Valsartan a 160/10
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- INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valmisar A 80/5 / Valmisar A 80/5 Valmisar A 160/5 / Valmisar A 160/5 Valmisar A 160/10 / Valmisar A 160/10
- Composition:
- Pharmacological Properties.
- Clinical characteristics.
- Special precautions for use.
- Method of Administration and Dosage
- Adverse reactions
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Valmisar A 80/5 / Valmisar A 80/5 Valmisar A 160/5 / Valmisar A 160/5 Valmisar A 160/10 / Valmisar A 160/10
Composition:
1 tablet of 80 mg/5 mg contains:
Active substances: valsartan 80 mg; amlodipine besylate equivalent to amlodipine 5 mg;
Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating Instacoat Universal Yellow A05G11327: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171), iron oxide yellow (E 172).
1 tablet of 160 mg/5 mg contains:
Active substances: valsartan 160 mg; amlodipine besylate equivalent to amlodipine 5 mg;
Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating Instacoat Universal Yellow A05G11327: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171), iron oxide yellow (E 172).
1 tablet of 160 mg/10 mg contains:
Active substances: valsartan 160 mg; amlodipine besylate equivalent to amlodipine 10 mg;
Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating Instacoat Universal Yellow A05G11323: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172).
Pharmaceutical form. Film-coated tablets.
Main physico-chemical properties:
Tablets 80 mg/5 mg – biconvex, film-coated, round tablets of dark yellow color, with "T28" engraved on one side and smooth on the other;
Tablets 160 mg/5 mg – biconvex, film-coated, oval-shaped tablets of dark yellow color, with "C94" engraved on one side and smooth on the other;
Tablets 160 mg/10 mg – biconvex, film-coated, oval-shaped tablets of pale yellow color, with "C95" engraved on one side and smooth on the other.
Pharmacotherapeutic group. Combined angiotensin II inhibitors.
ATC code: C09D B01.
Pharmacological Properties.
Pharmacodynamics.
Valmisar A 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 blood pressure more 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 consequent lowering of arterial blood pressure. Experimental data confirm that amlodipine binds at both dihydropyridine and non-dihydropyridine binding sites. Contraction of cardiac and vascular smooth muscle depends on the influx of extracellular calcium into these cells through specific ion channels.
Following administration of therapeutic doses to patients with hypertension, amlodipine induces 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 concentration 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 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 demonstrated that amlodipine lacks negative inotropic effects at therapeutic doses in both 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 hypertension or angina, no changes in electrocardiographic parameters were observed.
Amlodipine has demonstrated positive clinical effects 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 angiotensin-converting enzyme [ACE] inhibitor) as first-line therapy, versus the thiazide diuretic chlorthalidone 12.5–25 mg daily, in patients with mild to moderate 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 evidence of atherosclerosis (51.5% overall), 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 ischemic heart disease or non-fatal myocardial infarction. No significant difference in the primary endpoint was 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, potent, and specific angiotensin II receptor antagonist. It selectively blocks 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, counterbalancing AT1-mediated effects. Valsartan has no partial agonist activity at the AT1 receptor and exhibits 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. 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 receiving valsartan (2.6%) than in those receiving an ACE inhibitor (7.9%). In patients who previously experienced cough with an ACE inhibitor, this adverse effect occurred in 19.5% of those treated with valsartan and 19% of those treated with a thiazide diuretic, compared to 68.5% in the ACE inhibitor group (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 hypertension reduces arterial blood pressure without affecting pulse rate.
In most patients, after a single oral dose, onset of antihypertensive activity occurs within 2 hours, 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.
Valsartan has been shown to significantly reduce hospitalization rates in patients with chronic heart failure (NYHA class II–IV). The effect was more pronounced 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 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 (Veterans Affairs Nephropathy in Diabetes)—evaluated the use of combined ACE inhibitor and angiotensin receptor antagonist (ARA) therapy.
ONTARGET included patients with cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D 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 compared to monotherapy, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was demonstrated. Due to 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.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) aimed to assess 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 an increased risk of adverse events. Cardiovascular death and stroke occurred more frequently in the aliskiren group than in the placebo group, and the aliskiren group also experienced higher rates of adverse and serious adverse events of particular concern (hyperkalemia, hypotension, and renal dysfunction).
Valsartan/Amlodipine
The combination of amlodipine and valsartan provides dose-dependent additive blood pressure reduction across the entire therapeutic dose range. The antihypertensive effect after a single dose lasts 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 one year.
In a multicenter, randomized, double-blind, active-controlled, parallel-group trial, blood pressure normalization (seated diastolic pressure <90 mm Hg at end of trial) was assessed in patients whose blood pressure was inadequately controlled on valsartan monotherapy 160 mg. 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 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 assessed in patients with inadequate control on amlodipine monotherapy 10 mg. Blood pressure normalized in 78% of patients receiving 10 mg/160 mg amlodipine/valsartan, compared to 67% continuing on 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 mean seated diastolic pressure ≥110 mm Hg and <120 mm Hg. In this trial (baseline blood pressure 171/113 mm Hg), valsartan/amlodipine at doses 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 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 result in rapid blood pressure rebound.
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 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, peak 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 have shown that about 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 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 the area under the concentration-time curve (AUC) 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 with or without food.
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 has been identified in plasma at low concentrations (<10% of valsartan AUC) and is pharmacologically inactive.
Elimination. Valsartan exhibits multi-exponential elimination kinetics (T1/2α <1 hour, T1/2β ~9 hours). It is primarily excreted unchanged in feces (~83% of dose) and urine (~13% of dose). After intravenous administration, plasma clearance is approximately 2 L/hour, and renal clearance is ~0.62 L/hour (~30% of total clearance). The elimination half-life of valsartan is 6 hours.
Valsartan/Amlodipine
After oral administration of Valmisar A, Cmax of valsartan and amlodipine in plasma is reached at 3 and 6–8 hours, respectively. The rate and extent of absorption of Valmisar A 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)
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 elimination 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 the pharmacokinetics of amlodipine. As expected for a compound with only 30% of total plasma clearance being renal, no correlation between renal function and systemic exposure to valsartan was observed.
Hepatic Impairment
In patients with hepatic impairment, amlodipine clearance is reduced, resulting in an increase in AUC of approximately 40–60%. On average, AUC exposure to valsartan in patients with mild to moderate chronic liver disease is approximately twice that in healthy, age-, sex-, and weight-matched volunteers. 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.
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Hypersensitivity to the active substance, dihydropyridine derivatives, or to any of the excipients of the medicinal product.
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Severe hepatic impairment, biliary cirrhosis, or cholestasis.
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Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).
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Pregnancy and planned pregnancy (see section "Use during pregnancy or breastfeeding").
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Severe hypotension.
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Shock (including cardiogenic shock).
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Obstruction of the left ventricular outflow tract (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
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Hemodynamically unstable heart failure following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Drug interactions
Studies on drug interactions of Valmisar A with other medicinal products have not been conducted.
Medicinal products requiring caution when co-administered
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 enhance the hypotensive 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 hypotensive effect of the drug.
Medicinal products requiring caution when co-administered
CYP3A4 inhibitors
Concomitant administration 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 co-administered, plasma concentrations of amlodipine may change. Therefore, blood pressure should be monitored and dosage adjusted during and after co-administration, 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 animals, fatal cases of ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed after 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 Valmisar A is used concomitantly with diuretics.
Potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels
When agents affecting potassium levels are prescribed together with valsartan, frequent monitoring of plasma potassium levels should be anticipated.
Medicinal products requiring caution when co-administered
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid (>3 g/day), and non-selective 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 renal impairment and elevated serum potassium levels. Therefore, monitoring of renal function and ensuring adequate hydration at the start of treatment is 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 RAS with ARBs, ACE inhibitors, or aliskiren
Clinical trial results have shown that dual blockade of the RAS through 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 acting on the RAS. Therefore, concomitant use of ARBs (including valsartan) or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).
Other
No clinically significant drug interactions have been identified during monotherapy with valsartan 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 (CBV) depletion
Excessive hypotension was observed in patients with uncomplicated arterial hypertension (0.4%) treated with valsartan/amlodipine in placebo-controlled studies. Symptomatic hypotension may occur in patients with activated renin-angiotensin system (with reduced sodium and/or CBV content, or receiving high doses of diuretics) who are taking angiotensin receptor blockers. Correction of this condition is recommended prior to initiating valsartan/amlodipine therapy, or close medical monitoring at the beginning of treatment.
In case of arterial hypotension occurring during treatment with valsartan/amlodipine, the patient should be placed in a supine position and, if necessary, intravenous infusion of physiological saline should be administered. After stabilization of blood pressure, treatment may be continued.
Hyperkalemia
Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase potassium levels (e.g., heparin) should be used with caution, and frequent monitoring of serum potassium levels is required.
Renal artery stenosis
Valsartan/amlodipine 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 valsartan/amlodipine 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 AUC is increased in patients with hepatic impairment; dosage recommendations have not been established. Particular caution is necessary when administering valsartan/amlodipine to patients with mild to 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 to 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 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 facial, lip, pharyngeal, and/or tongue swelling, has been reported in patients taking valsartan. Some of these patients had a history of angioedema with other drugs, including ACE inhibitors. The drug should be discontinued immediately if angioedema occurs; re-administration is not recommended.
Heart failure/post-myocardial infarction state
Due to suppression of the RAAS, renal function impairment may occur in susceptible patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and ARAs 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 than with 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 RAAS
Data indicate that concomitant use of ACE inhibitors, ARAs, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, ARAs, 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 ARAs is not recommended in patients with diabetic nephropathy.
The use of Valmisar A 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, administration must 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, but 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).
If ARBs have been used from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull ossification is recommended.
Infants born to mothers who have taken ARBs should be closely monitored for the development of arterial hypotension.
Breastfeeding period
Amlodipine is excreted in 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.
Since information on the use of Valmisar A during breastfeeding is lacking, the drug is not recommended during lactation; 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 (using 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. Adverse effects on male fertility were observed in one rat study.
Ability to influence reaction speed when driving or operating machinery.
Dizziness or weakness may occur in patients taking Valmisar A after taking the drug; therefore, patients should take this into account when driving or operating potentially hazardous machinery.
Amlodipine may have a slight 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 Valmisar A. The recommended dose is 1 tablet per day. Valmisar A tablets may be taken regardless of food intake. It is recommended to take Valmisar A with a small amount of water.
Patients currently receiving valsartan and amlodipine as separate agents may be switched directly to Valmisar A containing equivalent doses of the components.
Prior to initiating fixed-dose combination therapy, individual dose titration with the individual components (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.
Maximum daily dose: 1 tablet of Valmisar A 5 mg/80 mg, or 1 tablet of Valmisar A 5 mg/160 mg, or 1 tablet of Valmisar A 10 mg/160 mg (maximum permitted doses of the components: 10 mg amlodipine, 320 mg valsartan).
Dosage in Specific Patient Populations
Renal Impairment
There are no available clinical data on the use of Valmisar A 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 Valmisar A with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m²).
Diabetes Mellitus
Concomitant use of Valmisar A with aliskiren is contraindicated in patients with diabetes mellitus.
Hepatic Impairment
Valmisar A is contraindicated in patients with severe hepatic impairment.
Valmisar A should be used with caution in patients with hepatic impairment or biliary obstruction. In patients with mild or 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 elderly patients with hypertension (see section "Indications") and hepatic impairment to amlodipine or Valmisar A, the lowest recommended dose of amlodipine should be initiated, either as monotherapy or as part of combination therapy.
Elderly Patients (Age 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 hypertension (see section "Indications") and hepatic impairment to amlodipine or Valmisar A, the lowest recommended dose of amlodipine should be initiated, either as monotherapy or as part of combination therapy.
Pediatric Population
The safety and efficacy of Valmisar A 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 medication have not been conducted. Therefore, until more complete information becomes available, Valmisar A is not recommended for use in pediatric patients.
Overdose
Symptoms
There is currently no experience with overdose of Valmisar A. The principal symptom of valsartan overdose is likely to be marked hypotension with dizziness. Overdose of amlodipine may lead to progressive peripheral vasodilation and possibly reflex tachycardia. Profound and potentially prolonged systemic hypotension, up to shock and fatal outcome, has been reported.
Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.
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 two hours after amlodipine intake.
Clinically significant hypotension resulting from Valmisar A overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the limbs, attention to circulating blood volume, and urine output. A vasoconstrictor agent may be used to restore vascular tone and blood pressure, provided there are no contraindications to its use. In persistent hypotension due to calcium channel blockade, intravenous calcium gluconate may be beneficial.
Hemodialysis is unlikely to effectively remove valsartan or amlodipine.
Adverse reactions
The safety of Valmisar A has been evaluated in five controlled clinical studies involving 5175 patients, of whom 2613 received valsartan in combination with amlodipine. The most commonly observed or significant or 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); frequency not known (frequency cannot be estimated from the available data).
| MedDRA system organ class |
Adverse reaction |
Frequency |
||
| Valmisar A |
Amlodipine |
Valsartan |
||
| Infections and infestations |
Nasopharyngitis |
Common |
-- |
-- |
| Influenza |
Common |
-- |
-- |
|
| Blood and lymphatic system disorders |
Decreased hemoglobin and hematocrit levels |
-- |
-- |
Frequency unknown |
| Leukopenia |
-- |
Very rare |
-- |
|
| Neutropenia |
-- |
-- |
Frequency unknown |
|
| Thrombocytopenia, sometimes with purpura |
-- |
Very rare |
Frequency unknown |
|
| Immune system disorders |
Hypersensitivity |
Uncommon |
Very rare |
Frequency unknown |
| 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 disorder |
Uncommon |
-- |
-- |
| Dizziness |
Uncommon |
Common |
-- |
|
| Postural dizziness |
Uncommon |
-- |
-- |
|
| Dysgeusia |
-- |
Uncommon |
-- |
|
| Extrapyramidal syndrome |
-- |
Frequency 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 |
Flushing |
-- |
Common |
-- |
| Hypotension |
Uncommon |
Uncommon |
-- |
|
| Orthostatic hypotension |
Uncommon |
-- |
-- |
|
| Vasculitis |
-- |
Very rare |
Frequency 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 |
Abnormal 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 |
Frequency unknown |
|
| Bullous dermatitis |
-- |
-- |
Frequency unknown |
|
| Erythema |
Uncommon |
-- |
-- |
|
| Multiform erythema |
-- |
Very rare |
-- |
|
| Exanthema |
Uncommon |
Uncommon |
-- |
|
| Hyperhidrosis |
Uncommon |
Uncommon |
-- |
|
| Photosensitivity |
-- |
Uncommon |
-- |
|
| Pruritus |
Uncommon |
Uncommon |
Frequency 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 |
-- |
Frequency unknown |
-- |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
Uncommon |
Uncommon |
-- |
| Back pain |
Uncommon |
Uncommon |
-- |
|
| Joint swelling |
Uncommon |
-- |
-- |
|
| Muscle cramps |
Uncommon |
Uncommon |
-- |
|
| Muscle pain |
-- |
Uncommon |
Frequency unknown |
|
| Ankle joint swelling |
-- |
Common |
-- |
|
| Heaviness sensation |
Uncommon |
-- |
-- |
|
| Renal and urinary disorders |
Increase in blood creatinine levels |
-- |
-- |
Frequency unknown |
| Urinary disorder |
-- |
Uncommon |
-- |
|
| Nocturia |
-- |
Uncommon |
-- |
|
| Polyakiuria |
Uncommon |
Uncommon |
-- |
|
| Polyuria |
Uncommon |
-- |
-- |
|
| Renal failure and renal function impairment |
-- |
-- |
Frequency 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 |
-- |
-- |
|
| Flushing, hot flushes |
Common |
-- |
-- |
|
| Chest pain, non-cardiac |
-- |
Uncommon |
-- |
|
| Edema |
Common |
Common |
-- |
|
| Peripheral edema |
Common |
-- |
-- |
|
| Pain |
-- |
Uncommon |
-- |
|
| Soft tissue swelling |
Common |
-- |
-- |
|
| Investigations |
Increased blood potassium levels |
-- |
-- |
Frequency unknown |
| Increased body weight |
-- |
Uncommon |
-- |
|
| Decreased body weight |
-- |
Uncommon |
-- |
|
* Mainly associated with cholestasis.
Additional information regarding the combination
Peripheral edema, a known adverse reaction of amlodipine, occurred overall less frequently in patients receiving the amlodipine/valsartan combination than in those receiving amlodipine alone. In double-blind controlled clinical trials, the mean incidence of peripheral edema, averaged 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 Valmisar A, 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 enzymes (usually associated with cholestasis), angioneurotic edema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity. |
| Frequency unknown |
Toxic epidermal necrolysis. |
Individual cases of extrapyramidal syndrome have been reported.
Valsartan
The additional adverse reactions listed below were observed during clinical trials with valsartan monotherapy, regardless of causal relationship to the study drug.
| Frequency unknown |
Decreased hemoglobin levels, decreased hematocrit levels, neutropenia, thrombocytopenia, increased serum potassium levels, elevated liver function tests, including increased serum bilirubin concentration, renal failure and kidney function disorders, increased serum creatinine levels, angioneurotic edema, myalgia, vasculitis, hypersensitivity reactions, including serum sickness. |
Shelf life. 2 years.
Storage conditions.
Store at a temperature not exceeding 30 °C in the original packaging.
Keep out of reach and sight of children.
Packaging.
10 tablets per blister; 1, 3, or 9 blisters per cardboard pack.
Prescription status. By prescription only.
Manufacturer. MACLEODS PHARMACEUTICALS LIMITED.
Manufacturer's address and place of business.
Village Theda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.