Expiration date: 03/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet contains:

amlodipine besilat of 6.94 mg

(corresponds to the content of amlodipine 5 mg) 

valsartan 80 or 160 mg

other ingredients: microcrystalline crospovidone the magnesium stearate silica colloidal anhydrous hypromellose (hydroxypropyl methylcellulose) titanium dioxide (E171) iron oxide yellow (E172) macrogol 4000 (polyethylene glycol 4000) talc 

in blister packs for 7, 10 or 14 PCs. in cardboard pack 1, 2, 4, 8, 14, 40 (according to table 7.) or 3, 9, 28 (10 tabl.) or 1, 2, 4, 7, 20 (for 14 pieces) blisters.

Tablets, film-coated. 1 tablet contains:

amlodipine besylate 13,87 mg

(corresponds to the content of amlodipine — 10 mg) 

valsartan 160 mg

other ingredients: microcrystalline crospovidone the magnesium stearate silica colloidal anhydrous hypromellose (hydroxypropyl methylcellulose) titanium dioxide (E171) iron oxide yellow (E172) iron oxide red (E172) macrogol 4000 (polyethylene glycol 4000) talc 

in blister packs for 7, 10 or 14 PCs. in cardboard pack 1, 2, 4, 8, 14, 40 (according to table 7.) or 3, 9, 28 (10 tabl.) or 1, 2, 4, 7, 20 (for 14 pieces) blisters.

Description pharmaceutical form:

Tablets, film-coated, 5/80 mg: dark yellow, round with beveled edges, with overprint "NVR" on one side and "NV" on the other.

Tablets, film-coated, 5/160 mg: dark yellow, oval beveled edges, with overprint "NVR" on one side and "ECE" on the other.

Tablets, film-coated, 10/160 mg: light yellow, oval beveled edges, with overprint "NVR" on one side and "UIC" on the other.

Pharmacokinetics:

Pharmacokinetics of valsartan and amlodipine is characterized by linearity.

Amlodipine

Suction. After intake of amlodipine in therapeutic doses, amlodipine Cmax in plasma is reached after 6-12 h. the Value of absolute bioavailability averages 64-80%. Eating does not affect the bioavailability of amlodipine.

Distribution. The apparent VSS is approximately 21 l/kg In studies with amlodipine in vitro it was shown that in patients with arterial hypertension approximately 97.5% of circulating drug binds with blood plasma proteins.

Metabolism. Amlodipine intensively (approximately 90%) metabolised in the liver with formation of active metabolites.

Excretion. Elimination of amlodipine from the plasma is biphasic with T1/2 approximately 30 to 50 hours Equilibrium concentration in plasma is reached after use within 7-8 days. 10% the unmodified amlodipine and 60% of amlodipine in the form of metabolites excreted by the kidneys.

Valsartan

Suction. After intake of valsartan Cmax in plasma achieved through 2-3 h. mean absolute bioavailability of 23%. The pharmacokinetic curve is downward valsartan multiexponential character (T1/2&alpha <1 h and T1/2&beta about 9 hours). When taking valsartan with food, there is a decrease in bioavailability (AUC) by 40% and Cmax in plasma by almost 50%, although about 8 h after administration of the drug the concentration of valsartan in plasma in the group of patients taking it with food, and in the group taking on an empty stomach, even. The reduction in AUC is not, however, a clinically significant reduction in therapeutic effect, therefore, valsartan can be assigned regardless of mealtime.

Distribution. VSS valsartan in equilibrium after the on/in the introduction was about 17 l, indicating the absence of extensive distribution of valsartan in the tissues. Valsartan is largely associated with serum proteins (94-97%), mainly to albumin.

Metabolism. Valsartan is not exposed to significant metabolism (about 20% of the dose is determined in the form of metabolites). The hydroxyl metabolite determined in plasma at low concentrations (less than 10% from the AUC valsartan). This metabolite is pharmacologically active.

Excretion. Valsartan is excreted primarily in unchanged form through the intestine (about 83% of dose) and renal (around 13% of the dose). After I/V administration, plasma Cl valsartan is about 2 l/h, renal Cl of 0.62 l/h (about 30% of total clearance). T1/2 valsartan is 6 hours.

Amlodipine/Valsartan

After ingestion of the drug Exforge Cmax of valsartan and amlodipine are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption of the drug equivalent to the bioavailability of valsartan and amlodipine when taking each of them in separate pills.

Pharmacokinetics in special clinical cases

Pharmacokinetic features of the drug Exforge in children under 18 years not installed.

Patients of advanced age.The time to reach Cmax of amlodipine in plasma of young and elderly patients alike. In elderly patients, amlodipine clearance is slightly reduced, leading to increase in AUC and T1/2.

In elderly patients, the systemic exposure to valsartan was slightly more pronounced than in young, but these results were not clinically significant. Because the tolerability of the drug in elderly and in younger patients is equally good, it is recommended to use conventional dosing regimens.

Patients with impaired renal function.In patients with impaired renal function the pharmacokinetic parameters of amlodipine did not significantly change. There was no correlation between renal function (clearance) and systemic exposure to valsartan (AUC) in patients with various degrees of renal dysfunction. No alteration to the initial dose in patients with initial and moderate renal impairment (Cl creatinine — 30-50 ml/min).

Patients with disorders of the liver.Patients with hepatic insufficiency have reduced clearance of amlodipine, which leads to an increase in AUC of approximately 40-60%. On average, patients with chronic liver disease of mild to moderate degree of bioavailability (AUC) of valsartan is doubled compared to healthy volunteers (appropriate age, sex and body mass).

Description pharmacological action:

Drug Exforge is a combination of 2 antihypertensive drugs with complementary other mechanism of control of blood pressure: amlodipine, a derivative of dihydropyridine belongs to the class of blockers "slow" calcium channels (bmkk), valsartan is a class of receptor antagonists of angiotensin II. The combination of these components has a complementary hypotensive effect that leads to a more pronounced reduction in BP compared with those on monotherapy of each drug.

Amlodipine

Amlodipine, a part of the drug Exforge inhibits transmembrane influx of calcium ions in and cardiomiotita gladkomyshechne cells receptacles. Mechanism of antigipertenzivnogo action of amlodipine is associated with direct relaxing effect on vascular smooth muscle causing reduction in peripheral vascular resistance and reduction in blood pressure.

After administration of therapeutic doses to patients with hypertension amlodipine causes vasodilation leading to decrease in blood pressure (with the patient "lying" and "standing"). Blood pressure reduction is not accompanied by significant changes in heart rate and catecholamine levels after prolonged use.

Drug concentrations in plasma correlate with clinical effect in both young and elderly patients.

Hypertension in patients with normal renal function amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, increasing glomerular filtration rate and effective renal blood flow without changes in filtration fraction and proteinuria.

As well as the application of other bmkk, the reception of amlodipine in patients with normal function of left ventricle (LV) causes a change in the hemodynamic parameters of cardiac function at rest and during exercise: there was a small increase in cardiac index without significant influence on the maximum rate of pressure rise in the LV (dP/dt), end-DBP and volume of LV. Hemodynamic studies in intact animals and humans have shown that the decrease in blood pressure under the influence of amlodipine in the range of therapeutic doses is not accompanied by negative inotropic effects even in case of simultaneous use with beta-blockers.

Amlodipine does not change sinoatrial node function or AV conduction in intact animals and humans. When using amlodipine in combination with beta-blockers in patients with hypertension or angina pectoris reduction in blood pressure is not accompanied by undesirable changes of ECG parameters.

Proven clinical efficacy of amlodipine in patients with chronic stable angina, vasospastic angina and angiographic proven coronary artery disease.

Valsartan

Valsartan is an active and specific antagonist of angiotensin II receptor intended for ingestion. It acts selectively on the receptor subtype AT1, which is responsible for the known effects of angiotensin II. The increase in the plasma concentration of free angiotensin II as a consequence of the blockade AT1-receptors is influenced by valsartan may stimulate the unblocked AT2 receptors, which counteract the effects of the blockade AT1-receptors. Valsartan does not have any pronounced agonistic activity against AT1-receptors. The affinity of valsartan for the AT1 receptor subtype approximately 20,000 times higher than for the AT2 receptor subtype.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin.

In the application of antagonists of angiotensin II no inhibition of ACE and the accumulation of bradykinin or substance P, therefore, the development of dry cough is unlikely.

In comparative clinical studies with valsartan, an ACE inhibitor, the incidence of dry cough was significantly lower (p<0.05) in patients who received valsartan (2.6% of patients treated with valsartan and 7.9 percent receiving ACE inhibitor). In a clinical study involving patients earlier in the treatment of ACE inhibitor developed a dry cough, the treatment with valsartan, this complication was noted in 19.5% of cases in the treatment of thiazide diuretic in 19% of cases. At the same time, in the group of patients treated with ACE inhibitor, cough was observed in 68.5% of cases (p<0.05). Valsartan does not enter into interaction and does not block the hormone receptors or ion channels of importance for the regulation of the functions of the cardiovascular system.

The treatment with valsartan in patients with arterial hypertension there is a decrease in AD, is not accompanied by changes in heart rate.

The antihypertensive effect is evident within 2 h in most patients after a single administration of the drug. The maximum decrease in blood pressure develops within 4-6 hours After taking the drug antihypertensive effect persists over 24 h. With repeated use, the maximum reduction in AD regardless of the dose is usually achieved within 2-4 weeks and maintained at that level during long-term therapy. Abrupt discontinuation of the valsartan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences. The use of valsartan in patients with chronic heart failure (II–IV class NYHA classification) leads to a significant decrease in admissions. This effect is most pronounced in patients not receiving ACE inhibitors or beta-blockers. When receiving valsartan in patients with left ventricular failure (stable clinical course) or with impaired LV function after myocardial infarction there is a decrease in cardiovascular mortality.

Amlodipine/Valsartan

In patients with hypertension treated with drug Exforge 1 time/day antihypertensive effect persisted for 24 hours

Drug Exforge in doses of 5/80 and 5/160 mg in patients with initial garden 153-157 mm Hg.St. and DBP &ge95 and <110 mm Hg.St., reduces AD by 20-28/14-19 mm Hg.St. (compared to 7-13/7-9 mm Hg.St. when receiving placebo).

Drug Exforge at a dose of 5/160 and 10/160 mg normalizes blood pressure (DBP reduction to a position "sitting" <90 mm Hg.St.) from 75 and 62% of patients with inadequate BP control on monotherapy with valsartan at a dose of 160 mg/day .

Drug Exforge at a dose of 10/160 mg normalizes blood pressure in 78% of patients with inadequate BP control on monotherapy with amlodipine at a dose of 10 mg.

In patients with arterial hypertension in combination of valsartan in a dose of 160 mg with amlodipine at doses of 10 and 5 mg achieved additional reductions in SBP and DBP 6.0/4.8 mm Hg.St. and 3.9/2.9 mm Hg.St. respectively, compared to patients who continued to receive only valsartan at a dose of 160 mg or amlodipine only at a dose of 5 and 10 mg.

For dose titration of the drug Exforge from 5/160 mg to 10/160 patients with arterial hypertension with DBP &ge110 and <120 mm Hg.St. a decrease in AD in position "sitting" on 36/29 mm Hg.St., comparable to the decrease in blood pressure during the titration of dose combination of ACE inhibitor and thiazide diuretic.

In two long-term studies with long follow-up period, effect of the drug Exforge maintained for 1 year. The sudden discontinuation of the drug Exforge is not accompanied by a sharp increase in blood pressure.

Patients achieved adequate control of blood pressure, but developed severe edema on the background of monotherapy with amlodipine in combination therapy achieved comparable control of blood pressure with less likelihood of developing edema.

The therapeutic efficacy of the drug Exforge not depend on the age, sex and race of the patient.

Indications:

Arterial hypertension (in patients, which shows the combined therapy).

Contraindications:

• hypersensitivity to amlodipine, valsartan and other components of the drug
  
• pregnancy.
  

The safety of the drug Exforge patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, in patients after recent kidney transplantation, as well as children and adolescents to 18 years not installed.

With caution:

• liver diseases (particularly when obstructive diseases of biliary tract) — valsartan is primarily excreted unchanged in the bile, whereas amlodipine is extensively metabolized in the liver
  
• severe violations of kidney function (Cl creatinine <10 ml/min) because data on the safety of the drug in such cases do not exist
  
• mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy as with other vasodilators
  
• hyperkalemia, deficiency of sodium and/or reducing the BCC.
  

Application of pregnancy and breast-feeding:

Given the mechanism of action of antagonists of angiotensin II receptors cannot be ruled out risk to the fetus. It is known that the appointment of ACE inhibitors that affect the renin-angiotensin-aldosterone system (RAAS), pregnant women in II and III trimester, causes damage or death to the developing fetus. According to a retrospective analysis of the use of ACE inhibitors during the first trimester of pregnancy was accompanied by the development of pathology of the fetus and newborn. When accidental receiving valsartan in pregnant described cases of spontaneous abortion, oligohydramnios and renal dysfunction in newborns.

Drug Exforge, like any other drug that has a direct impact on the RAAS, should not be administered during pregnancy and women wishing to get pregnant. Patients of childbearing age should be informed about the possible risk to the fetus associated with the use of drugs that affect the RAAS. If pregnancy is detected during treatment with the drug Exforge, the drug should be discontinued as soon as possible.

Unknown, penetrates whether valsartan and/or amlodipine in breast milk. Since the pilot studies have noted the allocation of valsartan with breast milk, it is not recommended to use the drug Exforge in the period of breastfeeding.

Side effects:

The safety of the drug Exforge evaluated more than 2,600 patients.

Evaluation criteria frequency of adverse reactions: very often (>10% of cases) often (1-10%) sometimes (0,1–1%) rare (0,001–0,1%) in some cases (<0,001%). Within each group defined by frequency adverse reactions are distributed in descending order of importance.

The respiratory system: often — nasopharyngitis, influenza.

Allergic and immunological reactions: seldom — hypersensitivity.

From the sensory organs: rare — visual disturbances, ringing in the ears, and sometimes dizziness associated with dysfunction of the vestibular apparatus.

Mental disorders: rare — anxiety.

CNS and peripheral nervous system: often — headache sometimes — dizziness, drowsiness, orthostatic dizziness, paresthesia.

The respiratory system: sometimes — cough, pain in the throat and larynx.

Of the cardiovascular system: sometimes — tachycardia, palpitations, orthostatic hypotension rare — sincopale state, expressed lower AD.

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

Dermatological reactions: sometimes — skin rash, erythema rare — rash, exanthema, itching.

From the side of musculoskeletal system: sometimes — swelling of joints, back pain, arthralgia rare — muscle spasms, feeling of heaviness in the whole body.

With the genitourinary system: rare — pollakiuria, polyuria, erectile dysfunction.

Other: often — pasty, facial edema, peripheral edema, fatigue, rush of blood to the face, asthenia, feeling of heat.

In a comparative and placebo-controlled clinical studies, the incidence of peripheral edema was significantly lower in patients treated with the combination of amlodipine with valsartan (5,8%) than in patients treated with amlodipine monotherapy (9%).

Laboratory indicators: increase in urea nitrogen in the blood (more than 3.1 mmol/l) was observed slightly more often in groups receiving amlodipine/valsartan (5.5%) and valsartan monotherapy (5.5 percent) compared with the placebo group (4.5 percent).

Adverse events previously reported with the use of each of the components can take place when applying Exforge, even if they were not observed in clinical trials.

Amlodipine

In those clinical trials, where amlodipine was used as a monotherapy, has also noted other adverse events (regardless of causality with the study drug): common — nausea rarely alopecia, the change in frequency of bowel movements, dyspepsia, dyspnoea, rhinitis, gastritis, gingival hyperplasia, gynecomastia, hyperglycemia, erectile dysfunction, frequent urination, leucopenia, malaise, mood lability, dry mouth, myalgia, peripheral neuropathy, pancreatitis, hepatitis, increased sweating, thrombocytopenia, vasculitis, angioedema, erythema multiforme.

In the long placebo-controlled study (PRAISE-2) in patients with heart failure III and IV class NYHA classification nonischemic etiology in the application of amlodipine, there was an increase in the incidence of pulmonary edema in the absence of significant differences in the incidence of worse heart failure compared with placebo.

In rare cases at the beginning of therapy with blockers of slow calcium channels or when the dose blockers slow calcium channels, especially in patients with severe coronary artery disease, there was an increase in frequency, duration and severity of angina or acute myocardial infarction. Also during therapy BCCI there have been cases of development of arrhythmia (including ventricular tachycardia and atrial fibrillation). It is not possible to distinguish the occurrence data of adverse events from the natural flow of the underlying disease.

Valsartan

In clinical studies with the use of valsartan as monotherapy was noted following adverse events (irrespective of causal relationship with study drug): a viral infection of upper respiratory tract infection, sinusitis, rhinitis, neutropenia, insomnia.

Neutropenia was detected in 1.9% of patients treated with valsartan and 1.6% of patients receiving ACE inhibitor.

In controlled clinical studies of 3.9 and 16.6% of patients with heart failure, treated with valsartan, increased creatinine and urea nitrogen the blood by more than 50%, respectively. For comparison — in patients treated with placebo, raising creatinine and urea nitrogen were observed in 0.9 and 6.3% of cases.

Doubling of serum creatinine were detected in 4.2% of patients after myocardial infarction treated with valsartan and 3.4% treated with captopril.

In controlled clinical trials 10% of patients with heart failure showed improved concentrations of serum potassium more than 20%. For comparison, in patients, receiving placebo, increasing the concentration of potassium was observed in 5.1% of cases.

Drug interactions:

Amlodipine

Monotherapy with amlodipine is not observed clinically significant interactions with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin sublingual application, digoxin, warfarin, atorvastatin, sildenafilum, Maalox (gel of aluminum hydroxide, magnesium hydroxide, simethicone), cimetidine, NSAIDs, antibiotics and oral hypoglycemic drugs.

Valsartan

It is established that monotherapy with valsartan missing a clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

While the use of biologically active additives, containing potassium, kalisberegatmi dioretikami, kalisoderjasimi salt substitutes or other drugs that may cause increased concentration of potassium in the blood (e.g. heparin) should be used with caution and frequent monitoring of potassium in the blood.

Method of application and dose:

Inside, squeezed small amounts of water, 1 times a day regardless of mealtime.

The recommended daily dose — 1 tab., containing amlodipine / valsartan at the dose of 5/80, 5/160, or 10/160 mg.

When administered to elderly patients, patients with initial or moderate renal impairment (Cl creatinine >30 ml/min), impaired liver function or liver disease, with symptoms of cholestasis: change of dosing regimen is not required.

Overdose:

Data on cases of drug overdose are currently available.

Symptoms: an overdose of valsartan, we can expect the development of a marked decline in blood pressure and dizziness. Overdose amlodipine may cause excessive peripheral vasodilation and possible reflex tachycardia. It was also reported on the occurrence of a pronounced and prolonged systemic arterial hypotension until the development of shock with a fatal outcome.

Treatment: in case of accidental overdose should cause vomiting (if the drug had been recently adopted), or to perform gastric lavage. The use of activated charcoal in healthy volunteers immediately or 2 h after administration of amlodipine significantly reduced the absorption.

When clinically expressed arterial hypotension caused by the drug Exforge, patients should be laid with raised legs, to take active measures to support the cardiovascular system, including frequent monitoring of cardiac function and the respiratory system, BCC and the amount of urine passed. In the absence of contraindications to restore vascular tone and BP is possible to use (with caution) vasoconstrictor. In/in the introduction of calcium gluconate may be effective for eliminating the blockade of calcium channels. The excretion of valsartan and amlodipine in the kidney is unlikely.

Special instructions:

If you need to cancel &beta-blockers before beginning therapy preparam Exforge, dose &beta-blocker should be reduced gradually. Because not amlodipine is a beta blocker, drug Exforge not prevent the development of withdrawal syndrome occurs when a dramatic treatment &beta-blockers.

A deficiency of sodium and/or reducing the BCC. In placebo-controlled trials in patients with uncomplicated arterial hypertension in 0.4% of cases was observed expressed arterial gipotenzia. In patients with an activated renin-angiotensin-aldosterone system (e.g. with a deficit BCC and/or sodium in patients receiving high doses of diuretics), upon receipt of angiotensin receptor blockers, may develop symptomatic arterial hypotension. Before beginning treatment drug Exforge should be performed correction of sodium in the body and/or BCC or start treatment under close medical supervision. In the case of arterial hypotension patients should be laid with raised legs, if necessary, to hold the on/in infusion of saline. After stabilization of blood pressure treatment drug Exforge can be continued.

Hyperkalemia. While the use of the drug with the biologically active additives, containing potassium, kalisberegatmi dioretikami, kalisoderjasimi salt substitutes, or other drugs that may cause increased concentration of potassium in the blood (such as heparin), you should exercise caution and conduct regular monitoring of potassium in the blood.

Effects on ability to drive vehicles and operate machinery. There are no data on the impact of the drug on the ability to drive vehicles and operate machinery. In connection with the possible occurrence of dizziness or fatigue should use caution when driving or operating machinery.