Exforge H 5 mg / 160 mg / 25 mg tablet number 14

Author Ольга Кияница

2017-05-11

Amount in a package No
Product form Pills
Manufacturer Novartis Pharma (Switzerland)
Registration certificate UA/12679/01/03
The main medicament Exforge
morion code 196573

Exforge H (EXFORGE H) user's manual

Composition

1 tablet 5 mg / 160 mg / 12.5 mg contains
active ingredients: amlodipine besylate 6.94 mg, equivalent to amlodipine base 5 mg, valsartan 160 mg and hydrochlorothiazide 12.5 mg

1 tablet of 10 mg / 160 mg / 12.5 mg contains
active ingredients: amlodipine besylate 13.87 mg, equivalent to amlodipine base 10 mg, valsartan 160 mg and hydrochlorothiazide 12.5 mg

1 tablet 5 mg / 160 mg / 25 mg contains
active ingredients: amlodipine besylate 6.94 mg, equivalent to amlodipine base 5 mg, valsartan 160 mg and hydrochlorothiazide 25 mg

1 tablet of 10 mg / 160 mg / 25 mg contains
active ingredients: amlodipine besylate 13.87 mg, equivalent to amlodipine base 10 mg, valsartan 160 mg and hydrochlorothiazide 25 mg

auxiliary substances: cellulose microcrystalline, crospovidone, silicon dioxide colloid, magnesium stearate, hypromellose, titanium dioxide (E 171), macrogol 4000, talc, iron oxide yellow (E172) - only for tablets of 5 mg / 160 mg / 25 mg, 10 mg / 160 mg / 12.5 mg, 10 mg / 160 mg / 25 mg iron oxide red (E172) - only for tablets of 10 mg / 160 mg / 12.5 mg.

Dosage form

Film-coated tablets.

Basic physical and chemical properties:

tablets 5 mg / 160 mg / 12.5 mg - oval biconvex tablets coated with a white film coating, with bevelled edges, with an impression of NVR on one side and VCL on the other;
tablets 10 mg / 160 mg / 12.5 mg - oval biconvex tablets covered with a film coating of pale yellow color, with bevelled edges, with an impression of "NVR" on one side and "VDL" on the other;
tablets 5 mg / 160 mg / 25 mg - oval biconvex tablets, covered with a film coating of yellow, with bevelled edges, with an impression of "NVR" on one side and "VEL" on the other;
tablets 10 mg / 160 mg / 25 mg - oval biconvex tablets, covered with a film coating of brownish-yellow color, with bevelled edges, with an impression of "NVR" on one side and "VNL" on the other.

Pharmacological group

Angiotensin II antagonists, other combinations. ATX Code C09D X01.

Pharmacological properties

Pharmacodynamics.

Exforge H contains three antihypertensive agents with complementary mechanisms for controlling blood pressure in patients with essential hypertension: amlodipine belongs to the class of calcium antagonists, valsartan to the class of angiotensin II antagonists, and hydrochlorothiazide to the class of thiazide diuretics. The combination of these three components is characterized by a complementary antihypertensive effect.

Amlodipine

Amlodipine, which is part of Exforge H, inhibits the transmembrane intake of calcium ions in the heart muscle and smooth muscle vessels. The mechanism of antihypertensive action of amlodipine occurs by direct relaxing action on the smooth muscle of the vessels, causing a decrease in peripheral vascular resistance and arterial pressure.

Amlodipine in therapeutic doses in patients with arterial hypertension causes vasodilation, which leads to a decrease in blood pressure in the supine and standing position. Such a decrease in blood pressure is not accompanied by marked changes in the heart rate or the level of catecholamines in blood plasma with prolonged use.

Concentrations in blood plasma correlate with the effect in young patients and in elderly patients.

In patients with arterial hypertension and normal renal function, amlodipine in therapeutic doses leads to a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without changing the filtration fraction or proteinuria.

Valsartan

Valsartan is active for oral use, a potent and specific antagonist of angiotensin II receptors. Valsartan acts selectively on the subtype of AO 1 receptors that are responsible for the known effects of angiotensin II.

The intake of valsartan in patients with arterial hypertension helps to lower blood pressure without affecting the pulse rate.

In most patients after oral administration of a single dose, the onset of an antihypertensive effect occurs within 2:00, and the maximum decrease in blood pressure is achieved within 4-6 hours. Antihypertensive effect lasts for 24 hours after application of the drug. With repeated use, the maximum reduction in blood pressure (with all dosage regimens) is usually achieved within 2-4 weeks.

Hydrochlorothiazide

The site of action of thiazide diuretics is mainly distal convoluted tubules of the kidneys. It has been confirmed that in the cortical layer of the kidneys there are leap-inhibitor receptors, which are the main binding center for thiazide diuretics and inhibition of NaCl transport to the distal convoluted tubules. The mechanism of action of thiazides is the inhibition of carriers of Na + Cl -, possibly by competition for the centers of Cl -, which in turn affects the mechanisms of reabsorption of electrolytes directly enhances the excretion of sodium and chlorine to approximately equivalent degree, and indirectly, due to a diuretic effect, reduces volume of plasma with subsequent increase of renin activity in blood plasma, aldosterone secretion and potassium excretion in urine, as well as potassium reduction in blood serum.

Pharmacokinetics.

Linearity

Amlodipine, valsartan and hydrochlorothiazide demonstrate linear pharmacokinetics.

Amlodipine / valsartan / hydrochlorothiazide

After oral administration of Exforge H with healthy adult volunteers, the maximum concentrations of amlodipine, valsartan and hydrochlorothiazide in blood plasma were achieved within 6-8 hours, 3:00 and 2:00, respectively. The speed and volume of absorption of amlodipine, valsartan and hydrochlorothiazide when Exforge H is used are similar to those observed with the use of its components as separate preparations.

Amlodipine

Absorption. After oral administration in therapeutic doses of amlodipine alone, the maximum concentration in the blood plasma was reached after 6-12 hours. Bioavailability was from 64% to 80%. Eating food does not affect the bioavailability of amlodipine.

Distribution. The distribution volume is approximately 21 l / kg. In vitro studies of amlodipine have shown that approximately 97.5% of the drug is in circulating blood, binds to blood plasma proteins.

Metabolism. Amlodipine is actively (about 90%) metabolized in the liver to inactive metabolites.

Conclusion . Amlodipine is excreted from the blood plasma in two stages, the final half-life is about 30-50 hours. The level of the equilibrium state in the blood plasma is achieved after continuous use for 7-8 days. 10% of the original amlodipine and 60% of the metabolites of amlodipine are excreted in the urine.

Valsartan

Absorption. After oral administration of valsartan alone, its maximum concentration is achieved in 2-4 hours. The average bioavailability is 23%. The intake of food reduces the exposure (as determined by AUC) of valsartan by approximately 40%, and the maximum concentration in the blood plasma (C max) is approximately 50%, although approximately 8:00 after application, the concentration of valsartan is similar in the fasting and postprandial administration groups food. However, such a decrease in AUC is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be used regardless of food intake.

Distribution. The volume of distribution of valsartan in the equilibrium state after intravenous administration is approximately 17 liters, indicating that valsartan does not divide extensively in the tissues. Valsartan actively binds to blood plasma proteins (94-97%), mainly with serum albumins.

Metabolism. Valsartan is not transformed to a large extent, since only about 20% of the dose is excreted as metabolites.Hydroxymetabolite has been identified in blood plasma at low concentrations (less than 10% of Valsartan AUC). This metabolite is pharmacologically inactive.

Conclusion . Valsartan is excreted mainly with feces (approximately 83% of the dose) and urine (13% of the dose), mainly in unchanged form. After the introduction of clearance, valsartan is about 2 l / h, and the renal clearance is 0.62 l / h (about 30% of the total clearance). The half-life of valsartan is 6:00.

Hydrochlorothiazide

Absorption. The absorption of hydrochlorothiazide after oral administration is rapid (T max - approximately 2:00). The increase in mean AUC is a linear and proportional dose when applied in the therapeutic dose range. No changes in the kinetics of hydrochlorothiazide were observed with repeated application, and cumulation was minimal when taken once a day. With simultaneous administration with food, both the increase and decrease in the systemic availability of hydrochlorothiazide were compared with fasting. The severity of these effects is insignificant and has little clinical significance. The bioavailability of hydrochlorothiazide is 60-80% after oral administration.

Distribution. The apparent volume of distribution is 4-8 l / kg. Hydrochlorothiazide in the circulating blood binds to blood plasma proteins (40-70%), mainly with serum albumins. Hydrochlorothiazide also accumulates in erythrocytes in levels 1.8 times higher than plasma levels.

Metabolism. Hydrochlorothiazide is excreted unchanged.

Conclusion . More than 95% of the absorbed dose is excreted unchanged in the urine. Kidney clearance consists of passive filtration and active secretion in the renal tubules. The half-life is 6-15 hours.

Individual patient groups

Children (up to 18 years)

There is no data on the pharmacokinetics in children.

Patients of advanced age (65 years and older)

Time to achieve C max amlodipine is similar in young and elderly patients. In elderly patients, clearance of amlodipine tends to decrease, causing an increase in the area under the curve (AUC) and half-life. The average systemic AUC value of valsartan is higher by 70% in elderly patients than in younger patients, so with caution increase the dose to such patients.

The systemic exposure of valsartan is somewhat higher in elderly patients compared to younger patients, but this is not clinically relevant.

Limited data indicate that the systemic clearance of hydrochlorothiazide is lower in both healthy elderly volunteers and in elderly patients with hypertension compared with younger healthy volunteers.

Since the three components of the drug are equally well tolerated by young patients and elderly patients, a routine dosing regimen is recommended.

Impaired renal function

Impaired renal function does not significantly affect the pharmacokinetics of amlodipine. As expected, for a drug whose renal clearance is only 30% of the total clearance, there was no correlation between renal function and systemic exposure of valsartan.

Therefore, patients with impaired renal function of mild and moderate severity can apply the drug in a usual initial dose.

Impaired liver function

In patients with impaired hepatic function, clearance of amlodipine is reduced, which leads to an increase in AUC of approximately 40-60%. On average, patients with mild and moderate chronic illnesses are exposed to valsartan exposure (determined by the AUC indicator) 2 times higher than in adult volunteers (grouped by age, sex and body weight). Caution should be given to patients with liver disease.

The combination of amlodipine / valsartan / hydrochlorothiazide was not tested for genotoxicity and carcinogenicity, as there was no evidence of interaction between these drugs, marketed for a long time. However, amlodipine, valsartan and hydrochlorothiazide were individually tested for genotoxicity and carcinogenicity; negative results were obtained.

Indications

Treatment of essential hypertension in adult patients with arterial pressure, an adequately controlled combination of amlodipine, valsartan and hydrochlorothiazide, which use three separate substances or two drugs, one of which is combined.

Contraindications

Hypersensitivity to active substances, other sulfonamides, dihydropyridine derivatives or to an auxiliary substance.
Pregnant women or women planning to become pregnant (see "Application during pregnancy or lactation")
Violation of the liver, biliary cirrhosis or cholestasis.
Severe renal dysfunction (glomerular filtration rate (GFR) <30 ml / min / 1.73 m 2), anuria, and also being on dialysis.
Simultaneous use of angiotensin receptor antagonists (ARBs), including valsartan, or ACE inhibitors (ALPs) with aliskiren in patients with diabetes mellitus or with impaired renal function (GFR <60 mg / min / 1.73 m2).
Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
Severe hypotension.
Shock (including cardiogenic shock).
Obstruction of the left ventricular outflow tract (eg, hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.

Interaction with other drugs and other interactions

Exforge H was not studied with other drugs. Table 1 provides only information on interactions with other drugs known for each individual active ingredient.

However, it is important to consider that Exforge H can strengthen the antihypertensive effect of other antihypertensive drugs.

Table 1

Simultaneous use is not recommended
Separate components of Exforge H Interactions with such agents are known The effect of interaction with other drugs
Valsartan and hydrochlorothiazide lithium

A reversible increase in serum lithium concentration and toxicity was reported during the simultaneous use of lithium with ACE inhibitors, angiotensin II receptor antagonists, including valsartan or thiazides such as hydrochlorothiazide.

Since renal clearance is reduced by thiazides, the risk of lithium toxicity can probably increase with Exforge H. Therefore, it is recommended that the level of lithium in serum be carefully monitored during the combined use of the drugs.

Valsartan Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other agents that can raise the level of potassium If the use of the drug is necessary affects the level of potassium in combination with valsartan it is recommended to check the potassium level in the blood plasma frequently.
Amlodipine Grapefruit or grapefruit juice The use of amlodipine with grapefruit or grapefruit juice is not recommended, because bioequivalence may increase in some patients, which leads to an increase in the effect of lowering blood pressure
Simultaneous use requires caution
Separate components of Exforge H Interactions with such agents are known The effect of interaction with other drugs
Amlodipine Inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, ritonavir) A study involving elderly patients showed that diltiazem inhibits the metabolism of amlodipine, possibly with the participation of CYP3A4 (plasma concentration increases by about 50% and the effect of amlodipine is enhanced). The likelihood that more potent inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in plasma is more pronounced than diltiazem.
  Inductors CYP3A4(anticonvulsants [such as carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidon], rifampicin, St. John's wort) Simultaneous application can lead to a decrease in the concentrations of amlodipine in the blood plasma. It was shown to conduct clinical monitoring with the possible adjustment of the dose of amlodipine treatment time inductor and after its withdrawal.
  simvastatin The use of multiple doses of 10 mg of amlodipine with 80 mg of simvastatin results in an increase in the exposure of simvastatin by 77% compared to the use of one simvastatin. It is recommended to reduce the daily dose of simvastatin to 20 mg for patients who use amlodipine.
  Dantrolene (infusion) In animals, fatal cases of ventricular fibrillation and cardiovascular collapse were observed in connection with hyperkalemia after the administration of verapamil and dantrolene intravenously. Because of the risk of hyperkalemia recommended to avoid concomitant use of calcium channel blockers such as amlodipine, patients susceptible to malignant hyperthermia, and in the treatment of malignant hyperthermia.
Valsartan and hydrochlorothiazide Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g / day) and nonselective NSAIDs NSAIDs can weaken the antihypertensive effect such as antagonists of angiotensin II, and while the use of hydrochlorothiazide. Moreover, the simultaneous use Exforge H and NSAIDs may lead to a deterioration of renal function and potassium levels in the serum. It is therefore recommended to monitor renal function at the beginning of treatment, as well as the proper patient hydration.
 

Inhibitors accumulation transporter (rifampicin, cyclosporin) or eflyuksnogo transporter (ritonavir)

 

The results of investigations in vitro with human liver tissue showed that valsartan is a substrate for hepatic transporter OATP1B1 and hepatic accumulation eflyuksnogo transporter MRP2. The simultaneous use of a carrier accumulation inhibitors (rifampicin, cyclosporin) or eflyuksnogo transporter (ritonavir) can increase the systemic exposure of valsartan.

 

Hydrochlorothiazide Alcohol, anesthetics and sedatives There may be potentiation of orthostatic hypotension.
  amantadine Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions, amantadine.
  Anticholinergics (such as atropine, biperiden) Bioavailability thiazide-type diuretics may increase anticholinergics (e.g. atropine, biperiden), apparently due to a decrease of gastrointestinal motility and gastric emptying rate.
 

Antidiabetic drugs (e.g. insulin and oral antidiabetics)

metformin

It may be necessary to re-adjust the dosage of insulin and oral antidiabetic agents.

 

 

 

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure associated with the use of hydrochlorothiazide.

  Beta-blockers and diazoxide Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics including hydrochlorothiazide may enhance the hyperglycemic effect of diazoxide.
  carbamazepine Patients receiving hydrochlorothiazide simultaneously with carbamazepine may develop hyponatremia. Therefore, such patients should be warned about the possibility of giponatriemichnih reactions, as well as in accordance to observe their condition.
  Cholestyramine and colestipol resins Absorption of thiazide diuretics, including hydrochlorothiazide, reduces cholestyramine or other anion exchange resins.
  cyclosporine Simultaneous treatment with cyclosporine may increase the risk of hyperuricemia and gouty complications of type.
  Cytotoxic agents (e.g. cyclophosphamide, methotrexate) Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.
  digitalis glycosides Tiazidindukovana hypokalemia or hypomagnesemia can occur as side effects that promote digitalisindukovanoi cardiac arrhythmias.
  Iodine-containing contrast agents If diuretikindukovanoi dehydration there is an increased risk of developing acute renal failure, especially with high doses of iodine products. Which should be hold rehydration.
  Drugs affecting potassium(with concomitant administration of diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives) Hypokalemic effect of hydrochlorothiazide may enhance the appointment saluretics, corticosteroids, laxatives, ACTH (ACTH), amphotericin, carbenoxolone, penicillin G and salicylic acid derivatives. If such drugs are administered with a combination of amlodipine / Valsartan / hydrochlorothiazide, it is advisable to monitor the level of potassium in the blood plasma.
  Medications used to treat gout (probenecid, sulfinpyrazone and allopurinol)

It may be necessary to dose adjustment of uricosuric drugs as hydrochlorothiazide may enhance the level of uric acid in serum krovi.Mozhet be necessary to increase the dose of probenecid or sulfinpirazona.

Simultaneous with the appointment of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.

  methyldopa There were isolated reports of the development of hemolytic anemia with concomitant use of hydrochlorothiazide and methyldopa.
  Skeletal muscle relaxants Nondepolarizing (such as tubocurarine) Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.
  Amines Pressor (eg norepinephrine, epinephrine) The effect of pressor amines may be weakened.
  Vitamin D and calcium salts The use of thiazide diuretics including hydrochlorothiazide, with vitamin D or calcium salts may potentiate increasing calcium levels in serum.

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

The simultaneous use of ARBs, including valsartan, ACE inhibitors or with aliskiren is contraindicated in patients with diabetes or impaired renal function (GFR <60 mg / min / 1.73 m 2).

Application features

Safety and effectiveness of amlodipine for hypertensive crisis have not explored.

Patients with sodium deficiency and dehydration

Patients with activated renin-angiotensin system ( patients with deficit of salts and / or dehydration, which are obtained at high doses of diuretics) that angiotensin II (Arai) receptor is used, there may be symptomatic hypotension. It is recommended to adjust a position prior to use of the drug Exforge H or closely monitor the patient at the beginning of treatment.

If use of the drug Exforge H marked hypotension occurs, the patient should take a horizontal position and lift his legs and, if necessary, enter the infusion with saline. Treatment may be continued after stabilization of arterial pressure.

Changes in levels of serum electrolytes

Amlodipine / valsartan / hydrochlorothiazide

Periodically, at appropriate intervals to monitor the blood serum levels of electrolytes, to determine the possible electrolyte imbalance.

Periodical determination of the level of electrolytes and potassium in serum should be performed at appropriate intervals to prevent possible electrolyte imbalance, especially in patients with risk factors such as renal function, treatment with other drugs and electrolyte imbalance in the anamnesis.

valsartan

Concomitant use with potassium-containing additives, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase the level of potassium (e.g. heparin) is not recommended. If necessary, to control the level of potassium.

Hydrochlorothiazide

It reported the development of hypokalemia in the treatment of thiazide diuretics, including hydrochlorothiazide.

Treatment of thiazide diuretics, including hydrochlorothiazide, associated with the development of hyponatremia and alkalosis hypochloremic. Thiazides, including hydrochlorothiazide, increases the excretion of magnesium in the urine, which can lead to hypomagnesemia. In the application of thiazide diuretics reduced calcium excretion, which may lead to hypercalcemia.

All patients receiving thiazide diuretics, it is necessary to periodically monitor the level of electrolytes, especially potassium, sodium and magnesium.

Renal function

No need for correction dose Exforge H patients with impaired renal mild and moderate severity function (GFR ≥30 mL / min / 1,7Zm 2). It is recommended to periodically monitor the level of potassium, creatinine and uric acid in the blood serum of patients with impaired renal function when using the drug Exforge N.

The simultaneous use of angiotensin receptor antagonists, including valsartan, ACE inhibitors or with aliskiren is contraindicated in patients with impaired renal function (GFR <60 mg / min / 1.73 m 2).

Renal artery stenosis

Exforge H should be used with caution in patients with hypertension unilateral or bilateral renal artery stenosis or stenosis separate kidneys because urea and creatinine levels in serum may increase.

kidney transplantation

At present there is no experience regarding the safety of the drug Exforge N patients who have recently performed a kidney transplant.

Abnormal liver function

Valsartan is mainly excreted unchanged in bile. amlodipine half-life period is prolonged and the index AUC (plasma concentration - time) higher in patients with impaired liver function dosage recommendations have not been established. For patients with impaired liver function mild to moderate, not accompanied by cholestasis, the maximum recommended dose is 80 mg of valsartan. For this reason Exforge H drug is not shown for this group of patients.

Angioedema.

Angioedema, including the larynx and glottis edema , which can lead to airway obstruction and / or swelling of the face, lips, throat and / or tongue have been observed in patients treated with valsartan. Some of these patients had a history of angioneurotic edema when taking other drugs, including ACE inhibitors (ACE). Application Exforge H should be stopped immediately when an angioedema repeated use is not recommended.

Heart failure and coronary artery disease / condition after myocardial infarction

Because inhibition of the renin-angiotensin- patients with increased sensitivity may be expected changes in renal function. Patients with severe heart failure in which kidney function is dependent on the activity of the renin-angiotensin, treatment with ACE inhibitors (ACEI) and angiotensin receptor antagonists lead to oliguria and / or progressive azotemia (rarely) with acute renal failure and / or death . Similar results were reported for valsartan.

Recommended used with caution in patients with heart failure and coronary artery diseases, especially in a maximum dose of Exforge H - 10 mg / 320 mg / 25 mg, as the data on the drug administration this group of patients is limited.

Stenosis of the aortic and mitral valves

As with other vasodilators administered with caution to patients with a stenosis of aortic and mitral valves low degree.

primary aldosteronism

Patients with primary hyperaldosteronism should be treated with the angiotensin II antagonist valsartan as they have not been activated renin-angiotensin system. Therefore Exforge H drug is not recommended for this group of patients.

Systemic lupus erythematosus

It reported that the thiazide diuretics including hydrochlorothiazide, exacerbated or activated for systemic lupus erythematosus.

Other metabolic disorders

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise the level of cholesterol, triglycerides and uric acid in the blood serum. It may be necessary to dose adjustment of insulin or oral antidiabetic agents in patients with diabetes.

Since Exforge H contains hydrochlorothiazide, it is not suitable for systemic hyperuricemia. Hydrochlorothiazide may raise the level of uric acid in blood serum due to the reduction of uric acid clearance and can cause exacerbation of hyperuricemia and gout sudden sensitive patients.

Thiazides may reduce urinary calcium excretion and cause periodic and insignificant increase of calcium in blood serum in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism . Discontinue use of thiazides before performing tests for parathyroid function.

photosensitivity

Cases of photosensitivity reactions reported with the use of thiazide diuretics. If photosensitivity occur during reception Exforge H drug is recommended to stop. If the recovery application diuretic is deemed necessary , it is recommended to protect exposed areas of the body from sunlight or artificial ultraviolet irradiation.

Zaktitokutova glaucoma

Hydrochlorothiazide, sulfonamide were associated with an allergic reaction, which resulted in the transient acute angle-closure glaucoma and myopia. Symptoms include acute onset of loss of visual acuity or eye pain and typically occur within the first hours or the first week after the start of treatment. Untreated glaucoma can lead to irreversible vision loss .

First of all it is necessary as soon as possible to stop the use of hydrochlorothiazide. If the intraocular pressure is controlled should consider the need for immediate medical or surgical treatment. Risk factors for the development of angle- closure glaucoma may be an allergic reaction to a sulfonamide or penicillin in history.

Are common

Precautions prescribed for patients who over-sensitivity to other angiotensin II receptor antagonists. The occurrence of hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

Elderly patients (65 years and older)

Recommended with care, in particular often controlling blood pressure, given to patients of advanced age, particularly H Exforge maximum dose of 10 mg / 320 mg / 25 mg, because of the use of data preparation to patients in this group is limited.

Dual blockade of the renin-angiotensin (RAAS)

The simultaneous use of angiotensin receptor antagonists, including valsartan, with other agents acting as RAAS may increase the cases of hypotension, hyperkalaemia and changes in renal function compared to the monotherapy. It is necessary to monitor the blood pressure, renal function and electrolyte levels in patients treated with Exforge H and other agents which act as the RAAS.

It should be used with caution angiotensin receptor antagonists, including valsartan, with other agents that block the RAAS, such as ACE inhibitors or aliskiren.

Simultaneous application Exforge H with angiotensin receptor antagonists, including valsartan, ACE inhibitors or with aliskiren is contraindicated in patients with impaired renal function (GFR <60 mg / min / 1.73 m 2) or with diabetes.

Use during pregnancy or breast-feeding

Pregnancy

amlodipine

The study of amlodipine safety during pregnancy has not been conducted. In animal studies, reproductive toxicity was observed with high dosages. Use during pregnancy is recommended only if there is no safer alternative drug and if the disease itself carries a greater risk to the mother and embryo.

Valsartan

The drug is contraindicated for pregnant women or women planning pregnancy. If during pregnancy the pregnancy is confirmed, its use should be stopped immediately and, if necessary, replaced with another drug approved for use in pregnant women.

Hydrochlorothiazide

The experience with hydrochlorothiazide during pregnancy, especially in the first trimester, is limited. Data obtained in the course of animal studies is not enough.

Hydrochlorothiazide penetrates the placenta. The pharmacological mechanism of the action of hydrochlorothiazide makes it possible to assert that the use of this drug during the II and III trimesters of pregnancy can disrupt fetoplacental perfusion and lead to the appearance of fetal and neonatal reactions such as jaundice, electrolyte imbalance and thrombocytopenia, and may also be associated with other adverse reactions , observed in adults.

Amlodipine / valsartan / hydrochlorothiazide

There is no experience of applying Exforge H to pregnant women. The available data on the components of the preparation make it possible to state that Exforge H is contraindicated.

Breastfeeding period

There is no information on the use of valsartan and / or amlodipine during breastfeeding. Hydrochlorothiazide is excreted in breast milk, so Exforge N is contraindicated during breastfeeding.

The ability to influence the reaction rate when driving vehicles or other mechanisms

Patients using Exforge H may experience dizziness or a feeling of weakness after taking the drug, so they should take this into account when driving vehicles and working with potentially dangerous mechanisms.

Amlodipine may moderately or moderately affect the ability to drive vehicles or work with other mechanisms. If patients experience dizziness, headache, fatigue, or nausea with amlodipine, their reaction may be impaired.

Dosing and Administration

Exforge H can be used regardless of food intake. Tablets should be swallowed whole, with water, at the same time of day, preferably in the morning.

Dosage

The recommended dose of Exforge H is 1 tablet per day, preferably in the morning.

Before switching to the use of Exforge H, the patient's condition should be controlled by unchanged doses of monopreparations taking simultaneously. The dose of Exforge H should depend on the doses of the individual components of the combination used at the time of drug change.

The maximum recommended dose of Exforge H is 10 mg / 320 mg / 25 mg.

Individual patient groups

Impaired renal function

Since the preparation contains hydrochlorothiazide, Exforge H is contraindicated in patients with anuria and severe impairment of renal function (creatinine clearance <30 mL / min).

The simultaneous use of Exforge H with aliskiren is contraindicated in patients with impaired renal function (GFR <60 mg / min / 1.73 m 2). There is no need for dose adjustment in patients with impaired renal function of mild and moderate severity.

Diabetes

The simultaneous use of Exforge H with aliskiren is contraindicated in patients with diabetes mellitus.

Impaired liver function

Since valsartan is part of the drug, Exforge H is contraindicated in patients with severe impairment of liver function.Patients with mild to moderate liver function impairment not accompanied by cholestasis receive a maximum recommended dose of valsartan of 80 mg, and therefore Exforge H is not indicated for this group of patients. Patients with impaired hepatic function of mild and moderate severity are not recommended for dosage of amlodipine.

Heart failure and coronary artery disease

The experience of using Exforge H, especially at maximum doses, patients with heart failure and coronary artery disease is limited. It is recommended to use the drug with caution in patients with heart failure and coronary artery disease, especially the maximum dose of Exforge H 10 mg / 320 mg / 25 mg.

Patients of advanced age (65 years and older)

It is recommended with caution, in particular, often controlling arterial pressure, to appoint elderly patients, especially the maximum dose of Exforge H 10 mg / 320 mg / 25 mg, since the use data for this group of patients is limited.

Pediatric populations

There is no relevant data on the use of Exforge H in pediatric populations (patients under the age of 18 years) according to indications arterial hypertension.

Children

Safety and effectiveness of use in children is not established, so the drug is not used in patients of this age group.

Overdose

Symptoms

There is no evidence of an overdose Exforge N. The main symptom of an overdose is possible severe arterial hypotension with dizziness. Overdose of amlodipine may lead to severe vasodilation of peripheral vessels and, possibly, reflex tachycardia. A pronounced and potential prolonged systemic hypotension, including shock with a lethal outcome, has been reported.

Treatment

Amlodipine / valsartan / hydrochlorothiazide

Clinically pronounced arterial hypotension with an overdose Exforge H requires active support of the cardiovascular system, including frequent monitoring of heart and respiratory system function, lower limbs in elevated position, control of circulating blood volume and diuresis. Vasoconstrictors may be appropriate for restoring vascular tone and blood pressure, provided that there is no contraindication for their use. The administration of calcium gluconate can be effective in reversing the effects of calcium channel blockade.

Amlodipine

If after taking the drug a little time has passed, consider the issue of inducing vomiting or rinsing the stomach. With the appointment of activated charcoal to healthy volunteers, immediately or after 2:00 after taking amlodipine, the absorption of amlodipine was expressed markedly.

It is unlikely that amlodipine is excreted during hemodialysis.

Valsartan

It is unlikely that valsartan is excreted during hemodialysis.

Hydrochlorothiazide

An overdose of hydrochlorothiazide is accompanied by a deficiency of electrolytes (hypokalemia, hypochloraemia) and hypovolemia due to excessive diuresis. Nausea and drowsiness are common symptoms of an overdose. Hypokalemia can lead to muscle spasms and / or worsening of arrhythmia associated with the simultaneous use of digitalis glycosides or some antiarrhythmic drugs.

The level to which hydrochlorothiazide is excreted during hemodialysis is not established.

Adverse Reactions

Side effects

The safety of Exforge® was evaluated in more than 2,600 patients.

Criteria for assessing the frequency of adverse reactions: very often (> 10% of cases); often (1-10%); sometimes (0.1-1%); rarely (0.001-0.1%); in some cases (<0.001%). Within the limits of each group allocated according to the frequency of occurrence, adverse reactions are distributed in order of decreasing importance.

From the respiratory system: often - nasopharyngitis, influenza.

Allergic and immunological reactions: rarely - hypersensitivity.

From the senses: rarely - visual impairment, tinnitus; sometimes - dizziness associated with impaired vestibular apparatus.

Mental disorders: rarely - anxiety.

From the side of the central nervous system and peripheral nervous system: often - headache; sometimes - dizziness, drowsiness, orthostatic dizziness, paresthesia.

From the respiratory system: sometimes - cough, pain in the throat and larynx.

From the cardiovascular system: sometimes - tachycardia, palpitation, orthostatic hypotension; rarely - syncopal condition, marked decrease in blood pressure.

From the digestive system: sometimes - diarrhea, nausea, abdominal pain, constipation, dry mouth.

Dermatological reactions: sometimes - skin rash, erythema; rarely - hyperhidrosis, exanthema, itching.

From the musculoskeletal system : sometimes - puffiness of the joints, back pain, arthralgia; rarely - muscle spasms, a feeling of heaviness in the whole body.

From the genitourinary system: rarely - pollakiuria, polyuria, erectile dysfunction.

Other: often - pastovnost, edema of the face, peripheral edema, increased fatigue, flushes of blood to the face, asthenia, a feeling of heat.

In the comparative and placebo-controlled wedge

The incidence of peripheral edema was significantly lower in patients receiving combination amlodipine with valsartan (5.8%) than in patients receiving amlodipine monotherapy (9%).

Laboratory indices: increased blood urea nitrogen (more than 3.1 mmol / L) was observed slightly more often in the groups receiving amlodipine / valsartan (5.5%) and valsartan as monotherapy (5.5%), compared with the group receiving placebo (4.5%).

Undesirable effects reported earlier in the use of each of the components may occur with Exforge, even if they have not been observed in clinical studies.

Amlodipine

In those clinical studies where amlodipine was used as a monotherapy, other adverse events were also noted (regardless of their causal relationship with the study drug): most often nausea; less often - alopecia, changes in the frequency of defecation, dyspepsia, dyspnea, rhinitis, gastritis, gingival hyperplasia, gynecomastia, hyperglycemia, erectile dysfunction, increased urination, leukopenia, general malaise, mood laxity, dry mouth, myalgia, peripheral neuropathy, pancreatitis, hepatitis, increased sweating, thrombocytopenia, vasculitis, angioedema, erythema multiforme.

In a prolonged placebo-controlled trial (PRAISE-2) in patients with grade III and IV cardiac insufficiency of the NYHA classification of non-ischemic etiology with amlodipine, there was an increase in the incidence of pulmonary edema with no significant differences in the incidence of worsening heart failure compared with placebo.

In rare cases, an increase in the frequency, duration and severity of angina or the development of acute myocardial infarction was noted at the beginning of therapy with slow calcium channel blockers or with an increase in the dose of slow calcium channel blockers, especially in patients with severe CAD. Also on the background of therapy

BCCI cases of arrhythmia have been observed (including ventricular tachycardia and atrial fibrillation). It is not possible to distinguish the occurrence of these undesirable phenomena from the natural course of the underlying disease.

Valsartan

In clinical trials with valsartan as monotherapy, the following adverse events were noted (regardless of their causal relationship with the study drug): viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia.

Neutropenia was detected in 1.9% of patients receiving valsartan, and 1.6% of patients receiving an ACE inhibitor.

In controlled clinical trials, in 3.9 and 16.6% of patients with heart failure who received valsartan, there was an increase in the level of creatinine and blood urea nitrogen by more than 50%, respectively. For comparison, in patients receiving placebo, an increase in creatinine and urea nitrogen was observed in 0.9 and 6.3% of cases.

Doubling of serum creatinine was found in 4.2% of patients after myocardial infarction, who received valsartan and 3.4% received captopril.

In controlled clinical trials, in 10% of patients with heart failure, there was an increase in serum potassium concentration by more than 20%. For comparison, in patients receiving placebo, an increase in potassium concentration was observed in 5.1% of cases.

Shelf life

2 years.

Storage conditions

Store at a temperature of no higher than 30 o C in a place protected from moisture. Keep out of the reach of children.

Packaging

For 14 tablets in a blister, 1 or 2 blisters in a cardboard box.

Category of leave

On prescription.

 

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