Amlodipine, Valsartan

Pharmacological properties

amlosartan contains two antihypertensive components with additional mechanisms for controlling hell in patients with essential 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, reducing hell to a greater extent than each of the components individually.

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 the smooth muscles of blood vessels, which leads to a decrease in peripheral vascular resistance and leads to a decrease in blood pressure. Experimental data confirm that amlodipine binds at the dihydropyridine and nonhydropyridine binding sites. The contractile processes of the heart muscle and vascular smooth muscle depend on the passage of extracellular calcium into these cells through specific ion channels.

After the administration of therapeutic doses to patients with hypertension, amlodipine causes vasodilation, which leads to a decrease in blood pressure in the patients lying and standing position. Such a decrease in blood pressure is not accompanied by a significant change in heart rate or plasma catecholamines with prolonged use.

The effect correlates with plasma concentrations in patients of young and old age.

In patients with hypertension and normal renal function, therapeutic doses of amlodipine lead to a decrease in renal vascular resistance and an increase in the level of glomerular filtration, as well as an effective renal plasma flow without changing the fraction that is filtered or proteinuria.

As with other calcium channel blockers, measurements of hemodynamics of cardiac function at rest and during exercise (or when walking) in patients with normal ventricular function treated with amlodipine generally showed a slight increase in cardiac index without a significant effect on the rate of change of pressure in the left ventricle or end diastolic pressure or volume of the left ventricle. In hemodynamic studies, amlodipine did not show a negative inotropic effect when using therapeutic doses in intact animals and humans, even when combined with beta-adrenoreceptor blockers in humans.

Amlodipine does not change the function of the sinus-atrial node or atrioventricular conduction in healthy animals or humans. In clinical studies in which amlodipine was used in combination with beta-adrenergic receptor blockers in patients with hypertension or angina pectoris, no ECG changes were noted.

Positive clinical effects of amlodipine were observed in patients with chronic stable angina pectoris, vasospastic angina pectoris and coronary artery disease confirmed by angiography.

Use in patients with hypertension. In the study of antihypertensive and lipid-lowering therapy for the prevention of a heart attack in mild to moderate hypertension in patients with at least one additional risk factor for the development of IHD using amlodipine (at a dose of 2.5-10 mg / day) or lisinopril (at a dose of 10-40 mg / day) as the first line of therapy compared with the use of chlortalidone thiazide diuretic (at a dose of 12.5–25 mg / day), it was revealed that there were no significant differences in the number of cases of IHD with a fatal outcome or myocardial infarction without a fatal outcome. The incidence of heart failure was significantly greater in the group of amlodipine compared with the group receiving chlortalidone. However, there were no significant differences in mortality for all reasons between the groups of amlodipine and chlortalidone.

Valsartan. Valsartan is an active, powerful, and specific antagonist of angiotensin receptors (ARA) II, which is intended for internal use.It acts selectively on AT subtype receptors₁which are rarely common and responsible for the effects of angiotensin II. Elevated angiotensin II levels due to AT blockade₁receptors with valsartan can stimulate free antibodies₂receptors, which balances the effect of AT₁receptors. Valsartan does not exhibit any partial agonist activity with respect to antibodies₁-receptors and has a much larger (about 20,000 times) affinity for AT₁receptors than to AT₂to receptors.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Given the lack of influence on ACE and potentiation of the activity of bradykinin or substance P, the use of ARA II, as a rule, is not accompanied by a cough. In clinical studies comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower in patients treated with valsartan than in patients taking an ACE inhibitor. Patients previously treated with ACE inhibitors developed a dry cough, with valsartan therapy this complication was noted in 19.5% of cases, and with a thiazide diuretic in 19% of cases, while in the group of patients treated with an ACE inhibitor, cough was observed in 68 , 5% of cases. Valsartan does not interact and does not block receptors of other hormones or ion channels, which, as you know, play an important role in the regulation of the functions of the cardiovascular system.

Prescribing the drug to patients with hypertension leads to a decrease in blood pressure, without affecting the heart rate.

In most patients, after a single dose of the drug is administered orally, the onset of antihypertensive activity is noted within 2 hours, and the maximum decrease in blood pressure is achieved in the range of 4-6 hours.

The antihypertensive effect persists for more than 24 hours after taking a single dose. Under the condition of regular use of the drug, the maximum therapeutic effect is usually achieved within 2-4 weeks and is maintained at the achieved level during prolonged therapy. Sudden withdrawal of valsartan does not lead to restoration of hypertension or other adverse clinical phenomena.

It was found that valsartan significantly reduces the hospitalization rate of patients with chronic heart failure (NYHA class II – IV). A more significant effect was achieved in patients who did not receive 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.

According to research data, ACE and ARA inhibitors should not be used in combination with patients with diabetic nephropathy, since an increased risk of hyperkalemia, acute kidney damage and / or hypotension has been established. When studying the feasibility of additional aliskiren therapy for treatment with ACE / ARA inhibitors in patients with type 2 diabetes and chronic kidney disease, cardiovascular diseases, or a combination of both, an increased risk of complications of therapy, the development of adverse events and serious adverse reactions of particular importance ( hyperkalemia, hypotension and impaired renal function) with the use of aliskiren.

Valsartan / Amlodipine. The combination of amlodipine and valsartan provides a dose-dependent additive reduction in blood pressure over the entire range of therapeutic doses. The antihypertensive effect after taking a single dose of the combination persists for 24 hours.

The valsartan / amlodipine combination was studied in studies involving patients with uncomplicated essential mild or moderate hypertension, except for patients with a high risk of cardiovascular disorders. The normalization of blood pressure was established in patients whose blood pressure was not controlled properly with monotherapy with valsartan at a dose of 160 mg.Blood pressure returned to normal in 75% of patients receiving 10 mg / 160 mg of amlodipine / valsartan, 62% of patients receiving 5 mg / 160 mg of amlodipine / valsartan compared with 53% of patients receiving 160 mg of valsartan. The addition of 10 mg and 5 mg of amlodipine caused an additional decrease in systolic / diastolic pressure compared with patients who used only 160 mg of valsartan.

With the addition of valsartan, the normalization of blood pressure was established in patients whose blood pressure was not adequately controlled using monotherapy with amlodipine at a dose of 10 mg. Blood pressure returned to normal in 78% of patients receiving 10 mg / 160 mg of amlodipine / valsartan compared with 67% of patients who continued to use only 10 mg of amlodipine. The addition of 160 mg of valsartan caused an additional decrease in systolic / diastolic pressure compared with patients who used only 10 mg of amlodipine.

The combination of amlodipine / valsartan from 5 mg / 160 mg to 10 mg / 160 mg in patients with essential hypertension more clearly reduces stable blood pressure compared with the dosage regimen of lisinopril / hydrochlorothiazide from 10 mg / 12.5 mg to 20 mg / 12.5 mg.

It is proved that the effect of the combination of valsartan / amlodipine persisted for more than 1 year. Sudden withdrawal of the drug did not lead to a rapid increase in blood pressure.

In patients in whom blood pressure is adequately controlled by amlodipine, with unacceptable edema, combination therapy can provide a similar control of blood pressure with a decrease in edema.

There is evidence that age, gender, race and body mass index (≥30 kg / m²30 kg / m²) did not affect the clinical response when using the combination of valsartan / amlodipine.

Studies of the combination of valsartan / amlodipine with the participation of patients from other populations, except for patients with hypertension, were not performed. There are studies of valsartan in patients with heart failure and in the post-infarction period. Amlodipine was studied in patients with chronic stable angina pectoris, vasospastic angina pectoris, and angiographically confirmed coronary artery disease.

Pharmacokinetics Linearity. Valsartan and amlodipine exhibit linear pharmacokinetics.

Amlodipine

Suction. Following internal administration of therapeutic doses of amlodipine alone, C_max in blood plasma is reached within 6-12 hours. The calculated absolute bioavailability is 64-80%. Eating does not affect the bioavailability of amlodipine.

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

Biotransformation. Amlodipine is intensively (about 90%) metabolized in the liver to inactive metabolites.

Breeding. The elimination of amlodipine from blood plasma is biphasic, with T_½ about 30-50 hours. Equilibrium plasma levels are achieved after continuous administration for 7-8 days. 10% of the initial amlodipine and 60% of amlodipine metabolites are excreted in the urine.

Valsartan

Suction. After taking the drug inside C_max valsartan in blood plasma is reached within 2-4 hours. The average absolute bioavailability of the drug is 23%. Food reduces exposure, as shown by the AUC of valsartan, by about 40%, and C_max - by 50%, although 8 hours after application, the concentration of valsartan in blood plasma is the same for the group taking the drug on an empty stomach and the group of patients who used the drug after eating. The decrease in AUC is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be taken regardless of food intake.

Distribution. The equilibrium volume of distribution of valsartan after iv administration is about 17 L, which indicates that valsartan is not distributed intensively in tissues.Valsartan is strongly bound to plasma proteins (94–97%), mainly to serum albumin.

Biotransformation. Valsartan is not significantly transformed, since only 20% of the dose passes into metabolites. In blood plasma in low concentrations (less than 10% AUC of valsartan), hydroxymetabolite is identified, which is pharmacologically inactive.

Breeding. Valsartan is characterized by multi-exponential excretion kinetics (T_½ α 1 h, T_½ β ≈9 h). Valsartan is excreted mainly in an unchanged state with feces (≈83% of the dose) and urine (about 13% of the dose). After intravenous administration, valsartan clearance in blood plasma is approximately 2 l / h, and its renal clearance is about 0.62 l / h (≈30% of the total clearance). T_½ valsartan - 6 hours

Valsartan / Amlodipine. Following oral administration of Amlosartan C_max valsartan and amlodipine in blood plasma is reached after 3 and 6-8 hours, respectively. The rate and extent of absorption of Amlosartan is equivalent to the bioavailability of valsartan and amlodipine when administered in separate tablets.

Special populations. Children. There are no data on the pharmacokinetics of the drug in children.

Elderly patients (over 65 years old). Time to reach C_max amlodipine in blood plasma is approximately the same in younger patients and elderly patients. In elderly patients, amlodipine clearance tends to decrease, which leads to an increase in AUC and an increase in T_½. The average systemic AUC of valsartan in the elderly is 70% higher than in patients of a younger age, so caution should be exercised when increasing the dose.

Renal failure. Impaired renal function does not significantly affect the pharmacokinetics of amlodipine. As expected with respect to a compound whose renal clearance is only 30% of the total plasma clearance, no correlation was observed between the state of renal function and systemic exposure of valsartan.

Impaired liver function. In patients with liver failure, amlodipine clearance decreases, which leads to an increase in AUC by approximately 40-60%. On average, in patients with mild to moderate chronic liver diseases, exposure (determined by AUC values) of valsartan is on average twice that of healthy volunteers (selected by age, gender, and body weight). Patients with liver disease should be careful when using the drug.

Indications

Essential hypertension in adult patients whose hell is not controlled by monotherapy with amlodipine or valsartan.

Application

Patients in whom hell is inadequately controlled with monodrugs of amlodipine or valsartan can be transferred to combination therapy with amlosartan. the recommended dose is 1 tablet per day. Amlosartan tablets can be taken without regard to meals. it is recommended to take amlosartan with a little water. tablets are not subject to division.

Patients taking valsartan and amlodipine separately can be transferred to Amlosartan containing the same doses of the components.

Before switching to a fixed-dose combination, individual dose selection with components (i.e., amplodipine and valsartan) is recommended. In case of clinical need, it is permissible to consider the possibility of direct replacement of monotherapy with a combination of fixed doses.

The maximum daily dose is 1 tablet of Amlosartan 5 mg / 80 mg or 1 tablet of Amlosartan 5 mg / 160 mg, or 1 tablet of Amlosartan 10 mg / 160 mg (the maximum allowable dose of the components of the drug is 10 mg by the content of amlodipine, 320 mg - by the content of valsartan )

Dosage for individual groups of patients. Impaired renal function. There are no clinical data available for use in patients with severe renal impairment.

Patients with impaired renal function of mild to moderate severity dose adjustment is not required. In patients with moderate renal impairment, it is recommended to monitor blood potassium and creatinine levels.

Concomitant use of Amlosartan with aliskiren is contraindicated in patients with impaired renal function (glomerular filtration rate (GFR) 60 mg / min / 1.73 m²).

Diabetes. The concomitant use of amlosartan with aliskiren is contraindicated in patients with diabetes mellitus.

Impaired liver function. Amlosartan is contraindicated in patients with severely impaired liver function.

With caution, Amlosartan should be used in patients with impaired liver function or obstructive biliary tract disease. For patients with mild or moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan.

Recommendations for dosing amlodipine in patients with mild or moderate impaired liver function have not been developed. When transferring such patients with hypertension (see INDICATIONS) and impaired liver function to amlodipine or Amlosartan, it is necessary to prescribe the lowest recommended dose of amlodipine in monotherapy or as part of combination therapy.

Elderly patients (over 65 years old). For elderly patients, the usual dosage regimens are recommended.

Caution should be exercised when increasing the dose of the drug for elderly patients.

When transferring such patients with AH (see INDICATIONS) and impaired liver function to amlodipine or Amlosartan, it is necessary to prescribe the minimum recommended dose of amlodipine in monotherapy or as part of combination therapy.

Pediatric populations. The safety and effectiveness of the combination of valsartan / amlodipine in children (under 18 years of age) has not been investigated. No data available.

Contraindications

- Hypersensitivity to the active substance, derivatives of dihydropyridine or any of the excipients of the drug;

• severe liver dysfunction, biliary cirrhosis or cholestasis;
• concomitant use of ARA, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or with impaired renal function (GFR 60 mg / min / 1.73 m²);
• pregnant women and women planning a pregnancy (see Use during pregnancy and lactation);
• severe hypotension;
• shock (including cardiogenic shock);
• obstruction of the excretory tract of the left ventricle (for example, hypertrophic obstructive cardiomyopathy and severe aortic stenosis);
• hemodynamically unstable heart failure after acute myocardial infarction.

Side effects

The safety of the valsartan / amlodipine combination has been evaluated in clinical trials. adverse reactions that were most often observed or were significant or severe: nasopharyngitis, flu, hypersensitivity, headache, fainting, orthostatic hypotension, edema, soft tissue swelling, facial swelling, peripheral edema, fatigue, facial flushing, asthenia and hot flashes.

When evaluating the incidence of adverse reactions, the following criteria were used: very often (≥1 / 10); often (from ≥1 / 100 to 1/10); infrequently (from ≥1 / 1000 to 1/100); rarely (from ≥1 / 10,000 to 1/1000); very rarely (1/10 000); unknown (frequency cannot be estimated from the available data).

* Mostly associated with cholestasis.

Additional information on the combination.Peripheral edema, a known side effect of amlodipine in patients using the combination of amplodipine / valsartan, was generally observed with a lower frequency than with amlodipine alone. The average frequency of peripheral edema, evenly distributed over the entire dose range, was 5.1% for the combination of amlodipine / valsartan.

Additional information on the components of the drug. Adverse reactions previously observed when using one of the components of the drug (amlodipine or valsartan) can also occur when using the drug Amlosartan, even if they were not noted during clinical trials or in the post-marketing period.

Amlodipine:

often: drowsiness, dizziness, palpitations, abdominal pain, nausea, ankle swelling;

infrequently: insomnia, mood changes (including anxiety), depression, tremors, dysgeusia, fainting, hypesthesia, visual impairment (including diplopia), tinnitus, hypotension, dyspnea, rhinitis, vomiting, dyspepsia, alopecia, purpura, discoloration of the skin, hyperhidrosis, itching, exanthema, myalgia, muscle cramps, pain, urination disorders, increased urination frequency, impotence, gynecomastia, chest pain, general malaise, increase or decrease in body weight;

rarely: confusion;

very rarely: leukopenia, thrombocytopenia, allergic reactions, hyperglycemia, hypertension, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, liver hyperplasia, hyperplasia, hyperplasia usually associated with cholestasis, angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke edema, photosensitivity.

There have been isolated cases of extrapyramidal syndrome.

Valsartan. The following additional side effects are