Valembik 5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valembic 5 (Valembic 5)

Composition:

Active substances: amlodipine, valsartan;

One film-coated tablet contains amlodipine besylate equivalent to amlodipine 5 mg and valsartan 160 mg;

Excipients: microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry yellow 03F520011 (hypromellose, titanium dioxide (E 171), polyethylene glycol 8000, talc, iron oxide yellow (E 172), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex, film-coated tablets, smooth on both sides, orange in color.

Pharmacotherapeutic group. Combined angiotensin II inhibitors.

ATC code C09D B01.

Pharmacological Properties.

Pharmacodynamics.

Valzembic 5 contains two antihypertensive components with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine, a calcium channel blocker, and valsartan, an angiotensin II antagonist. 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 cells. The antihypertensive mechanism of amlodipine is due to direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and 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.

After administration of therapeutic doses to patients with essential 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 normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changes in filtration fraction or 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 or 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 essential 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

The randomized, double-blind 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 the thiazide diuretic chlorthalidone 12.5–25 mg daily in patients with mild to moderate arterial hypertension.

A total of 33,357 hypertensive patients aged 55 years and older were randomized, with a mean follow-up 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), documented atherosclerotic cardiovascular disease (51.5%), type 2 diabetes (36.1%), high-density lipoprotein cholesterol <35 mg/dL (<0.906 mmol/L) (11.6%), left ventricular hypertrophy diagnosed by ECG or echocardiography (20.9%), or current smoking (21.9%).

The primary endpoint was fatal coronary heart disease or non-fatal myocardial infarction. 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 active and specific oral angiotensin II receptor antagonist. It selectively acts on the AT1 receptor subtype, which mediates the known effects of angiotensin II. Increased angiotensin II levels resulting from AT1 receptor blockade by valsartan may stimulate unopposed AT2 receptors, potentially counterbalancing AT1 effects. Valsartan has no partial agonist activity at AT1 receptors and exhibits approximately 20,000-fold greater affinity for AT1 than for AT2 receptors.

Valsartan does not inhibit ACE (also known as kininase II), the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin. Due to the lack of ACE inhibition and absence of potentiation of bradykinin or substance P, 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 receiving valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients previously treated with an ACE inhibitor and experiencing dry cough, switching to valsartan resolved the cough in 19.5% of cases, compared to 19% with a thiazide diuretic, while cough persisted in 68.5% of patients continuing ACE inhibitor therapy (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 blood pressure reduction 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), with a more pronounced effect in patients not receiving ACE inhibitors or beta-blockers. Valsartan also reduces cardiovascular mortality in clinically stable patients with left ventricular dysfunction or pathology 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 combined use of an ACE inhibitor and an angiotensin receptor antagonist (ARA).

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

In these trials, dual RAAS blockade did not show significant benefits on renal and/or cardiovascular outcomes or mortality compared to monotherapy, but was associated with increased risks of hyperkalemia, acute kidney injury, and/or hypotension. Given the similarity in pharmacokinetic properties, these findings are relevant to other ACE inhibitors and ARAs.

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

The ALTITUDE trial (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 ARA 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 numerically occurred more frequently in the aliskiren group than in the placebo group, and the aliskiren group also reported more adverse events and serious adverse events of special interest (hyperkalemia, hypotension, and renal dysfunction).

Valsartan/Amlodipine.

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

More than 1,400 patients with arterial hypertension were treated once daily in two placebo-controlled trials.

The combination was studied in two placebo-controlled trials involving patients with uncomplicated mild to moderate essential hypertension (mean seated diastolic pressure ≥95 and <110 mmHg).

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 one year.

In a multicenter, randomized, double-blind, active-controlled, parallel-group study, blood pressure normalization (diastolic pressure <90 mmHg at end of trial) was achieved in patients whose blood pressure was inadequately controlled on monotherapy with 160 mg valsartan. Blood pressure normalized 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 mmHg and 3.9/2.9 mmHg, respectively, compared to 160 mg valsartan alone.

In another multicenter, randomized, double-blind, active-controlled, parallel-group study, blood pressure normalization was achieved in patients whose blood pressure was inadequately controlled on 10 mg amlodipine monotherapy. Blood pressure normalized 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 mmHg compared to 10 mg amlodipine alone.

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

In two long-term studies, the antihypertensive effect was maintained for over one year. Abrupt discontinuation did not lead to rapid rebound hypertension.

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 clinical response to the combination.

The combination has not been studied in populations other than those with arterial hypertension. However, studies with valsartan have included patients with heart failure and post-myocardial infarction, and studies with 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 estimated at 64–80%. Food intake does not affect amlodipine bioavailability.

Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies show 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. Plasma elimination of amlodipine is biphasic, with a half-life of approximately 30–50 hours. Steady-state plasma levels are reached after 7–8 days of continuous dosing. About 10% of unchanged amlodipine and 60% of its metabolites are excreted in urine.

Valsartan.

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

Distribution. The steady-state volume of distribution 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 (approximately 13% of dose). After intravenous administration, plasma clearance 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 approximately 6 hours.

Valsartan/Amlodipine.

After oral administration of the combination, Cmax of valsartan and amlodipine in plasma is reached at 3 hours and 6–8 hours, respectively. The rate and extent of absorption of Valzembic 5 are bioequivalent to valsartan and amlodipine administered as individual agents.

Special Populations.

Children

Pharmacokinetic data in pediatric patients are not available.

Elderly Patients (aged 65 years and older)

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

Renal Impairment.

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

Hepatic Impairment.

In patients with hepatic impairment, amlodipine clearance is reduced, resulting in an increase in AUC by approximately 40–60%. In patients with mild to moderate chronic liver disease, valsartan exposure (as measured by AUC) is on average twice that observed in healthy, age-, sex-, and weight-matched volunteers. Patients with hepatic 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, 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 types of interactions.

Drug interactions

Drug interaction studies of Valymbic 5 with 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 antihypertensive effect of the combination.

Interactions related to amlodipine

Concomitant use not recommended

Grapefruit or grapefruit juice

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

Medicinal products requiring caution during concomitant use

CYP3A4 inhibitors

Concomitant use of amlodipine with moderate or strong 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, particularly with strong 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 used 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 the medicinal product is used concomitantly with diuretics.

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

When medicinal products that affect potassium levels are used 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 nonselective NSAIDs

Concomitant use of angiotensin II antagonists and NSAIDs may result in reduced 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, monitoring of renal function and ensuring adequate hydration are recommended at the start of treatment.

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 agent affecting the RAAS. 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

During monotherapy with valsartan, no clinically significant drug interactions have been identified with the following medicinal products: 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 deficiency.

Excessive hypotension was observed in patients with uncomplicated arterial hypertension (0.4%) during placebo-controlled trials. Symptomatic hypotension may occur in patients with activated renin-angiotensin system (RAS) (with reduced sodium and/or circulating blood volume, and in those receiving high doses of diuretics) who are taking angiotensin receptor blockers. Correction of this condition is recommended before initiating treatment with Valembic 5, or close medical monitoring during the initial phase of therapy.

In case of arterial hypotension during treatment with the medicinal product, the patient should be placed in a supine position and, if necessary, intravenous infusion of physiological saline should be administered. Treatment may be continued after stabilization of blood pressure.

Hyperkalemia.

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

Renal artery stenosis.

Valembic 5 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.

Kidney transplantation.

There is no experience with the safe use of Valembic 5 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 the medicinal product to patients with mild or moderate hepatic impairment or biliary obstructive disorders.

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 (RAS) is suppressed due to the underlying disease.

Angioedema.

Angioedema, including laryngeal and glottal edema that may lead to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling, has been observed in patients taking valsartan. Some of these patients had a history of angioedema with other medicinal products, including angiotensin-converting enzyme inhibitors (ACE inhibitors). Valembic 5 should be discontinued immediately if angioedema occurs; re-administration is not recommended.

Heart failure/post-myocardial infarction state.

Due to suppression of the RAS system, renal function impairment may occur in susceptible patients. In patients with severe heart failure, in whom renal function may depend on RAS activity, treatment with 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 following myocardial infarction.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA 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 documented mitral valve stenosis or severe aortic stenosis of low degree.

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 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 Valembic 5 has not been studied in patients with conditions other than arterial hypertension.

Use during pregnancy or breastfeeding.

Pregnancy.

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

Epidemiological data on the teratogenic risk following 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 the newborn (renal failure, arterial hypotension, hyperkalemia).

Ultrasound evaluation of fetal renal function and skull ossification is recommended following exposure to ARBs starting from the second trimester of pregnancy.

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

Lactation (breastfeeding).

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 the lack of information on the use of Valembic 5 during breastfeeding, the medicinal product is not recommended during this period; alternative medicinal products with a well-established safety profile 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, adjusted by body surface area (based on a 320 mg daily dose for 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 rat study, adverse effects on male fertility were observed.

Ability to affect reaction speed when driving or operating machinery.

Dizziness or weakness may occur in patients taking Valembic 5; therefore, patients should take this into account when driving or operating potentially hazardous machinery.

Amlodipine may have a mild to moderate effect on the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue, or nausea while taking amlodipine, their reaction time may be impaired.

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 Valymbik 5. The recommended dose is 1 tablet daily. Tablets may be taken independently of food intake. It is recommended to take Valymbik 5 with a small amount of water.

Patients currently receiving separate treatment with valsartan and amlodipine may be switched to Valymbik 5 containing equivalent doses of the components.

Prior to switching to fixed-dose combination therapy, individual dose titration with the individual components (i.e., amlodipine and valsartan) is recommended. However, direct substitution of monotherapy with fixed-dose combination therapy may be considered if clinically indicated.

Maximum daily dose – 1 tablet of Valymbik 5 mg/160 mg (maximum allowable doses of the drug components – 10 mg amlodipine, 320 mg valsartan).

Dosage for Specific Patient Groups

Renal Impairment

There are no available clinical data on the use of the drug in patients with severe renal impairment.

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

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

Diabetes Mellitus

Concomitant use of the drug with aliskiren is contraindicated in patients with diabetes mellitus.

Hepatic Impairment

The drug is contraindicated in patients with severe hepatic impairment.

Valymbik 5 should be used with caution in patients with hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan.

Dosage recommendations for amlodipine in patients with mild or moderate hepatic impairment have not been established. When switching patients with arterial hypertension (see section "Indications") and hepatic impairment to amlodipine or Valymbik 5, 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 Valymbik 5, the lowest recommended dose of amlodipine should be prescribed, either as monotherapy or as part of combination therapy.

Pediatric Population

The safety and efficacy of Valymbik 5 in children (under 18 years of age) have not been established. Data are lacking.

Children

Studies on the treatment of children (under 18 years of age) with this drug have not been conducted. Therefore, until more comprehensive data are available, Valymbik 5 is not recommended for use in children.

Overdose

Symptoms

There is currently no experience with Valymbik 5 overdose. The main symptom of valsartan overdose is likely to be pronounced arterial hypotension with dizziness. Amlodipine overdose may lead to progressive peripheral vasodilation and possibly reflex tachycardia. Cases of significant and potentially prolonged systemic hypotension have been reported, progressing to shock and fatal outcome.

Treatment

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

Clinically significant arterial hypotension caused by overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the limbs, and attention to circulating fluid volume and urinary output. A vasoconstrictor agent may be used to restore vascular tone and blood pressure, provided there are no contraindications to its use. In cases of persistent hypotension due to calcium channel blockade, intravenous administration of calcium gluconate may be beneficial.

Hemodialysis is unlikely to remove valsartan or amlodipine effectively.

Adverse Reactions

The safety of the medicinal product 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 swelling, facial swelling, 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 (≥1/10000, <1/1000); very rare (<1/10000); not known (frequency cannot be estimated from the available data).

* Mainly associated with cholestasis.

Additional information regarding the combination.

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

Additional information regarding the components of the medicinal product.

Adverse reactions previously observed with either component of the medicinal product (amlodipine or valsartan) may also occur with the use of Valymbik 5, even if they were not reported during clinical trials or in the post-marketing period.

Amlodipine.

Individual cases of extrapyramidal syndrome were reported.

Val­sar­tan.

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

Shelf life. 3 years.

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

Packaging. Film-coated tablets, 8 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Alembic Pharmaceuticals Limited.

Manufacturer's address and place of business.
Panellav, P.V. Tajpura, Taluka Halol, District Panchmahal, Gujarat – 389 350, India.