Romazik

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROMAZIC (ROMAZIC)

Composition:

Active substance: rosuvastatine;

One film-coated tablet contains 5 mg, 10 mg, 20 mg, or 40 mg of rosuvastatin, equivalent to 5.2 mg, 10.4 mg, 20.8 mg, or 41.6 mg of rosuvastatin calcium, respectively;

Excipients: lactose monohydrate, type 1; lactose monohydrate, type 2; microcrystalline cellulose; sodium citrate; crosspovidone type B; colloidal anhydrous silica; magnesium stearate; coating (Opadry II white 33G28523, hypromellose, lactose monohydrate, macrogol, triacetin, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg: round, biconvex, film-coated tablets, white or almost white, with "5" imprinted on one side;

10 mg: round, biconvex, film-coated tablets, white or almost white, with "10" imprinted on one side;

20 mg: round, biconvex, film-coated tablets, white or almost white, with "20" imprinted on one side;

40 mg: elongated, biconvex, film-coated tablets, white or almost white.

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

ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics.

Rosuvastatin reduces elevated levels of LDL-cholesterol, total cholesterol, and triglycerides, as well as increases HDL-cholesterol (high-density lipoprotein cholesterol) levels.

The drug also reduces levels of apolipoprotein B (ApoB), non-HDL-cholesterol, LDL-triglycerides, and VLDL-triglycerides, and increases apolipoprotein A-I (ApoA-I) levels (see table).

Rosuvastatin also reduces the ratios of LDL-cholesterol/HDL-cholesterol, total cholesterol/HDL-cholesterol, non-HDL-cholesterol/HDL-cholesterol, and ApoB/ApoA-I.

Table 1.

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

Dose	N	LDL-C	Total cholesterol	HDL-C	Triglycerides	nonHDL-C	ApoB	ApoA-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5	17	-45	-33	13	-35	-44	-38	4
10	17	-52	-36	14	-10	-48	-42	4
20	17	-55	-40	8	-23	-51	-46	5
40	18	-63	-46	10	-28	-60	-54	0

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

Pharmacokinetics.

Absorption

The maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. The absolute bioavailability is approximately 20 %.

Distribution

Rosuvastatin is extensively taken up by the liver, which is the primary site of cholesterol synthesis and LDL-cholesterol 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 is a weak substrate for cytochrome P450-mediated metabolism. CYP2C9 is the main isoenzyme involved, with CYP2C19, 3A4, and 2D6 playing a lesser role. 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 forms are considered clinically inactive. Rosuvastatin accounts for more than 90 % of the HMG-CoA reductase inhibitor activity in circulating blood.

Elimination

Approximately 90 % of the rosuvastatin dose is excreted unchanged in the feces (including both absorbed and unabsorbed active substance), and the remainder is excreted in the urine.

Approximately 5 % is excreted unchanged in the urine. The plasma elimination half-life is approximately 19 hours. The half-life does not increase with higher doses. The mean geometric plasma clearance rate is approximately 50 L/hour (coefficient of variation 21.7 %). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter plays an important role in the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. No changes in pharmacokinetic parameters are observed after repeated daily administration.

Special populations

Age and gender

Age and gender do not have a clinically significant effect on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").

Race

Pharmacokinetic studies demonstrate increased mean AUC and Cmax values in individuals of Mongoloid race (Japanese, Chinese, Filipino, Vietnamese, and Korean) compared to individuals of Caucasian race; in individuals of Asian race, mean AUC and Cmax values are increased by approximately 1.3-fold. Population pharmacokinetic analysis indicates no clinically significant differences in pharmacokinetics between Caucasian and African races.

Renal impairment

In a study involving patients with various degrees of renal impairment, mild to moderate renal disease did not affect plasma concentrations of rosuvastatin and the N-desmethyl metabolite. In patients with severe renal impairment (CrCl < 30 mL/min), plasma concentrations increased by 3-fold and the concentration of the N-desmethyl metabolite increased by 9-fold compared to healthy volunteers. Rosuvastatin plasma concentrations at steady state in patients undergoing hemodialysis were approximately 50 % higher than in healthy volunteers.

Hepatic impairment

In a study involving patients with various degrees of hepatic impairment, systemic exposure to rosuvastatin was not increased in patients with Child-Pugh scores of 7 or lower. However, in 2 patients with Child-Pugh scores of 8 and 9, systemic exposure was increased at least 2-fold compared to patients with lower Child-Pugh scores. There is no experience with the use of the drug in patients with Child-Pugh scores above 9.

Children

Pharmacokinetic parameters in children with heterozygous familial hypercholesterolemia aged 10 to 17 years have not been fully characterized. A small pharmacokinetic study of rosuvastatin (in tablet form) in 18 children demonstrated that drug exposure in children is comparable to that in adult patients. Additionally, results indicate no significant deviation from dose proportionality.

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 suitable.

Prevention of cardiovascular events

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

Contraindications.

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

The 40 mg dose of the medicinal product is contraindicated in patients with factors predisposing to myopathy/rhabdomyolysis. These factors include:

• Moderate renal impairment (creatinine clearance < 60 mL/min);
• Hypothyroidism;
• Personal or family history of hereditary muscular disorders;
• History of myotoxicity with another HMG-CoA reductase inhibitor or fibrate;
• Alcohol abuse;
• Conditions that may increase plasma levels of the drug;
• Mongoloid race;
• Concomitant use of fibrates

(see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics").

Interaction with other medicinal products and other forms of interaction.

Effect of concomitant medicinal products on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other forms of interaction", Table 2).

Cyclosporine

When rosuvastatin and cyclosporine are used concomitantly, rosuvastatin AUC values were on average 7 times higher than in healthy volunteers. Rosuvastatin is contraindicated in patients receiving cyclosporine (see section "Contraindications").

Concomitant use does not affect cyclosporine plasma concentrations.

Ezetimibe

Concomitant use of rosuvastatin 10 mg and ezetimibe 10 mg in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). However, a pharmacodynamic interaction between rosuvastatin and ezetimibe that could lead to adverse reactions cannot be excluded (see section "Special precautions").

Gemfibrozil and other lipid-lowering agents

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

Based on data from dedicated interaction studies, no clinically significant pharmacokinetic interaction with fenofibrate is expected, but a pharmacodynamic interaction may occur.

Gemfibrozil, fenofibrate, other fibrates, and niacin (nicotinic acid) at lipid-lowering doses (doses exceeding or equivalent to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because the latter may cause myopathy when used as monotherapy. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions"). Treatment of patients should also be initiated at a dose of 5 mg.

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 combined medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with approximately 3- and 7-fold increases in rosuvastatin AUC and Cmax, respectively. Concomitant use of rosuvastatin and certain combinations of protease inhibitors may be possible after careful consideration of rosuvastatin dose adjustment based on the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other forms of interaction", Table 2).

Antacids

Concomitant use of rosuvastatin and an antacid suspension containing aluminium and magnesium hydroxide reduces rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when the antacid was administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant use of rosuvastatin and erythromycin reduces rosuvastatin AUC (0-t) by 20% and Cmax by 30%. This interaction may occur due to enhanced 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 for these isoenzymes. No clinically significant interactions between rosuvastatin and fluconazole (inhibitor of CYP2C9 and CYP3A4) or ketoconazole (inhibitor of CYP2A6 and CYP3A4) were observed.

Interactions requiring rosuvastatin dose adjustment

When it is necessary to use Romazic with other medicinal products capable of increasing rosuvastatin exposure, the dose of the medicinal product should be adjusted. If an approximately 2-fold or greater increase in drug exposure (AUC) is expected, treatment with Romazic should be initiated at a dose of 5 mg once daily. The maximum daily dose should be adjusted so that the expected rosuvastatin exposure does not exceed the exposure observed with a 40 mg/day dose without concomitant interacting medicinal products; for example, when used with gemfibrozil, the rosuvastatin dose would be 20 mg (exposure increased 1.9-fold), when used with ritonavir/atazanavir combination – 10 mg (exposure increased 3.1-fold), and when used with cyclosporine – 5 mg (exposure increased 7.1-fold).

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

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

Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Simeprevir 150 mg once daily, 7 days	10 mg, single dose	↑ 2.8-fold
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Elbasvir 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5-fold
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4-fold
Dronedarone 400 mg twice daily	Not known	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4-fold **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold **
Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days	10 mg, single dose	↔
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	↔
Silymarin 140 mg three times daily, 5 days	10 mg, single dose	↔
Fenofibrate 67 mg three times daily, 7 days	10 mg, 7 days	↔
Rifampicin 450 mg once daily, 7 days	20 mg, single dose	↔
Ketoconazole 200 mg twice daily, 7 days	80 mg, single dose	↔
Fluconazole 200 mg once daily, 11 days	80 mg, single dose	↔
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baicalin 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%
Regorafenib 160 mg once daily, 14 days	5 mg single dose	↑ 3.8-fold
Velpatasvir 100 mg once daily	10 mg single dose	↑ 2.7-fold
Ombitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg single dose	↑ 2.6-fold
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg single dose	↑ 2.3-fold
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2-fold

* 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 percentage 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 table presents the most significant ratio observed.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or increasing its dose 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). Discontinuation of rosuvastatin or reduction of its dose may result in a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives increases AUC values for ethinylestradiol and norgestimate by 26% and 34%, respectively. This increase in plasma concentrations should be considered when selecting doses of oral contraceptives. There are no pharmacokinetic data available for patients taking rosuvastatin together with HRT; therefore, such an effect cannot be excluded. However, this combination has been widely used in clinical trials, and patients tolerated it well.

Other medicinal products

Based on data from dedicated interaction studies, no clinically relevant interaction with digoxin is expected.

Lo pinavir/ritonavir

In a pharmacological 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 for rosuvastatin, respectively. Interactions between rosuvastatin and other protease inhibitors have not been studied.

Fusidic acid

The risk of developing myopathy, including rhabdomyolysis, may be increased when fusidic acid is administered systemically together with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is not yet known. 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 for use").

Ticagrelor

Ticagrelor may cause renal impairment and may affect renal excretion of rosuvastatin, thereby increasing the risk of its accumulation. In some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, elevated creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of renal function and CPK levels is recommended when ticagrelor and rosuvastatin are used concomitantly.

Children

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

Special precautions for use.

Renal effects

Proteinuria (detected using dipstick testing), usually of tubular origin, has been observed in patients treated with rosuvastatin at the highest doses, particularly 40 mg. This proteinuria was generally transient or intermittent. Proteinuria is not a predictive factor for the development of acute or progressive renal disease; however, renal function should be considered for evaluation in patients receiving the 40 mg dose of the drug.

Skeletal muscle effects

Effects on skeletal muscle (myalgia, myopathy, and rarely rhabdomyolysis) have been reported in patients treated with rosuvastatin at any dose, particularly at doses exceeding 20 mg.

Very rare cases of rhabdomyolysis have been reported with ezetimibe used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded; therefore, such combination therapy should be used with caution.

As with other HMG-CoA reductase inhibitors, post-marketing experience has shown a higher incidence of rhabdomyolysis associated with rosuvastatin treatment when the 40 mg dose is used. Rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin, clinically presenting as persistent proximal muscle weakness and elevated serum creatine kinase levels. In such cases, additional neuromuscular and serological investigations and treatment with immunosuppressive agents may be required.

Cases of de novo occurrence or exacerbation of existing myasthenia gravis or ocular myasthenia have been reported following statin use (see section "Adverse reactions"). Treatment with Romazic should be discontinued if symptoms worsen. Recurrences have been reported upon re-administration of the same or another statin.

Creatine kinase measurement

Creatine kinase (CK) levels should not be measured immediately after strenuous physical exercise or in the presence of other likely causes of elevated CK, as this may lead to misinterpretation of results. If baseline CK levels are markedly elevated (more than 5 times the upper limit of normal), the test should be repeated after 5–7 days. Treatment with the drug should not be initiated if the repeat test confirms that the baseline CK level exceeds 5 times the upper limit of normal.

Before treatment

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

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of myotoxicity with another HMG-CoA reductase inhibitor or fibrate;
• alcohol abuse;
• age > 70 years;
• conditions that may increase plasma levels of the drug (see sections "Dosage and administration", "Interaction with other medicinal products and other types of interactions", and "Pharmacokinetics");
• concomitant use of fibrates.

In such patients, the risks of treatment should be weighed against potential benefits, and clinical monitoring is recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (more than 5 times the upper limit of normal).

During treatment

Patients should be advised to seek immediate medical attention if they experience unexpected muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be measured in such patients. Treatment should be discontinued if CK levels are markedly elevated (more than 5 times the upper limit of normal) or if symptoms are severe and cause daily discomfort (even if CK levels are less than 5 times the upper limit of normal). If symptoms resolve and CK levels return to normal, consideration may be given to re-initiating rosuvastatin or an alternative HMG-CoA reductase inhibitor at the lowest dose and under close monitoring.

Routine monitoring of CK levels in asymptomatic patients is not necessary. 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 persistent elevation of serum creatine kinase, even after discontinuation of statin therapy.

During clinical studies, no signs of increased skeletal muscle effects were observed in a small number of patients receiving rosuvastatin and concomitant therapy. 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, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, the combination of rosuvastatin and gemfibrozil is not recommended.

The benefits of further lipid-lowering effects with combined use of rosuvastatin with fibrates or niacin should be carefully weighed against the potential risks of such combinations. The 40 mg dose is contraindicated for concomitant use with fibrates (see sections "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after 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 attention 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 use of fusidic acid 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 acute serious conditions that may indicate myopathy or predispose to renal failure due to rhabdomyolysis (such as sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances; uncontrolled epileptic seizures).

Hepatic effects

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

Liver function tests should be performed before starting treatment and 3 months after initiation of therapy. Rosuvastatin should be discontinued or the dose reduced if serum transaminase levels exceed 3 times the upper limit of normal. During post-marketing use, a higher incidence of serious hepatic reactions (mainly increased serum transaminase levels) has been reported 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 rosuvastatin.

During the post-approval 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 rosuvastatin, the drug should be discontinued immediately. Reinitiation of rosuvastatin therapy should not be considered if no other cause is identified.

Race

Pharmacokinetic studies indicate increased exposure in individuals of Mongoloid race compared to those of Caucasian race. Dose adjustment of rosuvastatin is required for such patients (see sections "Dosage and administration", "Contraindications", and "Pharmacokinetics"). The initial dose of Romazic for Asian patients should be 5 mg. Increased plasma concentration of rosuvastatin has been observed in Asian patients (see sections "Special precautions for use" and "Pharmacokinetics"). Increased systemic exposure should be taken into account when treating Mongoloid 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 benefits 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 and with dose escalation of Romazic in patients receiving protease inhibitors should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the Romazic dose is adjusted (see sections "Dosage and administration" and "Interaction with other medicinal products and other types of interactions").

Interstitial lung disease

Rare cases of interstitial lung disease have been reported with the use of some statins, particularly with long-term treatment (see section "Adverse reactions"). Manifestations may include dyspnea, non-productive cough, and deterioration in general health (weakness, weight loss, fever). If interstitial lung disease is suspected in a patient, statin therapy should be discontinued.

Diabetes mellitus

Some evidence suggests that statins increase blood glucose levels and may induce hyperglycemia requiring antidiabetic treatment in some patients at high risk of developing diabetes in the future. However, this risk is outweighed by the reduction in vascular risk with statin use and 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.

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 the threshold for diagnosing diabetes, particularly in patients at high risk of developing diabetes.

Clinical studies have shown that rosuvastatin as monotherapy does not reduce baseline plasma cortisol concentration and does not affect adrenal reserve. Caution is required when rosuvastatin is used concomitantly with other medicinal products capable of reducing 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 and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported with rosuvastatin. Patients should be informed about signs and symptoms of severe skin reactions and closely monitored when the drug is prescribed. If signs and symptoms indicating such a reaction occur, the drug should be discontinued immediately and alternative treatment considered. If a serious reaction such as Stevens-Johnson syndrome or DRESS syndrome develops, treatment with the drug must be immediately discontinued and must never be restarted.

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics by Tanner staging in children aged 10 to 17 years taking 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 experience with the use of the drug in children and adolescents is limited, and the long-term effects of rosuvastatin use (>1 year) on sexual maturation are unknown.

In a clinical study in children and adolescents taking rosuvastatin for 52 weeks, CK levels >10 times the upper normal limit and muscle-related symptoms after physical exertion or increased physical activity were observed more frequently compared to adults (see section "Adverse reactions").

Lactose intolerance

This medicinal product should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any possible benefit from drug use during pregnancy. Data from animal studies on toxic effects on reproductive function are limited.

If pregnancy occurs during treatment with this drug, therapy should be discontinued immediately.

Since another medicinal product of this class passes into human breast milk and considering that HMG-CoA reductase inhibitors may cause serious adverse reactions in infants, women requiring treatment with Romazic should be advised not to breastfeed. There are no data on the passage of the drug into human breast milk (see section "Contraindications").

Ability to affect reaction speed while driving or operating machinery

Studies to determine the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted.

When driving or operating machinery, the possibility of dizziness during treatment should be taken into account.

Method of Administration and Dosage

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be maintained throughout the course of therapy. The dosage should be individually adjusted based on therapeutic goals and treatment efficacy, in accordance with current approved guidelines.

The medication can be taken at any time of day, regardless of food intake. The tablet should be swallowed whole with water.

Treatment of Hypercholesterolemia

The recommended initial dose is 5 mg or 10 mg orally once daily for patients who are initiating statin therapy as well as for those switching from other HMG-CoA reductase inhibitors. When selecting the initial dose for each individual patient, consideration should be given to baseline cholesterol levels, future risk of cardiovascular complications, and the potential risk of adverse reactions. If necessary, the dose may be gradually increased, but not more frequently than every 4 weeks. Due to the increased frequency of adverse reactions with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), dose titration to the maximum dose of 40 mg should only be considered for patients with severe hypercholesterolemia and high cardiovascular risk (particularly patients with familial hypercholesterolemia) who have not achieved the desired treatment response with a 20 mg dose and who will be under regular ongoing monitoring (see section "Special Warnings and Precautions"). Specialist supervision is recommended when prescribing the 40 mg dose.

Prevention of Cardiovascular Diseases

In clinical trials evaluating cardiovascular risk reduction, the drug was administered at a dose of 20 mg per day.

Use in Elderly Patients

For patients aged 70 years and older, the recommended initial dose is 5 mg (see section "Special Warnings and Precautions").

No additional dose adjustment is required based on age.

Dosage in Patients with Renal Impairment

No dose adjustment is necessary for patients with mild to moderate renal impairment.

For patients with moderate renal impairment (creatinine clearance < 60 mL/min), the recommended initial dose is 5 mg. The 40 mg dose is contraindicated in patients with moderate renal impairment. Rosuvastatin is contraindicated at any dose in patients with severe renal impairment (see sections "Contraindications" and "Pharmacokinetics").

Dosage in Patients with Hepatic Impairment

In patients with a Child-Pugh score of 7 or lower, systemic exposure to rosuvastatin is not increased. However, increased exposure has been observed in patients with a Child-Pugh score of 8 or 9 (see section "Pharmacokinetics"). In such patients, assessment of renal function should be considered (see section "Special Warnings and Precautions"). There is no experience with the use of the drug in patients with a Child-Pugh score exceeding 9. Rosuvastatin is contraindicated in patients with active liver disease.

Race

Increased systemic exposure has been observed in patients of Mongoloid race. For these patients, the recommended initial dose is 5 mg (see sections "Contraindications", "Special Warnings and Precautions", and "Pharmacokinetics").

The 40 mg dose of the drug is contraindicated in such patients.

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased exposure to rosuvastatin (see section "Pharmacokinetics"). Patients known to have such polymorphism types should be prescribed a lower daily dose of rosuvastatin.

Dosage in Patients Predisposed to Myopathy

For patients predisposed to developing myopathy, the recommended initial dose is 5 mg. The 40 mg dose is contraindicated in such patients (see section "Contraindications").

Concomitant Use

Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin 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 "Special Warnings and Precautions" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Where possible, alternative medicinal products should be considered, and temporary discontinuation of Romazik therapy may be necessary. If concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefit and risk of concomitant use should be carefully weighed, and the dose of Romazik should be appropriately adjusted (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

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

The drug is indicated for use in children and adolescents aged 10 to 17 years (boys at Tanner stage II or higher and girls who have had menarche at least 1 year prior).

The usual initial daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg once daily. The drug should be administered orally in doses ranging from 5 mg to 20 mg once daily. The dose should be increased according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment. The safety and efficacy of doses exceeding 20 mg have not been studied in this population.

40 mg tablets should not be used in children.

Children under 10 years of age

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

Overdose.

There is no specific antidote in case of overdose. Symptomatic treatment and supportive measures should be administered as needed. Liver function and creatine kinase (CK) levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse Reactions

Adverse reactions observed during rosuvastatin use were generally mild. In clinical trials, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

Adverse reactions are classified by frequency and system organ classes (SOC). Frequencies of 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);
• Not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Rare: Thrombocytopenia.

Immune system disorders

Rare: Hypersensitivity reactions, including angioedema.

Endocrine disorders

Common: Diabetes mellitus (frequency depends on presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglycerides, history of arterial hypertension)).

Psychiatric disorders

Frequency not known: Depression.

Nervous system disorders

Common: Headache, dizziness.

Very rare: Polyneuropathy, memory loss.

Frequency not known: Peripheral neuropathy, sleep disorders (including insomnia and nightmares).

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 levels of liver transaminases.

Very rare: Jaundice, hepatitis.

Skin and subcutaneous tissue disorders

Uncommon: Pruritus, rash, urticaria.

Frequency not known: Stevens-Johnson syndrome, drug-induced eosinophilia with systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders

Common: Myalgia.

Rare: Myopathy (including myositis) and rhabdomyolysis, lupus-like syndrome, muscle rupture.

Very rare: Arthralgia.

Frequency not known: Tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy, myasthenia gravis.

Renal and urinary disorders

Very rare: Hematuria.

Reproductive system and breast disorders

Very rare: Gynecomastia.

General disorders and administration site conditions

Common: Asthenia.

Frequency not known: Edema.

Eye disorders

Frequency not known: Ocular myasthenia.

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

Renal effects

Proteinuria (detected by dipstick testing), usually of tubular origin, has been observed in patients treated with rosuvastatin. A change in urinary protein level from absent or trace to ++ or higher was observed in < 1% of patients at certain time points during treatment with 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. With the 20 mg dose, a slight increase in proteinuria (from absent or trace to +) was observed. In most cases, proteinuria decreased or resolved spontaneously during continued therapy and was not a predictive factor for the development of acute or progressive kidney disease.

Cases of hematuria have been reported; according to study data, the frequency was low.

Musculoskeletal effects

Effects on skeletal muscle including myalgia, myopathy (including myositis), and rarely rhabdomyolysis have been reported in patients treated with rosuvastatin at any dose, particularly at doses above 20 mg.

Dose-dependent increases in creatine kinase (CK) levels have been observed in patients taking rosuvastatin; most cases were mild, asymptomatic, and transient. If CK levels rise (more than 5 times the upper limit of normal), treatment should be discontinued (see section "Special precautions").

Hepatic effects

As with other HMG-CoA reductase inhibitors, dose-dependent increases in transaminase activity have been observed in a small number of patients treated with rosuvastatin; most cases were mild, asymptomatic, and transient. Increases in HbA1c levels have also been observed during rosuvastatin therapy.

With the use of certain statins, the following adverse events have been reported:

• Sexual dysfunction;
• Isolated cases of interstitial lung disease, particularly with long-term use (see section "Special precautions").

The frequency of reports of rhabdomyolysis and serious renal and hepatic disorders (mainly increased hepatic transaminase activity) is higher with the 40 mg dose.

During post-marketing use of the drug Romazic, 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 with the drug.

Rarely, during the post-marketing period, cognitive disorders (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, resolve after discontinuation of statins, and have variable onset times (from 1 day to years) and resolution times (median 3 weeks).

Pediatric population

Elevated creatine kinase levels > 10 times the upper limit of normal 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 precautions"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a dry, light-protected place.

Keep out of reach of children.

Packaging.

Dosage strengths 5 mg, 10 mg, 20 mg:

10 tablets per blister, 3 blisters per cardboard box.

15 tablets per blister, 2 blisters per cardboard box.

Dosage strength 40 mg:

10 tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmaceutical Works «Polpharma» S.A., Poland.

Manufacturer's address.

19 Pelplinska Str., 83-200 Starogard Gdanski, Poland.