Valsar-am

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VALSAR-AM (VALSAR-AM)

Composition:

Active substances: amlodipine besylate and valsartan;

One film-coated tablet contains amlodipine besylate 6.934 mg, equivalent to amlodipine 5 mg and valsartan 160 mg, or amlodipine besylate 13.868 mg, equivalent to amlodipine 10 mg and valsartan 160 mg;

Excipients: microcrystalline cellulose; colloidal anhydrous silicon dioxide; sodium starch glycolate; povidone; pregelatinized starch; magnesium stearate; Opadry 03F82429 Yellow (hypromellose, talc, polyethylene glycol (macrogol), titanium dioxide (E 171), iron oxide yellow (E 172)) [only for tablets of 5 mg/160 mg]; Opadry 03F82428 Yellow (hypromellose, titanium dioxide (E 171), polyethylene glycol (macrogol), talc, iron oxide yellow (E 172), iron oxide red (E 172)) [only for tablets of 10 mg/160 mg].

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 5 mg/160 mg: yellow, oval-shaped, biconvex tablets with beveled edges, film-coated, marked by embossing «J» on one side and «37» on the other;

Tablets 10 mg/160 mg: light-yellow, oval-shaped, biconvex tablets with beveled edges, film-coated, marked by embossing «J» on one side and «38» on the other.

Pharmacotherapeutic group. Combined angiotensin II inhibitors.

ATC code C09DB01.

Pharmacological Properties

Pharmacodynamics

Valsar-AM contains two antihypertensive components with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine, belonging to the class of calcium channel antagonists, and valsartan, belonging to the class of angiotensin II antagonists. The combination of these ingredients provides an additive antihypertensive effect, reducing arterial pressure to a greater extent than either component alone.

Amlodipine

Amlodipine inhibits transmembrane influx of calcium ions into vascular and cardiac smooth muscle. The antihypertensive mechanism of amlodipine is due to direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and consequent lowering of arterial pressure. Experimental data confirm that amlodipine binds at both dihydropyridine and non-dihydropyridine binding sites. Contractile processes in cardiac and vascular smooth muscle depend on the influx of extracellular calcium into these cells through specific ion channels.

Following administration of therapeutic doses to patients with arterial hypertension, amlodipine induces vasodilation, leading to reduced arterial pressure in both supine and standing positions. This reduction in arterial pressure is not accompanied by significant changes in heart rate or plasma catecholamine levels during long-term treatment.

The effect correlates with plasma concentrations in both younger and elderly patients.

In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without altering the filtration fraction or causing proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or walking) in patients with normal ventricular function treated with amlodipine generally show a slight increase in cardiac index without significant effects on dP/dt, end-diastolic pressure, or left ventricular volume. Hemodynamic studies have shown that amlodipine does not exhibit negative inotropic effects at therapeutic doses in intact animals and humans, even when co-administered with beta-blockers.

Amlodipine does not alter sinus node function or atrioventricular conduction in healthy animals or humans. In clinical trials where amlodipine was used in combination with beta-blockers in patients with arterial hypertension or angina, no changes in electrocardiographic parameters were observed.

Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.

Use in Patients with Arterial Hypertension

A randomized, double-blind trial on morbidity and mortality—the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT)—was conducted to compare newer antihypertensive therapies: amlodipine 2.5–10 mg daily (a calcium channel blocker) or lisinopril 10–40 mg daily (an ACE inhibitor) as first-line therapy versus chlorthalidone 12.5–25 mg daily (a thiazide diuretic) in patients with mild to moderate arterial hypertension.

A total of 33,357 hypertensive patients aged 55 years and older were randomized and followed for a mean of 4.9 years. Each patient had at least one additional risk factor for ischemic heart disease, including prior myocardial infarction or stroke (>6 months before enrollment) or documented other cardiovascular disease with signs of atherosclerosis (51.5% overall), type 2 diabetes (36.1%), high-density lipoprotein cholesterol <35 mg/dL or <0.906 mmol/L (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), or current smoking at enrollment (21.9%).

The primary endpoint was fatal or non-fatal myocardial infarction due to ischemic heart disease. No significant differences in the primary endpoint were observed between amlodipine and chlorthalidone therapy: risk ratio (RR) 0.98, 95% CI (0.90–1.07), p = 0.65. Among secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular outcome) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, RR = 1.38, 95% CI (1.25–1.52), p < 0.001). However, no significant differences in all-cause mortality were observed between the amlodipine and chlorthalidone groups: RR = 0.96, 95% CI (0.89–1.02), p = 0.20.

Valsartan

Valsartan is an orally active, potent, and specific angiotensin II receptor antagonist. It acts selectively on AT1 subtype receptors, which mediate the effects of angiotensin II. Increased angiotensin II levels resulting from AT1 receptor blockade by valsartan may stimulate unopposed AT2 receptors, counterbalancing AT1-mediated effects. Valsartan has no partial agonist activity at AT1 receptors and has approximately 20,000-fold greater affinity for AT1 receptors than for AT2 receptors.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Due to the lack of effect on ACE and absence of potentiation of bradykinin or substance P activity, angiotensin II receptor antagonists generally do not cause cough. In clinical trials comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower (p < 0.05) in patients treated with valsartan than in those receiving ACE inhibitors (2.6% vs. 7.9%, respectively). In patients previously treated with an ACE inhibitor who developed dry cough, this adverse effect occurred in 19.5% of cases with valsartan, 19% with thiazide diuretics, and 68.5% with ACE inhibitors (p < 0.05). Valsartan does not interact with or block receptors of other hormones or ion channels known to play important roles in cardiovascular regulation.

Administration of valsartan to patients with arterial hypertension reduces arterial pressure without affecting pulse rate.

In most patients, antihypertensive activity begins within 2 hours after a single oral dose, with maximal reduction in arterial pressure 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 during long-term therapy. Abrupt discontinuation of valsartan does not lead to rebound hypertension or other adverse clinical effects.

Valsartan has been shown to significantly reduce hospitalization rates in patients with chronic heart failure (NYHA class II–IV). A more pronounced effect was observed in patients not receiving ACE inhibitors or beta-blockers. Valsartan has also been shown to reduce cardiovascular mortality in clinically stable patients with left ventricular dysfunction or left ventricular systolic dysfunction following myocardial infarction.

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

Two large randomized controlled trials—ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)—evaluated the use of combined ACE inhibitor and ARB therapy.

ONTARGET included patients with cardiovascular or cerebrovascular disease or type 2 diabetes with prior target organ damage. VA NEPHRON-D included patients with type 2 diabetes and diabetic nephropathy.

In these studies, no significant benefits in renal and/or cardiovascular outcomes or mortality were observed compared to monotherapy, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was demonstrated. Given the similarity in pharmacokinetic properties, these findings are relevant to other ACE inhibitors and ARBs.

Therefore, concomitant use of ACE inhibitors and ARBs is not recommended in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) aimed to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or ARB in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated early due to increased risk of adverse events. Cardiovascular death and stroke occurred numerically more frequently in the aliskiren group than in the placebo group, and the aliskiren group also reported more frequent adverse events and serious adverse events of special interest (hyperkalemia, hypotension, and renal function impairment).

Valsartan/Amlodipine

The combination of amlodipine and valsartan provides dose-dependent additive reduction in arterial pressure across the therapeutic dose range. The antihypertensive effect after a single dose persists for 24 hours.

More than 1,400 patients with arterial hypertension received valsartan/amlodipine once daily in two placebo-controlled trials.

Valsartan/amlodipine was studied in two placebo-controlled trials involving patients with uncomplicated mild to moderate essential hypertension (mean seated diastolic pressure ≥95 and <110 mm Hg).

Patients at high cardiovascular risk were excluded: those with heart failure, type 1 diabetes, poorly controlled type 2 diabetes, or history of myocardial infarction or stroke within the past year.

In a multicenter, randomized, double-blind, active-controlled, parallel-group trial, normalization of blood pressure (to seated diastolic pressure <90 mm Hg at the end of the study) was achieved in patients whose blood pressure was inadequately controlled on monotherapy with 160 mg valsartan. Blood pressure normalization was achieved in 75% of patients receiving 10 mg/160 mg amlodipine/valsartan, 62% receiving 5 mg/160 mg amlodipine/valsartan, compared to 53% receiving 160 mg valsartan alone. Adding 10 mg and 5 mg amlodipine resulted in additional reductions in systolic/diastolic pressure of 6/4.8 mm Hg and 3.9/2.9 mm Hg, respectively, compared to 160 mg valsartan alone.

In another multicenter, randomized, double-blind, active-controlled, parallel-group trial, blood pressure normalization was achieved in patients whose blood pressure was inadequately controlled on 10 mg amlodipine monotherapy. Blood pressure normalization occurred in 78% of patients receiving 10 mg/160 mg amlodipine/valsartan, compared to 67% continuing 10 mg amlodipine alone. Adding 160 mg valsartan resulted in an additional reduction in systolic/diastolic pressure of 2.9/2.1 mm Hg compared to 10 mg amlodipine alone.

Valsartan/amlodipine was studied in an active-controlled trial involving 130 patients with essential hypertension and seated diastolic pressure ≥110 mm Hg and <120 mm Hg. In this trial (baseline blood pressure 171/113 mm Hg), valsartan/amlodipine dosed from 5 mg/160 mg to 10 mg/160 mg reduced sustained blood pressure by 36/29 mm Hg, compared to 32/28 mm Hg with lisinopril/hydrochlorothiazide dosed from 10 mg/12.5 mg to 20 mg/12.5 mg.

In two long-term studies, the effect of valsartan/amlodipine was maintained for over one year. Abrupt discontinuation did not lead to rapid rebound in blood pressure.

In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may provide similar blood pressure control with reduced edema.

Age, sex, race, and body mass index (≥30 kg/m², <30 kg/m²) did not influence the clinical response to valsartan/amlodipine.

Studies of valsartan/amlodipine have not been conducted in populations other than those with arterial hypertension. However, studies of valsartan have included patients with heart failure and post-myocardial infarction, and studies of amlodipine have included patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.

Pharmacokinetics

Linearity

Valsartan and amlodipine exhibit linear pharmacokinetics.

Amlodipine

Absorption. After oral administration of therapeutic doses of amlodipine alone, maximum plasma concentration (Cmax) is reached within 6–12 hours. Absolute bioavailability is calculated to be between 64% and 80%. Food intake does not affect amlodipine bioavailability.

Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins in patients with essential hypertension.

Metabolism. Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.

Elimination. Amlodipine elimination from plasma is biphasic, with a half-life of approximately 30–50 hours. Steady-state plasma levels are achieved after 7–8 days of continuous administration. Ten percent of unchanged amlodipine and 60% of its metabolites are excreted in urine.

Valsartan

Absorption. After oral administration, Cmax of valsartan in plasma is reached within 2–4 hours. Mean absolute bioavailability is approximately 23%. Food reduces exposure, as measured by AUC (plasma concentration–time), by about 40% and Cmax by 50%, although plasma concentrations 8 hours after dosing are similar between fasting and postprandial groups. The reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered independently of food intake.

Distribution. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 L, indicating limited tissue distribution. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.

Metabolism. Valsartan undergoes minimal biotransformation, with only about 20% of the dose converted to metabolites. A hydroxymetabolite, identified in plasma at low concentrations (<10% of valsartan AUC), is pharmacologically inactive.

Elimination. Valsartan exhibits multi-exponential elimination kinetics (half-life T1/2α <1 hour and T1/2β approximately 9 hours). Valsartan is primarily excreted unchanged in feces (approximately 83% of dose) and urine (about 13% of dose). After intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is approximately 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Valsartan/Amlodipine

After oral administration of valsartan/amlodipine, Cmax of valsartan and amlodipine in plasma is reached at 3 hours and 6–8 hours, respectively. The rate and extent of absorption of amlodipine/valsartan are equivalent to the bioavailability of valsartan and amlodipine when administered as individual agents.

Special Populations

Children

Pharmacokinetic data in pediatric patients are not available.

Elderly Patients (aged 65 years and older)

Time to reach Cmax of amlodipine in plasma is similar in younger and elderly patients. In elderly patients, amlodipine clearance tends to be reduced, leading to increased AUC and prolonged half-life. Mean systemic AUC of valsartan is 70% higher in elderly individuals than in younger patients; therefore, caution is advised when increasing the dose.

Renal Impairment

Renal dysfunction does not significantly affect the pharmacokinetics of amlodipine. As expected for a compound with renal clearance accounting for only 30% of total plasma clearance, no correlation was observed between renal function status and systemic exposure to valsartan.

Hepatic Impairment

In patients with hepatic impairment, clearance of amlodipine is reduced, leading to an increase in AUC of approximately 40–60%. On average, exposure to valsartan (as measured by AUC) in patients with mild to moderate chronic liver disease is about twice that in healthy volunteers (matched for age, sex, and body weight). Patients with liver disease should use the drug with caution.

Clinical characteristics.

Indications.

Essential hypertension in adult patients whose blood pressure is not controlled by monotherapy with amlodipine or valsartan.

Contraindications.

• Hypersensitivity to the active substance, to dihydropyridine derivatives, or to any of the excipients of the medicinal product.

• Severe hepatic impairment, biliary cirrhosis, or cholestasis.

• Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²).

• Pregnancy and planned pregnancy (see section "Use during pregnancy or breastfeeding").

• Severe hypotension.

• Shock (including cardiogenic shock).

• Obstruction of the left ventricular outflow tract (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).

• Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Drug-drug interactions

Studies on drug-drug interactions between amlodipine/valsartan and other medicinal products have not been conducted.

Medicinal products requiring caution during concomitant use

Other antihypertensive agents

Commonly used antihypertensive agents (e.g., alpha-blockers, diuretics) and other medicinal products that may cause hypotensive adverse effects (e.g., tricyclic antidepressants, alpha-blockers used for the treatment of benign prostatic hyperplasia) may potentiate the hypotensive effect of the combination.

Interactions related to amlodipine

Concomitant use not recommended

Grapefruit or grapefruit juice

The use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients bioavailability may be increased, leading to an enhanced hypotensive effect of the drug.

Medicinal products requiring caution during concomitant use

CYP3A4 inhibitors

Concomitant use of amlodipine with more or less potent CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in systemic exposure to amlodipine. Clinical manifestations of such pharmacokinetic changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.

CYP3A4 inducers (anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John’s wort (Hypericum perforatum))

When known CYP3A4 inducers are used concomitantly, plasma concentrations of amlodipine may be altered. Therefore, blood pressure should be monitored and dosage adjusted during and after concomitant use, especially with potent CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum).

Simvastatin

Repeated administration of 10 mg amlodipine with 80 mg simvastatin results in a 77% increase in simvastatin exposure compared to simvastatin alone. It is recommended to reduce the daily dose of simvastatin to 20 mg in patients taking amlodipine.

Dantrolene (infusions)

In animal studies, fatal cases of ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients predisposed to malignant hyperthermia and during treatment of malignant hyperthermia.

Other

In clinical studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.

Interactions related to valsartan

Concomitant use not recommended

Lithium

When lithium is administered concomitantly with ACE inhibitors or angiotensin II receptor antagonists, including valsartan, reversible increases in serum lithium concentrations and lithium toxicity have been observed. Concomitant use of valsartan and lithium is not recommended. If such combination therapy is necessary, serum lithium levels should be closely monitored. The risk of increased lithium toxicity may be further elevated when amlodipine/valsartan is used concomitantly with diuretics.

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

If medicinal products affecting potassium channels are prescribed in combination with valsartan, frequent monitoring of plasma potassium levels should be anticipated.

Medicinal products requiring caution during concomitant use

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

Concomitant use of angiotensin II antagonists and NSAIDs may result in attenuation of the antihypertensive effect. Additionally, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels. Therefore, at the initiation of treatment, monitoring of renal function and ensuring adequate hydration are recommended.

Inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir)

In vitro studies using human liver tissue have shown that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir) may increase systemic exposure to valsartan.

Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren

Clinical trial results have shown that dual blockade of the RAAS with combined use of ACE inhibitors, ARBs, or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single RAAS-acting agent. Therefore, concomitant use of ARBs—including valsartan—or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²).

Other

With valsartan monotherapy, no clinically significant drug interactions have been identified with the following agents: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glipizide.

Special precautions for use.

The safety and efficacy of amlodipine in the treatment of hypertensive crisis have not been established.

Patients with sodium and/or circulating blood volume depletion.

Excessive hypotension was observed in patients with uncomplicated arterial hypertension (0.4%) during placebo-controlled studies with amlodipine/valsartan. Symptomatic hypotension may occur in patients with activated renin-angiotensin system (with reduced sodium content and/or circulating blood volume, or receiving high doses of diuretics) who are taking angiotensin receptor blockers. Correction of this condition is recommended before initiating amlodipine/valsartan therapy, or close medical supervision at the beginning of treatment.

If arterial hypotension occurs during amlodipine/valsartan therapy, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Therapy may be continued after stabilization of blood pressure.

Hyperkalemia.

Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase potassium levels (e.g., heparin, etc.) should be administered with caution, and frequent monitoring of serum potassium levels is required.

Renal artery stenosis.

Valsar-AM should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney, as serum urea and creatinine levels may increase.

Renal transplantation.

There is no experience with the safe use of Valsar-AM in patients who have recently undergone kidney transplantation.

Hepatic impairment.

Valsartan is primarily excreted unchanged in bile. The elimination half-life of amlodipine is prolonged and the AUC (plasma concentration–time) is increased in patients with hepatic impairment; dosage recommendations have not been established. Particular caution is required when administering Valsar-AM to patients with mild to moderate hepatic impairment or biliary obstruction.

The maximum recommended dose for patients with mild or moderate hepatic impairment without cholestasis is 80 mg of valsartan.

Renal impairment.

Dose adjustment is not required in patients with mild or moderate renal impairment (eGFR > 30 mL/min/1.73 m²). In patients with moderate renal impairment, monitoring of serum potassium and creatinine levels is recommended.

Concomitant use of angiotensin receptor antagonists, including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).

Primary hyperaldosteronism.

Patients with primary hyperaldosteronism should not receive the angiotensin II antagonist valsartan, as their renin-angiotensin system is already suppressed due to the underlying disease.

Angioedema.

Angioedema, including laryngeal and glottal edema that may lead to airway obstruction, and/or swelling of the face, lips, pharynx, and/or tongue, has been reported in patients taking valsartan. Some of these patients had a history of angioedema with other drugs, including angiotensin-converting enzyme inhibitors (ACE inhibitors). Valsar-AM should be discontinued immediately if angioedema occurs; re-administration is not recommended.

Intestinal angioedema.

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Heart failure/post-myocardial infarction state.

Due to suppression of the renin-angiotensin-aldosterone system (RAAS), renal function impairment may occur in sensitive patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, use of ACE inhibitors and angiotensin receptor antagonists has led to oliguria and/or progressive azotemia, and in rare cases, acute renal failure and/or death. Similar outcomes have been observed with valsartan. Renal function should be assessed in patients with heart failure or post-myocardial infarction.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association) class III and IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine compared to placebo, although there was no significant difference in the development or worsening of heart failure. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality.

Aortic and mitral valve stenosis.

As with other vasodilators, particular caution should be exercised in patients with diagnosed mitral valve stenosis or severe aortic stenosis of low gradient.

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

Data indicate that concomitant use of ACE inhibitors, ARBs, or aliskiren increases the risk of hypotension, hyperkalemia, and renal function impairment (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, ARBs, or aliskiren is not recommended.

If dual blockade is absolutely necessary, it should be performed only under specialist supervision with frequent and careful monitoring of renal function, electrolyte concentrations, and blood pressure. Concomitant use of ACE inhibitors and ARBs is not recommended in patients with diabetic nephropathy.

The use of amlodipine/valsartan has not been studied in patients with conditions other than arterial hypertension.

Use during pregnancy or breastfeeding.

Pregnancy

This medicinal product is contraindicated in pregnancy and in women who are planning to become pregnant. If pregnancy is confirmed during treatment with this product, it should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on teratogenic risk after exposure to ACE inhibitors 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, a similar risk may exist with drugs of this class.

Exposure to ARBs during the second and third trimesters is known to have toxic effects on the human fetus (impaired renal function, oligohydramnios, delayed skull ossification) and newborn (renal failure, arterial hypotension, hyperkalemia).

If ARBs have been used from the second trimester of pregnancy, ultrasound assessment of fetal renal function and skull ossification is recommended.

Newborns whose mothers received ARBs should be closely monitored for the development of arterial hypotension.

Breastfeeding period

Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant is estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Due to lack of information on the use of amlodipine/valsartan during breastfeeding, the product is not recommended during this period; alternative agents with established safety profiles should be preferred, especially when breastfeeding newborns or preterm infants.

Fertility

Clinical studies on the effect on fertility have not been conducted.

Valsartan

Valsartan did not cause adverse effects on the reproductive system in male and female rats following oral administration at doses up to 200 mg/kg/day. This dose is 6 times higher than the maximum recommended human dose, based on mg/m² (using a daily dose of 320 mg for an oral dose in a 60 kg patient).

Amlodipine

In some patients treated with calcium channel blockers, reversible biochemical changes in sperm heads have been reported. Clinical data on the effect of amlodipine on fertility are insufficient. In one study in rats, adverse effects on male fertility were observed.

Ability to influence reaction speed when driving vehicles or operating machinery.

Dizziness or a feeling of weakness may occur in patients taking Valsar-AM after administration of the drug; therefore, patients should take this into account when driving vehicles or operating potentially hazardous machinery.

Amlodipine may have a slight to moderate effect on the ability to drive vehicles or operate machinery. During treatment with amlodipine, patients may experience symptoms such as dizziness, headache, fatigue, or nausea, which may affect reaction speed.

Method of Administration and Dosage

Patients whose blood pressure is not adequately controlled with monotherapy using amlodipine or valsartan may be switched to combination therapy with the medication Valser-AM. The recommended dose is 1 tablet per day. Tablets may be taken regardless of food intake. It is recommended to take Valser-AM with a small amount of water.

Patients currently receiving valsartan and amlodipine as separate agents may be switched to Valser-AM containing equivalent doses of the components.

Prior to switching to fixed-dose combination therapy, individual dose titration of each component (i.e., amlodipine and valsartan) is recommended. However, in cases of clinical necessity, direct substitution of monotherapy with fixed-dose combination therapy may be considered.

The recommended maximum daily dose is 1 tablet of Valser-AM 5 mg/160 mg or 1 tablet of Valser-AM 10 mg/160 mg (maximum allowable doses of the components being 10 mg amlodipine and 320 mg valsartan).

Dosage for Specific Patient Groups

Renal Impairment

There are no available data on the use of the combination of amlodipine and valsartan in patients with severe renal impairment.

Dose adjustment is not required in patients with mild to moderate renal impairment. In patients with moderate renal impairment, monitoring of serum potassium and creatinine levels is recommended.

Concomitant use of amlodipine and valsartan with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).

Diabetes Mellitus

Concomitant use of amlodipine and valsartan with aliskiren is contraindicated in patients with diabetes mellitus.

Hepatic Impairment

Valser-AM is contraindicated in patients with severe hepatic impairment.

Valser-AM should be used with caution in patients with hepatic impairment or biliary obstruction. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. Dosage recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established. When switching such patients with arterial hypertension (see section "Indications") and hepatic impairment to amlodipine or Valser-AM, the lowest recommended dose of amlodipine should be initiated, either as monotherapy or as part of combination therapy.

Elderly Patients (aged 65 years and older)

Standard dosing regimens are recommended for elderly patients.

Caution should be exercised when increasing the dose in elderly patients.

When switching elderly patients with arterial hypertension (see section "Indications") and hepatic impairment to amlodipine or Valser-AM, the lowest recommended dose of amlodipine should be initiated, either as monotherapy or as part of combination therapy.

Pediatric Populations

The safety and efficacy of amlodipine and valsartan in children (under 18 years of age) have not been studied. Data are lacking.

Children

Studies on the treatment of children (under 18 years of age) with this medication have not been conducted. Therefore, until more comprehensive information becomes available, Valser-AM is not recommended for use in pediatric patients.

Overdose

Symptoms

There is currently no experience with overdose of amlodipine and valsartan. The main symptom of valsartan overdose is likely to be marked hypotension with dizziness. Amlodipine overdose may lead to progressive peripheral vasodilation and possibly reflex tachycardia. Significant and potentially prolonged systemic hypotension has been reported, progressing to shock and fatal outcomes.

Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, with delayed onset (24–48 hours after ingestion), requiring mechanical ventilation. Early resuscitative measures (including fluid loading) to support perfusion and cardiac output may act as triggering factors.

Treatment

If ingestion was recent, induce emesis or perform gastric lavage. Absorption of amlodipine is significantly reduced by administration of activated charcoal immediately or within 2 hours after amlodipine intake.

Clinically significant hypotension resulting from overdose of amlodipine and valsartan requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, attention to circulating fluid volume, and urine output. The patient should be placed in a supine position with elevated limbs. Vasoconstrictor agents may be used to restore vascular tone and blood pressure, provided there are no contraindications to their use. In cases of persistent hypotension due to calcium channel blockade, intravenous administration of calcium gluconate may be beneficial.

Hemodialysis is unlikely to effectively remove valsartan or amlodipine from the body.

Adverse reactions.

The safety of amlodipine/valsartan was evaluated in five controlled clinical studies involving 5175 patients, of whom 2613 received valsartan in combination with amlodipine. The most commonly observed or significant and severe adverse reactions were: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, edema, soft tissue edema, facial edema, peripheral edema, increased fatigue, facial flushing, asthenia, and hot flushes.

The following criteria were used to assess the frequency of adverse reactions: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000); not known (frequency cannot be estimated from the available data).

* Mainly associated with cholestasis.

Additional information on the combination

Peripheral edema, a known side effect of amlodipine, generally occurred less frequently in patients receiving the amlodipine/valsartan combination than with amlodipine alone. In double-blind controlled clinical studies, the average incidence of peripheral edema, uniformly distributed across the entire dose range, was 5.1% for the amlodipine/valsartan combination.

Additional information on the drug components

Adverse reactions previously observed with either component of the drug (amlodipine or valsartan) may also occur with the amlodipine/valsartan combination, even if they were not reported during clinical studies or in the post-marketing period.

Amlodipine.

Individual cases of extrapyramidal syndrome were observed.

Valsartan.

The additional adverse reactions listed below were observed during clinical trials of valsartan monotherapy, regardless of causal relationship to the investigational drug.

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are advised to report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging, protected from moisture and inaccessible to children.

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

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited - Unit VII, India / Aurobindo Pharma Limited - Unit VII, India.

Manufacturer's address and site of manufacturing activity.

Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India / Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.