Rosuvastatin-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

C10AA07 (Rosuvastatin)

Active Substance

Rosuvastatin (Rec.INN registered by WHO)

Dosage Forms

	Rosuvastatin-SZ	Film-coated tablets 5 mg: 20, 28, 30, 56, 60, 90 or 120 pcs.
		Film-coated tablets 10 mg: 20, 28, 30, 56, 60, 90 or 120 pcs.
		Film-coated tablets 20 mg: 20, 28, 30, 56, 60, 90 or 120 pcs.
		Film-coated tablets 40 mg: 20, 28, 30, 56, 60, 90 or 120 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink, round, biconvex; the core of the tablet on the cross-section is white or almost white.

	1 tab.
Rosuvastatin (in the form of rosuvastatin calcium)	5 mg

Excipients: lactose monohydrate (milk sugar), calcium hydrogen phosphate dihydrate, povidone (medium molecular weight polyvinylpyrrolidone), croscarmellose sodium (primellose), sodium stearyl fumarate, colloidal silicon dioxide (aerosil), microcrystalline cellulose.

Shell composition hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), aluminum lacquer based on the dye carmoisine (E122).

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
14 pcs. – contour cell packs (4) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – contour cell packs (4) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
90 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer bottles (1) – cardboard packs.
90 pcs. – polymer bottles (1) – cardboard packs.

Film-coated tablets pink, round, biconvex; the core of the tablet on the cross-section is white or almost white.

	1 tab.
Rosuvastatin (in the form of rosuvastatin calcium)	10 mg

Shell composition hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), aluminum lacquer based on the dye carmoisine (E122).

Film-coated tablets pink, round, biconvex; the core of the tablet on the cross-section is white or almost white.

	1 tab.
Rosuvastatin (in the form of rosuvastatin calcium)	20 mg

Shell composition hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), aluminum lacquer based on the dye carmoisine (E122).

Film-coated tablets pink, round, biconvex; the core of the tablet on the cross-section is white or almost white.

	1 tab.
Rosuvastatin (in the form of rosuvastatin calcium)	40 mg

Shell composition hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), aluminum lacquer based on the dye carmoisine (E122).

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agents; HMG-CoA reductase inhibitors

Pharmacological Action

Hypolipidemic drug.

Mechanism of action

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, a precursor of cholesterol. The main target of rosuvastatin action is the liver, where cholesterol (Ch) synthesis and low-density lipoprotein (LDL) catabolism occur.

Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of very low-density lipoprotein (VLDL) synthesis, thereby reducing the total amount of LDL and VLDL.

Pharmacodynamics

Rosuvastatin-SZ reduces elevated concentrations of LDL cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C), and also reduces the concentrations of apolipoprotein B (Apo-B), non-HDL cholesterol, VLDL cholesterol, VLDL triglycerides and increases the concentration of apolipoprotein A-I (ApoA-1) (see tables 1 and 2), reduces the LDL-C/HDL-C ratio, total cholesterol/HDL-C and non-HDL-C/HDL-C and the Apo-B/ApoA-1 ratio.

The therapeutic effect develops within one week after starting therapy with Rosuvastatin-SZ, reaching 90% of the maximum possible effect after 2 weeks of treatment. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular use of the drug.

Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (Fredrickson type IIa and IIb) (mean adjusted percentage change from baseline )

Dose	Number of patients	LDL-C	Total Cholesterol	HDL-C	TG	Non-HDL-C	ApoB	ApoA-I
Placebo	13	– 7	– 5	3	– 3	-7	– 3	0
10 mg	17	– 52	– 36	14	– 10	– 48	– 42	4
20 mg	17	– 55	– 40	8	– 23	– 51	– 46	5
40 mg	18	– 63	– 46	10	– 28	– 60	– 54	0

Table 2. Dose-dependent effect in patients with hypertriglyceridemia (Fredrickson type IIb and IV) (mean percentage change from baseline)

Dose	Number of patients	TG	LDL-C	Total Cholesterol	HDL-C	Non-HDL-C	VLDL-C	VLDL-TG
Placebo	26	1	5	1	– 3	2	2	6
10 mg	23	– 37	– 45	– 40	8	– 49	– 48	– 39
20 mg	27	– 37	– 31	– 34	22	– 43	– 49	– 40
40 mg	25	– 43	– 43	– 40	17	– 51	– 56	– 48

Clinical efficacy and safety

Rosuvastatin is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, sex or age, including in patients with diabetes mellitus and familial hypercholesterolemia.

In 80% of patients with Fredrickson type IIa and IIb hypercholesterolemia (mean baseline LDL-C concentration about 4.8 mmol/L) taking the drug at a dose of 10 mg, the LDL-C concentration reaches values less than 3 mmol/L.

In patients with heterozygous familial hypercholesterolemia receiving Rosuvastatin at a dose of 20-80 mg, positive dynamics of lipid profile parameters were noted (a study involving 435 patients). After titration to a daily dose of 40 mg (12 weeks of therapy), a 53% reduction in LDL-C concentration was noted. In 33% of patients, an LDL-C concentration of less than 3 mmol/L was achieved.

In patients with homozygous familial hypercholesterolemia taking Rosuvastatin at a dose of 20 mg and 40 mg, the mean reduction in LDL-C concentration was 22%.

In patients with hypertriglyceridemia with an initial TG concentration from 273 to 817 mg/dL who received Rosuvastatin at a dose of 5 mg to 40 mg once daily for 6 weeks, plasma TG concentration was significantly reduced (see Table 2).

An additive effect is noted in combination with fenofibrate on TG concentration and with nicotinic acid in lipid-lowering doses on HDL-C concentration (see section “Special Instructions”).

In the METEOR study involving 984 patients aged 45-70 years with a low risk of coronary artery disease (CAD) (10-year Framingham risk score < 10%), mean LDL-C concentration of 4.0 mmol/L (154.5 mg/dL) and subclinical atherosclerosis (assessed by carotid artery intima-media thickness - IMT), the effect of rosuvastatin on intima-media thickness was studied.

Patients received Rosuvastatin at a dose of 40 mg/day or placebo for 2 years. Rosuvastatin therapy significantly slowed the rate of progression of maximum IMT for 12 carotid artery segments compared to placebo, with a difference of -0.0145 mm/year [95% confidence interval (CI) from -0.0196 to -0.0093; p < 0.0001]. Compared to baseline values, the rosuvastatin group showed a decrease in maximum IMT of 0.0014 mm/year (0.12%/year (non-significant difference)) compared to an increase of 0.0131 mm/year (1.12%/year (p < 0.0001)) in the placebo group. To date, no direct relationship between IMT reduction and reduced risk of cardiovascular events has been demonstrated. The METEOR study was conducted in patients with low CAD risk, for whom the 40 mg dose of rosuvastatin is not recommended. The 40 mg dose should be used in patients with severe hypercholesterolemia and high cardiovascular risk.

Results from the JUPITER study (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) in 17,802 patients showed that Rosuvastatin significantly reduced the risk of cardiovascular complications (252 in the placebo group compared to 142 in the rosuvastatin group) (p < 0.001) with a 44% reduction in relative risk. The effectiveness of therapy was noted during the first 6 months of rosuvastatin use. A statistically significant 48% reduction in the combined endpoint, including death from cardiovascular causes, stroke and myocardial infarction (MI) (hazard ratio: 0.52, 95% CI 0.40-0.68, p < 0.001), a 54% reduction in the occurrence of fatal or non-fatal MI (hazard ratio: 0.46, 95% CI 0.30-0.70) and a 48% reduction in fatal or non-fatal stroke were observed. Overall mortality decreased by 20% in the rosuvastatin group (hazard ratio: 0.80, 95% CI 0.67-0.97, p = 0.02). The safety profile in patients taking Rosuvastatin 20 mg was generally similar to that in the placebo group.

Pharmacokinetics

Absorption

C_max of rosuvastatin in plasma is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

The V_d of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Metabolism

Rosuvastatin is metabolized primarily by the liver, which is the main site of cholesterol synthesis and LDL-C metabolism.

It undergoes limited metabolism (about 10%). Rosuvastatin is a non-profile substrate for metabolism by cytochrome P450 enzymes. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. The CYP2C19, CYP3A4 and CYP2D6 isoenzymes are involved to a lesser extent.

The main identified metabolites of rosuvastatin are N-desmethylrosuvastatin and lactone metabolites. N-desmethylrosuvastatin is approximately 50% less active than Rosuvastatin; lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

Excretion

About 90% of the rosuvastatin dose is excreted unchanged through the intestine (including absorbed and unabsorbed Rosuvastatin). The remainder is excreted by the kidneys. Plasma T_1/2 is approximately 19 hours. T_1/2 does not change with increasing drug dose. The mean geometric plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the membrane cholesterol transporter is involved in the “hepatic” uptake of rosuvastatin, playing an important role in the hepatic elimination of rosuvastatin.

Linearity/non-linearity

Systemic exposure to rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily administration.

Pharmacokinetics in special patient groups

Gender and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin.

Ethnic groups. Pharmacokinetic studies have shown an approximately two-fold increase in the median AUC and C_max of rosuvastatin in Mongoloid patients (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Caucasians; in Indians, a 1.3-fold increase in median AUC and C_max was shown. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasians and Negroids.

Renal impairment. In patients with mild to moderate renal impairment, plasma concentrations of rosuvastatin or N-desmethylrosuvastatin do not change significantly. In patients with severe renal impairment (CrCl < 30 ml/min), plasma concentrations of rosuvastatin are 3 times higher and concentrations of N-desmethylrosuvastatin are 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50% higher than in healthy volunteers.

Hepatic impairment

In a study involving patients with varying degrees of hepatic impairment, no increase in the T_1/2 of rosuvastatin was detected in patients with a Child-Pugh score of ≤ 7. In 2 patients with Child-Pugh scores of 8 and 9, an increase in T_1/2 of at least 2 times compared to patients with lower scores was noted. There is no experience with rosuvastatin in patients with a Child-Pugh score of > 9.

Genetic polymorphism

HMG-CoA reductase inhibitors, including Rosuvastatin, bind to the OATP1B1 and BCRP transport proteins. Carriers of the SLC01B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes showed an increase in the AUC of rosuvastatin by 1.6 and 2.4 times, respectively, compared to carriers of the SLC01B1 c.521TT and ABCG2 c.421CC genotypes.

Indications

Adults aged 18 years and older

Primary hypercholesterolemia according to the Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet, when diet and other non-drug treatments (e.g., exercise, weight loss) are insufficient;
Familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (e.g., LDL apheresis), or in cases where such therapy is not sufficiently effective;
Hypertriglyceridemia (Fredrickson type IV) as an adjunct to diet;
To slow the progression of atherosclerosis as an adjunct to diet in patients who are indicated for therapy to reduce total cholesterol and LDL-C concentrations;
Primary prevention of major cardiovascular complications (stroke, myocardial infarction, arterial revascularization) in adult patients without clinical signs of coronary artery disease but with an increased risk of its development (age over 50 years for men and over 60 years for women, elevated C-reactive protein concentration (≥ 2 mg/L) in the presence of at least one additional risk factor, such as arterial hypertension, low HDL-C concentration, smoking, family history of early-onset coronary artery disease).

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
E78.0	Pure hypercholesterolemia
E78.1	Pure hyperglyceridemia
E78.2	Mixed hyperlipidemia
I21	Acute myocardial infarction
I63	Cerebral infarction
I70	Atherosclerosis

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Orally. Do not chew or crush the tablet, swallow it whole with water. Can be taken at any time of day, regardless of meals.

Before starting therapy with Rosuvastatin-SZ, the patient should begin a standard hypocholesterolemic diet and continue to adhere to it during treatment. The dose of the drug should be individually selected depending on the goals of therapy and the therapeutic response to treatment, taking into account current recommendations for target lipid concentrations.

The recommended initial dose for patients starting the drug or for patients switched from other HMG-CoA reductase inhibitors is 5 mg or 10 mg once daily. When choosing the initial dose, individual cholesterol levels should be guided by and the possible risk of cardiovascular complications should be taken into account, and the potential risk of developing side effects should also be assessed. If necessary, the dose can be increased to a higher one after 4 weeks.

Due to the possible development of side effects when taking a 40 mg dose compared to lower doses of the drug, increasing the dose to 40 mg after additional administration of a dose above the recommended initial dose for 4 weeks of therapy can only be carried out in patients with severe hypercholesterolemia and high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) who have not achieved the desired treatment result with a 20 mg dose and who will be under specialist supervision. Particularly careful monitoring of patients receiving the drug at a dose of 40 mg is recommended.

Prescribing a 40 mg dose is not recommended for patients who have not previously consulted a doctor.

After 2-4 weeks of therapy and/or when increasing the dose of Rosuvastatin-SZ, monitoring of lipid metabolism parameters is necessary (dose adjustment may be required if necessary).

Elderly patients do not require dose adjustment.

Patients with mild or moderate renal impairment do not require dose adjustment. Patients with severe renal impairment (CrCl < 30 ml/min) are contraindicated to use Rosuvastatin-SZ. The use of the drug at a dose of 40 mg is contraindicated in patients with moderate renal impairment (CrCl 30-60 ml/min) (see sections “Pharmacokinetics”, “Special Instructions”). Patients with moderate renal impairment are recommended an initial dose of the drug of 5 mg.

Rosuvastatin-SZ is contraindicated in patients with active liver disease (see section “Contraindications”).

Special Populations

Ethnic groups

When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increase in the systemic concentration of rosuvastatin was noted among Japanese and Chinese (see section “Special Instructions”). This fact should be taken into account when prescribing Rosuvastatin-SZ to these groups of patients. When prescribing doses of 10 mg and 20 mg, the recommended initial dose for patients of Mongoloid race is 5 mg. Prescribing the drug at a dose of 40 mg is contraindicated for patients of Mongoloid race (see section “Contraindications”).

Genetic polymorphism

Carriers of the SLC01B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes showed an increase in rosuvastatin exposure (AUC) compared to carriers of the SLCOIBI c.521TT and ABCG2 c.421CC genotypes. For patients who are carriers of the c.521CC or c.421AA genotypes, the recommended maximum dose of Rosuvastatin-SZ is 20 mg once daily (see sections “Pharmacokinetics”, “Special Instructions” and “Drug Interactions”).

Patients predisposed to myopathy

Prescribing the drug at a dose of 40 mg is contraindicated in patients with factors that may indicate a predisposition to the development of myopathy (see section “Contraindications”). The recommended initial dose for this group of patients is 5 mg (see section “Contraindications”).

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, OATP1B1, an organic anion transporting polypeptide involved in the uptake of statins by hepatocytes, and BCRP, an efflux transporter). When Rosuvastatin-SZ is used concomitantly with drugs (such as cyclosporine, some HIV protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the plasma concentration of rosuvastatin due to interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may increase (see sections “Special Instructions” and “Drug Interactions”). The instructions for use of these drugs should be reviewed before prescribing them concomitantly with Rosuvastatin-SZ. In such cases, the possibility of prescribing alternative therapy or temporarily discontinuing Rosuvastatin-SZ should be assessed. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Rosuvastatin-SZ should be assessed and the possibility of reducing its dose should be considered (see section “Drug Interactions”).

Children

The safety and efficacy of rosuvastatin in children aged 0 to 18 years have not been established to date. Data on use are limited.

Adverse Reactions

Reported adverse reactions are usually mild and self-limiting. In controlled clinical studies, < 4% of patients receiving Rosuvastatin discontinued the study prematurely due to adverse reactions.

Table 1 lists the adverse reactions of rosuvastatin based on clinical studies and extensive post-marketing use; adverse reactions are distributed by system-organ class with an indication of their frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency unknown (cannot be estimated from the available data).

Table 1. Adverse reactions of rosuvastatin based on clinical studies and post-marketing use

Common	Uncommon	Rare	Very rare	Frequency unknown
Blood and lymphatic system disorders
		Thrombocytopenia
Immune system disorders
		Hypersensitivity reactions, including angioedema
Endocrine disorders
Diabetes mellitus¹
Psychiatric disorders
				Depression
Nervous system disorders
Headache, dizziness			Polyneuropathy, memory loss	Peripheral neuropathy, sleep disorders (including insomnia and nightmares)
Respiratory disorders
				Cough, dyspnea
Gastrointestinal disorders
Constipation, nausea, abdominal pain		Pancreatitis		Diarrhea
Hepatobiliary disorders
		Increased hepatic transaminase activity	Jaundice, hepatitis
Skin and subcutaneous tissue disorders
	Pruritus, skin rash, urticaria			Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome)
Musculoskeletal and connective tissue disorders
Myalgia		Myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle rupture	Arthralgia	Tendinopathies, sometimes complicated by tendon rupture, immune-mediated necrotizing myopathy
Renal and urinary disorders
			Hematuria
Reproductive system and breast disorders
			Gynecomastia
General disorders and administration site conditions
	Asthenia			Edema

¹ frequency will depend on the presence or absence of risk factors (fasting blood glucose concentration ≥ 5.6 mmol/L, BMI >30 kg/m², elevated TG concentration, history of arterial hypertension)

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

Description of selected adverse reactions

Renal disorders

In patients receiving Rosuvastatin, urinalysis using a test strip revealed proteinuria, predominantly of the tubular type. Changes in urine protein amount (from none or trace to ++ or more) observed at any time during treatment occurred in less than 1% of patients receiving 10-20 mg rosuvastatin and in approximately 3% of patients receiving 40 mg rosuvastatin. A slight increase in the frequency of changes in urine protein amount (from none or trace to +) was noted when taking a 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously during ongoing therapy. A review of clinical trial results and post-marketing experience to date has not revealed a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria has been observed in patients receiving Rosuvastatin, and clinical trial results indicate that this occurs rarely.

Musculoskeletal disorders

When using rosuvastatin at all doses and, in particular, when taking rosuvastatin doses exceeding 20 mg, the following effects on skeletal muscle have been reported: myalgia, myopathy (including myositis), and in rare cases, rhabdomyolysis with or without acute renal failure.

A dose-dependent increase in CPK activity was observed in patients taking Rosuvastatin. In most cases, it was minor, asymptomatic, and temporary. If CPK activity increases (more than 5 times the ULN), therapy should be discontinued (see section “Special Instructions”).

Hepatic disorders

As with other HMG-CoA reductase inhibitors, a small number of patients using Rosuvastatin experienced a dose-dependent increase in transaminase activity, with most cases being minor, asymptomatic, and short-lived.

The following adverse reactions have been reported with the use of some statins

Sexual dysfunction;

Very rare cases of interstitial lung disease, especially with long-term use of rosuvastatin (see section “Special Instructions”).

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

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

Hypersensitivity to rosuvastatin or to any of the excipients included in the drug;
Active liver disease, including persistent elevation of serum transaminase activity and any elevation of serum transaminase activity (more than 3 times the ULN);
Severe renal impairment (CrCl < 30 ml/min);
Myopathy;
Predisposition to the development of myotoxic complications;
Concomitant use of cyclosporine;
Pregnancy;
Breastfeeding period;
Lack of adequate contraceptive methods in women;
Galactose intolerance, lactase deficiency, glucose-galactose malabsorption.

For use in a daily dose of 40 mg

Patients with risk factors for the development of myopathy/rhabdomyolysis;
Moderate renal impairment (CrCl < 60 ml/min);
Hypothyroidism;
Personal or family history of muscle diseases;
History of myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates;
Excessive alcohol consumption;
Conditions that may lead to an increase in the plasma concentration of rosuvastatin;
Concomitant use of fibrates;
Patients of Mongoloid race.

With caution

Presence of risk for the development of myopathy/rhabdomyolysis – renal impairment, hypothyroidism, personal or family history of hereditary muscle diseases and previous history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates, excessive alcohol consumption, age ≥ 65 years; conditions in which an increase in the plasma concentration of rosuvastatin has been noted, racial affiliation (Mongoloid race), concomitant use with fibrates, history of liver disease, sepsis, arterial hypotension, extensive surgical interventions, trauma, severe metabolic, endocrine or electrolyte disturbances or uncontrolled seizures.

When taken in a daily dose of 40 mg: mild renal impairment (CrCl > 60 ml/min).

Use in Pregnancy and Lactation

Pregnancy

Rosuvastatin-SZ is contraindicated during pregnancy.

Women of reproductive age should use adequate contraceptive methods.

Since cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefit of using the drug in pregnant women. If pregnancy occurs during therapy, the drug should be discontinued immediately.

Breastfeeding period

The drug Rosuvastatin-SZ is contraindicated during breastfeeding.

Data regarding the excretion of rosuvastatin in breast milk are not available, so during breastfeeding, the drug should be discontinued (see section “Contraindications”).

Fertility

Data on the effect of rosuvastatin on human reproductive function are not available.

Use in Hepatic Impairment

The use of the drug is contraindicated in active liver diseases, including persistent elevation of serum transaminase activity and any elevation of serum transaminase activity (more than 3 times the ULN).

The drug should be prescribed with caution to patients with a history of liver disease.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure (CrCl less than 30 ml/min).

The use of the drug at a dose of 40 mg is contraindicated in moderate and severe renal failure (CrCl less than 60 ml/min). In mild renal failure (CrCl greater than 60 ml/min), the drug at a dose of 40 mg should be prescribed with caution.

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

The drug should be prescribed with caution to patients over 65 years of age.

Special Precautions

Patients with impaired liver function

There is no data or experience with the drug in patients with more than 9 points on the Child-Pugh scale.

Renal effects

In patients receiving Rosuvastatin-SZ at high doses (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria did not indicate acute kidney disease or progression of kidney disease. In patients taking the drug at a dose of 40 mg, monitoring of renal function parameters during treatment is recommended.

Musculoskeletal system

When using Rosuvastatin-SZ at all doses and, especially when taking the drug in doses exceeding 20 mg, the following effects on skeletal muscle have been reported: myalgia, myopathy, and in rare cases, rhabdomyolysis.

CPK determination

CPK activity should not be determined after intense physical exertion or in the presence of other possible causes of increased CPK activity, as this may lead to misinterpretation of the results obtained. If baseline CPK activity is significantly elevated (5 times higher than ULN), a repeat measurement should be performed after 5-7 days. Therapy should not be initiated if the repeat test confirms baseline CPK activity (more than 5 times ULN).

Before starting therapy

When prescribing rosuvastatin, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis, the risk-benefit ratio of therapy should be considered, and clinical monitoring should be carried out.

During therapy

The patient should be informed of the need to immediately inform the doctor of any cases of unexpected muscle pain, muscle weakness or cramps, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (more than 5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is less than 5 times ULN). If symptoms disappear and CPK activity returns to normal, the question of re-prescribing Rosuvastatin-SZ or other HMG-CoA reductase inhibitors at lower doses with careful monitoring of the patient should be considered.

Routine monitoring of CPK activity in the absence of symptoms is not advisable.

Very rare cases of immune-mediated necrotizing myopathy with clinical manifestations of persistent proximal muscle weakness and increased serum CPK activity during treatment or upon discontinuation of statins, including rosuvastatin, have been noted. Additional investigations of the muscular and nervous systems, serological tests, and therapy with immunosuppressive agents may be required.

No signs of increased effect on skeletal muscles have been observed with the administration of Rosuvastatin-SZ and concomitant therapy. However, an increased number of cases of myositis and myopathy have been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin in lipid-lowering doses (≥ 1 g/day), antifungal agents from the azole group, HIV protease inhibitors, and antibiotics from the macrolide group. Gemfibrozil increases the risk of myopathy when used concomitantly with some HMG-CoA reductase inhibitors. Therefore, the concomitant use of Rosuvastatin-SZ and gemfibrozil is not recommended. The risk-benefit ratio should be carefully weighed when using Rosuvastatin-SZ concomitantly with fibrates or niacin in lipid-lowering doses. The use of Rosuvastatin-SZ at a dose of 40 mg concomitantly with fibrates is contraindicated.

Lipid metabolism parameters should be monitored 2-4 weeks after the start of treatment and/or upon dose increase of Rosuvastatin-SZ (dose adjustment may be required if necessary).

Liver Function

Liver function tests should be performed before the start of therapy and 3 months after the start of therapy. Administration of Rosuvastatin-SZ should be discontinued or the dose reduced if serum transaminase activity is 3 times the upper limit of normal.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for the underlying diseases should be conducted before starting treatment with rosuvastatin.

Special Populations. Ethnic Differences

Pharmacokinetic studies in patients of Mongoloid race have shown an increase in the systemic concentration of rosuvastatin compared to the values obtained among Caucasian patients.

HIV Protease Inhibitors

Concomitant use of the drug with HIV protease inhibitors is not recommended.

Interstitial Lung Disease

Isolated cases of interstitial lung disease have been reported with the use of some statins, especially over a long period. Manifestations of the disease may include dyspnea, non-productive cough, and deterioration in general well-being (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Type 2 Diabetes Mellitus

In patients with glucose concentrations from 5.6 to 6.9 mmol/L, therapy with rosuvastatin was associated with an increased risk of developing type 2 diabetes mellitus.

Excipients

The drug Rosuvastatin-SZ contains lactose monohydrate. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

The drug Rosuvastatin-SZ contains an aluminum lake based on the dye carmoisine E 122, which may cause allergic reactions.

Effect on Ability to Drive and Use Machines

No studies have been conducted on the effect of Rosuvastatin-SZ on the ability to drive vehicles and use mechanisms. However, based on its pharmacodynamic properties, Rosuvastatin should not have such an effect. Caution should be exercised when driving vehicles or performing work that requires increased concentration and speed of psychomotor reactions (dizziness may occur during therapy).

Overdose

Treatment There is no specific treatment for rosuvastatin overdose. Symptomatic treatment and measures aimed at maintaining the functions of vital organs and systems are recommended. Liver function and CPK activity should be monitored. Hemodialysis is unlikely to be effective.

Drug Interactions

Effect of Concomitantly Administered Drugs on Rosuvastatin

Transporter Protein Inhibitors: Rosuvastatin binds to certain transporter proteins, particularly OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transporter proteins may be accompanied by an increase in rosuvastatin plasma concentration and an increased risk of myopathy (see Table 1).

Cyclosporine: with concomitant use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see Table 1). Rosuvastatin-SZ is contraindicated in patients concomitantly using cyclosporine. Concomitant use of these drugs does not affect the plasma concentration of cyclosporine.

Protease Inhibitors: although the exact mechanism of interaction is unknown, concomitant administration with a protease inhibitor may lead to a significant increase in the AUC of rosuvastatin (see Table 1). For example, in a pharmacokinetic study, concomitant use of 10 mg rosuvastatin and a combination product containing 2 protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in approximately 3-fold and 7-fold increases in the AUC and C_max of rosuvastatin, respectively. Concomitant use of Rosuvastatin-SZ and some combinations of protease inhibitors is possible after careful evaluation of the possibility of rosuvastatin dose adjustment based on the expected increase in rosuvastatin AUC (see Table 1).

This dose combination is not suitable as first-line therapy. Combination treatment should only be started after selecting an appropriate dose of Rosuvastatin-SZ based on the expected increase in rosuvastatin exposure level (see Table 1).

Gemfibrozil and Other Lipid-Lowering Agents: Concomitant use of rosuvastatin and gemfibrozil leads to a 2-fold increase in the C_max and AUC of rosuvastatin in plasma. Based on specific interaction data, no pharmacokinetically significant interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and niacin (nicotinic acid) in lipid-lowering doses (≥ 1 g/day) increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, probably because they can cause myopathy when used as monotherapy. The use of Rosuvastatin-SZ at a dose of 40 mg is contraindicated when co-administered with fibrates. Such patients should start therapy with a 5 mg dose.

Ezetimibe: Concomitant use of Rosuvastatin-SZ at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by a 1.2-fold increase in the AUC of rosuvastatin in patients with hypercholesterolemia (see Table 1). A pharmacodynamic interaction between rosuvastatin and ezetimibe regarding adverse reactions cannot be ruled out.

Antacids: Concomitant use of Rosuvastatin-SZ and an antacid in the form of a suspension containing aluminum and magnesium hydroxide led to a decrease in the AUC of rosuvastatin by approximately 50%. This effect is less pronounced if the antacid was taken 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Erythromycin: Concomitant use of rosuvastatin and erythromycin led to a 20% decrease in the AUC of rosuvastatin and a 30% decrease in the C_max of rosuvastatin. This interaction may occur as a result of increased intestinal motility caused by erythromycin intake.

Cytochrome P450 Isoenzymes: Results from in vivo and in vitro studies have shown that Rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Furthermore, Rosuvastatin is a weak substrate for these enzymes. Therefore, no interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 isoenzymes is expected. No clinically significant interaction of rosuvastatin with fluconazole (an inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of CYP2A6 and CYP3A4 isoenzymes) was observed.

Interaction with Drugs Requiring Rosuvastatin Dose Adjustment (see Table 1)

The dose of Rosuvastatin-SZ should be adjusted if it is necessary to use it concomitantly with drugs that increase rosuvastatin exposure. If an increase in exposure of 2-fold or more is expected, the initial dose of Rosuvastatin-SZ should be 5 mg once daily. The maximum daily dose of Rosuvastatin-SZ should also be adjusted so that the expected rosuvastatin exposure does not exceed that for a 40 mg dose taken without concomitant administration of drugs interacting with rosuvastatin. For example, the maximum daily dose of Rosuvastatin-SZ when used concomitantly with gemfibrozil is 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir – 10 mg (3.1-fold increase in exposure).

Table 1. Effect of Concomitant Therapy on Rosuvastatin Exposure (AUC, data presented in descending order of exposure magnitude) – results of published clinical studies

Increase in Rosuvastatin AUC by 2-fold or more
Dosing regimen of drugs interacting with rosuvastatin	Rosuvastatin dosing regimen	Change in Rosuvastatin AUC¹
Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/ 100 mg) + voxilaprevir 100 mg once daily, 15 days	10 mg single dose	7.4-fold increase
Cyclosporine 75-200 mg twice daily, 6 months	10 mg once daily, 10 days	7.1-fold increase
Darolutamide 600 mg twice daily, 5 days	5 mg single dose	5.2-fold increase
Regorafenib 160 mg once daily, 14 days	5 mg single dose	3.8-fold increase
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg single dose	3.1-fold increase
Velpatasvir 100 mg once daily	10 mg single dose	2.7-fold increase
Ombitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg/dasabuvir 400 mg twice daily.	5 mg single dose	2.6-fold increase
Teriflunomide	No data	2.5-fold increase
Grazoprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg single dose	2.3-fold increase
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg single dose	2.2-fold increase
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	2.1-fold increase
Capmatinib 400 mg twice daily	10 mg single dose	2.1-fold increase
Clopidogrel 300 mg (loading dose), then 75 mg after 24 h	20 mg single dose	2-fold increase
Fostamatinib 100 mg twice daily	20 mg single dose	2-fold increase
Febuxostat 120 mg once daily	10 mg single dose	1.9-fold increase
Gemfibrozil 600 mg twice daily, 7 days	80 mg single dose	1.9-fold increase
Increase in Rosuvastatin AUC by less than 2-fold
Dosing regimen of drugs interacting with rosuvastatin	Rosuvastatin dosing regimen	Change in Rosuvastatin AUC¹
Eltrombopag 75 mg once daily, 5 days	10 mg single dose	1.6-fold increase
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	1.5-fold increase
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg single dose	1.4-fold increase
Dronedarone 400 mg twice daily	No data	1.4-fold increase
Itraconazole 200 mg once daily, 5 days	10 mg single dose	1.4-fold increase²
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	1.2-fold increase²
Decrease in Rosuvastatin AUC
Dosing regimen of drugs interacting with rosuvastatin	Rosuvastatin dosing regimen	Change in Rosuvastatin AUC¹
Erythromycin 500 mg four times daily, 7 days	80 mg single dose	20% decrease
Baicalin 50 mg three times daily, 14 days	20 mg single dose	47% decrease

¹ Data presented as a fold-change in AUC represent the ratio of this parameter value during concomitant therapy to the parameter value during rosuvastatin monotherapy. Data presented as % represent the % difference between the AUC parameter during concomitant therapy and the parameter value during rosuvastatin monotherapy.

² Several drug interaction studies with rosuvastatin at different doses have been conducted; the table shows the most significant ratios.

The following drugs and their combinations did not have a clinically significant effect on rosuvastatin exposure when used concomitantly: aleglitazar 0.3 mg 7 days; fenofibrate 67 mg three times daily 7 days; fluconazole 200 mg once daily 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily 8 days; ketoconazole 200 mg twice daily 7 days; rifampicin 450 mg once daily 7 days; silymarin 140 mg three times daily 5 days.

Effect of Rosuvastatin Use on Concomitantly Administered Drugs

Vitamin K Antagonists: As with other HMG-CoA reductase inhibitors, initiation of therapy or an increase in the dose of Rosuvastatin-SZ in patients concomitantly receiving vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in INR. Discontinuation or reduction of the dose of Rosuvastatin-SZ may lead to a decrease in INR. In such cases, monitoring of INR is recommended.

Oral Contraceptives/Hormone Replacement Therapy: Concomitant use of rosuvastatin and oral contraceptives increased the AUC of ethinyl estradiol and the AUC of norgestrel by 26% and 34%, respectively. This increase in plasma concentration should be considered when selecting the dose of oral contraceptives. Pharmacokinetic data on the concomitant use of Rosuvastatin-SZ and hormone replacement therapy are lacking; therefore, a similar effect with the use of these drugs cannot be ruled out. However, this combination has been widely used by women during clinical trials and was well tolerated by patients.

Other Drugs

Digoxin Based on the results of specific drug interaction studies, no clinically significant interaction between rosuvastatin and digoxin is expected.

Fusidic Acid Drug interaction studies of rosuvastatin with fusidic acid have not been conducted. When systemic therapy with fusidic acid and statins is used concomitantly, the risk of myopathy, including rhabdomyolysis, may be increased. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) has not yet been studied. Cases of rhabdomyolysis (including fatal) have been reported in patients using this combination.

If systemic therapy with fusidic acid is necessary, treatment with Rosuvastatin-SZ should be discontinued for the duration of fusidic acid intake.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer

Medixlife (Author)

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