Lipirator

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIPIDOSTOR (LIPIRASTORE)

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains 5 mg, 10 mg, 20 mg, or 40 mg of rosuvastatin as rosuvastatin calcium;

Excipients: lactose monohydrate; microcrystalline cellulose, crospovidone, hydroxypropylcellulose, sodium bicarbonate, talc, magnesium stearate;

Film coating:

for 5 mg tablets: Opadry II Yellow 32K520068 (hypromellose, lactose monohydrate, titanium dioxide, triacetin, tartrazine (E 102), red carmine AC, indigocarmine);

for 10 mg, 20 mg, 40 mg tablets: Opadry II Pink 32K540033 (hypromellose, lactose monohydrate, titanium dioxide, triacetin, yellow sunset FCF (E 110), red carmine AC, indigocarmine).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

5 mg tablets – light yellow to yellow colored, round, biconvex tablets with beveled edges, film-coated, marked with "H" on one side and "R3" on the other;

10 mg tablets – light pink to pink colored, round, biconvex tablets with beveled edges, film-coated, marked with "H" on one side and "R4" on the other;

20 mg tablets – light pink to pink colored, round, biconvex tablets with beveled edges, film-coated, marked with "H" on one side and "R5" on the other;

40 mg tablets – light pink to pink colored, oval, biconvex tablets with beveled edges, film-coated, marked with "H" on one side and "R6" on the other.

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

ATC code C10AA07.

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 cholesterol reduction.

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

Pharmacodynamic effect

Rosuvastatin reduces elevated levels of LDL cholesterol (LDL-C), total cholesterol, and triglycerides, and increases high-density lipoprotein cholesterol (HDL-C). It also reduces levels of apoB, non-HDL-C, VLDL-C, VLDL-TG, and increases levels of apoA-I (see Table 1). Rosuvastatin 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)

Dose	N	LDL-C	Total Cholesterol	HDL-C	Triglycerides	Non-HDL-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. Maximum effect is usually achieved within 4 weeks and persists thereafter.

Pharmacokinetics.

Absorption

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 albumin.

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-mediated metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from 2C19, 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 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 active substance), with the remainder excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours and does not increase with dose escalation. The geometric mean value of plasma drug clearance is approximately 50 L/h (coefficient of variation – 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C, which 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 repeated daily administration.

Special patient populations

Age and gender

No clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin has been observed in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").

Race

Pharmacokinetic studies have shown that median values of the area under the plasma concentration-time curve (AUC) and Cmax 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 Negroid race patients.

Renal impairment

In a study in patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in individuals with mild or moderate renal insufficiency. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentration of rosuvastatin was three times higher, and levels of the N-desmethyl metabolite were nine times higher than in healthy volunteers. Steady-state plasma concentration of rosuvastatin in patients undergoing hemodialysis was approximately 50% higher than in healthy volunteers.

Hepatic impairment

In a study of patients with varying degrees of hepatic impairment, no evidence of increased rosuvastatin exposure was observed in patients with a Child–Pugh score of 7 or less. However, in two patients with Child–Pugh scores of 8 and 9, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients with a Child–Pugh score greater than 9 is lacking.

Genetic polymorphism

The disposition 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 certain 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 should be prescribed a lower daily dose of rosuvastatin.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 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 treatment over more than two 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 compliance and other non-pharmacological methods (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.

The medicinal product LipiRastor is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of the medicinal product;
• in patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology, and any serum transaminase elevations exceeding three times the upper limit of normal (ULN);
• in patients with severe renal impairment (creatinine clearance < 30 mL/min);
• in patients with myopathy;
• in patients concurrently receiving the combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions");
• in patients concurrently receiving cyclosporine;
• during pregnancy and breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures.

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

Risk factors include:

• moderate renal impairment (creatinine clearance < 60 mL/min);
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of myotoxicity during treatment with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• conditions that may lead to increased plasma concentration of the medicinal product;
• Mongoloid race;
• concomitant use of fibrates.

Interaction with other medicinal products and other types of interactions.

Effect of concomitant medications on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transport proteins, particularly the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant administration of rosuvastatin with medicinal products that inhibit these transport proteins may increase rosuvastatin plasma concentrations and increase the risk of myopathy (see sections "Interaction with other medicinal products and other types of interactions", "Special warnings and precautions for use", "Dosage and administration", 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). Rosuvastatin is contraindicated in patients who are concurrently 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 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 increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of rosuvastatin and certain combinations of protease inhibitors may be possible after careful consideration of dose adjustment of LipiRastor, in view of the expected increase in rosuvastatin exposure (see sections "Interaction with other medicinal products and other types of interactions", "Special warnings and precautions for use", "Dosage and administration", Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant administration of rosuvastatin and gemfibrozil resulted in a doubling of rosuvastatin AUC and Cmax (see section "Special warnings and precautions for use").

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 (> or equal to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used individually.

The 40 mg dose is contraindicated when coadministered with fibrates (see sections "Contraindications" and "Special warnings and precautions for use"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe

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

Antacid medicinal products

Concomitant administration of rosuvastatin with suspensions of antacids containing aluminum or magnesium hydroxide reduced rosuvastatin plasma concentrations 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 administration of rosuvastatin and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal peristalsis caused by erythromycin.

Ticagrelor

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

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. Additionally, 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 coadministration of rosuvastatin with other medicinal products that may increase rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in AUC is expected, rosuvastatin therapy should be initiated at 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure does not exceed that observed with 40 mg/day without interacting medicinal products. For example, when coadministered with gemfibrozil, the rosuvastatin dose should be 20 mg (exposure increase 1.9-fold); when coadministered with ritonavir/atazanavir combination, the dose should be 10 mg (exposure increase 3.1-fold).

If the medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose need not be reduced, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

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

Increased rosuvastatin AUC by 2 times or more than 2 times
Dosing regimen of interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxelaprevir (400 mg–100 mg–100 mg) + voxelaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4 times
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1 times
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2 times
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8 times
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1 times
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7 times
Obritaprevir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6 times
Teriflunomide	data not available	↑ 2.5 times
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3 times
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2 times
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1 times
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1 times
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2 times
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2 times
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9 times
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9 times
Increased rosuvastatin AUC less than 2 times
Dosing regimen of interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Elvitegravir 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6 times
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5 times
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4 times
Dronedarone 400 mg twice daily	data not available	↑ 1.4 times **
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4 times **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2 times **
Decreased rosuvastatin AUC
Dosing regimen of interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
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 %

* Data presented as fold change 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 the symbol ↑, decreases by ↓.

** Several interaction studies were conducted at different doses of rosuvastatin; the most significant ratios are presented in Table 2.

Medicinal products/combinations that showed no clinically significant effect on rosuvastatin AUC ratio when co-administered: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg three times daily for 7 days; fluconazole 200 mg once daily for 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily for 8 days; ketoconazole 200 mg twice daily for 7 days; rifampicin 450 mg once daily for 7 days; silymarin 140 mg three times daily for 5 days.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or dose escalation in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation or dose reduction of rosuvastatin 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 rosuvastatin 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 medicinal products in patients receiving rosuvastatin and HRT concurrently; 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.

Fusidic acid

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may increase when fusidic acid is used systemically in combination with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is not fully understood. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin therapy should be discontinued for the duration of fusidic acid treatment (see section "Special warnings and precautions for use").

Paediatric population

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 dipstick analysis), predominantly of tubular origin, mostly transient or intermittent, has been observed in patients treated with high doses of rosuvastatin, particularly 40 mg. Proteinuria was not a marker for the development of acute or progressive kidney disease (see section "Adverse reactions"). The frequency of reports of serious renal adverse reactions in post-marketing studies was higher with the 40 mg dose. Renal function should be regularly monitored in patients taking LipiRastor 40 mg.

Skeletal muscle effects

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients treated with rosuvastatin at any dose, particularly above 20 mg. Very rare cases of rhabdomyolysis have been reported with ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction"), therefore such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, the frequency of post-marketing reports of rhabdomyolysis associated with rosuvastatin use was higher at the 40 mg dose.

Creatine kinase (CK) levels

CK levels should not be measured following strenuous physical exercise or in the presence of other possible causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 times ULN), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK is more than 5 times ULN, treatment with the medicinal product should not be initiated.

Before initiating treatment

LipiRastor, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma levels of the medicinal product (see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", and "Posology and method of administration");
• concomitant use of fibrates.

In such patients, the risk associated with treatment should be weighed against the expected benefit; clinical monitoring is also recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (> 5 times ULN).

During treatment

Patients should be advised to report immediately any unexplained muscle pain, weakness, or tenderness, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The medicinal product should be discontinued if CK levels are markedly elevated (> 5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision. 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 features of IMNM include proximal muscle weakness and persistently elevated serum CK levels, even after discontinuation of statins.

In isolated cases, statins have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, LipiRastor should be discontinued. Recurrences have been reported upon re-challenge with the same or another statin.

Clinical trials did not show increased skeletal muscle effects in a small number of patients receiving rosuvast inflammatorily. However, increased incidence of myositis and myopathy has been observed in patients treated with 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, co-administration of rosuvastatin with gemfibrozil is not recommended. The benefit of further lipid-lowering with rosuvastatin in combination with fibrates or niacin should be carefully weighed against the potential risk associated with such combinations. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rosuvastatin should not be co-administered with systemic fusidic acid or within 7 days of stopping fusidic acid treatment. In patients requiring systemic fusidic acid, statin therapy should be discontinued for the duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). Patients should seek immediate medical advice if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In individual cases where prolonged systemic fusidic acid therapy is required, e.g., for treatment of severe infections, concomitant use of rosuvastatin and fusidic acid should be considered only on an individual basis and under close medical supervision.

Rosuvastatin should not be administered to patients with acute serious conditions indicating myopathy or risk of renal failure due to rhabdomyolysis (such as sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with rosuvastatin use, which may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed about signs and symptoms of severe skin reactions, and careful monitoring during treatment is required. If signs or symptoms suggestive of such reactions occur, rosuvastatin should be discontinued immediately and alternative therapy considered.

If a patient develops a serious reaction such as Stevens-Johnson syndrome or DRESS related to LipiRastor, re-initiation of treatment with this drug is contraindicated.

Hepatic effects

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

Liver function tests should be performed before starting treatment and again after 3 months. Rosuvastatin should be discontinued or the dose reduced if serum transaminase levels exceed three times the ULN. The frequency of reports of serious hepatic adverse reactions (mainly elevated liver transaminases) in the post-marketing period was higher with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating rosuvastatin therapy.

Race

Pharmacokinetic studies indicate approximately twofold higher exposure in Mongoloid race patients compared to Caucasian patients (see sections "Pharmacological properties", "Contraindications", and "Posology and method of administration").

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in patients receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with rosuvastatin in HIV-infected patients receiving protease inhibitors and the potential for increased plasma levels of rosuvastatin at the start of therapy and during dose titration should be considered. Concomitant use of the medicinal product 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 "Posology and method of administration").

Interstitial lung disease

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

Diabetes mellitus

Evidence suggests that statins as a class 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 cardiovascular risk with statin therapy outweighs this risk, so it should not be a reason to discontinue statin treatment. 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 the JUPITER trial, 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, and secondary sexual characteristics by Tanner staging in children aged 6 to 17 years receiving rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacological properties"). In a clinical trial in children and adolescents receiving rosuvastatin for 52 weeks, CK elevations >10 times ULN and muscle symptoms after physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding

LipiRastor 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 benefit from using the medicinal product during pregnancy. Animal reproductive toxicity data are limited. If a patient becomes pregnant while taking this medicinal product, treatment should be discontinued immediately.

Rosuvastatin passes into rat milk. There are no data on passage into human breast milk (see section "Contraindications").

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. However, due to its pharmacodynamic properties, it is unlikely that rosuvastatin affects such ability. When driving or operating machinery, the possibility of dizziness occurring during treatment should be considered.

Method of Administration and Dosage

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout the treatment period. The dosage should be individually adjusted based on the therapeutic goal and the patient's response to treatment, following recommendations from current accepted guidelines.

Lipirastor can be taken at any time of day, with or without food.

Treatment of Hypercholesterolemia

The recommended initial dose is 5 mg or 10 mg orally once daily, both for patients who have not previously been treated with statins and for those switching from another HMG-CoA reductase inhibitor. The selection of the initial dose should take into account the individual patient's cholesterol levels, future cardiovascular risk, and the potential for adverse reactions. Dose increases, if necessary, should be made at 4-week intervals (see section "Pharmacological Properties"). Since adverse reactions occur more frequently with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), dose titration to 40 mg should be reserved only for patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved treatment goals with a 20 mg dose and who will be under regular monitoring (see section "Special Warnings and Precautions for Use"). Specialist supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Disease

In a cardiovascular risk reduction study, the drug was administered at a dose of 20 mg once daily (see section "Pharmacological Properties").

Elderly Patients

The recommended initial dose for patients aged >70 years is 5 mg (see section "Special Warnings and Precautions for Use"). No other age-related dosage adjustments are required.

Patients with Renal Impairment

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

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

Patients with Hepatic Impairment

No increase in systemic exposure to rosuvastatin was observed in patients with hepatic impairment scoring 7 or less on the Child-Pugh scale. However, systemic exposure increased in patients scoring 8 or 9 on the Child-Pugh scale (see section "Pharmacological Properties"). Renal function assessment is advisable in such patients (see section "Special Warnings and Precautions for Use"). Experience with the drug in patients scoring more than 9 on the Child-Pugh scale is lacking. Rosuvastatin is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to the drug has been observed in patients of Mongoloid race (see sections "Pharmacological Properties", "Contraindications", and "Special Warnings and Precautions for Use"). The recommended initial dose for patients of Asian origin is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic Polymorphism

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

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").

Concomitant Medications

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 drugs that may increase its plasma concentration 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 Interactions" and "Special Warnings and Precautions for Use"). Alternative therapies should be considered whenever possible, and rosuvastatin therapy may need to be temporarily discontinued. If concomitant use of these drugs with rosuvastatin cannot be avoided, the benefit and risk of combination therapy should be carefully weighed, and the rosuvastatin dose should be carefully selected (see section "Interaction with Other Medicinal Products and Other Forms of Interactions").

Children

The use of the drug in 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 mg to 10 mg orally once daily. The 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 mg to 20 mg orally once daily. The safety and efficacy of doses exceeding 20 mg in this population have not been studied.

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 for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

Homoygous 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 mg 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 individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

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

Tablets of 40 mg are not to be used in children.

Children under 6 years of age

The safety and efficacy of the drug in children under 6 years of age have not been studied. Therefore, Lipirastor is not recommended for use in children under 6 years of age.

Overdose.

There is no specific antidote for overdose. In case of overdose, symptomatic and supportive treatment 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 are generally mild and transient. In controlled clinical trials, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

Below is the safety profile of rosuvastatin based on data from clinical studies and extensive post-marketing experience. Adverse reactions are classified by frequency and organ system. Frequency categories are defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and 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 mellitus¹.

Psychiatric disorders.
Not known: depression.

Nervous system disorders.
Common: headache, dizziness. Very rare: polyneuropathy, memory loss. Not known: peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis.

Eye disorders.
Not known: ocular myasthenia.

Respiratory, thoracic and mediastinal disorders.
Not known: cough, dyspnea.

Gastrointestinal disorders.
Common: constipation, nausea, abdominal pain. Rare: pancreatitis. Not known: diarrhea.

Hepatobiliary disorders.
Rare: increased levels of liver transaminases. Very rare: jaundice, hepatitis.

Skin and subcutaneous tissue disorders.
Uncommon: pruritus, rash, urticaria. Not known: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders.
Common: myalgia. Rare: myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle rupture. Very rare: arthralgia. Not known: tendon disorders, sometimes complicated by rupture, immune-mediated necrotizing myopathy.

Renal and urinary disorders.
Very rare: hematuria.

Reproductive system and breast disorders.
Very rare: gynecomastia.

General disorders and administration site conditions.
Common: asthenia. Not known: edema.

¹ Frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglycerides, history of hypertension).

As with other HMG-CoA reductase inhibitors, the incidence of adverse reactions tends to be dose-dependent.

Renal effects

Proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients taking rosuvastatin. Changes in urinary protein content from negative or trace to ++ or higher were observed in < 1% of patients receiving 10 mg or 20 mg doses and in approximately 3% of patients receiving 40 mg. A slight increase in the frequency of changes from negative or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued treatment. Based on clinical studies and post-marketing data, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Hematuria has been reported during rosuvastatin use; available data suggest it is infrequent.

Musculoskeletal effects

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

In patients taking rosuvastatin, dose-dependent increases in creatine kinase (CK) levels have been observed; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 times the upper limit of normal), treatment should be discontinued (see section "Special precautions").

Hepatic effects

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

With some statins, reports of sexual dysfunction and isolated cases of interstitial lung disease, particularly with long-term use, have been reported (see section "Special precautions").

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

Pediatric population

Elevated CK levels (> 10 times 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.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk profile of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.
10 tablets per blister; 3 or 9 blisters per cardboard box.

Prescription status.
Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.