Valembik 10
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valembic 10 (Valembic 10)
Composition:
Active substances: amlodipine, valsartan;
One film-coated tablet contains amlodipine besylate equivalent to 10 mg of amlodipine and 160 mg of valsartan;
Excipients: microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry Yellow 03F52005 (hypromellose, titanium dioxide (E 171), polyethylene glycol 6000, talc, iron oxide yellow (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: oval-shaped, biconvex, film-coated tablets, smooth on both sides, yellow in color.
Pharmacotherapeutic group. Combined angiotensin II inhibitors.
ATC code C09DB01.
Pharmacological Properties.
Pharmacodynamics.
Valembic 10 contains two antihypertensive components with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium channel antagonists, and valsartan belongs to the class of angiotensin II antagonists. The combination of these ingredients produces an additive antihypertensive effect, reducing blood pressure to a greater extent than either component alone.
Amlodipine.
Amlodipine inhibits transmembrane influx of calcium ions into vascular and cardiac smooth muscles. The mechanism of amlodipine's antihypertensive action is due to direct relaxation of vascular smooth muscle, resulting in reduced peripheral vascular resistance and consequent lowering of arterial blood 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 causes vasodilation, leading to reduced arterial blood pressure in both supine and standing positions. This reduction in blood 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 young 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 showed 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 has no negative inotropic effect when administered at therapeutic doses in healthy 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 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 trial on morbidity and mortality – Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) – was conducted to compare newer therapeutic approaches: 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 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 (overall 51.5%), type 2 diabetes (36.1%), high-density lipoprotein cholesterol concentration <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: hazard ratio (HR) 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%, HR = 1.38, 95% CI (1.25–1.52), p < 0.001). However, no significant difference in all-cause mortality was observed between the amlodipine and chlorthalidone groups: HR = 0.96, 95% CI (0.89–1.02), p = 0.20.
Valsartan.
Valsartan is an orally active and specific angiotensin II receptor antagonist. It selectively acts on AT1 subtype receptors, which are predominantly responsible for the 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 exhibits no partial agonist activity at AT1 receptors and has approximately 20,000-fold greater affinity for AT1 than AT2 receptors.
Valsartan does not inhibit ACE (also known as kininase II), the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin. Because of its 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 an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who previously received an ACE inhibitor and developed dry cough, this adverse effect occurred in 19.5% of cases with valsartan treatment and in 19% with thiazide diuretic treatment, whereas cough was observed in 68.5% of patients receiving an ACE inhibitor (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 the drug to patients with arterial hypertension leads to reduced blood 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, 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.
It has been established that valsartan significantly reduces 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 pathology or left ventricular 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 – Veterans Affairs Nephropathy in Diabetes study) evaluated combination therapy with an ACE inhibitor and an angiotensin receptor blocker (ARB).
The ONTARGET trial included patients with cardiovascular or cerebrovascular disease or type 2 diabetes with confirmed target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.
In these studies, no significant benefits on renal and/or cardiovascular outcomes or mortality were observed with dual RAAS blockade compared to monotherapy. However, an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was demonstrated. Given the similarity in pharmacokinetic properties, these findings are also 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) was a study designed 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 study was terminated early due to an increased risk of adverse events. Cardiovascular death and stroke occurred numerically more often 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 dysfunction) compared to the placebo group.
Valsartan/amlodipine.
The combination of amlodipine and valsartan provides dose-dependent additive reduction in arterial blood pressure across the entire therapeutic dose range. The antihypertensive effect after a single dose of the combination persists for 24 hours.
More than 1,400 patients with arterial hypertension were treated once daily with the combination 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 blood pressure ≥95 and <110 mmHg).
Patients at high risk of cardiovascular events 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 trial, blood pressure normalization (defined as diastolic blood pressure <90 mmHg at the end of the trial) was achieved in patients whose blood pressure was inadequately controlled on monotherapy with valsartan 160 mg. Blood pressure was 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 blood pressure of 6/4.8 mmHg and 3.9/2.9 mmHg, respectively, compared to valsartan 160 mg monotherapy.
In another multicenter, randomized, double-blind, active-controlled, parallel-group trial, blood pressure normalization (diastolic blood pressure <90 mmHg at the end of the trial) was achieved in patients whose blood pressure was inadequately controlled on amlodipine 10 mg monotherapy. Blood pressure was normalized in 78% of patients receiving 10 mg/160 mg amlodipine/valsartan compared to 67% continuing on amlodipine 10 mg alone. Adding 160 mg valsartan resulted in an additional reduction in systolic/diastolic blood pressure of 2.9/2.1 mmHg compared to amlodipine 10 mg monotherapy.
The combination was studied in an active-controlled trial involving 130 patients with essential hypertension and seated diastolic blood pressure ≥110 mmHg and <120 mmHg. In this trial (baseline blood pressure 171/113 mmHg), treatment with the combination at doses from 5 mg/160 mg to 10 mg/160 mg reduced seated blood pressure by 36/29 mmHg compared to 32/28 mmHg with lisinopril/hydrochlorothiazide 10 mg/12.5 mg up to 20 mg/12.5 mg.
In two long-term studies, the antihypertensive effect of the combination 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 the combination.
Studies of the combination in populations other than those with arterial hypertension have not been conducted. However, studies with valsartan have been performed in patients with heart failure and post-myocardial infarction, and studies with amlodipine in 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 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 is eliminated in a biphasic manner, with an elimination half-life of approximately 30–50 hours. Steady-state plasma levels are achieved 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 exposure, as measured by AUC (area under the plasma concentration-time curve), by about 40% and Cmax by about 50%. However, plasma concentrations 8 hours after dosing are similar between fasting and fed conditions. 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 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 (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 of valsartan is approximately 2 L/h, with renal clearance of about 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 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 Valembic 10 are bioequivalent to valsartan and amlodipine administered as individual agents.
Special Populations.
Children
Pharmacokinetic data on the combination in pediatric patients are lacking.
Elderly patients (aged 65 years and older)
Time to reach Cmax of amlodipine in plasma is similar in younger and elderly patients. However, clearance of amlodipine tends to be reduced in elderly patients, leading to increased AUC and prolonged elimination half-life. Mean systemic AUC of valsartan is 70% higher in elderly individuals compared to 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 only 30% of total plasma clearance occurring via renal excretion, no correlation was observed between renal function and systemic exposure to valsartan.
Hepatic impairment.
In patients with hepatic impairment, clearance of amlodipine is reduced, leading to an increase in AUC by approximately 40–60%. In patients with mild to moderate chronic liver disease, exposure (as measured by AUC) to valsartan is on average twice that observed 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, 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 (ARAs), 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 Valymbik 10 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 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
Cytochrome P450 3A4 (CYP3A4) inhibitors
Concomitant use of amlodipine with moderate or 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 required.
Cytochrome P450 3A4 (CYP3A4) inducers (antiepileptic drugs (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John’s wort (Hypericum perforatum))
Concomitant use of known CYP3A4 inducers may alter amlodipine plasma concentrations. Therefore, blood pressure should be monitored and dosage adjusted during and after concomitant use, particularly 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 have been observed following intravenous administration of verapamil and dantrolene due to hyperkalemia. Because of 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 reported. 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 this combination is used with diuretics.
Potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels
If medicinal products that affect potassium levels are used concomitantly with valsartan, frequent monitoring of plasma potassium levels is recommended.
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 attenuate 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 therapy, monitoring of renal function and 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 ARAs, ACE inhibitors, or aliskiren
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, ARAs, 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 ARAs—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
No clinically significant drug interactions have been identified during monotherapy with valsartan when co-administered with the following medicinal products: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.
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 studies. Symptomatic hypotension may occur in patients with activated renin-angiotensin system (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 prior to administration of Valymbic 10, or close medical monitoring at the beginning of therapy.
If arterial hypotension occurs 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 drugs that may increase potassium levels (e.g., heparin, etc.) should be used with caution, and frequent monitoring of serum potassium levels should be anticipated.
Renal artery stenosis.
Valymbic 10 should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, as serum urea and creatinine levels may increase.
Kidney transplantation.
There is no experience with the safe use of Valymbic 10 in patients who have recently undergone kidney transplantation.
Hepatic impairment.
Valsartan is primarily excreted unchanged via 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 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 take the angiotensin II antagonist valsartan, as their renin-angiotensin system (RAS) is disrupted 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 drugs, including angiotensin-converting enzyme (ACE) inhibitors. Administration of Valymbic 10 should be discontinued immediately if angioedema occurs; re-administration is not recommended.
Heart failure/post-myocardial infarction state.
Due to suppression of the RAAS system, renal dysfunction may occur in sensitive patients. In patients with severe heart failure, in whom kidney function may depend on RAAS (renin-angiotensin-aldosterone system) activity, administration 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 after myocardial infarction.
In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association) class III–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 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 impaired renal function (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 Valymbic 10 has not been studied in patients with other conditions besides 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, its use should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.
Epidemiological data on the risk of teratogenicity 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 on 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 Valymbic 10 during lactation, the medicinal product is not recommended during breastfeeding; alternative drugs 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 on a mg/m² basis (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 study in rats, adverse effects on male fertility were observed.
Ability to influence reaction speed when driving or operating machinery.
Dizziness or weakness may occur in patients taking Valymbic 10 after administration of the medicinal product; 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 during treatment with amlodipine, their reaction time may be impaired.
Method of Administration and Dosage
Patients whose arterial pressure is not adequately controlled with monotherapy using amlodipine or valsartan may be switched to combination therapy with Valymbik 10. The recommended dose is:
1 tablet per day. Tablets may be taken independently of food intake. It is recommended to take Valymbik 10 with a small amount of water.
Patients currently receiving valsartan and amlodipine as separate agents may be switched to Valymbik 10 containing the same 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. In cases of clinical necessity, direct substitution of monotherapy with a fixed-dose combination may be considered.
Maximum daily dose – 1 tablet of Valymbik 10 mg/160 mg (maximum permitted doses of the drug components – 10 mg amlodipine, 320 mg valsartan).
Dosage in 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 this drug with aliskiren is contraindicated in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).
Diabetes Mellitus
Concomitant use of this drug with aliskiren is contraindicated in patients with diabetes mellitus.
Hepatic Impairment
The drug is contraindicated in patients with severe hepatic impairment.
Valymbik 10 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 or moderate hepatic impairment have not been established. When switching such patients with arterial hypertension (see section "Indications") and hepatic impairment to amlodipine or Valymbik 10, the lowest recommended dose of amlodipine used in monotherapy or in combination therapy should be prescribed.
Elderly Patients (aged 65 years and older)
Standard dosage 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 10, the lowest recommended dose of amlodipine in monotherapy or in combination therapy should be prescribed.
Pediatric Population
The safety and efficacy of Valymbik 10 in children (under 18 years of age) have not been established. Data are lacking.
Children
Studies on treatment with this drug in children (under 18 years of age) have not been conducted. Therefore, until more comprehensive information becomes available, Valymbik 10 is not recommended for use in children.
Overdose
Symptoms
There is currently no experience with overdose of Valymbik 10. The main symptom of valsartan overdose is likely to be marked arterial hypotension with dizziness. Amlodipine overdose may lead to progressive peripheral vasodilation and possibly reflex tachycardia. Reports include significant and potentially prolonged systemic hypotension, up to shock and fatal outcome.
Treatment
If the drug has been recently ingested, 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 drug overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the limbs, 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 calcium gluconate may be beneficial.
Hemodialysis is unlikely to remove valsartan or amlodipine effectively.
Adverse Reactions
The safety of the drug was evaluated in 5 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 (≥1/10 000, <1/1000); very rare (<1/10 000); unknown (frequency cannot be estimated from the available data).
| MedDRA system organ class |
Adverse reaction |
Frequency |
||
| Valymbic 10 |
Amlodipine |
Valsartan |
||
| Infections and infestations |
Nasopharyngitis |
Common |
-- |
-- |
| Influenza |
Common |
-- |
-- |
|
| Blood and lymphatic system disorders |
Decreased hemoglobin and hematocrit levels |
-- |
-- |
Unknown |
| Leukopenia |
-- |
Very rare |
-- |
|
| Neutropenia |
-- |
-- |
Unknown |
|
| Thrombocytopenia, sometimes with purpura |
-- |
Very rare |
Unknown |
|
| Immune system disorders |
Hypersensitivity |
Uncommon |
Very rare |
Not known |
| Nutritional and metabolism disorders |
Anorexia |
Uncommon |
-- |
-- |
| Hypercalcemia |
Uncommon |
-- |
-- |
|
| Hyperglycemia |
-- |
Very rare |
-- |
|
| Hyperlipidemia |
Uncommon |
-- |
-- |
|
| Hyperuricemia |
Uncommon |
-- |
-- |
|
| Hypokalemia |
Common |
-- |
-- |
|
| Hyponatremia |
Uncommon |
-- |
-- |
|
| Psychiatric disorders |
Depression |
-- |
Uncommon |
-- |
| Anxiety |
Uncommon |
-- |
-- |
|
| Insomnia/sleep disorders |
-- |
Uncommon |
-- |
|
| Mood swings |
-- |
Uncommon |
-- |
|
| Confusion |
-- |
Uncommon |
-- |
|
| Nervous system disorders |
Coordination disorders |
Uncommon |
-- |
-- |
| Dizziness |
Uncommon |
Common |
-- |
|
| Postural dizziness |
Uncommon |
-- |
-- |
|
| Dysgeusia |
-- |
Uncommon |
-- |
|
| Extrapyramidal syndrome |
-- |
Unknown |
-- |
|
| Headache |
Common |
Common |
-- |
|
| Hypertension |
-- |
Very rare |
-- |
|
| Paraesthesia |
Uncommon |
Uncommon |
-- |
|
| Peripheral neuropathy, neuropathy |
-- |
Very rare |
-- |
|
| Somnolence |
Uncommon |
Common |
-- |
|
| Syncope |
-- |
Uncommon |
-- |
|
| Tremor |
-- |
Uncommon |
-- |
|
| Hypoesthesia |
-- |
Uncommon |
-- |
|
| Eye disorders |
Visual disturbance |
Uncommon |
Uncommon |
-- |
| Blurred vision |
Uncommon |
Uncommon |
-- |
|
| Ear and labyrinth disorders |
Tinnitus |
Uncommon |
Uncommon |
-- |
| Dizziness |
Uncommon |
-- |
Uncommon |
|
| Cardiac disorders |
Palpitations |
Uncommon |
Common |
-- |
| Syncope |
Uncommon |
-- |
-- |
|
| Tachycardia |
Uncommon |
-- |
-- |
|
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
-- |
Very rare |
-- |
|
| Myocardial infarction |
-- |
Very rare |
-- |
|
| Vascular disorders |
Hyperemia |
-- |
Common |
-- |
| Hypotension |
Uncommon |
Uncommon |
-- |
|
| Orthostatic hypotension |
Uncommon |
-- |
-- |
|
| Angioedema |
-- |
Very rare |
Unknown |
|
| Respiratory system disorders |
Cough |
Uncommon |
Very rare |
Very rare |
| Dyspnea |
-- |
Uncommon |
-- |
|
| Pharyngolaryngeal pain |
Uncommon |
-- |
-- |
|
| Rhinitis |
-- |
Uncommon |
-- |
|
| Gastrointestinal disorders |
Abdominal discomfort and upper abdominal pain |
Uncommon |
Common |
Uncommon |
| Change in defecation rhythm |
-- |
Uncommon |
-- |
|
| Constipation |
Uncommon |
-- |
-- |
|
| Diarrhea |
Uncommon |
Uncommon |
-- |
|
| Dry mouth |
Uncommon |
Uncommon |
-- |
|
| Dyspepsia |
-- |
Uncommon |
-- |
|
| Gastritis |
-- |
Very rare |
-- |
|
| Gingival hyperplasia |
-- |
Very rare |
-- |
|
| Nausea |
Uncommon |
Common |
-- |
|
| Pancreatitis |
-- |
Very rare |
-- |
|
| Vomiting |
-- |
Uncommon |
-- |
|
| Hepatobiliary disorders |
Atypical liver function tests, including increased blood bilirubin levels |
-- |
Very rare* |
Unknown |
| Hepatitis |
-- |
Very rare |
-- |
|
| Intrahepatic cholestasis, jaundice |
-- |
Very rare |
-- |
|
| Skin and subcutaneous tissue disorders |
Alopecia |
-- |
Uncommon |
-- |
| Angioedema |
-- |
Very rare |
Unknown |
|
| Bullous dermatitis |
-- |
-- |
Unknown |
|
| Erythema |
Uncommon |
-- |
-- |
|
| Multiform erythema |
-- |
Very rare |
-- |
|
| Exanthema |
Uncommon |
Uncommon |
-- |
|
| Hyperhidrosis |
Uncommon |
Uncommon |
-- |
|
| Photosensitivity |
-- |
Uncommon |
-- |
|
| Pruritus |
Uncommon |
Uncommon |
Unknown |
|
| Purpura |
-- |
Uncommon |
-- |
|
| Rash |
Uncommon |
Uncommon |
Unknown |
|
| Skin discoloration |
-- |
Uncommon |
-- |
|
| Urticaria and other forms of rash |
-- |
Very rare |
-- |
|
| Exfoliative dermatitis |
-- |
Very rare |
-- |
|
| Stevens-Johnson syndrome |
-- |
Very rare |
-- |
|
| Quincke's edema |
-- |
Very rare |
-- |
|
| Toxic epidermal necrolysis |
-- |
Unknown |
-- |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
Uncommon |
Uncommon |
-- |
| Back pain |
Uncommon |
Uncommon |
-- |
|
| Joint swelling |
Uncommon |
-- |
-- |
|
| Muscle cramps |
Uncommon |
Uncommon |
-- |
|
| Muscle pain |
-- |
Uncommon |
Unknown |
|
| Ankle swelling |
-- |
Common |
-- |
|
| Heaviness sensation |
Uncommon |
-- |
-- |
|
| Renal and urinary disorders |
Increased blood creatinine levels |
-- |
-- |
Unknown |
| Urinary disorder |
-- |
Uncommon |
-- |
|
| Nocturia |
-- |
Uncommon |
-- |
|
| Polyuria |
Uncommon |
Uncommon |
-- |
|
| Polyuria |
Uncommon |
-- |
-- |
|
| Renal failure and impaired kidney function |
-- |
-- |
Unknown |
|
| Reproductive system disorders |
Impotence |
-- |
Uncommon |
-- |
| Erectile dysfunction |
Uncommon |
-- |
-- |
|
| Gynecomastia |
-- |
Uncommon |
-- |
|
| General disorders |
Asthenia |
Common |
Uncommon |
-- |
| Discomfort, malaise |
-- |
Uncommon |
-- |
|
| Increased fatigue |
Common |
Common |
Uncommon |
|
| Facial swelling |
Common |
-- |
-- |
|
| Hyperemia, flushing |
Common |
-- |
-- |
|
| Chest pain, non-cardiac |
-- |
Uncommon |
-- |
|
| Edema |
Common |
Common |
-- |
|
| Peripheral edema |
Common |
-- |
-- |
|
| Pain |
-- |
Uncommon |
-- |
|
| Soft tissue swelling |
Common |
-- |
-- |
|
| Investigations |
Increased blood potassium levels |
-- |
-- |
Unknown |
| Increased body weight |
-- |
Uncommon |
-- |
|
| Decreased body weight |
-- |
Uncommon |
-- |
|
* Mainly associated with cholestasis.
Additional information regarding the combination.
Peripheral edema, a known side effect of amlodipine, generally occurred less frequently in patients receiving the amlodipine/valsartan combination than in those receiving amlodipine alone. In double-blind, controlled clinical trials, the average incidence of peripheral edema, uniformly distributed across the entire dose range, was 5.1% for the amlodipine/valsartan combination.
Additional information regarding the drug components.
Adverse reactions previously observed with either component of the drug (amlodipine or valsartan) may also occur with Valymbik 10, even if they were not reported during clinical trials or in the post-marketing period.
Amlodipine.
| Common |
Somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling. |
| Uncommon |
Insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypesthesia, visual disturbances (including diplopia), tinnitus, hypotension, dyspnea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, urinary disorders, increased frequency of urination, impotence, gynecomastia, chest pain, malaise, weight gain or weight loss. |
| Rare |
Confusion. |
| Very rare |
Leukopenia, thrombocytopenia, allergic reactions, hyperglycemia, hypertension, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, increased liver enzyme levels, usually associated with cholestasis, angioneurotic edema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity. |
| Not known |
Toxic epidermal necrolysis. |
Individual cases of extrapyramidal syndrome have been reported.
Valsartan.
The additional adverse reactions listed below have been observed during clinical trials of valsartan monotherapy, regardless of causal relationship to the investigational drug.
| Unknown |
Decreased hemoglobin levels, decreased hematocrit levels, neutropenia, thrombocytopenia, increased serum potassium levels, increased liver function tests, including serum bilirubin concentration, renal failure and kidney function disorders, increased serum creatinine levels, angioedema, myalgia, vasculitis, hypersensitivity reactions, including serum sickness. |
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 in a blister pack of 8, 1 blister pack per cardboard box.
Prescription status. Prescription only.
Manufacturer. Alembic Pharmaceuticals Limited.
Manufacturer's address and place of business.
Panelav, PV Tajpura, Taluka: Halol, District: Panchmahal, Gujarat – 389 350, India.