Vanatex a

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VANATEX A (VANATEX A)

Composition:

Active substances: amlodipine in the form of amlodipine maleate, valsartan;

One film-coated tablet contains amlodipine in the form of amlodipine maleate 5 mg and valsartan 80 mg, or amlodipine in the form of amlodipine maleate 10 mg and valsartan 160 mg;

Excipients:

Core: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: hypromellose, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172), macrogol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets, 5 mg/80 mg: round, biconvex, dark yellow, film-coated tablets;

Film-coated tablets, 10 mg/160 mg: oval, biconvex, light yellow, film-coated tablets, with "10" imprinted on one side.

Pharmacotherapeutic group. Cardiovascular agents. Agents acting on the renin-angiotensin system. Angiotensin II receptor blockers (ARBs), combinations. Angiotensin II receptor blockers (ARBs) and calcium channel blockers. Valsartan and amlodipine. ATC code C09DB01.

Pharmacological properties.

Pharmacodynamics.

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

The combination of amlodipine and valsartan provides dose-dependent additive reductions in blood pressure across their therapeutic dose ranges. The antihypertensive effect of a single dose of the combination drug lasts for 24 hours.

Amlodipine

Amlodipine inhibits transmembrane influx of calcium ions into vascular and cardiac smooth muscle. The antihypertensive mechanism of amlodipine is directly related to its vasodilatory effect on vascular smooth muscle, resulting in reduced peripheral vascular resistance and decreased 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.

After administration of therapeutic doses to patients with essential 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 concentrations in both young 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.

Hemodynamic measurements of cardiac function at rest and during exercise in patients with normal ventricular function treated with amlodipine generally show a slight increase in cardiac index without significant effects on dP/dt, left ventricular end-diastolic pressure, or volume. In hemodynamic studies, amlodipine showed no negative inotropic effect when administered at therapeutic doses in intact animals and humans, even when co-administered with beta-blockers.

Amlodipine does not alter sinus node function or atrioventricular conduction in healthy animals or humans. In clinical studies 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.

Valsartan

Valsartan is an orally active and specific angiotensin II receptor antagonist. It selectively blocks the AT1 subtype receptors, which are predominantly responsible for the effects of angiotensin II. Increased levels of angiotensin II due to AT1 receptor blockade by valsartan may stimulate unopposed AT2 receptors, which may counterbalance the effects of AT1 receptor activation. Valsartan has no partial agonist activity at AT1 receptors and has approximately 20,000-fold greater affinity for AT1 receptors than for AT2 receptors.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Angiotensin II antagonists do not cause cough, as they do not affect ACE activity or increase bradykinin and substance P production.

Valsartan does not interact with or block receptors of other hormones or ion channels that play a significant role in cardiovascular regulation.

Administration of the drug to patients with arterial hypertension results in reduced blood pressure without affecting pulse rate.

In most patients, after a single oral dose, antihypertensive activity begins within 2 hours, and maximal blood pressure reduction is achieved within 4–6 hours.

The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, the maximum therapeutic effect is usually achieved within 2–4 weeks and is maintained at this level during long-term therapy. Abrupt discontinuation of valsartan does not lead to rebound hypertension or other adverse clinical events.

Pharmacokinetics.

Linearity.

Valsartan and amlodipine exhibit linear pharmacokinetics.

Amlodipine/valsartan

After oral administration of amlodipine/valsartan, peak plasma concentrations of valsartan and amlodipine are reached at approximately 3 hours and 6–8 hours, respectively. The rate and extent of absorption of amlodipine/valsartan are equivalent to the bioavailability of valsartan and amlodipine when administered as separate tablets.

Amlodipine

Absorption. After oral administration of therapeutic doses of amlodipine, maximum plasma concentration (Cmax) is reached within 6–12 hours. Absolute bioavailability is estimated to be between 64% and 80%. Food significantly affects amlodipine bioavailability.

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

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

Elimination. Amlodipine elimination from plasma is biphasic, with an elimination half-life of approximately 30–50 hours. Steady-state plasma levels are reached after 7–8 days of continuous administration. About 10% of unchanged amlodipine and 60% of amlodipine metabolites are excreted in urine.

Valsartan

Absorption. After oral administration, Cmax of valsartan in plasma is reached within 2–4 hours. The mean absolute bioavailability of the drug is approximately 23%. Food reduces valsartan exposure (AUC) by approximately 40% and Cmax by 50%. However, plasma concentrations of valsartan 8 hours after administration are similar in fasting and fed groups. The reduction in AUC is not clinically significant in terms of therapeutic effect; therefore, valsartan can be administered with or without food.

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

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

Elimination. Valsartan is primarily excreted unchanged in feces (approximately 83% of the dose) and urine (approximately 13% of the dose). After intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is approximately 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Pharmacokinetics in specific patient populations.

Pediatric patients (under 18 years of age)

Pharmacokinetic data in pediatric patients are lacking.

Elderly patients (65 years of age and older)

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

Renal impairment

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

Hepatic impairment

In patients with hepatic insufficiency, 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 volunteers (matched for age, sex, and body weight). Patients with liver disease should use the drug with caution.

Clinical characteristics.

Indications.

Essential hypertension in 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 amlodipine/valsartan with medicinal products containing aliskiren in patients with diabetes mellitus and renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).

Contraindicated in pregnancy and in women planning to become pregnant (see "Use during pregnancy or breastfeeding").

Severe arterial hypotension.

Shock (including cardiogenic shock).

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

Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Studies on interactions of this medicinal product 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

Not recommended concomitant use

Grapefruit or grapefruit juice

Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase bioavailability in some patients, leading to an enhanced effect on elevated blood pressure.

Necessary safety measures during concomitant use

CYP3A4 inhibitors

Concomitant use of amlodipine with strong and moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine's effect. The clinical manifestations of such pharmacokinetic variations may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required.

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. Clinical monitoring of blood pressure with possible dose adjustment of amlodipine is recommended during and after concomitant therapy, particularly with strong CYP3A4 inducers [e.g., rifampicin, St. John’s wort (Hypericum perforatum)].

Simvastatin

Co-administration of multiple doses of amlodipine 10 mg with simvastatin 80 mg increases the effect of simvastatin by 77% compared to simvastatin alone. In patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.

Dantrolene (infusion)

In animals, fatal ventricular fibrillation and cardiovascular collapse have been observed due to hyperkalemia following verapamil administration and intravenous dantrolene. Due to the risk of hyperkalemia, concomitant administration of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Consider the following when used concomitantly

Based on clinical interaction studies, amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.

Interactions related to valsartan

Not recommended concomitant use

Lithium

Toxic effects and transient increases in serum lithium concentrations have been reported during concomitant use of lithium with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, including valsartan. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use. The risk of lithium toxicity is increased if the patient is also taking a diuretic when using amlodipine/valsartan.

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

Serum potassium levels should be monitored if a medicinal product affecting potassium levels is prescribed in combination with valsartan.

Necessary safety measures during concomitant use

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

When angiotensin II antagonists are used concomitantly with NSAIDs, the antihypertensive effect may be reduced. In addition, concomitant use of angiotensin II antagonists and NSAIDs increases the risk of worsening renal function and elevated serum potassium. Therefore, renal function should be assessed at the start of treatment, and adequate hydration of the patient is recommended.

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

In vitro study results indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant administration 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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin receptor blockers (ARBs), or aliskiren has been associated with a higher incidence of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to using a single RAAS-acting medicinal product.

Others

No clinically significant interactions have been observed during valsartan monotherapy with the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide.

Special precautions for use

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

Patients with dehydration and/or markedly reduced sodium levels

Excessive hypotension has been reported in patients with uncomplicated arterial hypertension receiving amlodipine/valsartan. Symptomatic hypotension may occur in patients with activated renin-angiotensin system (e.g., patients with dehydration and/or markedly reduced sodium levels who are taking high-dose diuretics) when treated with angiotensin receptor blockers. Prior to initiating amlodipine/valsartan, such conditions should be corrected, and close medical supervision is recommended at the beginning of treatment.

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

Hyperkalemia

Concomitant use with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin) should be performed with caution, and serum potassium levels should be monitored frequently.

Renal artery stenosis

Amlodipine/valsartan should be used with caution in the treatment of arterial hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney, as serum urea and creatinine levels may increase in such patients.

Kidney transplantation

There is currently no experience with the safe use of amlodipine/valsartan in patients who have recently undergone kidney transplantation.

Use in patients with hepatic impairment

Valsartan is primarily eliminated unchanged via the bile. The elimination half-life of amlodipine and AUC (area under the plasma concentration-time curve) are increased in patients with hepatic impairment; however, dosage recommendations have not been established. Particular caution is advised when prescribing amlodipine/valsartan to patients with mild to moderate hepatic impairment or with obstructive biliary disorders.

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

Use in patients with renal impairment

Dose adjustment of amlodipine/valsartan 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.

Primary hyperaldosteronism

Angiotensin II antagonist valsartan should not be prescribed to patients with primary hyperaldosteronism, as their renin-angiotensin system is suppressed by the underlying disease.

Angioedema

Cases of Quincke's edema, including laryngeal and pharyngeal edema with airway obstruction and/or facial, lip, pharyngeal, and/or tongue swelling, have been reported in patients receiving valsartan. Some of these patients had a history of angioedema during treatment with other medicinal products, including ACE inhibitors.

If a patient develops angioedema, treatment with amlodipine/valsartan must be discontinued immediately and must not be restarted.

Use in patients with heart failure/post-myocardial infarction

As a consequence of renin-angiotensin-aldosterone system (RAAS) inhibition, changes in renal function may be expected in patients with risk factors. In patients with severe heart failure, whose renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia, and (rarely) with acute renal failure and/or fatal outcomes. Similar events have been observed with valsartan. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.

Increased incidence of pulmonary edema has been reported in patients with acute non-ischemic heart failure (NYHA functional class III and IV) treated with amlodipine, despite no significant difference in worsening heart failure compared to placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular complications and mortality.

Aortic and mitral valve stenosis

As with other vasodilating agents, particular caution is required when treating patients with mitral stenosis or significant non-severe aortic stenosis.

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

Data indicate that concomitant use of ACE inhibitors, angiotensin receptor blockers (ARBs), or aliskiren increases the risk of hypotension, hyperkalemia, and decreased 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 considered absolutely necessary, such treatment should be administered only under specialist supervision with frequent and careful monitoring of renal function, electrolytes, and blood pressure. ACE inhibitors and ARBs should not be co-administered in patients with diabetic nephropathy.

The effect of amlodipine/valsartan has been studied only in arterial hypertension.

Vanatex A contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product is contraindicated in pregnant women and women who are planning pregnancy.

Amlodipine

The safety of amlodipine use in pregnant women has not been established. Reproductive toxicity has been observed in animal studies at high doses.

Valsartan

Epidemiological data on teratogenic risk following ACE inhibitor use during the first trimester of pregnancy are inconclusive. However, a slight increase in risk cannot be excluded. There are no data from controlled epidemiological studies on the risk of using angiotensin II receptor antagonists (AT2-receptor antagonists). Even if continued use of AT2-receptor antagonists is necessary in women planning pregnancy, they should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is confirmed, AT2-receptor antagonists should be discontinued immediately, and alternative therapy initiated if needed.

Use of AT2-receptor antagonists during the second and third trimesters is known to cause fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If AT2-receptor antagonists were used during the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull is recommended.

Infants whose mothers have taken AT2-receptor antagonists require careful monitoring for arterial hypotension.

Breastfeeding period

Amlodipine is excreted in breast milk. The infant’s exposure, expressed as a fraction of the maternal dose, has been estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on the infant is unknown. There is no information available on the use of valsartan during breastfeeding. Therefore, amlodipine/valsartan is not recommended for this patient group. Alternative treatments with better-established safety profiles during breastfeeding should be preferred, especially in the case of newborns or preterm infants.

Fertility

There are no clinical studies on the effect of amlodipine/valsartan on fertility.

Valsartan

Effect on ability to drive and use machines

Patients taking amlodipine/valsartan and driving or operating machinery should be aware that dizziness or fatigue may occasionally occur.

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

Method of Administration and Dosage

For patients whose blood pressure is not adequately controlled with monotherapy using amlodipine or valsartan alone, combination therapy with the drug Vanatex A may be used. The recommended dose is 1 tablet per day. Vanatex A tablets can be taken independently of food intake, swallowed with a small amount of water.

Prior to switching to the fixed-dose combination, dose titration of the individual components (amlodipine and valsartan) is recommended. If clinically appropriate, direct transition from monotherapy to the fixed-dose combination may be considered.

For convenience, patients who have been receiving valsartan and amlodipine as separate tablets/capsules may be switched to Vanatex A tablets containing equivalent doses of the components.

Use in Patients with Renal Impairment

Clinical data in patients with acute renal failure are lacking. Dose adjustment is not required in patients with mild to moderate renal impairment. In patients with moderate renal impairment, monitoring of potassium and creatinine levels is recommended.

Use in Patients with Hepatic Impairment

Vanatex A is contraindicated in patients with acute hepatic failure.

Caution should be exercised when prescribing Vanatex A to patients with hepatic impairment or biliary obstruction. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. Dosage recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established. When switching hypertensive patients with impaired liver function to amlodipine or Vanatex A, the lowest possible dose of amlodipine should be initiated, either as monotherapy or as a component of a combination drug, respectively.

Diabetes Mellitus

Concomitant use of Vanatex A with aliskiren is contraindicated in patients with diabetes mellitus.

Elderly Patients (≥ 65 years)

Dose escalation in elderly patients should be performed with caution. When switching elderly hypertensive patients with impaired liver function to amlodipine or Vanatex A, the lowest possible dose of amlodipine should be prescribed, either as monotherapy or as a component of a combination medicinal product, respectively.

Children

Use in children (under 18 years of age) is not recommended.

Overdose

Symptoms

Experience with amlodipine/valsartan overdose is lacking. The main sign of valsartan overdose is pronounced arterial hypotension with dizziness. Amlodipine overdose may lead to excessive peripheral vasodilation and reflex tachycardia. Cases of significant and prolonged systemic arterial hypotension, including shock with fatal outcome, have 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. Early resuscitative measures (including fluid loading) to support perfusion and cardiac output may act as precipitating factors.

Treatment

If only a short time has passed after oral administration, vomiting may be induced or gastric lavage performed. Administration of activated charcoal to healthy volunteers immediately or within 2 hours after amlodipine intake significantly reduced amlodipine absorption. Clinically significant hypotension due to amlodipine/valsartan overdose requires active cardiovascular support, including cardiac and respiratory monitoring, circulating volume assessment, and urine output monitoring. The patient should be placed in a supine position with legs elevated. Vasoconstrictive agents may be used to restore vascular tone and blood pressure, provided there are no contraindications to their use. Intravenous calcium gluconate may be beneficial in counteracting the effects of calcium channel blockade.

Valsartan and amlodipine are not removed from the body by hemodialysis.

Adverse Reactions

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

Adverse effects that may occur during treatment are classified by frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (frequency cannot be estimated from available data).

* Mainly associated with cholestasis.

Additional information regarding the combination

Peripheral edema, a known adverse effect of amlodipine, occurred generally less frequently in patients receiving the amlodipine/valsartan combination than with amlodipine alone. In double-blind, controlled clinical trials, the average incidence of peripheral edema, uniformly distributed across the entire dose range, was 5.1% with 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 Vanatex A, even if they were not reported during clinical trials or in the post-marketing period.

Amlodipine

Isolated cases of extrapyramidal syndrome have been reported.

Valsartan

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

14 film-coated tablets in a blister; 2 blisters or 7 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Pharmaceutical Works «POLPHARMA» S.A.

Pharmaceutical Works «POLPHARMA» S.A.

Address of the manufacturer and place of business.

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.