Valrox

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VALAROX (VALAROX®)

Composition:

Active substances: rosuvastatin, valsartan;

One film-coated tablet contains 10 mg rosuvastatin as rosuvastatin calcium and 80 mg valsartan, or 20 mg rosuvastatin as rosuvastatin calcium and 80 mg valsartan, or 10 mg rosuvastatin as rosuvastatin calcium and 160 mg valsartan, or 20 mg rosuvastatin as rosuvastatin calcium and 160 mg valsartan;

Excipients: microcrystalline cellulose (type 102), lactose monohydrate, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, mannitol (E 421), povidone K 25, sodium lauryl sulfate, yellow iron oxide (E 172);

Film coating: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3000, talc, red iron oxide (E 172) (except for the 20 mg/160 mg dosage), yellow iron oxide (E 172) (except for the 20 mg/80 mg and 10 mg/80 mg dosages).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

10 mg/80 mg tablets: dark pink, round, slightly biconvex, film-coated tablets with beveled edges and engraved «K4» on one side;

20 mg/80 mg tablets: dark pink, capsule-shaped, slightly biconvex, film-coated tablets with engraved «K3» on one side;

10 mg/160 mg tablets: dark pink, oval, biconvex, film-coated tablets with engraved «K2» on one side;

20 mg/160 mg tablets: slightly brownish-yellow, oval, biconvex, film-coated tablets with engraved «K1» on one side.

Pharmacotherapeutic group. Lipid-lowering agents in combination with other medicinal products. Rosuvastatin and valsartan. ATC code C10BX10.

Pharmacological properties.

Pharmacodynamics.

Valsartan

Valsartan is an active, potent, and specific angiotensin II receptor antagonist intended for oral administration. It selectively acts on AT1 subtype receptors, which mediate the effects of angiotensin II. Increased levels of angiotensin II due to AT1 receptor blockade by valsartan may stimulate unblocked AT2 receptors, which exert effects opposite to those of AT1 receptors. Valsartan has no agonistic activity at AT1 receptors and exhibits much greater affinity (approximately 20,000 times higher) for AT1 receptors than for AT2 receptors. There is no evidence that valsartan interacts with or blocks receptors of other hormones or ion channels known to play an important role in cardiovascular regulation.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Since valsartan does not affect ACE and therefore does not increase bradykinin or substance P levels, it is unlikely to be associated with cough. In clinical studies comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who had previously experienced dry cough during ACE inhibitor therapy, this adverse effect occurred in 19.5% of cases during treatment with valsartan and in 19% of cases during treatment with a thiazide diuretic, whereas cough was observed in 68.5% of patients in the group treated with an ACE inhibitor (P < 0.05).

Arterial hypertension

Administration of the drug to patients with arterial hypertension results in a reduction in blood pressure without affecting pulse rate.

In most patients, after a single oral dose, the antihypertensive effect develops within 2 hours, and maximum reduction in blood pressure is achieved within 4–6 hours.

The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, the maximal therapeutic effect is usually achieved within 2–4 weeks and is maintained at this level during long-term therapy.

When combined with hydrochlorothiazide, a significant additional reduction in blood pressure (BP) is achieved.

Sudden discontinuation of valsartan does not lead to rebound hypertension or other adverse clinical manifestations.

Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)

When combining an ACE inhibitor with an angiotensin II receptor blocker in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes, and in patients with type 2 diabetes and diabetic nephropathy, an increased risk of hyperkalemia, acute kidney injury, and/or hypotension has been observed compared to monotherapy. Due to the similar pharmacodynamic properties of these drugs, such outcomes are also expected with other ACE inhibitors and angiotensin II receptor blockers.

Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

When aliskiren was added to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both, numerically more cardiovascular deaths and strokes occurred in the aliskiren group than in the placebo group, and adverse events and serious adverse events of special interest (hyperkalemia, hypotension, and hepatic dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Rosuvastatin

Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase, the enzyme that determines the rate-limiting step in the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a cholesterol precursor. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol-lowering effects.

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

Rosuvastatin reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C) levels. It also reduces levels of apolipoprotein B (ApoB), non-HDL cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), and triglycerides in VLDL, while increasing levels of apolipoprotein A-I (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

Efficacy of doses in patients with primary hypercholesterolemia (types IIa and IIb) (adjusted mean percentage change from baseline)

Dose	Number	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. The maximum effect is generally achieved after 4 weeks and is maintained thereafter.

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

The most common adverse reactions leading to discontinuation of rosuvastatin are myalgia, abdominal pain, and rash. The most frequently reported adverse reactions occurring at the same rate or more frequently than with placebo are urinary tract infections, nasopharyngitis, back pain, and myalgia.

Pharmacokinetics.

Absorption

Valsartan

After oral administration of the drug, maximum plasma concentration (Cmax) of valsartan is reached within 2–4 hours; when administered as a solution, it is reached within 1–2 hours. The mean absolute bioavailability of tablets and solution is 23% and 39%, respectively. Food intake reduces valsartan exposure by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%, although plasma concentrations of valsartan are similar in the fasting and postprandial groups approximately 8 hours after administration. However, this reduction in exposure does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered either with food or between meals.

Rosuvastatin

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

Distribution

Valsartan

The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 L, indicating that valsartan does not extensively distribute into tissues. Valsartan is highly bound to plasma proteins (94–97%), primarily to albumin.

Rosuvastatin

Rosuvastatin is extensively metabolized in 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 to albumin.

Metabolism

Valsartan

Valsartan is not significantly biotransformed, as only about 20% of the dose is excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Rosuvastatin

Metabolism of rosuvastatin is limited (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a very weak substrate for cytochrome P450-mediated metabolism. CYP2C9 is the main isoenzyme involved in metabolism, while isoenzymes 2C19, 3A4, and 2D6 are less involved. The main identified metabolites are N-desmethyl and lactone forms. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone form is considered clinically inactive.

Elimination

Valsartan

Valsartan exhibits multiphasic elimination kinetics (t1/2α < 1 hour and t1/2β approximately 9 hours). Valsartan is primarily eliminated via the biliary tract in feces (about 83% of the dose) and via the kidneys in urine (about 13% of the dose), mostly unchanged. After intravenous administration, the plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Rosuvastatin

Approximately 90% of the dose of rosuvastatin is excreted unchanged in feces (comprising both absorbed and unabsorbed active substance), and the remainder is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 20 hours. The half-life does not increase at higher doses. The mean geometric value of plasma 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. This transporter plays an important role in the elimination of rosuvastatin from the liver.

Linearity/Non-linearity

Rosuvastatin

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

Special patient groups

Age and sex

Age and sex do not significantly affect the pharmacokinetics of rosuvastatin in adults. Pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see "Children" below).

A slight increase in valsartan exposure has been observed in some elderly patients compared to younger individuals, although the clinical significance of this is unknown.

Race

Pharmacokinetic studies demonstrate approximately a 2-fold increase in median AUC and Cmax values of rosuvastatin in Asian populations (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to Caucasian patients; in Indians, an increase of approximately 1.3-fold in median AUC and Cmax values is observed. Population pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasian and Black populations.

Renal impairment

In a study involving patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or its N-desmethyl metabolite were observed in patients with mild or moderate renal insufficiency. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin increased 3-fold and N-desmethyl metabolite concentrations increased 9-fold compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

As expected for compounds with renal clearance accounting for only 30% of total plasma clearance, no correlation between renal function and systemic exposure to valsartan was observed. Therefore, dose adjustment is not required for patients with renal impairment (creatinine clearance > 10 mL/min). There is currently no experience with safe use in patients with creatinine clearance < 10 mL/min or in patients on dialysis; thus, valsartan should be used with caution in these patient categories. Valsartan is highly bound to plasma proteins and is unlikely to be removed by hemodialysis.

Hepatic impairment

In a study involving 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 lower. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure increased at least 2-fold compared to patients with lower Child-Pugh scores. There is no experience with administration of the drug to patients with a Child-Pugh score above 9.

Approximately 70% of the absorbed dose of valsartan is excreted in bile, primarily unchanged. Valsartan does not undergo significant biotransformation. Compared to patients with normal liver function, patients with mild to moderate hepatic impairment showed a 2-fold increase in AUC. However, no correlation was found between plasma concentration of valsartan and the degree of hepatic impairment. The effect of valsartan in patients with severe hepatic impairment has not been studied.

Children

Pharmacokinetic parameters in pediatric patients with heterozygous familial hypercholesterolemia aged 10 to 17 years have not been fully characterized. A small pharmacokinetic study of rosuvastatin (in tablet form) involving patients up to 18 years of age showed that drug exposure in pediatric patients corresponds to that in adult patients. Additionally, results indicate that dose-proportional exposure is not significantly altered.

In a study involving 26 children with hypertension (aged 1 to 16 years) who received a single dose of valsartan suspension (mean dose range: 0.9 to 2 mg/kg, maximum dose 80 mg), clearance (L/h/kg) of valsartan was comparable across the age group from 1 to 16 years and corresponded to clearance in adults receiving the same drug.

Genetic polymorphism

Transport proteins OATP1B1 and BCRP are involved in the pharmacokinetics of HMG-CoA reductase inhibitors, including rosuvastatin. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. Specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher rosuvastatin exposure (AUC) compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. This specific genotyping is generally not used in clinical practice, but patients identified with these polymorphisms should be prescribed a lower daily dose of rosuvastatin.

Children with renal impairment

The use of the drug in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for these patients. For children with creatinine clearance > 30 mL/min, dose adjustment is not required. Renal function and serum potassium levels should be carefully monitored.

Clinical characteristics.

Indications.

Valarox is indicated as replacement therapy for arterial hypertension in adult patients whose condition is adequately controlled with concomitant administration of valsartan and rosuvastatin at the same doses, and who are at high risk of first occurrence of cardiovascular complications (for prevention of cardiovascular complications) or in the presence of the following conditions:

• Primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb);
• Homozygous familial hypercholesterolemia.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Active liver disease, including liver disease of unknown etiology, persistent elevations of serum transaminases, and elevations of any serum transaminase more than three times the upper limit of normal.
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Myopathy.
• Concomitant use of the combination sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of cyclosporine.
• Pregnancy and breastfeeding. Also contraindicated in women of childbearing potential who are not using appropriate contraceptive measures.
• Severe hepatic impairment, biliary cirrhosis, or cholestasis.
• Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
• Pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interaction.

Interactions of Valarox with other medicinal products have not been studied.

Interactions related to valsartan

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with drugs of the ARB, ACE inhibitors, or aliskiren groups

Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS blocker (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Concomitant use not recommended

Lithium

Transient increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium and ACE inhibitors. Due to lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If combination therapy is necessary, careful monitoring of plasma lithium levels is recommended.

Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase potassium levels

If use of a drug affecting potassium levels is required in combination with valsartan, monitoring of plasma potassium levels is recommended.

Concomitant use requiring caution

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs

When angiotensin II antagonists are used concomitantly with NSAIDs, attenuation of the antihypertensive effect may occur. Also, concomitant use of angiotensin II antagonists and NSAIDs increases the risk of worsening renal function and may lead to increased serum potassium levels.

Therefore, monitoring of renal function at the start of treatment and adequate hydration of the patient are recommended.

Transporters

In vitro studies have shown that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these findings is unknown. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation or discontinuation of concomitant therapy with these medicinal products.

Other interactions

Studies have not revealed any clinically significant interaction between valsartan and any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.

Children

Since renal dysfunction is common in children and adolescents with arterial hypertension, concomitant use of valsartan with other substances that inhibit the RAAS, which may increase serum potassium levels, should be done with caution. Renal function and serum potassium levels should be monitored.

Interactions related to rosuvastatin

Effect of concomitant medicinal products on rosuvastatin exposure

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transport proteins, including OATP1B1, which mediates hepatic uptake, and the efflux transporter BCRP. Concomitant use with medicinal products that are inhibitors of these transport proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Dosage and administration", "Special precautions for use", and 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 receiving cyclosporine concomitantly (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 the medicinal product with certain protease inhibitor combinations may be possible after careful consideration of rosuvastatin dose adjustment due to the expected increase in exposure (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions for use", "Dosage and administration", and Table 2).

Gemfibrozil and other lipid-lowering agents

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

Based on data from specific interaction studies, no significant pharmacokinetic interaction with fenofibrate is expected, but pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and niacin (nicotinic acid) at lipid-lowering doses (≥ 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they may cause myopathy even when used alone. The 30 mg and 40 mg doses are contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special precautions for use"). Treatment in such cases should be initiated at a dose of 5 mg.

Ezetimibe

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

Antacids

Concomitant use of rosuvastatin with suspensions of antacids containing aluminum and magnesium hydroxide resulted in approximately a 50% reduction in rosuvastatin plasma concentration. This effect was less pronounced when the antacid was administered 2 hours after Valarox. The clinical significance of this interaction has not been established.

Erythromycin

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

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. Furthermore, 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 adjustment of rosuvastatin dose (see also Table 2)

If concomitant use of rosuvastatin with other medicinal products that increase rosuvastatin exposure is necessary, the dose of rosuvastatin should be adjusted. If an increase in exposure (AUC) of approximately 2-fold or more is expected, treatment should be initiated with 5 mg rosuvastatin once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure does not exceed the exposure observed with 40 mg rosuvastatin daily without interacting medicinal products. For example, when used with gemfibrozil, the maximum rosuvastatin dose would be 20 mg (1.9-fold increase), and when used with atazanavir/ritonavir combination, 10 mg rosuvastatin (3.1-fold increase).

Tickagrelor may affect renal excretion of rosuvastatin, increasing the risk of rosuvastatin accumulation. Although the exact mechanism is unknown, in some cases concomitant use of ticagrelor and rosuvastatin has led to impaired renal function, increased creatine phosphokinase (CPK) levels, and rhabdomyolysis.

If rosuvastatin AUC increases by less than 2-fold, the initial dose does not need to 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.

Increase in rosuvastatin AUC by 2-fold or more
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine 75–200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Roxadustat 200 mg every other day	10 mg, single dose	↑ 2.9-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
Teriflunomide	Unknown	↑ 2.5-fold
Grazoprevir 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
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1-fold
Clopidogrel 300 mg loading dose, followed by 75 mg every 24 hours	20 mg, single dose	↑ 2-fold
Tafamidis 61 mg twice daily on days 1 and 2, then once daily from day 3 to day 9	10 mg, single dose	↑ 2.0-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0-fold
Febuxostat 120 mg once daily	10 mg, single dose	1.9-fold
Increase in rosuvastatin AUC less than 2-fold
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Elvitegravir 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	Unknown	↑ 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 **
Decrease in rosuvastatin AUC
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	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 change by x-fold represent the ratio between administration of rosuvastatin in combination versus alone. Data presented as % change represent the percentage difference relative to values when rosuvastatin is administered alone.

Increases are indicated by ↑, decreases by ↓.

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

Medicinal products/combinations that showed no clinically significant effect on the AUC of rosuvastatin when co-administered: 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 on medicinal products when co-administered

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of treatment or dose adjustment of Valrox, when co-administered with vitamin K antagonists (e.g. warfarin or other coumarin anticoagulants), may lead to an increase in the international normalized ratio (INR). Discontinuation or dose reduction of Valrox may lead to a decrease in INR. Appropriate monitoring of INR is recommended in such situations.

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 norgestimate, respectively. The increased plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients concurrently receiving rosuvastatin and HRT; therefore, a potential interaction cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on data from 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 be increased when fusidic acid is systemically co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic) is currently unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin therapy should be discontinued for the entire duration of fusidic acid treatment (see section "Special 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

Cases of proteinuria (detected by dipstick testing), predominantly of tubular origin and mostly transient or short-lived, have been observed in patients treated with high doses of rosuvastatin, particularly 40 mg. Proteinuria does not indicate acute or progressive renal disease (see section "Adverse reactions"). Renal adverse events were reported more frequently in the post-marketing period with the 40 mg dose. Renal function should be monitored regularly in patients receiving rosuvastatin at doses of 30 or 40 mg.

There is no safety experience with use in patients with creatinine clearance < 10 mL/min or in patients on dialysis; therefore, valsartan should be used with caution. Dose adjustment is not required in adult patients with creatinine clearance > 10 mL/min (see sections "Pharmacokinetics" and "Dosage and administration"). Concomitant use of angiotensin receptor antagonists, including valsartan, or angiotensin-converting enzyme (ACE) inhibitors (ACEIs), with aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

It is known that concomitant use of ACE inhibitors, angiotensin receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalaemia, and changes in renal function, including acute renal failure. Due to dual blockade of the RAAS, concomitant use of ACE inhibitors and angiotensin receptor antagonists or aliskiren is not recommended (see sections "Pharmacokinetics" and "Adverse effects"). In cases of exceptional necessity for dual blockade, renal function, electrolyte levels, and blood pressure should be closely monitored under medical supervision. Concomitant use of ACE inhibitors and angiotensin receptor antagonists is not recommended in patients with diabetic nephropathy.

Renal artery stenosis

The safety of valsartan in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney has not been established. Short-term administration of valsartan to 12 patients with secondary renovascular hypertension and unilateral renal stenosis did not cause significant changes in renal haemodynamics, serum creatinine, or blood urea levels. However, other agents affecting the renin-angiotensin system may increase blood urea and serum creatinine in patients with unilateral renal stenosis; therefore, renal function should be monitored in patients receiving valsartan.

Renal transplantation

There is no experience with the safe use of valsartan in patients who have recently undergone renal transplantation.

Hyperkalaemia

Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin) is not recommended.

If concomitant use of a medicinal product affecting potassium levels is necessary with valsartan, monitoring of plasma potassium levels is recommended.

Patients with volume and/or sodium depletion

In patients with volume and/or sodium depletion due to treatment with high doses of diuretics, symptomatic hypotension may rarely occur, especially after the first dose of valsartan. Such conditions should be corrected prior to initiating valsartan therapy, for example, by reducing the diuretic dose.

Effects on skeletal muscle

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis have been observed in patients treated with all doses of rosuvastatin, particularly doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with ezetimibe when used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded; therefore, such combination should be used with caution (see section "Interaction with other medicinal products and other forms of interaction"). As with other HMG-CoA reductase inhibitors, rhabdomyolysis cases associated with rosuvastatin have been reported more frequently in the post-marketing period with the 40 mg dose.

In several cases, statins have been reported to induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, Valarox should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Creatine phosphokinase (CPK) measurement

CPK levels should not be measured after strenuous physical exercise or when other potential causes of elevated CPK levels are present, as this may interfere with interpretation of results. If baseline CPK levels are markedly elevated [> 5 × ULN (upper limit of normal)], a confirmatory test should be performed within 5–7 days. If the repeat test confirms levels > 5 × ULN, treatment should not be initiated.

Before treatment

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

• renal dysfunction;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of muscle disorders induced by other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma levels of the drug (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Dosage and administration");
• concomitant use of fibrates.

In such patients, the potential risks and benefits of treatment should be carefully weighed; clinical monitoring is also recommended. Treatment should not be initiated if baseline CPK levels are markedly elevated (> 5 × ULN).

During treatment

Patients should be advised to promptly report unexplained muscle pain, muscle weakness, or cramps, especially if accompanied by malaise or fever. CPK levels should be measured in such patients. Treatment should be discontinued if CPK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and interfere with daily activities (even if CPK ≤ 5 × ULN). If symptoms resolve and CPK levels return to normal, Valarox or an alternative HMG-CoA reductase inhibitor may be reinitiated at the lowest dose with close monitoring. Routine monitoring of CPK levels in patients without the above symptoms is not required.

Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with statins, including rosuvastatin. IMNM is clinically characterized by proximal muscle weakness and elevated CPK levels that persist despite discontinuation of statin therapy.

In clinical trials, no enhanced effects on skeletal muscle were observed in a small number of patients receiving rosuvastatin and concomitant medications. However, an increased incidence of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors; therefore, Valarox is not recommended for use in combination with gemfibrozil. The beneficial effects of further lipid level changes with concomitant use of Valarox and fibrates or niacin should be weighed against the potential risks of such combination therapy. Concomitant use of rosuvastatin 30 mg or 40 mg with fibrates is contraindicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse effects").

Valarox should not be used concomitantly with fusidic acid or within 7 days after discontinuation of fusidic acid treatment. For patients requiring systemic fusidic acid therapy, statin treatment should be discontinued for the entire duration of fusidic acid therapy. Cases of rhabdomyolysis (including fatal outcomes) 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 attention if they experience symptoms such as muscle weakness, pain, or fatigue. Statin therapy may be resumed 7 days after the last dose of fusidic acid.

In exceptional cases where prolonged systemic fusidic acid therapy is necessary, e.g., for the treatment of severe infections, concomitant use of Valarox and fusidic acid may be considered only under close medical supervision.

Valarox should not be administered to patients with acute, serious conditions that predispose to myopathy or increase the risk of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances; uncontrolled seizures).

Hepatic effects

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

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

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

Race

Pharmacokinetic studies have shown increased systemic exposure to the drug in patients of Mongoloid race compared to Caucasians (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Dosage and 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 Valarox in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations at the start of therapy or dose escalation in patients receiving protease inhibitors should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Interstitial lung disease

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

Diabetes mellitus

Some evidence suggests that statins increase blood glucose levels and may induce hyperglycaemia requiring treatment in some patients at high risk of developing diabetes mellitus. However, the reduction in vascular risk with statin therapy outweighs this risk, which should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to current guidelines.

In clinical trials, the overall incidence of diabetes mellitus 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.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not use Valarox, as the renin-angiotensin-aldosterone system is not activated in these patients.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

Valarox should be used with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy, as with other vasodilating agents.

Pregnancy

Initiation of angiotensin II receptor antagonists (ARBs) during pregnancy is not recommended. Women planning pregnancy should be switched to alternative antihypertensive therapy with a proven safety profile during pregnancy. If pregnancy is detected, ARB therapy should be discontinued immediately, and alternative therapy should be initiated if possible (see sections "Contraindications" and "Use during pregnancy or lactation").

History of angioedema

Angioedema (including laryngeal and glottal oedema leading to airway obstruction, and/or oedema of the face, lips, pharynx, and/or tongue) has been observed in patients receiving valsartan; some of these patients had a history of angioedema with other medicinal products, including ACE inhibitors. If angioedema occurs, Valarox should be discontinued immediately. Re-administration of the drug is contraindicated.

Intestinal angioedema

Intestinal angioedema has been reported in patients receiving angiotensin II receptor antagonists (see "Adverse reactions"). Symptoms include abdominal pain, nausea, vomiting, and diarrhoea. Symptoms resolve after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, the drug should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Psychiatric disorders

Psychiatric events such as hallucinations, paranoia, and sleep disorders, in the context of psychotic events, have been associated with the use of sacubitril/valsartan. If such events occur, treatment should be discontinued and discontinuation of Valarox considered.

Severe skin adverse reactions

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

If a patient has experienced a serious reaction such as SJS or DRESS during treatment with Valarox, re-administration of this medicinal product is not permitted.

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

Use during pregnancy or lactation.

Valarox is contraindicated during pregnancy and breastfeeding.

Pregnancy

Rosuvastatin

Women of childbearing potential should use appropriate contraceptive methods.

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 of using the drug during pregnancy. Reproductive toxicity has been observed in some animal studies. If a patient becomes pregnant while taking the drug, treatment should be discontinued immediately.

Valsartan

Use of angiotensin II receptor antagonists (ARBs) is contraindicated during pregnancy.

Epidemiological data on the risk of teratogenicity after ACE inhibitor use during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Although controlled epidemiological data on angiotensin II receptor antagonists (ARBs) are lacking, there is a risk of teratogenicity with drugs of this class. Women planning pregnancy should be switched to alternative antihypertensive agents with a proven safety profile during pregnancy. If pregnancy is confirmed during ARB treatment, it should be discontinued immediately, and if necessary, replaced with another medicinal product approved for use in pregnant women.

ARBs are known to have toxic effects on the human fetus during the second and third trimesters (reduced renal function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, hypotension, hyperkalaemia).

Ultrasound monitoring of fetal renal function and skull ossification is recommended when ARBs are used from the second trimester of pregnancy.

Newborns whose mothers received ARBs should be closely monitored for the development of hypotension (see sections "Contraindications" and "Special precautions for use").

Lactation

Published data indicate that rosuvastatin passes into human breast milk. Rosuvastatin passes into the milk of rats. Due to the mechanism of action of rosuvastatin, there is a potential risk of adverse reactions in infants.

Since information on the use of the drug during lactation is lacking, it is not recommended during breastfeeding; alternative agents with a well-established safety profile should be preferred, especially when breastfeeding newborns or preterm infants.

Fertility

Valsartan did not affect reproductive function in male and female rats following oral administration at doses up to 200 mg/kg/day. This dose is 6 times the recommended human dose based on mg/m² (calculated for oral administration of 320 mg/day in a 60 kg patient).

Ability to affect reaction speed when driving or operating machinery.

No studies on the effects of Valarox on the ability to drive or operate machinery have been conducted. However, dizziness may occur during treatment, and this should be taken into account when driving or operating machinery.

Dosage and Administration

Dosage

Prior to initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which must be maintained throughout the course of therapy.

The recommended dose of Valarox is 1 tablet daily.

Fixed-dose combination therapy is not suitable for initial treatment.

Before switching to Valarox, patients must be stabilized on individual doses of the separate components administered concomitantly. The dose of Valarox should be based on the doses of the individual components at the time of transition.

If dose adjustment of any active substance in the fixed-dose combination is required for any reason (e.g., newly diagnosed condition, change in patient status, or drug interactions), individual components should be used again to determine the appropriate dosage.

Additional Information for Special Patient Populations

Elderly Patients

Dose adjustment is not required.

Patients with Renal Impairment

Dose adjustment is not necessary in patients with mild to moderate renal impairment. Valarox is contraindicated in patients with severe renal impairment (see sections “Pharmacokinetics” and “Contraindications”). Concomitant use with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²) (see section “Contraindications”).

Patients with Hepatic Impairment

No increase in systemic exposure to rosuvastatin was observed in patients with Child-Pugh scores of 7 or less. However, increased systemic exposure was observed in patients with Child-Pugh scores of 8 and 9 (see section “Pharmacokinetics”). Liver function should be assessed in these patients (see section “Special Warnings and Precautions for Use”). Experience with Valarox in patients with Child-Pugh scores above 9 is lacking. Valarox is contraindicated in patients with active liver disease (see section “Contraindications”), severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis (see sections “Pharmacokinetics”, “Contraindications”, and “Special Warnings and Precautions for Use”). In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg.

Race

Increased systemic exposure to the drug has been observed in patients of Mongoloid race (see sections “Pharmacokinetics”, “Contraindications”, and “Special Warnings and Precautions for Use”).

Genetic Polymorphisms

Specific genetic polymorphisms are known to increase rosuvastatin exposure (see section “Pharmacokinetics”). Patients with such polymorphisms should be considered for a reduced daily dose of rosuvastatin.

Concomitant Therapy

Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when rosuvastatin is co-administered with certain medicinal products that can increase plasma concentrations of rosuvastatin via interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir in combination with atazanavir, lopinavir, and/or tipranavir) (see sections “Interactions with Other Medicinal Products and Other Forms of Interactions” and “Special Warnings and Precautions for Use”). Alternative treatments should be considered, and temporary discontinuation of rosuvastatin therapy should be considered if necessary. In situations where concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefit-risk balance should be carefully evaluated and the rosuvastatin dose should be carefully selected (see section “Interactions with Other Medicinal Products and Other Forms of Interactions”).

Children

Safety and efficacy in pediatric patients (under 18 years of age) have not been established. Valarox is contraindicated in patients under 18 years of age.

Overdose

Symptoms

Overdose with valsartan may result in marked hypotension, which may lead to decreased consciousness, circulatory failure, and/or shock.

Treatment

Therapeutic measures depend on the time of ingestion of the excessive dose, type, and severity of symptoms; stabilization of the circulatory system is of primary importance.

In case of hypotension, the patient should be placed in a supine position, and blood volume should be corrected.

It is unlikely that valsartan can be removed from the body by hemodialysis.

There is no specific antidote for rosuvastatin overdose. Treatment is symptomatic. Supportive measures should be implemented as needed. Creatine kinase (CK) levels should be monitored, and liver function tests should be performed. Hemodialysis is unlikely to be beneficial.

Adverse reactions.

Adverse reactions observed during rosuvastatin use are generally mild and transient. Less than 4% of patients discontinued rosuvastatin due to adverse reactions.

When valsartan was administered to adult patients with arterial hypertension, the frequency of adverse reactions corresponded to that observed with placebo. The frequency of adverse reactions was not related to dose or duration of treatment. No association with patient's sex, age, or race has been demonstrated.

Table 3 presents adverse effects observed during rosuvastatin and valsartan use based on data from clinical and post-marketing studies. Adverse reactions are classified by frequency and organ system: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Table 3

System Organ Class	Adverse Reactions	Frequency
		Valsartan	Rosuvastatin
Blood and lymphatic system	Thrombocytopenia	Not known	Uncommon
	Decreased hemoglobin, hematocrit, neutropenia	Not known	-
Immune system	Hypersensitivity reactions, including angioedema	-	Uncommon
	Hypersensitivity reactions, including serum sickness	Not known	-
Endocrine system	Diabetes mellitus1	-	Common
Metabolism and nutrition	Increased serum potassium, hyponatremia	Not known	-
Psychiatric	Depression	-	Not known
	Hallucinations	Uncommon	-
	Sleep disorders	Uncommon	-
	Paranoia	Very rare	-
Nervous system	Dizziness, headache	-	Common
	Peripheral neuropathy, memory loss	-	Very rare
	Peripheral neuropathy, sleep disorders (including insomnia and night terrors)	-	Not known
	Myasthenia gravis	Not known	-
Ear and labyrinth	Vertigo	Uncommon	-
Eye	Ocular myasthenia	Not known	-
Vascular	Vasculitis	Not known	-
Respiratory, thoracic and mediastinal	Dyspnea	-	Not known
	Cough	Uncommon	Not known
Gastrointestinal	Abdominal pain	Uncommon	Common
	Nausea	-	Common
	Constipation	-	Common
	Pancreatitis	-	Uncommon
	Diarrhea	-	Not known
	Intestinal angioneurotic edema	Very rare	-
Hepatobiliary	Hepatitis	-	Very rare
	Jaundice	-	Very rare
	Elevated liver transaminases	-	Uncommon
	Elevated liver function tests, including serum bilirubin concentration	Not known	-
Skin and subcutaneous tissue	Rash, pruritus	Not known	Uncommon
	Urticaria	-	Uncommon
	Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)	-	Not known
	Angioedema	Not known
Muscle and connective tissue	Myalgia	Not known	Common
	Myopathy (including myositis), lupus-like syndrome, muscle rupture	-	Uncommon
	Rhabdomyolysis	-	Uncommon
	Arthralgia	-	Very rare
	Immune-mediated necrotizing myopathy (IMNM)	-	Not known
	Tendon disorders, sometimes complicated by rupture	-	Not known
Renal and urinary	Hematuria	-	Very rare
	Renal failure or impaired renal function, increased serum creatinine	Not known	-
Reproductive system and breast	Gynecomastia	-	Very rare
General disorders	Asthenia	-	Common
	Edema	-	Not known
	Fatigue	Uncommon	-

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

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

Description of selected adverse reactions

Renal effects

Cases of proteinuria, predominantly of tubular origin (detected by “dipstick test”), have been observed in patients treated with rosuvastatin. Changes in urinary protein content from absent or trace to ++ or higher were recorded over time in < 1% of patients receiving the 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of proteinuria from absent or trace to + was observed with the 20 mg dose. In most cases, the degree of proteinuria decreased or resolved spontaneously while continuing treatment. Review of clinical trial and post-marketing surveillance data has not revealed a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria has been observed in patients treated with rosuvastatin, and clinical trial data indicate a low frequency.

Musculoskeletal effects

Skeletal muscle-related events such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure, have been observed with any dose of rosuvastatin, particularly with doses > 20 mg.

In patients taking rosuvastatin, dose-dependent increases in creatine kinase (CK) levels have been observed; in most cases, this phenomenon was mild, asymptomatic, and transient. If CK levels are elevated (> 5 × ULN), treatment should be discontinued (see section “Dosage and Administration”).

Hepatic effects

As with other HMG-CoA reductase inhibitors, a dose-dependent increase in transaminase levels has been observed in a small number of patients treated with rosuvastatin; in most cases, this was mild, asymptomatic, and transient.

Adverse reactions observed with some statins:

• Sexual dysfunction;
• Rare cases of interstitial lung disease, particularly with long-term therapy (see section “Dosage and Administration”).

Rhabdomyolysis and serious renal and hepatic dysfunction (predominantly manifested as increased hepatic transaminases) have been observed more frequently with the 40 mg dose.

Children

In children and adolescents, increases in CK > 10 × ULN and muscle symptoms have been reported more frequently after exercise or significant physical exertion. The safety profile of rosuvastatin in children, adolescents, and adults is similar.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

No special temperature storage conditions are required for this medicinal product.

Store in the original packaging to protect from moisture.

Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer’s address and place of business.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.