastatin). The remainder is excreted in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not change with increasing dose. The mean geometric clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves a cholesterol transporter that plays an important role in the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with multiple daily doses.

Special patient populations

Age and gender

There is no clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults.

The pharmacokinetics of rosuvastatin in children with heterozygous familial hypercholesterolemia is similar to that in adult volunteers (see section "Children").

Ethnic groups

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

Patients with renal impairment

In patients with mild or moderate renal dysfunction, plasma concentrations of rosuvastatin and N-desmethyl metabolite are not significantly altered. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin are 3 times higher and N-desmethyl metabolite concentrations are 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

Patients with hepatic impairment

In patients with varying degrees of hepatic impairment, no increase in the elimination half-life of rosuvastatin was observed in patients with Child-Pugh scores of 7 or lower. However, in two patients with Child-Pugh scores of 8 and 9, the elimination half-life was prolonged at least twofold. Experience with rosuvastatin use in patients with Child-Pugh scores above 9 is lacking.

Genetic polymorphism

HMG-CoA reductase inhibitors, including rosuvastatin, bind to transport proteins OATP1B1 and BCRP. Patients with polymorphisms in the SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genes have an increased risk of elevated rosuvastatin AUC. In specific polymorphic forms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin AUC is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Specific genotyping is not required in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of Rosuvator.

Children

Data from two pharmacokinetic studies of rosuvastatin in children aged 10 to 17 years with heterozygous familial hypercholesterolemia indicate that the AUC of the drug in children is similar to or lower than that in adult patients. Significant dose-proportional deviations are not expected.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

For adults, adolescents, and children aged 10 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 homozygous familial hypercholesterolemia, as an adjunct to diet and other lipid-lowering treatments (e.g., LDL apheresis) or when such treatments are not appropriate.

Prevention of cardiovascular events

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.

• Hypersensitivity to rosuvastatin or to any of the excipients in the formulation.
• Active liver disease, including persistent elevations of serum transaminases of unknown etiology, as well as elevations of serum transaminases exceeding the upper limit of normal (ULN) by more than 3 times.
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Myopathy.
• Concomitant use of cyclosporine.
• Pregnancy or breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures.

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

Risk factors include:

• Moderate renal impairment (creatinine clearance < 60 mL/min);
• Hypothyroidism;
• Personal or family history of hereditary muscle disorders;
• History of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates;
• Alcohol abuse;
• Conditions that may lead to increased plasma concentration of the drug;
• Mongoloid race;
• Concomitant use of fibrates.

Interaction with other medicinal products and other types of interactions.

Effects of concomitant medications on rosuvastatin

Inhibitors of transporter proteins. Rosuvastatin is a substrate for certain transporter proteins, including OATP1B1, which mediates hepatic uptake, and the efflux transporter BCRP. Concomitant administration of rosuvastatin with medicinal products that inhibit these transporter proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other types of interactions", Table 2).

Cyclosporine

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

Concomitant use did not affect cyclosporine plasma concentrations.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin AUC (see Table 2). For example, pharmacokinetic study data indicate that concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of Rovator and certain protease inhibitor combinations may be possible after careful consideration of dose adjustment of Rovator based on the expected increase in rosuvastatin AUC (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions", "Dosage and administration", Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant use of rosuvastatin and gemfibrozil led to a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special precautions").

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (nicotinic acid) (> or = 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose of rosuvastatin is contraindicated when used concomitantly with fibrates (see sections "Contraindications" and "Special precautions"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe

Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (see Table 2). Pharmacodynamic interaction between Rovator and ezetimibe, potentially leading to adverse effects, cannot be excluded (see section "Special precautions").

Antacids

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

Erythromycin

Concomitant use of rosuvastatin and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Cytochrome P450 enzymes

In vitro and in vivo study results indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, interactions with medicinal products due to 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

When it is necessary to use Rovator with other medicinal products capable of increasing rosuvastatin AUC, the dose of Rovator should be adjusted. If an approximately 2-fold or greater increase in AUC is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected AUC of rosuvastatin does not exceed the AUC observed with a 40 mg/day dose without interacting medicinal products; for example, when used with gemfibrozil, the maximum rosuvastatin dose would be 20 mg (1.9-fold increase in AUC), and when used with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in AUC).

Table 2

Effect of concomitant medicinal products on rosuvastatin AUC

(AUC; in descending order of magnitude)

* Data presented as fold change represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as percent change represent the percentage difference relative to values observed with rosuvastatin 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.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of treatment with Rozvator or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the International Normalized Ratio (INR). Discontinuation of Rozvator or reduction of its dose may lead to a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of Rozvator and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, 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 who are concurrently taking rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, this combination has been widely used in women during clinical trials and was well tolerated.

Other medicinal products

Digoxin

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

Lopinavir/ritonavir. In a pharmacological interaction study, concomitant administration of rosuvastatin 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 rosuvast inflamm respectively. Interaction between rosuvastatin and other protease inhibitors has not been studied.

Fusidic acid

The risk of developing myopathy, including rhabdomyolysis, may be increased with concomitant systemic use of fusidic acid and statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is currently unknown. Cases of rhabdomyolysis (including rare fatal cases) have been reported in patients receiving this combination.

If systemic administration of fusidic acid is necessary, treatment with rosuvastatin should be discontinued for the duration of fusidic acid therapy (see section "Special precautions").

Children

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

Special precautions for use.

Renal effects

Proteinuria detected by urine dipstick testing, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and in most cases was transient or intermittent. Proteinuria was not a predictor of acute or progressive kidney disease (see section "Adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. In patients receiving the 40 mg dose, renal function should be monitored regularly during follow-up.

Skeletal muscle effects

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients treated with all doses of rosuvastatin, particularly at doses exceeding 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded; therefore, such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, rhabdomyolysis associated with rosuvastatin has been reported more frequently in the post-marketing period at the 40 mg dose.

Creatine kinase (CK) measurement

Creatine kinase (CK) levels should not be measured following significant physical exertion or in the presence of other potential causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (>5 times the upper limit of normal [ULN]), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK exceeds 5 times ULN, treatment should not be initiated.

Before treatment

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

• renal impairment;
• hypothyroidism;
• personal or family history of inherited muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age >70 years;
• conditions that may lead to increased plasma concentrations of the drug;
• concomitant use of fibrates.

When prescribing the drug to such patients, the risk-benefit ratio of therapy should be carefully considered; recommended continuous clinical monitoring is advised. Treatment should not be initiated if CK levels are significantly elevated prior to therapy (>5×ULN).

During treatment

Patients should be advised to promptly report to their physician any unexplained muscle pain, muscle weakness, or cramps, especially if accompanied by malaise or fever. In such cases, CK levels should be checked. Therapy should be discontinued in case of significant CK elevation (>5×ULN) or in case of severe muscle symptoms causing discomfort (even if CK ≤5×UL0N). After resolution of symptoms and return of CK levels to normal range, resumption of rosuvastatin therapy or an alternative HMG-CoA reductase inhibitor at the lowest dose with appropriate patient monitoring may be considered. Routine monitoring of CK levels in the absence of symptoms is not required.

Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin. Clinical manifestations of IMNM include proximal muscle weakness and elevated serum CK levels, which persist even after discontinuation of statins.

Clinical studies have not provided evidence of increased skeletal muscle effects in a small number of patients taking rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid derivatives, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, concomitant use of rosuvastatin and gemfibrozil is not recommended. The benefit of additional lipid-lowering effect from combining rosuvastatin with fibrates or niacin should be carefully weighed against the potential risks of such combination therapy. The 40 mg dose of rosuvastatin is contraindicated when co-administered with fibrates.

Rosuvastatin should not be used concomitantly with systemic preparations containing fusidic acid, and for 7 days following discontinuation of fusidic acid. Patients requiring systemic fusidic acid therapy should discontinue statin treatment during this period. Cases of rhabdomyolysis (including rare fatal cases) have been reported in patients taking fusidic acid in combination with statins. Patients should seek immediate medical advice if they experience symptoms of muscle weakness or pain. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases, if prolonged systemic fusidic acid therapy is required (e.g., for treatment of severe infections), the need for concomitant use of rosuvastatin and fusidic acid should be carefully considered on a case-by-case basis under close medical supervision.

Rosuvastatin should not be used in patients with serious acute conditions typical of myopathy or conditions predisposing to renal failure secondary to rhabdomyolysis (e.g., sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Myasthenia gravis, ocular myasthenia

There have been several reports of statins inducing de novo myasthenia gravis or exacerbating pre-existing myasthenia gravis or ocular myasthenia. If symptoms worsen, the drug should be discontinued. Recurrences have been reported upon re-challenge with the same or another statin.

Hepatic effects

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

Liver function should be assessed before initiating treatment and after 3 months of therapy. If serum transaminase levels exceed three times the ULN, Rosuvator should be discontinued. Serious hepatic dysfunction (predominantly elevated hepatic transaminases) has 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 Rosuvator.

Race

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

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 rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the start of therapy or dose escalation in patients on protease inhibitors should be considered. Concomitant use of rosuvastatin with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Lactose intolerance

This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with some statins, particularly after 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

Evidence suggests that statins may increase blood glucose levels and may lead to 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, 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.

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and sexual maturation (Tanner stages) in children aged 10 to 17 years treated with rosuvastatin is limited to a 1-year duration. After 52 weeks of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). Clinical trial experience with rosuvastatin in children and adolescents is limited, and long-term effects (>1 year) on sexual maturation are unknown.

In a clinical study in children and adolescents treated with rosuvastatin for 52 weeks, CK elevations >10 times ULN and muscle-related symptoms following physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

Use during pregnancy or breastfeeding

The use of rosuvastatin during pregnancy or breastfeeding is contraindicated.

Women of childbearing potential should use effective contraception.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition during pregnancy outweighs any therapeutic benefit. Animal studies indicate limited delayed toxicity. If pregnancy occurs during treatment, therapy should be discontinued immediately.

Since another drug in this class is excreted in human breast milk and considering that HMG-CoA reductase inhibitors may cause serious adverse reactions in infants, women requiring rosuvastatin therapy should be advised not to breastfeed. Data on the excretion of rosuvastatin in human breast milk are not available (see section "Contraindications").

Ability to drive and use machines

Studies on the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted. However, given its pharmacodynamic properties, it is unlikely that rosuvastatin affects this ability. Nevertheless, dizziness during treatment should be considered when driving or operating machinery.

Method of Administration and Dosage

Prior to initiating therapy, patients should be placed on a standard low-cholesterol diet, which should be maintained throughout treatment. Dosages should be individually adjusted according to therapeutic goals and patient response, in accordance with current established guidelines.

Rosuvastatin can be taken at any time of day, independent of food intake.

The tablet should not be chewed or crushed. It should be swallowed whole with water. If the required dose of rosuvastatin cannot be achieved with 10 mg or 20 mg Rovator tablets, alternative rosuvastatin-containing medicinal products with appropriate dosage strengths should be used.

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. The selection of the initial dose should take into account the patient's individual cholesterol levels, future cardiovascular risk, and the potential risk of adverse reactions (see below). Dose adjustments, if necessary, should be made after 4 weeks. Due to the increased frequency of adverse reactions, increasing the dose to 40 mg is recommended only for the treatment of patients with severe hypercholesterolemia or high cardiovascular risk (particularly in patients with familial hypercholesterolemia) when 20 mg daily does not achieve the desired therapeutic effect, and provided regular medical monitoring is conducted.

Prevention of Cardiovascular Events

In clinical trials evaluating the effect of the drug on reducing the risk of cardiovascular complications, the dose used was 20 mg once daily.

Use in Elderly Patients

For patients aged 70 years and older, the recommended initial dose is 5 mg. Further dose adjustments based solely on age are not required.

Dosing in Patients with Renal Impairment

Dose adjustment is not required in patients with mild or moderate renal impairment.

For patients with moderate renal impairment (creatinine clearance < 60 mL/min), the recommended initial dose is 5 mg. The use of rosuvastatin in patients with severe renal impairment is contraindicated 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 has been reported in patients with a Child-Pugh score of 8 or 9. Renal function should be assessed in these patients. There is no clinical experience with rosuvastatin in patients with a Child-Pugh score of 9. Rovator is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to rosuvastatin has been observed in Asian patients. The recommended initial dose for patients of Asian origin is 5 mg. The 40 mg dose is contraindicated in these patients.

Dosing in Patients Predisposed to Myopathy

The recommended initial dose for patients with risk factors for myopathy is 5 mg (see section "Special Warnings and Precautions for Use").

The 40 mg dose is contraindicated in some of these patients (see section "Contraindications").

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased exposure to rosuvastatin (see section "Pharmacokinetics"). Patients known to have such polymorphisms are recommended to receive a lower daily dose of Rovator.

Concomitant Use

Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when Rovator is co-administered with certain medicinal products that may increase plasma concentrations of rosuvastatin due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir) (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"). Alternative medicinal products should be considered whenever possible, and temporary discontinuation of Rovator therapy may be necessary. If concomitant use of these medicinal products with Rovator cannot be avoided, the benefit-risk ratio should be carefully evaluated and the dose of Rovator adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

In pediatric practice, the drug should be prescribed only by a physician. It is indicated for children and adolescents aged 10 to 17 years (boys after reaching Tanner Stage II or higher of pubertal development, girls no earlier than 1 year after menarche).

The usual initial daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg once daily. The usual dose range is 5–20 mg orally once daily. Dose increases should be based on individual response and tolerability, in accordance with recommendations for pediatric use. Prior to initiating rosuvastatin therapy, children should be placed on a standard low-cholesterol diet, which should be maintained during treatment. The safety and efficacy of doses exceeding 20 mg in this population have not been established.

Children under 10 years of age

Experience with the use of rosuvastatin in children under 10 years of age is limited to a small number of patients (aged 8 to 10 years) with homozygous familial hypercholesterolemia. Therefore, rosuvastatin is not recommended for use in children under 10 years of age.

Overdose

There is no specific antidote for overdose. Treatment should be symptomatic and supportive. Monitoring of liver function and creatine kinase (CK) levels is required. Hemodialysis is unlikely to be effective.

Adverse Reactions

Adverse events observed during rosuvastatin use are generally mild and transient. Adverse reactions are classified by frequency and system organ classes.

By frequency, adverse reactions are categorized as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).

Blood system:
Rare – thrombocytopenia.

Immune system:
Rare – hypersensitivity reactions, including angioedema.

Endocrine system:
Common – diabetes mellitus¹.

Psychiatric disorders:
Frequency not known – depression.

Nervous system:
Common – headache, dizziness; very rare – polyneuropathy, memory loss; frequency not known – peripheral neuropathy, sleep disorders including insomnia and night terrors, myasthenia gravis.

Eye disorders:
Frequency not known – ocular myasthenia.

Respiratory, thoracic and mediastinal disorders:
Frequency not known – cough, dyspnea.

Gastrointestinal disorders:
Common – constipation, nausea, abdominal pain; rare – pancreatitis; frequency not known – diarrhea.

Hepatobiliary disorders:
Rare – increased hepatic transaminase activity; very rare – jaundice, hepatitis.

Skin and subcutaneous tissue disorders:
Uncommon – pruritus, rash, urticaria; frequency not known – Stevens-Johnson syndrome.

Musculoskeletal, connective tissue and bone disorders:
Common – myalgia; rare – myopathy (including myositis), rhabdomyolysis; very rare – arthralgia; frequency not known – immune-mediated necrotizing myopathy, tendon disorders, sometimes complicated by tendon rupture.

Renal and urinary disorders:
Very rare – hematuria.

Reproductive system and breast disorders:
Very rare – gynecomastia.

General disorders:
Common – asthenia; frequency not known – edema.

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions depends on the dose of the drug.

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).

Renal effects

Tubular proteinuria has been observed during rosuvastatin treatment, detected by urine dipstick testing. Changes in urinary protein levels from absent or trace to ++ or higher were reported in <1% of patients receiving 10 mg or 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. Based on clinical studies and post-marketing surveillance, there is currently no evidence of a causal relationship between proteinuria and acute or progressive renal disease.

Cases of hematuria have been reported during treatment; study data indicate low frequency.

Skeletal muscle effects

Skeletal muscle disorders such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure have been reported with all doses of rosuvastatin, particularly at doses > 20 mg.

Dose-dependent increases in creatine kinase (CK) levels have been observed in patients receiving rosuvastatin. In most cases, this effect was mild, asymptomatic, and transient. If CK levels increase to > 5× ULN, further treatment should be discontinued.

Hepatic effects

As with other HMG-CoA reductase inhibitors, dose-dependent increases in transaminase activity have been observed in a small number of patients receiving rosuvastatin. In most cases, this effect was mild, asymptomatic, and transient. Increases in HbA1c levels have also been observed with rosuvastatin use.

With some statins, the following adverse events have been reported: sexual dysfunction, interstitial lung disease, particularly during long-term therapy.

The incidence of rhabdomyolysis and serious renal and hepatic disorders (predominantly manifested by marked increases in hepatic transaminase activity) increases when the drug is used at a 40 mg dose.

During post-marketing use, cases of fatal and non-fatal hepatic failure have been identified. Because 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, during the post-marketing period, cognitive disturbances (e.g., memory impairment, forgetfulness, amnesia, confusion) associated with statin use have been reported. Such cognitive issues have been reported with all statins. The events described in these reports are generally mild, reversible upon statin discontinuation, and have variable onset times (from 1 day to years) and resolution times (median of 3 weeks).

Pediatric population

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

Shelf life: 2 years.

Storage conditions: Store in a dry place, out of reach of children, at temperatures not exceeding 30 °C.

Packaging: 7 tablets in a blister pack, 4 blisters in a cardboard box.

Prescription status: Prescription only.

Manufacturer:

Sun Pharmaceutical Industries Limited.

Manufacturer's address:

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.