Exforge

Active material: Amlodipine, Valsartan
When ATH: C09DB01
CCF: Antihypertensive drugs
ICD-10 codes (testimony): I10
When CSF: 01.09.16.06
Manufacturer: NOVARTIS PHARMA AG (Switzerland)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, Film-coated dark yellow, Round with beveled edges, overprinted “NVR” on one side and “NV” – another.

Excipients: microcrystalline cellulose, krospovydon, magnesium stearate, colloidal silicon dioxide, gipromelloza (hydroxypropyl), Titanium dioxide (E171), iron oxide yellow (E172), macrogol 4000 (polyethylene glycol 4000), talc.

7 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.

Pills, Film-coated dark yellow, oval with bevelled edges, overprinted “NVR” on one side and “ECE” – another.

Excipients: microcrystalline cellulose, krospovydon, magnesium stearate, colloidal silicon dioxide, gipromelloza (hydroxypropyl), Titanium dioxide (E171), iron oxide yellow (E172), macrogol 4000 (polyethylene glycol 4000), talc.

7 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.

Pills, Film-coated light yellow, oval with bevelled edges, overprinted “NVR” on one side and “UIC” – another.

Excipients: microcrystalline cellulose, krospovydon, magnesium stearate, colloidal silicon dioxide, gipromelloza (hydroxypropyl), Titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), macrogol 4000 (polyethylene glycol 4000), talc.

7 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.

* international non-proprietary name, recommended by the WHO – valzartan.

Pharmacological action

Combined antihypertensive drug, containing active substances with complementary mechanisms of blood pressure control. Amlodipine, dihydropyridine derivative, It refers to a class of calcium channel blockers slow (BMKK), valsartan – to the class of angiotensin II receptor antagonists. The combination of these components has a complement antihypertensive effect, which leads to a marked reduction of blood pressure as compared to that on the background of each drug alone.

Amlodipine

Amlodipine, which is part of Exforge, It inhibits the transmembrane entry of calcium ions into cardiac myocytes and vascular smooth muscle cells. The mechanism of the antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle, causes a decrease in peripheral vascular resistance and reduction in blood pressure.

Upon receiving therapeutic doses in patients with hypertensive amlodipine causes vasodilatation, leading to a decrease in blood pressure (with the patient lying down and standing up). The decrease in blood pressure are not accompanied by a significant change in heart rate and catecholamine levels with prolonged use.

Drug concentrations in plasma is correlated with clinical effect in both young, and elderly patients.

When hypertension in patients with normal renal function, therapeutic doses of amlodipine reduces renal vascular resistance, increase in glomerular filtration rate and effective renal plasma flow without changing filtration fraction and proteinuria.

As well as the application of other BCCI, amlodipine in patients with normal left ventricular function causes a change in hemodynamic parameters of cardiac function at rest and during exercise: It noted a slight increase in cardiac index without significant effect on the maximum rate of pressure rise in the left ventricular, end-diastolic pressure and volume of the left ventricle. Hemodynamic studies in intact animals and humans have shown, that the reduction of blood pressure under the influence of amlodipine in the therapeutic dose range is not accompanied by negative inotropic action even while the use of beta-blockers.

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

Proven clinical effectiveness of amlodipine in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

Valsartan

Valsartan – active and specific angiotensin II receptor antagonist, intended for ingestion. It acts selectively on the receptor subtype AT₁, which are responsible for the known effects of angiotensin II. Increased plasma concentrations of the free because of the blockade of angiotensin II AT₁-receptors under the influence of the valsartan may stimulate the unblocked AT₂-receptors, that counteract the effects of stimulation of AT₁-receptors. Valsartan not have any agonist activity expressed in relation to AT₁-receptors. Affinity valsartan k receptor subtype AT₁ about 20 000 times higher, receptor subtypes than AT₂.

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

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

In comparative clinical studies with valsartan with an ACE inhibitor the incidence of dry cough was significantly lower (p<0.05) patients, poluchavshih valsartan (in 2.6% patients, poluchavshih valsartan, and 7.9% – treated with an ACE inhibitor). In a clinical study, included patients, who earlier in the treatment of ACE inhibitor developed a dry cough, valsartan in treating this complication was observed in 19.5% cases, thiazide diuretics in the treatment of – in 19% cases. In the same time, in patients, treated with an ACE inhibitor, cough was observed in 68.5% cases (p<0.05). Valsartan does not interact and does not block other hormone receptors or ion channels, It is important for the regulation of the cardiovascular system.

In the treatment with valsartan in patients with hypertension there is a decrease in blood pressure, not accompanied by a change in heart rate.

The antihypertensive effect is manifested within 2 hours in most patients after a single administration of the drug. The maximum reduction in blood pressure develops after 4-6 no. After taking the drug the duration of the hypotensive effect is maintained over 24 no. Repeated use of the maximum reduction in blood pressure, regardless of the dose is normally achieved within 2-4 Sun. and maintained at that level during long-term therapy. Sudden discontinuation of valsartan is not accompanied by a sharp increase in blood pressure or other unwanted clinical consequences. The use of valsartan in patients with chronic heart failure (II-IV functional class NYHA classification) It leads to a significant decrease in the number of hospitalizations. This effect is most pronounced in patients, not receiving ACE inhibitors or beta-blockers. Upon receipt of valsartan in patients with left ventricular failure (stable clinical course) or left ventricular dysfunction after myocardial infarction observed reduction in cardiovascular mortality.

Amlodipine / Valsartan

In patients with hypertension, treated with Exforge 1 time / day of the antihypertensive effect was maintained for 24 no.

Exforge doses 5/80 mg 5/160 mg in patients with baseline systolic blood pressure 153-157 mm Hg. Article. AD≥95 and diastolic mm Hg. Article. less 110 mm Hg. Article. lowers blood pressure 20-28/14-19 mm Hg. Article. (compared with 7-13/7-9 mm Hg. Article. placebo).

At a dose of Exforge 10/160 mg 5/160 mg normalizes blood pressure (decrease in diastolic blood pressure in the sitting position less 90 mm Hg. Article. at end) in 75% and 62% patients with inadequate blood pressure control on monotherapy with valsartan 160 mg / day.

At a dose of Exforge 10/160 normalizes blood pressure in mg 78% patients with inadequate blood pressure control on monotherapy with amlodipine 10 mg. In patients with hypertension with the combination of valsartan dose 160 mg amlodipine doses 10 mg 5 mg achieved an additional reduction in systolic and diastolic blood pressure 6.0/4.8 mm Hg. Article. and 3.9/2.9 mm Hg. Article. respectively, compared to patients, who continued to receive only a dose of valsartan 160 Only mg or amlodipine 5 and 10 mg.

In the titration of the dose of Exforge 5/160 mg 10/160 mg in patients with arterial hypertension and diastolic blood pressure>110 mm Hg. Article. less 120 mm Hg. Article. a decrease in blood pressure in the sitting position on the 36/29 mm Hg. Art., comparable with the reduction of blood pressure when titrated dose combination of an ACE inhibitor and a thiazide diuretic.

In two long-term studies with a long follow-up the effect of Exforge was maintained for 1 year. Sudden discontinuation of Exforge is not accompanied by a sharp rise in blood pressure.

Patients, to achieve adequate control of blood pressure, But is pronounced swelling of monotherapy with amlodipine, when using combination therapy achieved comparable blood pressure control with less probability of edema.

Therapeutic efficacy Exforge not depend on the age, sex and race of the patient.

Pharmacokinetics

The pharmacokinetics of valsartan and amlodipine are characterized by the linearity.

Amlodipine

Absorption

After ingestion of therapeutic doses of amlodipine C_max amlodipine plasma levels achieved after 6-12 no. The magnitude of the absolute bioavailability averages 64-80%. Eating does not affect the bioavailability of amlodipine.

Distribution

V_d approximately 21 l / kg. In studies in vitro demonstrated amlodipine, In patients with hypertension about 97.5% circulating drug is bound to plasma proteins.

Metabolism

Amlodipine intensivno (about 90%) It is metabolized in the liver with the formation of active metabolites.

Deduction

Excretion of amlodipine from the plasma is biphasic with T_1/2 about 30 to 50 hours. C_ss plasma levels are achieved after prolonged use for 7-8 days. 10% unaltered amlodipine and 60% amlodipine metabolites are excreted by the kidneys.

Valsartan

Absorption

After oral administration of valsartan C_max plasma levels achieved after 2-3 no. The average absolute bioavailability of 23%. Concentration-time curve of valsartan has the character of a downward multieksponentsialny (T_1/2a <1 ч и T_1/2b about 9 no). When receiving valsartan with food there is a decrease in bioavailability (of the AUC) on 40% and C_max plasma almost 50%, at approximately 8 hours after administration of valsartan concentration in blood plasma in patients, taking it with food, and the group, which took on an empty stomach, aligned. Decrease AUC, However, not accompanied by a clinically significant reduction in therapeutic effect, Valsartan may be administered so regardless of mealtime.

Distribution

V_d valsartan at steady state after the / in the introduction was about 17 l, which indicates the absence of extensive tissue distribution of valsartan. Valsartan largely bound to serum proteins (94-97%), mostly to albumin.

Metabolism

Valsartan is not subjected to metabolism expressed (about 20% the dose is defined as metabolites). Hydroxy metabolite in the plasma is determined in low concentrations (less than 10% by AUC of valsartan). Pharmacologically active metabolite Эtot.

Deduction

Valsartan is derived largely unaltered through the intestine (about 83% dose) and kidneys (about 13% dose). After the on / in the, plasma clearance of valsartan is about 2 l / h and the renal clearance is 0.62 l / (about 30% total clearance). T_1/2 Valsartan is 6 no.

Amlodipine / Valsartan

After oral administration of the drug Exforge C_max valsartan and amlodipine are reached in 3 and h 6-8 h, respectively. The rate and extent of absorption of Exforge equivalent bioavailability of valsartan and amlodipine upon receipt of each in separate tablets.

Pharmacokinetics in special clinical situations

The pharmacokinetic characteristics of the use of Exforge in children under 18 years have not been established.

The time to reach C_max amlodipine plasma in young and elderly patients equally. Elderly patients slightly decreased clearance of amlodipine, which leads to an increase in AUC and T_1/2.

Elderly patients systemic exposure to valsartan was somewhat more pronounced, than in young patients, however, it was not clinically significant. Since the components of the drug tolerated in elderly and younger patients is equally good, the usual recommended dosage regimens.

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine did not significantly change. There was no correlation between renal function (CC) and systemic exposure to valsartan (AUC) in patients with various degrees of renal impairment. Do not you want to change the starting dose in patients with initial and moderate renal impairment (CC 30-50 ml / min).

Patients with hepatic insufficiency have decreased clearance of amlodipine, which leads to an increase in AUC of about 40-60%. Average, in patients with chronic liver disease of mild to moderate degree of bioavailability (AUC) Valsartan is doubled compared to healthy volunteers (appropriate age, sex and body weight).

Testimony

- Arterial hypertension (for patients, which shows the combination therapy).

Dosage regimen

The drug is taken orally, with a little water, 1 times / day, regardless of mealtime.

The recommended daily dose – 1 tab. dose 5/80 mg or 5/160 mg or 10/160 mg.

In appointing elderly patients, patients with early or moderate renal impairment (CC>30 ml / min), with impaired liver function or liver disease, yavleniyami with cholestasis, change the dosing is not required.

Side effect

The safety of Exforge estimated more, than 2600 patients.

Criteria for assessing the frequency of adverse reactions: Often – more 10% cases; often – 1%-10%; sometimes – 0.1-1%; rarely – 0.001-0.1%; in some cases – less 0.001%. Within each group,, highlighted by frequency of occurrence, side reactions are allocated in decreasing order of importance.

The respiratory system: often – nazofaringit, flu; sometimes – cough, pain in the throat and larynx.

From the senses: rarely – visual impairment, noise in ears; sometimes – dizziness, associated with dysfunction of the vestibular system.

From the central and peripheral nervous system: often – headache; sometimes – dizziness, drowsiness, orthostatic dizziness, paresthesia; rarely – anxiety.

Cardio-vascular system: sometimes – tachycardia, heartbeat, orthostatic hypotension; rarely – syncope, marked reduction in blood pressure.

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

Dermatological reactions: sometimes – skin rash, эritema; rarely – hyperhidrosis, rash, itch.

On the part of the musculoskeletal system: sometimes – swelling of joints, backache, artralgii; rarely – muscle spasms, a feeling of heaviness in the whole body.

From the urinary system: rarely – thamuria, polyuria.

On the part of the reproductive system: rarely – erectile dysfunction.

Other: often – pastoznost, swelling of the face, peripheral edema, fatigue, flushing, asthenia, feeling the heat.

In comparative and placebo-controlled clinical trials, the frequency of peripheral edema was significantly lower in patients, treated with a combination of amlodipine with valsartan (5.8%), than patients, amlodipine monotherapy (9%).

From the laboratory parameters: increase in blood urea nitrogen (more 3.1 mmol / l) observed slightly more often in groups, poluchavshih amlodipine / valsartan (5.5%) valcartan and as monotherapy (5.5%), compared with the group, placebo (4.5%).

Allergic reactions: rarely – hypersensitivity to the drug.

Adverse events, previously reported in the application of each of the components, may occur in the application of Exforge, even if they have not been observed in clinical trials.

Amlodipine

In clinical studies, wherein amlodipine used as monotherapy, There were also other undesirable effects (irrespective of their causal relationship to the study drug): common – nausea; less often – alopecia, the change in frequency of defecation, dyspepsia, breathlessness, rhinitis, gastritis, gingival hyperplasia, mucosal, gynecomastia, giperglikemiâ, erectile dysfunction, increased urination, leukopenia, general malaise, mood lability, dry mouth, myalgia, perifericheskaya neuropathy, pancreatitis, hepatitis, increased perspiration, thrombocytopenia, vasculitis, angioedema, erythema multiforme.

For continuous placebo-controlled study (PRAISE-2) in patients with heart failure III and IV functional class NYHA classification nonischemic etiology, when using amlodipine was an increase in the incidence of pulmonary edema, in the absence of significant differences in the incidence of worsening of heart failure as compared to placebo.

Valsartan

In clinical studies, the application of valsartan monotherapy, We noted the following adverse events (irrespective of their causal relationship to the study drug): viral infections, upper respiratory tract infection, sinusitis, rhinitis, neutropenia, insomnia.

In controlled clinical trials 3.9% and 16.6% Patients with heart failure, poluchavshih valsartan, there was an increase in serum creatinine and blood urea nitrogen over 50% respectively. For comparison – patients, placebo, increase of creatinine and urea nitrogen were observed in 0.9% and 6.3% cases.

The doubling of serum creatinine was detected in 4.2% patients after myocardial infarction, receiving valsartan and 3.4% treated with captopril.

In controlled clinical trials 10% Patients with heart failure have seen an increase in serum potassium concentration over 20%. For comparison, patients, placebo, increasing the concentration of potassium was observed in 5.1%. cases.

Contraindications

- Pregnancy;

- Hypersensitivity to the drug.

The safety of Exforge in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, in patients after undergoing a kidney transplant recently,, as well as children and adolescents up to 18 s is not installed.

FROM caution prescribers with: hepatic dysfunction (especially with obstructive biliary tract disease); severe renal impairment (CC<10 ml / min); Patients with mitral stenosis or aortic, hypertrophic obstructive cardiomyopathy; when hyperkalemia, deficiency in the body of sodium and / or decreased CBV.

Pregnancy and lactation

Exforge, as well as any other drug, directly affect the renin-angiotensin-aldosterone system (They go), should not be administered during pregnancy and women, wishing to get pregnant. If pregnancy is detected during treatment with Exforge, the drug should be discontinued as soon as possible.

Patients of childbearing age You must be informed of the potential risk to the fetus, associated with the use of drugs, affect the RAAS.

Considering the mechanism of action of angiotensin II receptor antagonists, you can not eliminate the risk to the fetus. Known, that ACE inhibitors, affecting the RAAS, pregnant women in II and III trimesters, resulting in damage to or destruction of the developing fetus. According to a retrospective analysis of the use of ACE inhibitors in the I trimester of pregnancy, accompanied by the development of the fetus and newborn pathology. Accidental received valsartan in pregnant described cases of spontaneous abortions, oligohydramnios and renal dysfunction in neonates.

Unknown, stand whether valsartan and / or amlodipine with breast milk. Since experimental studies It noted the allocation of valsartan with breast milk, Exforge used during lactation (breast-feeding) not recommended.

Cautions

Caution must be exercised in the appointment of Exforge in patients with liver diseases (especially with obstructive biliary tract disease). Valsartan is derived mainly unchanged in the bile, whereas amlodipine is extensively metabolized in the liver.

Patients with initial and moderate renal impairment (CC 30-50 ml / min) dosage adjustment of Exforge is not required. Caution should be exercised when administering the drug to patients with severely impaired renal function (CC<10 ml / min), t. to. data on the safety of the drug in such cases are not received.

As well as the use of other vasodilators, Be particularly careful when administering the drug to patients with mitral stenosis and aortic, hypertrophic obstructive cardiomyopathy.

If necessary, cancel the beta-blocker therapy before Exforge dose of beta-blockers should be reduced gradually. Since amlodipine is not a beta-blocker, Exforge use of the drug does not prevent the development of withdrawal, occurs when a dramatic treatment of beta-blockers.

In placebo-controlled trials in patients with uncomplicated hypertension in 0.4% cases, there are marked hypotension. Patients with activated RAAS (eg, with a deficit of BCC and / or sodium in patients, receiving high doses of diuretics), when receiving angiotensin receptor blockers, may develop symptomatic hypotension. Before starting treatment with Exforge should carry out the correction of sodium in the body and / or bcc or start treatment under close medical supervision.

In the case of hypotension the patient should be put to the raised legs, if necessary, hold / in infusion saline. After stabilization of blood pressure treatment Exforge can be extended.

With the simultaneous use of the drug with biologically active additives, containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other agents, which may cause an increase in potassium concentration in the blood (eg, Heparin), care should be taken to carry out regular monitoring of the concentration of potassium in the blood.

Effects on ability to drive vehicles and management mechanisms

There are no data on the effect of the drug on the ability to drive vehicles and to work with the mechanisms. In connection with the possible occurrence of dizziness or fatigue should be careful when driving or operating machinery.

Overdose

Data on cases of drug overdose on currently available.

In case of overdose can be expected to develop valsartan significant decrease in blood pressure and dizziness. Overdose amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. It was also reported occurrence of severe and prolonged systemic hypotension up to the development of fatal shock.

Treatment: Accidental overdose, induce vomiting (if the drug has recently been adopted) or conduct gastric lavage, assign activated carbon. The use of activated carbon in healthy volunteers immediately or after 2 h after administration of amlodipine significantly reduces its absorption. If symptomatic hypotension, caused Exforge, should put the patient with elevated legs, take proactive measures to support the cardiovascular system, including frequent monitoring of cardiac function and respiratory system, BCC and urine output. In the absence of contraindications to restore vascular tone and blood pressure can be applied (carefully) vasoconstrictor. In / in the introduction of calcium gluconate may be effective for the removal of calcium channel blockade. Withdrawal of valsartan and amlodipine during hemodialysis is unlikely.

Drug Interactions

Amlodipine

When amlodipine monotherapy were observed clinically significant interaction with thiazide diuretics, beta-blockers, ACE inhibitors, Long-acting nitrates, nitroglycerin sublingual application, digoksinom, varfarinom, atorvastatin, sildenafilom, maaloksom (aluminum hydroxide gel, magnesium hydroxide, simethicone), cimetidine, NSAIDs, antibiotics and oral hypoglycemic drugs.

Valsartan

Established, that valsartan monotherapy no clinically significant interaction with the following medicines: cimetidine, warfarin, furosemid, Digoxin, atenolol, Indomethacin, gidroxlorotiazid, amlodipine, glibenclamide.

While the use of biologically active additives, containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other agents, which may cause an increase in potassium concentration in the blood (eg, Heparin), Caution should be exercised and carried out frequent monitoring of potassium concentration in the blood.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children, dry place at temperatures no higher than 30 ° C. Shelf life – 2 year.