Pharmacological properties of the drug Exforge
Pharmacodynamics. Exforge contains two antihypertensive components with additional mechanisms for controlling blood pressure in patients with essential hypertension (arterial hypertension): amlodipine belongs to the class of calcium antagonists, and valsartan belongs to the class of angiotensin II antagonists. The combination of these ingredients has an additive antihypertensive effect, lowering blood pressure to a greater extent than either component alone. Amlodipine Amlodipine inhibits the transmembrane penetration of calcium ions into the smooth muscles of the heart and blood vessels. The mechanism of the antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle, which causes a decrease in peripheral vascular resistance and leads to a decrease in blood pressure. Experimental data confirm that amlodipine binds at dihydropyridine and non-hydropyridine linkages. The process of contraction of cardiac muscle and vascular smooth muscle depends on the passage of extracellular calcium into the cell through specific ion channels. After administering a therapeutic dose to patients with essential hypertension (arterial hypertension), amlodipine causes vasodilation, which leads to a decrease in blood pressure in the supine and standing positions. This decrease in blood pressure is not accompanied by a significant change in heart rate or plasma catecholamine levels with prolonged use. The effect correlates with the concentration of the active substance in the blood plasma in young and elderly patients. In patients with normal renal function, a therapeutic dose of amlodipine leads to a decrease in renal vascular resistance and an increase in the level of glomerular filtration, as well as an improvement in renal blood flow without changes in the filtered fraction or proteinuria. Studies of cardiac hemodynamic function at rest and during exercise in patients with normal ventricular function receiving amlodipine therapy generally showed a slight increase in cardiac index without a significant effect on the change in pressure (dP/dt) in the left ventricle. Based on the results of studies conducted in animals and humans, amlodipine did not exhibit a negative inotropic effect when used in therapeutic doses, even when combined with beta-adrenergic blockers, and did not affect the function of the AV node or atrioventricular conduction. In clinical studies in patients with essential hypertension (arterial hypertension) or angina pectoris, no changes in ECG parameters were detected when amlodipine was used in combination with beta-adrenergic blockers. The use of amlodipine had a positive clinical effect in patients with chronic stable angina, vasospastic angina and coronary artery disease confirmed by angiography. Valsartan - (INN valsartanum - valsartan) Valsartan is an active and specific angiotensin II receptor antagonist, intended for oral use. It acts selectively on receptors of the AT1 subtype, which are rare and responsible for the effects of angiotensin II. Increased levels of angiotensin II due to blockade of AT1 receptors by valsartan can stimulate free AT2 receptors, which balances the effect of AT1 receptors. Valsartan does not have any partial agonist activity at the AT1 receptor and has a much greater (approximately 20,000-fold) affinity for the AT1 receptor than for the AT2 receptor. Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin, and no side effects due to bradykinin have been noted. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly lower (p≤0.05) in patients receiving valsartan than in patients receiving an ACE inhibitor (2.6% versus 7.9% respectively). In patients who were previously treated with an ACE inhibitor, a dry cough developed as a side effect. When treated with valsartan, this side effect was noted in 19.5% of cases, when treated with a thiazide diuretic - in 19%, while in the group of patients receiving an ACE inhibitor, cough was detected in 68.5% of cases (p≤0.05 ). Valsartan does not interact with or block other hormone receptors or ion channels, which are known to play an important role in regulating the function of the cardiovascular system. The use of the drug in patients with hypertension (arterial hypertension) leads to a decrease in blood pressure without affecting heart rate. In most patients, after oral administration of a single dose of valsartan, the onset of the antihypertensive effect is noted within 2 hours, and the maximum reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after taking a single dose. With regular use of the drug, the maximum therapeutic effect is usually achieved within 2–4 weeks and is maintained at the achieved level during long-term therapy. Abrupt discontinuation of valsartan does not lead to resumption of hypertension or other adverse clinical effects. Valsartan has been found to significantly reduce hospitalization rates in patients with chronic heart failure (NYHA class II–IV). A more significant effect was achieved in patients who were not taking ACE inhibitors or beta-adrenergic blockers. It was also found that valsartan reduced cardiovascular mortality in clinically stable patients with left ventricular pathology or left ventricular dysfunction after myocardial infarction. Valsartan/amlodipine More than 1,400 patients with hypertension were treated with Exforge once daily in two placebo-controlled studies. The antihypertensive effect of a single dose of the drug lasted about 24 hours. Exforge (amlodipine besylate/valsartan) was studied in two placebo-controlled studies in patients with hypertension (arterial hypertension) and diastolic blood pressure between ≥95 and ≤110 mm Hg. Art. In the first stage of the study (initial blood pressure 153/99 mm Hg), Exforge in doses of 5/80 mg, 5/160 mg and 5/320 mg reduced blood pressure by 20–23/14–16 mm Hg. Art. compared to 7/7 mm Hg. Art. for placebo. In the second stage of the study (initial blood pressure 157/99 mm Hg), Exforge in doses of 10/160 mg and 10/320 mg reduced blood pressure by 28/18–19 mm Hg. Art. compared to 13/9 mm Hg. Art. for placebo. In a multicenter, randomized, double-blind, actively controlled study in parallel groups, normalization of blood pressure (diastolic blood pressure ≤90 mm Hg at the end of the trial) was established in 75% of patients using 10/160 mg of amlodipine/valsartan, in 62% of patients using 5/ 160 mg amlodipine/valsartan compared with 53% of patients using 160 mg valsartan alone. The simultaneous administration of 5 or 10 mg of amlodipine caused an additional reduction in systolic/diastolic blood pressure by 6/4.8 mm Hg. Art. and 3.9/2.9 mm Hg. Art. respectively, compared with patients using only 160 mg of valsartan. In a multicenter, randomized, double-blind, active-controlled, parallel-group study, normalization of blood pressure was established (diastolic blood pressure 90 mm Hg at the end of the trial) in 78% of patients using 10/160 mg amlodipine/valsartan compared with 67% of patients who continued to use only 10 mg amlodipine. The combined administration of 160 mg of valsartan caused an additional reduction in systolic/diastolic blood pressure by 2.9/2.1 mm Hg. Art. compared with patients using only 10 mg amlodipine. Exforge was studied in an actively controlled study in 130 patients with essential hypertension (arterial hypertension) and diastolic blood pressure between ≥110 and ≤120 mmHg. Art. In this study (baseline BP 171/113 mmHg), an Exforge dosing regimen of 5/160 mg to 10/160 mg reduced steady-state BP by 36/29 mmHg. Art. compared to 32/28 mm Hg. Art. when using the dosing regimen of lisinopril/hydrochlorothiazide 10/12.5 mg to 20/12.5 mg. In two long-term studies, it was proven that the effect of Exforge lasted 1 year. Sudden discontinuation of the drug did not lead to a rapid increase in blood pressure. In patients whose blood pressure is adequately controlled with amlodipine when peripheral edema occurs, combination therapy may provide similar blood pressure control while reducing the edema. Pharmacokinetics. Valsartan and amlodipine exhibit linear pharmacokinetics. Amlodipine After oral administration in a therapeutic dose, the maximum concentration of amlodipine in the blood plasma is achieved within 6–12 hours. The calculated absolute bioavailability is 64–80%. Food significantly affects the bioavailability of amlodipine. The volume of distribution is approximately 21 l/kg. In vitro studies of amlodipine have proven that in patients with essential hypertension (arterial hypertension), about 97.5% of the circulating drug is bound to plasma proteins. Amlodipine is intensively (about 90%) metabolized in the liver to inactive metabolites. The elimination of amlodipine from blood plasma is biphasic with a half-life of about 30–50 hours. Equilibrium plasma levels are achieved after continuous administration for 7–8 days. 10% of the original amlodipine and 60% of its metabolites are excreted in the urine. Valsartan After oral administration, the maximum concentration of valsartan in the blood plasma is achieved within 2–4 hours. The bioavailability of the drug averages 23%. The pharmacokinetic curve of valsartan has a descending multi-exponential character (half-life α ≤1 hour and β about 9 hours). Food reduces the exposure of valsartan AUC by approximately 40% and the maximum plasma concentration by 50%, although 8 hours after administration, the plasma concentration of valsartan is the same for the group of patients taking the drug on an empty stomach and the group of patients taking the drug after eating. 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. The steady-state volume of distribution of valsartan after intravenous administration is about 17 L, which indicates that valsartan is not distributed intensively in tissues. Valsartan binds tightly to plasma proteins (94–97%), mainly to serum albumin. Valsartan is not significantly transformed, since only 20% of the dose is converted into metabolites. A hydroxymetabolite, which is pharmacologically inactive, has been identified in blood plasma at low concentrations (≤10% of valsartan). Valsartan is excreted primarily unchanged in feces (approximately 83% of the dose) and urine (approximately 13% of the dose). After intravenous administration, the plasma clearance of valsartan is approximately 2 l/h, and its renal clearance is about 0.62 l/h (about 30% of the total clearance). The half-life of valsartan is 6 hours. Valsartan/amlodipine After oral administration of Exforge, maximum plasma concentrations of valsartan and amlodipine are achieved within 3 hours and 6–8 hours, respectively. The rate and extent of absorption of Exforge are equivalent to the bioavailability of valsartan and amlodipine. Special groups of patients Patients with renal failure Impaired renal function does not significantly affect the pharmacokinetics of amlodipine. There is no real correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) when valsartan is used in patients with varying degrees of renal impairment. Therefore, patients with mild to moderate renal impairment take the usual starting dose. Patients with Hepatic Impairment In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in an increase in AUC of approximately 40–60%. In patients with mild to moderate hepatic impairment, exposure (as determined by AUC values) to valsartan is on average twice that of healthy volunteers (selected by age, sex and body weight). Patients with liver disease should be careful when using the drug.
Description of the dosage form
Film-coated tablets, 5/80 mg: dark yellow, round with beveled edges, imprinted “NVR” on one side and “NV” on the other.
Film-coated tablets, 5/160 mg: dark yellow, oval with beveled edges, imprinted “NVR” on one side and “ECE” on the other.
Film-coated tablets, 10/160 mg: light yellow, oval with beveled edges, imprinted “NVR” on one side and “UIC” on the other.
Use of the drug Exforge
Patients whose blood pressure is inadequately regulated by one of the monodrugs (amlodipine or valsartan) can be transferred to combination therapy with Exforge. Recommended dose - 1 tablet per day; It is recommended to take the drug with water. Patients taking valsartan and amlodipine separately can be switched to Exforge, which contains the same doses of components. For elderly patients, the usual dosing regimens are recommended. The maximum daily dose is 1 tablet of Exforge 5/80 mg, or 1 tablet of Exforge 5/160 mg, or 1 tablet of Exforge 10/160 mg (the maximum permissible doses of the drug components are 10 mg for amlodipine content, 160 mg for valsartan content).
Compound
Exforge tablets have active ingredients such as amlodipine and valsartan , as well as the following additional components: talc, MCC, magnesium stearate, hypromellose, colloidal silicon dioxide, titanium dioxide, crospovidone, yellow iron oxide, macrogol 4000. Co
-Exforge, in turn , has the following composition:
- active ingredients – amlodipine , valsartan , hydrochlorothiazide ;
- additional substances: MCC, colloidal silicon dioxide, hypromellose, crospovidone, macrogol, magnesium stearate, titanium dioxide, talc.
Side effects of the drug Exforge
The following adverse reactions are classified by organ, system and frequency of occurrence, with the most common listed first. Classification of the frequency of occurrence of adverse reactions: very often (≥1/10); often (1/100, ≤1/10); sometimes (1/1000, ≤1/100); rare (1/10,000, ≤1/1000); very rare (≤1/10,000), including isolated reports. For each frequency group, adverse reactions are listed in order of increasing severity.
Infections are common | Nasopharyngitis, flu-like symptoms |
Eye disorders are rare | Visual impairment |
Mental disorders are rare | Excitation |
CNS disorders often sometimes | Headache Dizziness, drowsiness, postural dizziness, paresthesia |
Hearing and balance disorders are sometimes rare | Dizziness Tinnitus |
Cardiovascular disorders sometimes rare | Tachycardia, palpitations, orthostatic hypotension Syncope, hypotension |
Respiratory system disorders sometimes | Cough, sore throat and larynx |
Gastrointestinal disorders sometimes | Abdominal pain, constipation, diarrhea, nausea, dry mouth |
Skin and subcutaneous tissue disorders sometimes rare | Skin rash, erythema Increased sweating, urticaria, skin rash, exanthema |
Musculoskeletal disorders sometimes rare | Swelling of the joints, back pain, arthalgia Muscle cramps, feeling of heaviness in the muscles |
Disorders of the kidneys and urinary system are rare | Frequent urination, increased urine output, increased blood urea nitrogen levels |
Reproductive system disorders are rare | Erectile dysfunction |
General disorders are rare | Peripheral edema, facial edema, lower extremity edema, fatigue, hot flashes, asthenia |
Additional information regarding components Exforge may cause adverse reactions previously reported for one of the components of the drug, even if such reactions were not noted in clinical trials. Amlodipine The following additional adverse reactions were observed in clinical trials with amlodipine monotherapy, regardless of causal relationship to the drug studied. The most commonly reported adverse reaction was vomiting. Sometimes the following adverse reactions were identified: alopecia, constipation, dyspepsia, shortness of breath, rhinitis, gastritis, gingival hyperplasia, gynecomastia, hyperglycemia, impotence, increased frequency of urination, leukopenia, mood changes, peripheral neuropathy, pancreatitis, hepatitis, thrombocytopenia, vasculitis, angioedema, erythema, pulmonary edema. Valsartan In clinical trials with valsartan monotherapy, regardless of the cause-and-effect relationship with the study drug, the following additional side effects were noted: viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia, increased levels of creatinine in the blood, urea nitrogen.
Special instructions for the use of Exforge
Patients with a deficiency in the body of sodium and/or bcc In patients with uncomplicated hypertension (arterial hypertension), excessive hypotension was detected. In patients with an activated renin-angiotensin system (with a reduced sodium content in the blood and/or circulating volume and receiving diuretics in high doses) while taking angiotensin receptor blockers, symptomatic hypotension may occur. This condition should be corrected before using Exforge and the patient should be closely monitored at the start of therapy. If hypotension occurs when using Exforge, the patient should be placed in a horizontal position and, if necessary, given an intravenous infusion of physiological solution. Continue treatment until blood pressure stabilizes. Hyperkalemia Caution should be exercised during concomitant treatment with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium or other drugs that may increase potassium levels (heparin, etc.), as well as regular monitoring of blood potassium levels. Withdrawal of beta-adrenergic blockers Amlodipine is not a beta-adrenergic blocker and therefore does not protect against the danger of sudden withdrawal of beta-adrenergic blockers, so the dose of drugs in this group should be reduced gradually. Renal artery stenosis There are no data on the use of Exforge in patients with unilateral or bilateral renal artery stenosis. Kidney transplantation There is no experience with the safe use of Exforge in patients with a recent kidney transplant. Impaired liver function Valsartan is excreted mainly unchanged in bile, while amlodipine is extensively metabolized in the liver. Particular caution is required when using Exforge in patients with impaired liver function or obstructive disorders of the gallbladder. Impaired renal function For patients with mild to moderate renal impairment, there is no need to adjust the dose of Exforge. For patients with severe renal impairment (creatinine clearance ≤10 ml/min), there are no data on the use of the drug, so it is recommended to prescribe the drug with caution to this category of patients. Aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy As with other vasodilators, the drug should be used with extreme caution in patients diagnosed with aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy. The drug should be used with caution in cases of unstable angina. Use during pregnancy or breastfeeding Considering the mechanism of action of angiotensin II antagonists, a risk to the fetus cannot be excluded. It has been reported that the use of ACE inhibitors, a specific class of drugs acting on the renin-angiotensin-aldosterone system, in the second and third trimester of pregnancy can cause damage and death of the fetus. In addition, based on available retrospective data, the use of ACE inhibitors in the third trimester of pregnancy is associated with a potential risk of developing congenital defects in the fetus. Spontaneous miscarriages, oligohydramnios, and renal dysfunction in newborns have been reported if a woman inadvertently took valsartan during pregnancy. Like any drug that directly affects the renin-angiotensin-aldosterone system, Exforge is not used during pregnancy or in women planning pregnancy. A physician prescribing any drug that acts on the renin-angiotensin-aldosterone system should warn a woman planning a pregnancy about the potential risk of taking these drugs to the unborn child. If pregnancy occurs during therapy, Exforge should be stopped immediately. It is unknown whether valsartan and/or amlodipine passes into breast milk, so it is not recommended to use the drug during breastfeeding. If drug therapy is necessary for the mother, breastfeeding should be stopped. Children Studies on the use of this drug in children under 18 years of age have not been conducted. Therefore, until more complete information is obtained, Exforge is not recommended for the treatment of this category of patients. The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies regarding the effect of the drug on the ability to drive vehicles and work with potentially dangerous mechanisms have not been conducted. However, patients who experience dizziness or a feeling of weakness after taking the drug should refrain from driving vehicles or operating potentially dangerous machinery.
Drug interactions Exforge
Amlodipine When monotherapy with amlodipine, no clinically significant drug interactions have been established with the following drugs: thiazide diuretics, β-adrenergic receptor blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, antacids, cimetidine, NSAIDs, antibiotics, oral hypoglycemic agents facilities. Valsartan During monotherapy with valsartan, clinically significant drug interactions with the following drugs have not been established: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Concomitant use with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase blood potassium levels (heparin, etc.) requires caution. Serum potassium levels should be regularly monitored.
Exforge drug overdose, symptoms and treatment
There is currently no experience studying Exforge overdose. The main symptom of an overdose of valsartan is probably severe arterial hypotension with dizziness. An overdose of amlodipine can lead to increasing peripheral vasodilation and, possibly, reflex tachycardia. Significant and potentially prolonged systemic hypotension, including shock and death, have been reported. If the drug has been taken recently, induce vomiting or rinse the stomach. The absorption of amlodipine is significantly reduced when activated charcoal is used immediately or within 2 hours after taking amlodipine. Clinically significant hypotension caused by Exforge overdose requires active support of the cardiovascular system, including frequent monitoring of cardiac and respiratory functions, elevation of the lower extremities above the horizontal level, control of blood volume and urination. To restore vascular tone and blood pressure, vasoconstrictors can be used in the absence of contraindications for their use. With a persistent decrease in blood pressure, which is a consequence of blockade of calcium channels, it may be advisable to administer calcium gluconate solution intravenously.
Release form
Film-coated tablets, 5 mg/80 mg, 5 mg/160 mg or 10 mg/160 mg. 7, 10 or 14 pcs. in a blister; 1, 2, 4, 8, 14 or 40 blisters of 7 tablets; 3, 9 or 28 blisters of 10 tablets; 1. 2, 4, 7, or 20 blisters of 14 tablets are placed in a cardboard box.
Film-coated tablets, 5 mg + 320 mg or 10 mg + 320 mg. 7 or 14 tablets in a PVC/PVDC blister. 1 blister of 7 tablets; 1, 2, 4, 7 blisters of 14 tablets each are placed in a cardboard box.
