Aprovask (Amlodipin, Irbesartan)

1 tablet - amlodipine besylate 14 mg, which corresponds to the content of amlodipine 5 mg, irbesartan 150 mg.

Excipients: microcrystalline cellulose 50 microns - 54 mg, croscarmellose sodium - 12 mg, hypromellose - 5 mg, microcrystalline cellulose 100 microns - 10 mg, silicon dioxide - 2.5 mg, magnesium stearate - 2.5 mg.

The composition of the film shell: Opadrai pink - 10 mg, including hypromellose - 57.75%, titanium dioxide - 29.366%, macrogol-400 - 9.08%, macrogol-8000 - 3.3%, iron dye red oxide - 0.504%.

Combined antihypertensive drug. The pharmacodynamic properties of each of the active substances that make up the drug Aprovask®, irbesartan and amlodipine contribute to their additive antihypertensive effect when used in combination compared to those when using each of these drugs separately. 

Both angiotensin II receptor antagonists (ARA II) and slow calcium channel blockers reduce blood pressure by reducing peripheral vascular resistance, blocking calcium entry into the cell, and decreasing angiotensin II-mediated vasoconstrictor action are complementary mechanisms.

Irbesartan

Irbesartan is a selective, potent ARA II (subtype-AT1). Angiotensin II is an important component of the RAAS involved in the pathophysiology of the development of arterial hypertension and in sodium ion homeostasis. Irbesartan does not require metabolic activation to manifest its action.

Irbesartan blocks the strong vasoconstrictor and aldosterone-secreting action of angiotensin II due to selective antagonism to angiotensin II receptors (subtype-AT1), which are located in the cells of the smooth muscles of the vessels and adrenal cortex. 

Irbesartan has no AT1 receptor agonist activity. Its affinity for AT1 receptors is 8500 times greater than for AT2 receptors (receptors that have not been shown to be associated with maintaining equilibrium [homeostasis] of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), nor does it affect other hormonal receptors or ion channels in the cardiovascular system that are involved in the regulation of blood pressure and homeostasis of sodium ions. Irbesartan blockade of AT1 receptors breaks the feedback loop in the renin-angiotensin system, increasing the plasma concentrations of renin and angiotensin II. 

When using irbesartan, the plasma concentration of aldosterone decreases, however, when using the drug in the recommended doses, there are no significant changes in serum potassium (the average increase in serum potassium is less than 0.1 mEq / L). Irbesartan has no significant effect on serum triglyceride, cholesterol or glucose concentrations. 

Irbesartan does not affect serum uric acid concentrations or renal excretion of uric acid. 

The antihypertensive effect of irbesartan develops after taking the first dose and becomes significant within 1-2 weeks of treatment with the maximum effect occurring after 4-6 weeks. In long-term observational studies, the effect of irbesartan persisted for more than 1 year.

A single dose of irbesartan at doses up to 900 mg / day caused a dose-dependent decrease in blood pressure. A single dose of irbesartan at doses of 150-300 mg / day led to a greater decrease in systolic (SBP) / diastolic (DBP) blood pressure (24 hours after the dose) in the supine or sitting position (on average by 8-13 / 5-8 mm Hg) than with a placebo. The effect of the drug 24 hours after the dose was 60-70% of the corresponding maximum decrease in DBP and SBP. Optimal efficacy in reducing blood pressure within 24 hours is achieved with a single dose of the drug per day.

Blood pressure decreases approximately to the same extent in the standing and lying positions. The orthostatic effect is rare and, as with ACE inhibitors, may be expected in patients with hyponatremia or hypovolemia.

The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients who fail to achieve target BP values ​​during monotherapy with irbesartan, the addition of small doses of hydrochlorothiazide (12.5 mg) to irbesartan 1 time / day leads to an additional (compared to the effect of adding placebo) decrease in SBP / DBP, determined after 24 hours after taking them, by 7-10 / 3-6 mm Hg. Art., respectively.

Age and gender do not affect the effectiveness of irbesartan. As in the case of treatment with other drugs that affect the RAAS, in patients of the Negroid race, a weaker antihypertensive effect is observed with monotherapy with irbesartan. When irbesartan is taken with small doses of hydrochlorothiazide (for example, 12.5 mg / day), the antihypertensive effect in patients of the black race approaches that of patients of the Caucasian race.

After the abolition of irbesartan, blood pressure gradually returns to its original level. No withdrawal syndrome was observed when irbesartan was discontinued.

Amlodipine

Amlodipine is a blocker of slow calcium channels from the group of dihydropyridine derivatives, which inhibits the transmembrane entry of calcium ions into myocardial cells and vascular smooth muscles. The mechanism of the antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle.

The exact mechanism by which amlodipine reduces the frequency and severity of angina attacks is not fully understood, but amlodipine reduces myocardial ischemia due to the following two effects.

1) Amlodipine expands peripheral arterioles and thereby reduces the systemic vascular resistance, the so-called afterload. Because When taking amlodipine, the heart rate practically does not increase, this decrease in the load on the heart muscle reduces the energy consumption of the myocardium and its oxygen demand.

2) The mechanism of the antianginal action of amlodipine is also, apparently, associated with the expansion of the main coronary arteries and coronary arterioles, both in the zones of the myocardium with normal blood flow, and in the ischemic zones of the myocardium. This expansion of the coronary vessels increases the delivery of oxygen to the myocardium in patients with coronary artery spasm (Prinzmetal's angina or variant angina).

In patients with arterial hypertension, taking amlodipine 1 time / day provides a clinically significant decrease in blood pressure in the supine and standing position for 24 hours. Due to the slow onset of its action, amlodipine is not intended to relieve hypertensive crises.

In patients with angina pectoris, a single dose of amlodipine during the day when performing an exercise test increases the total time of physical activity, the time before the onset of an angina attack and the time before the appearance of ST segment depression on an ECG with a depth of 1 mm. 

In addition, taking the drug reduces the daily number of angina attacks and the daily need for taking nitroglycerin tablets.

When taking amlodipine, no undesirable metabolic effects or changes in blood lipid concentrations were observed. Amlodipine can be prescribed to patients with bronchial asthma, diabetes mellitus and gout.

Clinical evidence of the efficacy of the fixed dose combination of irbesartan and amlodipine was obtained from two multicenter, prospective, open-label, parallel-group, blinded efficacy studies: the I-ADD and I-COMBINE studies. The results of both studies demonstrated significantly greater efficacy of fixed-dose combinations of irbesartan and amlodipine compared with amlodipine monotherapy or irbesartan monotherapy.

Pregnancy

When taking irbesartan at doses ≥ 50 mg / kg body weight / day (which, when converted to kg body weight, is approximately equivalent to the maximum recommended dose of irbesartan in humans [MRDIC], which is 300 mg / day) in pregnant rats from 0 to 20 days of gestation in fetuses transient effects were observed in rats (slight or moderate enlargement of the renal pelvis, hydroureter and / or absence of renal papillae). 

When taking irbesartan at doses ≥ 180 mg / kg of body weight / day (approximately equivalent to 4 * MRDIC calculated per kg of body weight) in pregnant rats from 0 to 20 days of gestation, the development of subcutaneous edema was observed in rat fetuses. 

Since these developmental anomalies were not observed when the oral administration of irbesartan was limited at doses of 50, 150 and 450 mg / kg of body weight / day in pregnant rats from 6 to 15 days of gestation, they, apparently, are late gestational effects of irbesartan. 

In rabbits, the use of irbesartan at a dose of 30 mg / kg bw / day was associated with maternal mortality and abortion. Surviving females who received this dose, equivalent to 1.5 * MRDICH calculated per kg of body weight, had a slight increase in fetal resorption and, accordingly, a decrease in the number of live fetuses in the litter. 

It was found that irbesartan crosses the placental barrier in rats and rabbits. In rats and rabbits, no teratogenic effects of amlodipine were detected.

There are no sufficient and well-controlled studies of the use of Aprovask® in pregnant women. Fetal exposure to ACE inhibitors, which were taken by pregnant women in the second and third trimesters of pregnancy, resulted in damage and death of the developing fetus. 

Like any other drugs that directly affect the RAAS, Aprovask® is contraindicated during pregnancy. 

Aprovask® should not be used in women of childbearing potential if they are not using effective methods of contraception. If pregnancy is detected during treatment with Aprovask®, you should stop taking it as soon as possible (see the section "Contraindications"),

Breastfeeding period

The drug Aprovask® is contraindicated during the period of breastfeeding (see section "Contraindications"). 

• Hypersensitivity to irbesartan, amlodipine and other dihydropyridine derivatives, as well as to excipients of the drug,
•  
• Cardiogenic shock.
• Clinically significant aortic stenosis.
• Unstable angina (except for Prinzmetal's angina).
• Pregnancy.
• Breastfeeding period.
• Age up to 18 years (efficacy and safety have not been established).
• Simultaneous use with medicinal products containing aliskiren in patients with diabetes mellitus or with moderate to severe renal failure (glomerular filtration rate [GFR] <60 ml / min / 1.73 m "body surface) (see sections" Interaction with other medicinal products means "and" Special instructions ").
• Concomitant use with angiotensin-converting enzyme (and ACE) inhibitors in patients with diabetic nephropathy (see sections "Interaction with other drugs" and "Special instructions").

Carefully

• In patients with hypovolemia and hyponatremia, arising, for example, with intensive treatment with diuretics, hemodialysis, adherence to a diet with limited consumption of table salt, diarrhea, vomiting (danger of excessive decrease in blood pressure, see the section "Special instructions"),
• In patients whose renal function depends on RAAS activity (such as patients with arterial hypertension with renal artery stenosis of one or both kidneys, patients with chronic heart failure III-1V functional class [NYHA classification]), treatment with drugs that affect RAAS, has been associated with the development of oliguria and / or progressive azotemia and rarely - acute renal failure and / or death, the risk of which cannot be excluded when taking APAII, including irbesartan) (see the section "Special instructions").
• In patients with chronic heart failure of II-IV functional class according to the NYHA classification of non-ischemic etiology (due to the content of the drug amlodipine, the use of which in such patients was associated with an increase in reports of the development of pulmonary edema compared with placebo, despite the absence of differences in frequency of progression of heart failure) (see section "Special instructions").
• In patients with hepatic impairment (risk of increased t1 / 2 of amlodipine - see the section "Special instructions").
• In patients with renal insufficiency and after kidney transplantation (due to the content of irbesartan in the drug, it is recommended to control the potassium content and the concentration of creatinine in the blood); after a recent kidney transplant (lack of experience with the clinical use of irbesartan).
• In patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM).
• In patients with ischemic heart disease and / or clinically significant atherosclerosis of the cerebral vessels (with an excessive decrease in blood pressure there is a risk of increased ischemic disorders, up to the development of acute myocardial infarction and stroke).
• In patients with sick sinus syndrome (due to the content of amlodipine in the drug).

The incidence of ADRs, which were reported with post-marketing use of the drug, was defined as "frequency unknown", since information about these ADRs came from spontaneous reports, without specifying the number of patients. taking the drug.

In clinical trials comparing fixed-dose combinations of irbesartan / amlodipine with monotherapy with irbesartan or amlodipine, the types and frequency of treatment-related adverse events, possibly related to the study treatment, were similar to those observed in previous clinical trials or in post-marketing reports in monotherapy with irbesartan and amlodipine. The most common adverse event was peripheral edema, mainly associated with amlodipine.

Adverse events observed during treatment and possibly related to the study drug in clinical trials of irbesartan / amlodipine (I-ADD, I-COMBINE and I-COMBO)
Fixed combination irbesartan / amlodipine

General disorders and disorders at the injection site
Often: peripheral edema, edema.
Uncommon: asthenia.

Hearing disorders and labyrinthine disorders
Uncommon: vertigo.

Cardiac disorders
Often: palpitations.
Uncommon: sinus bradycardia.

Nervous system disorders
Often: dizziness, headache, drowsiness.
Uncommon: paresthesia.

Genital and breast disorders
Uncommon: erectile dysfunction.

Respiratory system, chest and mediastinal
disorders Uncommon: cough.

Vascular disorders
Often: orthostatic hypotension.
Uncommon: excessive decrease in blood pressure.

Disorders from the gastrointestinal tract
Often: swelling of the gums.
Uncommon: nausea, pain in the upper abdomen, constipation.

Renal and urinary tract disorders
Often: proteinuria.
Uncommon: azotemia, hypercreatininemia.

Metabolic and nutritional disorders
Uncommon: hyperkalemia.

Musculoskeletal and connective tissue disorders
Uncommon: joint stiffness, arthralgia, myalgia.

Adverse events observed with the use of irbesartan in clinical trials (including clinical studies I-ADD, I-COMBINE and I-COMBO) and with its post-marketing

Immune system disorders
Frequency unknown: hypersensitivity reactions (allergic reactions).

Metabolic and nutritional disorders
Frequency unknown: hyperkalemia.

Hearing disorders and labyrinthine disorders
Often: vertigo.
Frequency unknown: tinnitus

Nervous system disorders
Often: dizziness, headache *.
Uncommon: orthostatic dizziness.

Cardiac disorders
Uncommon: tachycardia.

Disorders from the skin and subcutaneous tissues
Frequency unknown: leukocytoclastic vasculitis.

Respiratory system, chest and mediastinal
disorders Uncommon: cough.

Disorders from the gastrointestinal tract
Often: nausea / vomiting, pain in the upper abdomen, disorders of the tongue, glossodynia (burning sensation and soreness in the tongue).
Frequency unknown: dysgeusia (taste perversion).
Uncommon: diarrhea, dyspepsia, heartburn.

Disorders from the liver and biliary tract
Frequency unknown: jaundice, increased performance of functional "liver" tests, hepatitis.

Skin and subcutaneous tissue disorders
Uncommon: alopecia.
Frequency unknown: angioedema, urticaria.

Disorders from the musculoskeletal system and connective tissue
Frequency unknown: myalgia.

Renal and urinary tract
disorders Frequency unknown: impaired renal function, including isolated cases of renal failure in patients with risk factors for its development.

Genital and breast disorders
Uncommon: erectile dysfunction.

General disorders and disorders at the injection site
Often: increased fatigue *, edema.
Uncommon: chest pain.
Frequency unknown: asthenia.

Injury, intoxication and complications of manipulation
Uncommon: falls.

Adverse events observed with the use of amlodipine in clinical trials (including clinical trials I-ADD, I-COMBINE and I-COMBO)

Blood and lymphatic system disorders
Very rare: thrombocytopenia.

Immune system disorders
Very rare: allergic reactions.

Metabolic and nutritional disorders
Very rare: hyperglycemia.

Mental disorders
Uncommon: insomnia, mood lability.

Nervous system disorders
Often: dizziness, headache *, drowsiness.
Uncommon: hypesthesia, paresthesia, tremors, taste perversions, syncope.
Very rare: peripheral neuropathy.

Violations of the organ of vision
Uncommon: visual disturbances.

Hearing disorders and labyrinth disorders.
Uncommon: ringing in the ears, vertigo.

Cardiac disorders
Often: palpitations.
Very rare: myocardial infarction, cardiac arrhythmias, ventricular tachycardia and atrial fibrillation (atrial fibrillation).

Vascular disorders
Often: "hot flushes" of blood to the skin with a feeling of heat, redness of the skin *.
Uncommon: excessive decrease in blood pressure.
Very rare: vasculitis.

Respiratory, chest and mediastinal disorders
Often: cough.
Uncommon: shortness of breath, rhinitis.
Very rare: coughing.

Digestive system disorders
Often: nausea, abdominal pain, glossodynia, glossitis.
Infrequently; dyspepsia, vomiting, changes in the rhythm of bowel movements, dryness of the mucous membranes of the oral cavity.
Very rare: pancreatitis, gastritis, gingival hyperplasia.

Liver and biliary tract disorders
Very rare: hepatitis, jaundice and increased activity of "liver" enzymes (mainly associated with cholestasis).

Skin and subcutaneous tissue disorders
Common: contact dermatitis.
Uncommon: skin rash, itching, purpura, increased sweating, changes in skin pigmentation (the appearance of discolored skin areas), alopecia.
Very rare: angioedema, erythema multiforme, urticaria.

Musculoskeletal and connective tissue disorders
Uncommon: arthralgia, muscle cramps, myalgia, back pain.

Disorders of the kidneys and urinary tract
Uncommon: increased frequency of urination, painful urge to urinate, nocturia.

Violations of the genitals and mammary gland
Uncommon: impotence, gynecomastia.

General disorders and disorders at the injection site
Often: increased fatigue, edema *, peripheral edema.
Uncommon: chest pains, asthenia, feeling unwell, pain.
Rarely: facial edema.

Laboratory and instrumental data
Uncommon: weight gain, weight loss.

There have been no studies on drug interactions of Aprovask® with other drugs.

Irbesartan
Based on in vitro studies, no interactions with drugs whose metabolism is carried out by the following cytochrome P450 isoenzymes should be expected: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.

Irbesartan is predominantly metabolized by the CYP2C9 isoenzyme, however, during clinical interaction studies, when irbesartan was taken simultaneously with warfarin, which is metabolized by the CYP2C9 isoenzyme. no significant pharmacokinetic interactions were observed.

The pharmacokinetic parameters of irbesartan are not disturbed when used simultaneously with nifedipine and hydrochlorothiazide.

Irbesartan does not alter the pharmacokinetics of simvastatin, which is metabolized by the CYP3A4 isoenzyme, or digoxin (a P-glycoprotein substrate).

The combination of the drug Aprovask with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal failure (GFR less than 60 ml / min / 1.73 m2 of body surface area) and is not recommended in other patients. ACE inhibitors: The use of the drug Aprovask® in combination with an ACE inhibitor is contraindicated in patients with diabetic nephropathy and is not recommended for other patients.

Based on the experience gained with the use of other drugs that affect the RAAS, the simultaneous use of irbesartan with potassium preparations: salt substitutes containing potassium; potassium-sparing diuretics or other drugs that can increase plasma potassium (heparin) can sometimes significantly increase serum potassium, which requires careful monitoring of plasma potassium levels in patients during treatment.

In elderly patients, patients with hypovolemia (due to taking diuretics) or with impaired renal function, the simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, together with ARAII, including irbesartan, can lead to impairment of function kidney, including the development of acute renal failure. These effects are usually reversible. Renal function should be monitored periodically in patients concomitantly taking APAII and NSAIDs, including selective COX-2 inhibitors.

Lithium: against the background of the combined use of irbesartan with lithium preparations, an increase in lithium concentrations in the blood plasma and the toxic effect of lithium have been described. In patients taking irbesartan in conjunction with lithium preparations, the concentration of lithium in the blood plasma should be monitored.

Amlodipine
Amlodipine has been safely combined with thiazide diuretics, beta-blockers, alpha-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, NSAIDs, antibiotics and hypoglycemic agents for oral administration.

Data from in vitro studies with human blood plasma have shown that amlodipine does not affect the binding of digoxin to the protein. phenytoin, warfarin, or indomethacin.

Cimetidine: Simultaneous administration of amlodipine and cimetidine did not interfere with the pharmacokinetics of amlodipine.

Grapefruit juice: The simultaneous intake of 240 mg of grapefruit juice with a single dose of 10 mg amlodipine in 20 healthy volunteers did not have a significant effect on the pharmacokinetics of amlodipine.

Sildenafil: with the simultaneous use of amlodipine and sildenafil, each of the drugs independently showed an antihypertensive effect.

Atorvastatin: simultaneous course administration of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg led to unreliable changes in the pharmacokinetic parameters of atorvastatin in the state of achieving Css.

Digoxin: Concomitant administration of amlodipine with digoxin did not alter serum digoxin concentration or digoxin renal clearance in healthy volunteers.

Warfarin: concomitant use of amlodipine and did not change prothrombin time when taking warfarin.

Cyclosporine: Pharmacokinetic studies with cyclosporine have demonstrated that amlodipine has no significant effect on the pharmacokinetics of cyclosporine.

Tacrolimus: With the simultaneous use of tacrolimus and amlodipine, it is possible to increase the concentration of tacrolimus in the blood plasma. It is necessary to monitor the concentration of tacrolimus in the blood plasma and, if necessary, adjust its dose.

Simvastatin: Concomitant use of amlodipine with simvastatin may increase the exposure of simvastatin compared to simvastatin monotherapy. With the simultaneous use of simvastatin and amlodipine, it is necessary to limit the daily dose of simvastatin to 20 mg.

Usually, the initial and maintenance dose of Aprovask® is 1 tablet per day.

The drug Aprovask® should be used in patients who fail to achieve target BP values ​​during monotherapy with irbesartan or amlodipine monotherapy, or to continue treatment in patients who are already taking irbesartan and amlodipine as separate tablets. 

Doses should be selected individually, first with the use of separate preparations of irbesartan and amlodipine. Doses are selected depending on the response of blood pressure to the therapy and the target blood pressure. 

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