Valarox film-coated tablets 10mg + 80mg blister No. 30

Instructions Valarox film-coated tablets 10mg + 80mg blister No. 30

Composition

active ingredient: rosuvastatin, valsartan;

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

excipients: microcrystalline cellulose (type 102), lactose monohydrate, croscarmellose sodium, colloidal anhydrous silica, 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 dosage 20 mg/160 mg), yellow iron oxide (E 172) (except for dosage 20 mg/80 mg and 10 mg/80 mg).

Dosage form

. Film-coated tablets.

Main physicochemical properties:

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

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

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

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

Pharmacotherapeutic group

Lipid-lowering agents. HMG-CoA reductase inhibitors, other combinations. ATC code C10BX10.

Pharmacological properties

Pharmacodynamics.

Valsartan

Valsartan is a potent and specific angiotensin II receptor antagonist for oral administration. It acts selectively on the AT1 receptor subtype, which is responsible for the effects of angiotensin II. Increased levels of angiotensin II due to blockade of AT1 receptors by valsartan may stimulate unblocked AT2 receptors, which have effects opposite to those of AT1 receptors. Valsartan has no agonist activity at AT1 receptors and has a much higher (approximately 20,000-fold) affinity for AT1 receptors than for AT2 receptors. Valsartan is not known to interact with or block receptors for other hormones or ion channels known to play an important role in the regulation of cardiovascular function.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and destroys 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 trials comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in patients treated with an ACE inhibitor (2.6% versus 7.9%, respectively). Patients previously treated with an ACE inhibitor developed a dry cough, with valsartan treatment occurring in 19.5% of cases, and with thiazide diuretic treatment in 19% of cases, while in the group of patients treated with an ACE inhibitor, cough was observed in 68.5% of cases (P < 0.05).

Arterial hypertension

The use of the drug in patients with arterial hypertension leads to a decrease in blood pressure without affecting the pulse rate.

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

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

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

Abrupt withdrawal of valsartan does not lead to a return of arterial hypertension or other adverse clinical events.

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

When an ACE inhibitor is used in combination with an angiotensin II receptor blocker in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus and in patients with type 2 diabetes mellitus and diabetic nephropathy, an increased risk of hyperkalemia, acute kidney injury and/or hypotension has been observed compared to monotherapy. Given their similar pharmacodynamic properties, these effects are also valid for other ACE inhibitors and angiotensin II receptor blockers.

When aliskiren was added to standard therapy with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both, cardiovascular deaths and stroke were numerically more frequent 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 rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for lowering cholesterol levels.

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

Rosuvastatin reduces elevated LDL-cholesterol (LDL-C), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C). It also reduces apoprotein B (ApoB), non-HDL-cholesterol (non-HDL-C), VLDL-cholesterol (LDL-C), VLDL-triglycerides, and increases apoprotein A-I (ApoA-I) levels (see Table 1). Rosuvastatin also reduces the LDL-C/HDL-C, total-C/HDL-C, and non-HDL-C/HDL-C ratios, and ApoB/ApoA-I.

Table 1

Dose effectiveness in patients with primary hypercholesterolemia (type IIa and IIb) (adjusted mean percent change from baseline)

The therapeutic effect is achieved within 1 week after the start of the drug, 90% of the maximum effect after 2 weeks. The maximum effect is usually 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 mellitus or familial hypercholesterolemia.

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

Pharmacokinetics.

Absorption

Valsartan

After oral administration of the drug, maximum plasma concentrations of valsartan (Cmax) are reached within 2–4 hours, and in the form of a solution - after 1–2 hours. The average absolute bioavailability of tablets and solution of the drug is 23% and 39%, respectively. Food intake reduces exposure to valsartan by approximately 40%, the maximum plasma concentration (Cmax) by approximately 50%, although approximately 8 hours after administration of the drug, plasma concentrations of valsartan are similar in the fasting and fed groups. However, this decrease in exposure is not accompanied by a clinically significant decrease in the therapeutic effect, and therefore valsartan can be used either with or without food.

Rosuvastatin

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

Distribution

Valsartan

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

Metabolism

Valsartan

Valsartan is not extensively biotransformed, with only about 20% of the dose 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 is limited (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a very poor substrate for cytochrome P450-mediated metabolism. CYP2C9 was the major isoenzyme involved in metabolism, while isoenzymes 2C19, 3A4 and 2D6 were involved to a lesser extent. The main metabolites identified are N-desmethyl and lactone. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone form is considered clinically inactive.

Breeding

Valsartan

Valsartan shows multiexponential decay kinetics (t1/2α < 1 hour and t1/2β approximately 9 hours). Valsartan is mainly excreted via the biliary tract in the feces (about 83% of the dose) and the kidneys in the urine (about 13% of the dose), mostly unchanged. After intravenous administration, the plasma clearance of valsartan is approximately 2 l/h, and its renal clearance is 0.62 l/h (about 30% of the total clearance). The half-life of valsartan is 6 hours.

Rosuvastatin

Approximately 90% of the rosuvastatin dose is excreted unchanged in the feces (consisting of absorbed and unabsorbed active substance), and the remainder is excreted in the urine. Approximately 5% is excreted unchanged in the urine. The plasma half-life is approximately 20 hours. The half-life does not increase at high doses. The geometric mean plasma clearance is approximately 50 l/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, rosuvastatin is taken up by the liver with the participation of the membrane transporter OATP-C. This transporter plays an important role in the elimination of rosuvastatin from the liver.

Linearity/nonlinearity

Rosuvastatin

Systemic exposure to rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change when taking multiple daily doses.

Certain patient groups

Age and gender

The pharmacokinetics of rosuvastatin in adults were not significantly affected by age or gender. The 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 was observed in some elderly patients compared to young subjects, however, the clinical significance of this is unknown.

Race

Pharmacokinetic studies demonstrate an increase of approximately 2 times in the median AUC and Cmax of rosuvastatin in Asians (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with patients of the Caucasian race; in Indians there is an increase of approximately 1.3 times in the median AUC and Cmax. Population pharmacokinetic analysis did not reveal any clinically significant differences in pharmacokinetics between representatives of the Caucasian and Negroid races.

Kidney dysfunction

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 subjects with mild or moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 ml/min), plasma concentrations of rosuvastatin increased 3-fold and those of N-desmethyl increased 9-fold compared with those in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

As expected for compounds whose renal clearance is only 30% of total plasma clearance, no relationship between renal function and systemic exposure to valsartan was observed. Therefore, no dose adjustment is necessary for patients with impaired renal function (creatinine clearance > 10 ml/min). There is currently no experience of safe use in patients with creatinine clearance < 10 ml/min or in patients undergoing dialysis, therefore valsartan should be used with caution in these patients. Valsartan is highly bound to plasma proteins and is unlikely to be removed by haemodialysis.

Liver dysfunction

In a study involving patients with varying degrees of hepatic impairment, there was no evidence of increased exposure to rosuvastatin in patients with Child-Pugh scores of 7 or lower. However, two patients with Child-Pugh scores of 8 and 9 had at least a 2-fold increase in systemic exposure compared to patients with lower Child-Pugh scores. There is no experience in patients with Child-Pugh scores greater than 9.

Approximately 70% of the absorbed dose of valsartan is excreted in the bile, mainly unchanged. Valsartan is not significantly metabolized. Compared with healthy subjects, patients with mild to moderate hepatic impairment had a two-fold increase in AUC. However, no relationship was found between plasma valsartan concentrations and the degree of hepatic impairment. Valsartan has not been studied in patients with severe hepatic impairment.

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 (tablet form) in patients up to 18 years of age showed that the drug exposure in pediatric patients is consistent with that in adult patients. In addition, the results indicate that there should be no significant dose-proportional deviation.

In a study of 26 hypertensive children (aged 1 to 16 years) given a single dose of valsartan suspension (mean 0.9 to 2 mg/kg, maximum 80 mg), the clearance (l/h/kg) of valsartan was comparable in the 1 to 16 year age group and was similar to that in adults receiving the same drug.

Genetic polymorphism

The 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 exposure to rosuvastatin. The individual polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher exposure to rosuvastatin (AUC) compared with the genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. This specific genotyping is not routinely used in clinical practice, but a lower daily dose of rosuvastatin is recommended for patients with these types of polymorphisms.

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 in such patients. For children with creatinine clearance > 30 ml/min, no dose adjustment is necessary. Renal function and serum potassium should be closely monitored.

Indication

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

- primary hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed dyslipidemia (type IIb);

- homozygous familial hypercholesterolemia.

Contraindication

- Hypersensitivity to the active substance or to any of the excipients of the drug.

- Active liver disease, including of unknown etiology, persistent elevation of serum transaminases and elevation of any serum transaminase more than 3 times the upper limit of normal.

- Severe renal impairment (creatinine clearance < 30 ml/min).

- Myopathy.

- Concomitant use of cyclosporine.

- Pregnancy and breastfeeding. Also contraindicated in women of reproductive age who are not using appropriate contraception.

- Severe liver dysfunction, biliary cirrhosis or cholestasis.

- Concomitant use with aliskiren for patients with diabetes mellitus or renal insufficiency (GFR < 60 ml/min/1.73m2).

- Children under 18 years of age.

Interaction with other medicinal products and other types of interactions

The interactions of Valarox with other drugs have not been studied.

Interactions related to valsartan

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

Research 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 side effects, such as hypotension, hyperkalemia and decreased renal function (including acute renal failure), compared with the use of a single RAAS blocker (see sections "Contraindications", "Special instructions for use", "Pharmacodynamics").

Concomitant use is not recommended.

Lithium

Transient increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium and ACE inhibitors. If the combination proves necessary, careful monitoring of plasma lithium levels is recommended.

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

If there is a need to take a medicinal product that affects potassium levels in combination with valsartan, monitoring of potassium levels in the blood plasma is recommended.

Concomitant use requiring caution

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

Concomitant use of angiotensin II antagonists with NSAIDs may result in attenuation of the antihypertensive effect. Concomitant use of angiotensin II antagonists and NSAIDs increases the risk of worsening of renal function and may lead to increases in serum potassium.

Therefore, monitoring of renal function at the beginning of treatment is recommended, as well as adequate fluid intake.

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

No interaction was determined.

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

Children

Since concomitant renal dysfunction is common in children and adolescents with hypertension, caution should be exercised when valsartan is used concomitantly with other agents that inhibit the RAAS, which may increase serum potassium levels. Renal function and serum potassium should be monitored.

Interactions related to rosuvastatin

Effect of concomitant medications on rosuvastatin exposure

Transport protein inhibitors

Rosuvastatin is a substrate for certain transport proteins, including OATP1B1, which provides hepatic transport, and the efflux transporter BCRP. Concomitant use with medicinal products that are inhibitors of these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections 4.2 and 4.4, 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 concomitant cyclosporine (see section "Contraindications"). Concomitant use did not affect the plasma concentrations of cyclosporine.

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, co-administration of 10 mg of rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was accompanied by an increase in rosuvastatin AUC and Cmax by approximately 3- and 7-fold, respectively. Co-administration of the drug and some combinations of protease inhibitors is possible after careful consideration of the dose adjustment of rosuvastatin, based on the expected increase in its exposure (see sections “Method of administration and dosage”, “Special instructions for use”, “Interaction with other medicinal products and other forms of interaction”, Table 2).

Gemfibrozil and other lipid-lowering drugs

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

Based on specific interaction studies, no significant pharmacokinetic 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) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they can also cause myopathy when used alone. The 30 and 40 mg doses are contraindicated with concomitant use of fibrates.

Treatment in such cases should be started with a dose of 5 mg.

Ezetimibe

Co-administration of 10 mg of rosuvastatin and 10 mg of ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). A pharmacodynamic interaction between Valarox and ezetimibe, which could lead to adverse events, cannot be excluded (see section 4.4).

Antacids

Concomitant administration of rosuvastatin with antacid suspensions containing aluminum and magnesium hydroxide resulted in a decrease in plasma concentrations of rosuvastatin by approximately 50%. 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 decreased rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to increased intestinal motility due to erythromycin.

Cytochrome P450 enzymes

In vitro and in vivo studies have shown that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, drug interactions resulting from 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).

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

Table 2

Effect of concomitant medications on rosuvastatin exposure (AUC; in descending order of magnitude) based on published clinical trial data

* Data presented as x-fold change represents the ratio between rosuvastatin in combination and alone. Data presented as % change represents the percentage difference relative to rosuvastatin alone.

Increase is indicated by the ↑ icon, no change is indicated by the ↔ icon, and decrease is indicated by the ↓ icon.

** Several interaction studies have been conducted at different doses of rosuvastatin, the most significant relationship is shown in the table.

Effect of rosuvastatin on concomitant medications

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, at the beginning of treatment or when adjusting the dose of Valarox, concomitant use of 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 Valarox may lead to a decrease in the INR. In such situations, appropriate monitoring of INR is desirable.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant use of rosuvastatin and oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. The increase in plasma levels should be taken into account when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of the drugs in patients taking rosuvastatin and HRT simultaneously, so the possibility of an interaction cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicines

Digoxin

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

Fusidic acid

The risk of myopathy, including rhabdomyolysis, may be increased by concomitant systemic use of fusidic acid with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic) is not yet known. There have been reports of rhabdomyolysis (including fatal outcomes) in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin should be discontinued for the duration of fusidic acid treatment (see section 4.4).

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

Application features

Effects on the kidneys

In patients taking rosuvastatin at high doses, especially 40 mg, cases of proteinuria (determined by the “strip test”) were observed, mainly tubular in origin and in most cases transient or short-lived. Proteinuria did not indicate acute or progressive renal disease (see section “Adverse reactions”). Adverse renal events in the post-marketing period were observed more often with the use of a dose of 40 mg. In patients taking the drug at a dose of 30 or 40 mg, renal function should be checked regularly. There is no experience of safety in patients with creatinine clearance < 10 ml/min and patients on dialysis, therefore valsartan should be used with caution. For adult patients with creatinine clearance > 10 ml/min, no dose adjustment is necessary (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”). The concomitant use of angiotensin receptor antagonists, including valsartan or angiotensin-converting enzyme inhibitors (ACEIs), with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.3 and 4.5).

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

Concomitant use of ACE inhibitors and angiotensin II receptor antagonists or aliskiren is known to increase the risk of hypotension, hyperkalemia and changes in renal function, including acute renal failure. Due to dual blockade of the RAAS, the concomitant use of ACE inhibitors and angiotensin II receptor antagonists or aliskiren is not recommended (see sections 4.8 and 5.2). If dual blockade is absolutely necessary, renal function, electrolytes and blood pressure should be monitored under medical supervision. ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly 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 vasorenal arterial hypertension and unilateral renal stenosis did not cause significant changes in renal hemodynamics, serum creatinine, or blood urea nitrogen. However, other agents that affect the renin-angiotensin system may increase serum urea and creatinine in patients with unilateral renal stenosis, and renal function should be monitored in patients taking valsartan.

Kidney transplantation

There is no experience with the safe use of valsartan in patients with a recent kidney transplant.

Hyperkalemia

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

If there is a need to take a medicinal product that affects potassium levels in combination 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 high doses of diuretics, symptomatic hypotension may rarely occur, especially after the first dose of valsartan. Such conditions should be corrected before valsartan is administered, e.g. by reducing the dose of the diuretic.

Effects on skeletal muscles

Skeletal muscle disorders, such as myalgia, myopathy and rarely rhabdomyolysis, have been observed in patients receiving all doses of rosuvastatin, especially doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded, and therefore this combination should be used with caution (see section 4.8). As with rosuvastatin,