Expiration date: 11/2025
Release form, composition and packaging
Tablets, film-coated white color, oval, lenticular, with the mark and bevel to risk on one side.
1 tablet contains:
besylate amlodipine 7 or 14 mg, that corresponds to the content of amlodipine 5 or 10 mg
irbesartan 150 or 300 mg
Excipients: microcrystalline cellulose 50 µm - 132 mg croscarmellose sodium 24 mg, hypromellose 6 MPa.s - 10 mg microcrystalline cellulose 100 µm - 10 mg, silicon dioxide 5 mg magnesium stearate 5 mg.
The composition of the film shell: Opadry white (polymer - 62.5%, titanium dioxide (E171) - 31.25%, macrogol 400 - 6.25%) - 20 mg.
7 PCs. - blisters (2) - packs of cardboard.
7 PCs. - blisters (4) - packs of cardboard.
Clinico-pharmacological group: Antihypertensive drug
Pharmaco-therapeutic group: Antihypertensive combination means (a blocker of slow calcium channels of angiotensin II receptor antagonist)
Testimony
— arterial hypertension (with the ineffectiveness of monotherapy with irbesartan or amlodipine).
The dosage regimen
The drug is taken orally. Swallow the tablet with water. Aprovasc®can be taken simultaneously with meals and on an empty stomach (i.e., regardless of meal times).
Usual initial and maintenance dose Aprovasc® is 1 tab./day. Aprovasc® should be used in patients who fail to achieve target values of blood pressure when monotherapy with irbesartan or amlodipine monotherapy, or continued treatment of patients already receiving irbesartan and amlodipine as separate tablets. Doses should be selected individually, first with the use of the drugs irbesartan and amlodipine. Dose selected depending on the reaction of HELL to the therapy and target blood pressure values. The maximum recommended dose Aprovasc®is 150 mg/10 mg, or 300 mg/10 mg per day (due to the fact that maximum daily dose of amlodipine is 10 mg).
As a rule, elderly patients and patients with impaired renal function dose reduction is not required.
In patients with impaired liver Aprovasc® should be used with caution in connection with the presence in the composition of the drug amlodipine.
Side effects
The frequency of adverse events/reactions (AE/MS) reported in clinical studies on the use of a combination of fixed-dose irbesartan and amlodipine (clinical studies I-ADD, I-and I ????IN?-COMBO), in clinical studies on the use of irbesartan and at its post-marketing use and in clinical studies on the use of amlodipine was determined according to the who classification as follows: very often (? 10%); often (? 1% and < 10%); infrequently (? 0.1% and < 1%); rare (? 0.01% and < 0.1%); very rarely (< 0.01%), the frequency is unknown - according to the available data it is impossible to estimate the frequency of occurrence of AES/HP.
Frequency HP reported during post-marketing use of the drug, defined as "frequency unknown" because information about those HP came from spontaneous reports, without specifying the number of patients taking the drug.
In clinical studies comparing combinations of fixed-dose irbesartan/amlodipine monotherapy with irbesartan or amlodipine, frequency and types occurs during treatment adverse events possibly related to study treatment were similar to those observed in earlier clinical trials or in post-marketing reports of monotherapy with irbesartan and amlodipine. The most common AES were peripheral edema, mainly associated with amlodipine.
Adverse events observed during treatment and possibly related to study medication in clinical studies of irbesartan/amlodipine (I-ADD-I-COMBINE-COMBO)
The fixed combination irbesartan/amlodipine
Common reactions: often - peripheral edema, edema; rarely, asthenia.
On the part of the organ of hearing and labyrinth disorders: infrequent - vertigo.
Of the cardiovascular system: often- palpitations, orthostatic hypotension; infrequent - sinus bradycardia, excessive decrease in blood pressure.
From the nervous system: often - dizziness, headache, drowsiness; rarely - paresthesia.
From the reproductive system: often - erectile dysfunction.
The respiratory system: rarely - cough.
From the digestive system: often - swelling of the gums; infrequently - nausea, pain in upper abdomen, constipation.
From the urinary system: often - proteinuria; rarely, azotemia, hypercreatininemia.
From a metabolism: rarely - hyperkalemia.
From the side of musculoskeletal system: infrequent - joint stiffness, arthralgia, myalgia.
Adverse events, observed with the use of irbesartan in clinical research (including clinical research I-ADD-I-COMBINE-COMBO) and its post-marketing use
The immune system: frequency unknown - hypersensitivity reactions (allergic reactions), including angioedema, urticaria.
From the metabolic: frequency unknown - hyperkalemia.
On the part of the organ of hearing and labyrinth disorders: common - vertigo; frequency is unknown - noise in the ears.
From the nervous system: often - dizziness, headache*; infrequently - orthostatic dizziness.
* the incidence of headache in studies I-ADD-I-COMBINE-COMBO was rated as "rarely".
From the side of cardiovascular system: rarely - tachycardia.
The skin and subcutaneous tissue: frequency unknown - leukocytoclastic vasculitis.
The respiratory system: rarely - cough.
From the digestive system: often - nausea/vomiting, pain in the upper abdomen, violations of the language, including dysgeusia (taste perversion), glossodynia (burning sensation and pain in the tongue), glossitis (inflammation of tongue); often - diarrhea, dyspepsia, heartburn; frequency is unknown - jaundice, increased liver function tests, hepatitis.
The skin and subcutaneous tissue: rare - alopecia.
From the side of musculoskeletal system: frequency unknown - myalgia.
From the urinary system: the frequency is unknown - impaired renal function including isolated cases of renal failure in patients with risk factors for its development.
From the reproductive system: often - erectile dysfunction.
Common reactions: often - increased fatigue*, edema; rarely, chest pain; frequency is unknown - asthenia.
* the incidence of fatigue in studies I-ADD-I-COMBINE-COMBO was rated as "rarely".
Injuries, intoxication and complications of manipulation: rarely - downs.
Adverse events, observed in the application of amlodipine in clinical research (including clinical research I-ADD-I-COMBINE-COMBO)
With the hematopoietic system: rarely - thrombocytopenia.
The immune system: very rarely - allergic reactions, including angioneurotic edema, urticaria.
From the metabolic: very rarely - hyperglycemia.
Mental disorders: rarely - insomnia, mood lability.
From the nervous system: often - dizziness, headache*, somnolence; rarely, hypoesthesia, paresthesia, tremor, taste perversion, syncope; very rare - peripheral neuropathy.
* the incidence of headache in studies I-ADD-I-COMBINE-SONGO were rated as "rarely".
On the part of the organ of vision: infrequent - visual disturbances.
On the part of the organ of hearing and labyrinth disorders: infrequent - tinnitus, vertigo.
Of the cardiovascular system: often- palpitations, "tides" of blood to the skin with a feeling of heat, redness of the skin*; very rarely myocardial infarction, arrhythmias, ventricular tachycardia and atrial fibrillation (atrial fibrillation), vasculitis.
* the incidence of redness of the skin in studies I-ADD-I-COMBINE-COMBO was rated as "rarely".
The respiratory system: often - cough; rarely, dyspnea, rhinitis; very rarely - cough.
From the digestive system: often - nausea, abdominal pain, glossodynia, glossitis; rarely - dyspepsia, vomiting, change in bowel habits, dry mucous membranes of the mouth; very rarely - pancreatitis, gastritis, gingival hyperplasia hepatitis, jaundice and increased liver enzymes (mostly associated with cholestasis).
The skin and subcutaneous tissue: often - contact dermatitis; rare - skin rash, pruritus, purpura, increased sweating, discoloration of the skin (the appearance of discolored areas of the skin), alopecia; very rarely - erythema multiforme.
From the side of musculoskeletal system: infrequently - artralgia, muscle cramps, myalgia, back pain.
From the urinary system: rarely - increased frequency of urination, painful urge to urinate, nocturia.
Part of the reproductive system: rarely - impotence, gynecomastia.
Common reactions: often - increased fatigue, swelling*, peripheral edema; rarely, chest pain, asthenia, feeling of malaise, pain; rarely - edema of the face.
* according to the studies I-ADD-I-COMBINE-COMBO frequency of occurrence of edema: "infrequently".
Laboratory and instrumental data: rare - increased body mass, decrease body mass.
Contraindications
— hypersensitivity to irbesartan, amlodipine and other derivatives of dihydropyridine, as well as auxiliary substances of the drug;
— cardiogenic shock;
— clinically significant aortic stenosis;
— unstable angina (with the exception of strokes Prinzmetala);
— pregnancy;
— the period of breastfeeding;
— child and adolescence to 18 years (efficacy and safety not established);
— concomitant use of medicinal products containing aliskiren in patients with diabetes or moderate-to-severe renal insufficiency (glomerular filtration rate [GFR] < 60 ml/min/1.73 m2 of body surface);
— concurrent use with ACE inhibitors in patients with diabetic nephropathy.
With caution:
In patients with hypovolemia and hyponatremia, arising, for example, with intensive diuretic treatment, dialysis, a diet with restriction of salt consumption, diarrhea, vomiting.
In patients whose renal function depends on the activity of RAAS (such as patients with arterial hypertension with renal artery stenosis of one or both kidneys, patients with chronic heart failure III-IV functional class NYHA classification), treatment with drugs that affect the RAAS were 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 ARA II, including irbesartan).
In patients with chronic heart failure II-IV functional class NYHA classification nonischemic etiology (because of the content in the composition of the drug amlodipine, which in these patients was associated with increased reports of pulmonary edema development compared with taking a placebo, despite the lack of differences in the rate of progression of heart failure).
In patients with hepatic insufficiency (risk of increasing T1/2 of amlodipine).
In patients with renal insufficiency and after renal transplantation (because of the content in the composition of the drug irbesartan, it is recommended that monitoring of potassium and creatinine concentration in the blood); after a recent kidney transplantation (no experience of clinical application of irbesartan).
In patients with stenosis of the aortic and mitral valve, or hypertrophic obstructive cardiomyopathy (HACMP).
In patients with coronary artery disease and/or clinically significant atherosclerosis of the brain (excessive decrease in blood pressure there is a risk of increasing coronary disorders until the development of acute myocardial infarction and stroke).
In patients with SSSU (because of the content in the composition of the drug amlodipine).
Application of pregnancy and breastfeeding
No adequate and well-controlled studies of the drug Aprovasc® in pregnant women. Effects on fetus ACE inhibitors who took pregnant women in II and III trimester of pregnancy, causing damage and death to the developing fetus. As any other drugs that act directly on the RAAS, Aprovasc® is contraindicated in pregnancy.
Aprovasc® should not be used in women of childbearing age not using effective methods of contraception. In case of pregnancy during treatment Aprovasc®, you should ASAP stop taking it.
Aprovasc® is contraindicated during breastfeeding.
In preclinical studies when administered orally to pregnant rats from 0 to 20 days of gestation irbesartan at doses > 50 mg/kg of body weight/day (which at recalculation on kg of body weight is roughly equivalent to the maximum recommended dose of irbesartan in humans [MRDISC] of 300 mg/day) in fetuses of rats there were transient effects (minor or moderate expansion of the renal pelvis, hydroureter and/or absence of renal papillae). After oral administration, irbesartan at doses ?180 mg/kg of body weight/day (approximately equivalent to 4×MGIC when converted to kg of body weight) to pregnant rats from 0 to 20 days of gestation in rat fetuses was observed the development of subcutaneous edema. Because these impairments were not observed in a limited oral administration of irbesartan at doses of 50, 150 and 450 mg/kg of body weight/day to pregnant rats from 6 to 15 day of gestation, they seem to be late gestational effects of irbesartan. In rabbits, the use of irbesartan in a dose of 30 mg/kg of body weight/day were associated with maternal mortality and aborting. Surviving females receiving a dose equivalent to 1.5×MGIC, when converted to kg of body weight had a slight increase in the resorption of fetuses and, consequently, reducing 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 was not revealed teratogenic effects of amlodipine.
Application for violations of liver function
As with other blockers "slow" calcium channels, T1/2?????????? is increased in patients with impaired liver function, and recommendations for its dispensing mode when the liver is not established. Aproves therefore, the drug should be used with caution in such patients.
Application for violations of renal function
As a consequence of inhibiting the RAAS, you can expect changes in renal function in predisposed to this patients. In patients whose renal function depends on the activity of RAAS (patients with arterial hypertension with renal artery stenosis of one or both kidneys, or patients with chronic heart failure III-IV functional class [NYHA classification]), treatment with other drugs that affect the RAAS were associated with the development of oliguria and/or progressive azotemia and rarely with renal failure and/or death. We cannot exclude the possibility of such effect in the application of ARA II, including irbesartan.
The children
Contraindicated in children under the age of 18 years (efficacy and safety not established);
Use in elderly patients
Patients who received irbesartan in clinical studies, was not observed any differences in the effectiveness or safety of irbesartan in patients of older age (65 and over) compared to patients of younger age.
Special instructions
Excessive decrease in blood pressure: patients with hypovolemia and hyponatremia
Irbesartan was seldom excessive decrease in blood pressure in patients with arterial hypertension without other comorbidities. How and when taking ACE inhibitors, may be expected excessive reduction in blood pressure with corresponding symptoms in patients with hypovolemia and hyponatremia, including patients who undergo intensive diuretic therapy, and/or patients with limited consumption of table salt or patients on hemodialysis. Hyponatremia and hypovolemia should be corrected before starting treatment with the drug Aprovasc® or you should consider using the drug in lower doses.
Patients with chronic heart failure
In the long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with chronic heart failure III-IV functional class (NYHA classification) of nonischemic etiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant differences in the rate of progression of heart failure compared to placebo.
Liver failure
As with other blockers of slow calcium channels, T1/2 amlodipine is increased in patients with impaired liver function, and recommendations for its dispensing mode when the liver is not established. Therefore, the drug Aprovasc® should be used with caution in such patients.
Hypertensive crisis
The safety and efficacy of the drug Aprovasc® in hypertensive crisis is not installed.
The effect on kidney function
As a consequence of inhibiting the RAAS, you can expect changes in renal function in predisposed to this patients. In patients whose renal function depends on the activity of RAAS (patients with arterial hypertension with renal artery stenosis of one or both kidneys, or patients with chronic heart failure III-IV functional class [NYHA classification]), treatment with other drugs that affect the RAAS were associated with the development of oliguria and/or progressive azotemia and rarely with renal failure and/or death. We cannot exclude the possibility of such effect in the application of ARA II, including irbesartan.
Dual blockade of the RAAS with a combination of the drug Aprovasc® with medicines containing aliskiren and ACE inhibitor
Dual RAAS blockade with the combination of the drug Aprovasc® with ACE inhibitor or aliskiren is not recommended because there is increased risk of a sharp decline in blood pressure, hyperkalemia and renal dysfunction.
In patients with diabetes or renal insufficiency moderate and severe (GFR < 60 ml/min/1.73 m2 of body surface) of the drug Aprovasc® in combination with aliskiren contraindicated.
Patients with diabetic nephropathy do not use this medicine Aprovasc® in combination with ACE inhibitors.
Use in elderly patients
Clinical studies have not observed any distinction in the effectiveness or safety of irbesartan in elderly patients (65 years and older) compared to patients of younger age.
Use in Pediatrics
Safety and effectiveness in children have currently not installed.
Effects on ability to drive vehicles and management mechanisms
The influence of the drug Aprovasc® on the ability to drive vehicles or doing other potentially hazardous activities, require increased attention, has not been studied. However, based on pharmacodynamic properties, the influence of the drug Aprovasc® this ability is unlikely. In case of dizziness, vertigo, weakness of driving vehicles or doing other potentially hazardous activities is not recommended.
Overdose
Symptoms: when adults receiving irbesartan in doses up to 900 mg/day showed no toxicity.
Available data for amlodipine suggest that a strong overdose may cause marked peripheral vasodilation and, possibly, to the development of reflex tachycardia. It was reported on the development of pronounced and prolonged excessive loss AD, until the development of shock with fatal outcome.
Treatment: the patient should be under close medical supervision. Treatment should be symptomatic and supportive basic vital functions of the body.
No specific information on the treatment of overdose irbesartan. Proposed measures in case of overdose of the drug Aprovasc® include gastric lavage. Administration of activated charcoal to healthy volunteers immediately after or 2 hours after ingestion of 10 mg of amlodipine showed a slight decrease amlodipine absorption.
Due to the fact that amlodipine is characterized by a high degree of binding with proteins of blood, irbesartan is not removed from the body by hemodialysis, it is unlikely that overdose can be useful for hemodialysis.
In severe overdose, should begin active monitoring of cardiac activity and respiration. The need for frequent measurement of blood pressure. A clinically significant decrease in blood pressure due to amlodipine overdose calls for active cardiovascular maintenance activities, including the giving of the exalted position of limbs. You should control volume and urine output. May require the introduction of vasoconstrictor drugs to restore vascular tone and blood pressure (in the absence of contraindications to their introduction). In/in the introduction of calcium gluconate may be useful in the aftermath of the blockade of calcium channels.
Drug interactions
The combination of irbesartan and amlodipine
Based on the pharmacokinetic studies in which irbesartan and amlodipine taken separately and in combination, there was no pharmacokinetic interaction between irbesartan and amlodipine.
Not been conducted studies on drug interactions drug Approves® with other drugs.
Irbesartan
Based on these in vitro studies do not expect any interaction with drugs, metabolic process which is carried out with the participation isozymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.
Irbesartan is metabolized with the participation of isoenzyme CYP2C9, however, during clinical interaction studies, when received simultaneously with irbesartan warfarin, which is metabolized via the CYP2C9 isoenzyme, there was no significant pharmacokinetic interaction.
The pharmacokinetic parameters irbesartana not change with its concomitant use with nifedipine and hydrochlorothiazide.
Irbesartan does not alter the pharmacokinetics of simvastatin, which is metabolized through CYP3A4, or digoxin (substrate of P-glycoprotein).
The combination of the drug Aprovasc® with products containing aliskiren are contraindicated in patients with diabetes or moderate-to-severe renal insufficiency (GFR < 60 ml/min/1.73 m2 of body surface) and is not recommended in other patients.
The use of the drug Aprovasc® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended other patients.
Based on the experience of the use of other drugs that affect the RAAS, concomitant use of potassium-sparing diuretics, potassium supplements or salt containing potassium may increase serum potassium concentration.
In elderly patients, patients with hypovolemia (due to diuretics) or with impaired renal function concurrent use of NSAIDs, including selective COX-2 inhibitors in conjunction with ARA II, including irbesartan, may result in deterioration of renal function, including acute renal failure. These effects are usually reversible. You should periodically monitor renal function in patients simultaneously receiving ARA-II and NSAIDs, including selective COX-2 inhibitors.
Against the background of combined use of irbesartan the drug lithium was described, the increase of lithium concentration in blood plasma and toxic effects of lithium. In patients taking irbesartan together with the drug lithium, should be monitored concentrations of lithium in plasma.
Amlodipine
Amlodipine safely combined with thiazide diuretics, beta-blockers, alpha-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin use, NSAIDs, antibiotics and hypoglycemic agents for oral administration.
The data in vitro studies with human plasma showed that amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin or indomethacin.
Concomitant use of amlodipine and cimetidine did not violate the pharmacokinetics of amlodipine.
Simultaneous administration of 250 mg of grapefruit juice with a single dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
In the combined reception of amlodipine and sildenafil each of the products independently demonstrated reduce blood pressure effect.
Simultaneous directional receiving amlodipine at a dose of 10 mg and atorvastatin 80 mg led to implausible changes in the pharmacokinetic parameters of atorvastatin in the attainment of Css.
Simultaneous administration of amlodipine with digoxin did not change digoxin concentration in serum or renal clearance of digoxin in healthy volunteers.
Simultaneous administration of amlodipine does not affect prothrombin time when taking warfarin.
Pharmacokinetic studies with cyclosporine have demonstrated that amlodipine has no significant effect on the pharmacokinetics of cyclosporine.
