Aprovasc tabs 300mg + 10mg #28

Aprovasc instruction

You can buy Aprovasc here

Clinico-pharmacological group

Combined antihypertensive drug (slow calcium channel blocker + angiotensin II receptor antagonist)

Active ingredients

- irbesartan
- amlodipine (amlodipine)

Release form, composition and packaging

Tablets, film coated white, oval, biconvex, with risk and bevel to risk on one side.
1 tab.
Amlodipine besylate 14 mg,
which corresponds to the content of amlodipine 10 mg
irbesartan 300 mg
Excipients: microcrystalline cellulose 50 microns - 132 mg, croscarmellose sodium - 24 mg, hypromellose 6 mPa.s - 10 mg, microcrystalline cellulose 100 microns - 10 mg, silicon dioxide - 5 mg, magnesium stearate - 5 mg.
The composition of the shell: white opadry (hypromellose - 62.5%, titanium dioxide (E171) - 31.25%, macrogol 400 - 6.25%) - 20 mg.

pharmachologic effect

The pharmacodynamic properties of each of the active substances that make up Aprovasc, irbesartan and amlodipine contribute to their additive antihypertensive effect when used in combination as compared to those of each of these drugs separately. Both angiotensin II receptor antagonists (ARA II) and slow calcium channel blockers reduce blood pressure by reducing the peripheral resistance of blood vessels, blocking calcium in the cell and reducing the angiotensin II caused by exposure to vasoconstrictor effects that complement each other.

Irbesartan

Irbesartan is a highly selective selective APA II (subtype-AT1). Angiotensin II is an important component of the RAAS, which is involved in the pathophysiology of the development of arterial hypertension and in the homeostasis of sodium ions. Irbesartan does not need metabolic activation to manifest its action.
Irbesartan blocks a strong vasoconstrictor and aldosterone-secreting effects of angiotensin II due to selective antagonism of angiotensin II receptors (subtype AT1) located in the smooth muscle cells of the adrenal cortex and vessels. Irbesartan has no agonistic activity towards AT1 receptors. Its affinity for AT1 receptors is 8,500 times greater than for AT2 receptors (receptors that have not been shown to be linked to maintaining equilibrium [homeostasis] of the cardiovascular system).
Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), and does not affect other hormonal receptors or ion channels in the cardiovascular system involved in the regulation of blood pressure and sodium ion homeostasis. The blockade with AT1 receptor irbesartan breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II. When using irbesartan, the plasma concentration of aldosterone is reduced, however, when using Aprovasc in recommended doses, there is no significant change in the serum potassium content (the average increase in serum potassium is less than 0.1 mEq / l). Irbesartan has no significant effect on the concentration of triglycerides, cholesterol or glucose in serum. Irbesartan does not affect the serum concentrations of uric acid or the excretion of uric acid by the kidneys.
The antihypertensive effect of irbesartan develops after taking the first dose with a significant development of therapeutic action within 1-2 weeks of treatment with a 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 in doses up to 900 mg / day caused a dose-dependent decrease in blood pressure. A single dose of irbesartan in doses of 150-300 mg / day led to a greater decrease in systolic (AAD) / diastolic (DBP) blood pressure (24 hours after a dose) in the supine or sitting position (an average of 8-13 / 5-8 mm Hg. Art.), than that when receiving a placebo. The effect of the drug 24 hours after the dose was 60-70% of the corresponding maximum reduction in DBP and SBP. Optimum efficacy in reducing blood pressure within 24 hours is achieved with a single dose of Aprovasc per day.
BP decreases to approximately the same degree in standing and lying. The orthostatic effect is rare, and, as with the use of ACE inhibitors, its occurrence can be expected in patients with hyponatremia or hypovolemia.
The antihypertensive effect of irbesartan and thiazide diuretics is additive. In patients who fail to achieve the target BP values ​​with monotherapy with irbesartan, adding small doses of hydrochlorothiazide (12.5 mg) to the administration of irbesartan 1 time / day results in an additional (compared to the placebo effect) reduction of GARDEN / DBP determined after 24 hours after taking them, at 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, patients of the Negroid race have a weaker antihypertensive effect in 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 Negroid race approaches that in patients of the Caucasian race.
After the abolition of irbesartan, blood pressure gradually returns to its original level. Withdrawal when discontinuing irbesartan was not observed.

Amlodipine

Amlodipine is a blocker of slow calcium channels from the group of dihydropyridine derivatives, which inhibits the transmembrane transport of calcium ions into the cells of the myocardium and vascular smooth muscle. The mechanism of 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 established, but amlodipine reduces myocardial ischemia due to the two effects listed below.
1. Amlodipine expands peripheral arterioles and due to this reduces round focal disease, the so-called afterload. Since The heart rate when taking amlodipine 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 myocardial zones with normal blood flow and in ischemic myocardial zones. This expansion of the coronary vessels increases the delivery of oxygen to the myocardium in patients with spasm of the coronary arteries (with Prinzmetal angina pectoris or variant angina pectoris).
In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure while lying down and standing for 24 hours. Due to the slow onset of its action, amlodipine is not intended to relieve hypertensive crises.
In patients with angina pectoris, amlodipine is taken once a day during exercise with exercise, which increases the total time for exercise, the time before the onset of angina pectoris and the time before the appearance of ST-segment depression on an ECG of 1 mm depth. In addition, taking the drug reduces the daily number of strokes 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 asthma, diabetes and gout.
Clinical evidence of the efficacy of a combination of fixed-dose irbesartan and amlodipine was obtained in two multicenter, prospective, open-label studies of parallel groups with a blind assessment of performance indicators: the I-ADD and I-COMBINE studies. The results of both studies demonstrated a significantly greater efficacy of combinations with fixed doses of irbesartan and amlodipine compared with amlodipine monotherapy or irbesartan monotherapy.

Pharmacokinetics of Aprovasc

Irbesartan

Suction
Irbesartan is an active drug when administered orally, which does not need biotransformation for the manifestation of its activity. After oral administration, irbesartan is rapidly and completely absorbed. Cmax of irbesartan in blood plasma is reached within 1.5-2 hours after ingestion. The absolute bioavailability of irbesartan when administered orally is 60-80%. Eating does not affect the bioavailability of irbesartan.
Distribution
Binding to plasma proteins is approximately 96%, irbesartan is almost not associated with blood cells. Vd of irbesartan is 53-93 l / kg.
After ingestion or intravenous administration of 14C of irbesartan, the proportion of unchanged irbesartan in plasma accounts for 80-85% of the radioactivity circulating in the systemic circulation.
Metabolism
Irbesartan is metabolized in the liver by conjugation with glucuronic acid and oxidation. The main metabolite found in the systemic circulation is irbesartan glucuronide (approximately 6%). Irbesartan undergoes oxidation, mainly with the participation of CYP2C9 isoenzyme; CYP3A4 isoenzyme plays a minor role in the metabolism of irbesartan. Irbesartan is not metabolized by most isoenzymes commonly involved in drug metabolism, such as isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 or CYP2E1, and does not reliably induce or inhibit these isoenzymes. Irbesartan does not inhibit the CYP3A4 isoenzyme.
Removal
T1 / 2 of irbesartan is 11–15 hours. The total clearance for intravenous injection of irbesartan is 157–176 ml / min, of which 3–3.5 ml / min is renal clearance.
Irbesartan and its metabolites are excreted both by the liver (with bile) and the kidneys. After ingestion or after intravenous administration of 14C of irbesartan, about 20% of the radioactivity is detected in the urine with a small residual amount in the feces. Less than 2% of the dose is excreted by the kidneys as unchanged irbesartan.
Irbesartan, when used in the therapeutic range of doses, has linear pharmacokinetics. Css is achieved on the third day after the start of taking Aprovasc 1 time / day. There is a limited accumulation of irbesartan in the blood plasma (<20%) on the background of the course taking the drug 1 time / day.

Pharmacokinetics in special clinical situations

In women with arterial hypertension, compared with men with arterial hypertension, higher (by 11–44%) plasma concentrations of irbesartan were observed after a single dose, however, against the background course of irbesartan, there were no differences in the accumulation of irbesartan or his t1 / 2. There were no gender-related differences in the clinical efficacy of irbesartan.
Elderly patients without arterial hypertension (men and women) (65-80 years old) with clinically normal renal function and liver AUC and Cmax in the blood plasma were approximately 20-50% higher than in younger patients (18-40 years), however, T1 / 2 in young and elderly patients were comparable. No significant, age-related differences in the clinical efficacy of irbesartan were observed.
Patients of the Negroid race with normal values ​​of BP AUC and T1 / 2 of irbesartan were approximately 20–25% higher than in patients of the European race with normal values ​​of BP, however, Cmax of irbesartan was almost the same.
In patients with renal insufficiency (regardless of its severity) and in patients on hemodialysis, the pharmacokinetics of irbesartan does not significantly change. Irbesartan is not removed from the blood by hemodialysis.
In patients with hepatic insufficiency due to mild or moderate liver cirrhosis, the pharmacokinetics of irbesartan are not significantly altered.
Studies of the efficacy and safety of irbesartan in children have not been conducted.

Amlodipine

Suction
After ingestion in therapeutic doses, amlodipine is well absorbed, Cmax in the blood is achieved 6-12 hours after administration. Absolute bioavailability is 64-90%. Meal does not violate the absorption of amlodipine.
Distribution
Amlodipine Vd is approximately 21 L / kg. In vitro studies have shown that the binding of amlodipine in the systemic circulation to plasma proteins is approximately 97.5%.
Metabolism and excretion
Amlodipine is extensively metabolized in the liver to form inactive metabolites.
T1 / 2 from blood plasma is approximately 35-50 hours when taken 1 time / day. The kidneys excrete 10% of unchanged amlodipine and 60% of its metabolites.

Pharmacokinetics in special clinical situations

In elderly and younger people, the time to achieve Cmax of amlodipine in the blood is the same. In older patients, the clearance of amlodipine tends to decrease, resulting in an increase in AUC and T1 / 2.
In children 6–12 years old and adolescents 13–17 years old, the amlodipine clearance when taking the medicine orally was 22.5 and 27.4 l / h, respectively, in boys and 16.4 and 21.3 l / h, respectively, in girls. There was a large variability in the systemic exposure of amlodipine in different children and adolescents. Data obtained from the use of Aprovasc in children under 6 years of age are limited.
Like other slow calcium channel blockers, an increase in amlodipine T1 / 2 is possible with liver failure.
In patients with chronic heart failure (in all age groups), an increase in AUC and T1 / 2 was observed.
Pharmacokinetics when using the combination of irbesartan / amlodipine in adults
The simultaneous administration of irbesartan and amlodipine in the form of fixed combinations in tablets or in free combinations did not affect the pharmacokinetics of each of the active substances of this combination.
Three fixed dose combinations of irbesartan and amlodipine (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg) are bioequivalent free dose combinations (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg) both in terms of speed and degree of absorption.
When taken alone or at the same time in doses of 300 mg and 10 mg, the time to reach the median Cmax of irbesartan and amlodipine in the blood plasma remains unchanged, that is, 0.75-1 h and 5 h after administration, respectively. Similarly, Cmax and AUC of irbesartan and amlodipine when taken alone or at the same time in doses of 300 mg and 10 mg are in the same ranges, resulting in a joint reception of the relative bioavailability of irbesartan is 95%, and amlodipine - 98%.
The average T1 / 2 for irbesartan and amlodipine, taken individually or in combination, is almost the same: 17.6 hours versus 17.7 hours for irbesartan and 58.5 hours versus 52.1 hours for amlodipine. Removal of irbesartan and amlodipine does not change when they are taken separately or together.
The pharmacokinetics of irbesartan and amlodipine were linear with the use of irbesartan in doses from 150 mg to 300 mg and amlodipine in doses from 5 mg to 10 mg.
Pharmacokinetics when using the combination of irbesartan / amlodipine in children
There is no information on the use of the fixed combination of irbesartan and amlodipine in children.

Indications

- arterial hypertension (with the ineffectiveness of monotherapy with irbesartan or amlodipine).

Contraindications for Aprovasc

- Hypersensitivity to irbesartan, amlodipine and other derivatives of dihydropyridine, as well as to the excipients of the drug;
- cardiogenic shock;
- clinically significant aortic stenosis;
- Unstable angina (with the exception of Prinzmetal stenocardia);
- pregnancy;
- breastfeeding period;
- age up to 18 years (efficiency and safety have not been established);
- simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or with moderate and severe renal insufficiency (GFR <60 ml / min / 1.73 m2);
- simultaneous use with ACE inhibitors in patients with diabetic nephropathy.

Carefully

In patients with hypovolemia and hyponatremia, arising, for example, with intensive treatment with diuretics, hemodialysis, diet with restriction of salt intake, diarrhea, vomiting.
In patients whose kidney function depends on the activity of the RAAS (such as patients with arterial hypertension with stenosis of the renal artery of one or both kidneys, patients with chronic heart failure of the III-IV functional class according to NYHA classification), treatment with drugs affecting the RAAS, was 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 APA II, including irbesartan).
In patients with chronic heart failure II-IV functional class according to the NYHA classification of non-ischemic etiology (due to the content of amlodipine in the composition, the use of which in these patients was associated with an increase in reports of the development of pulmonary edema compared with placebo frequency of progression of heart failure).
In patients with hepatic impairment (risk of increased T1 / 2 amlodipine).
In patients with renal insufficiency and after kidney transplantation (due to the content of irbesartan in the composition, it is recommended to control the content of potassium 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 (GOKMP).
Patients with coronary artery 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 SSSU (due to the content of amlodipine in the composition of Aprovasc).

Dosage

Inside, drinking water, regardless of the meal.
The initial and maintenance dose of the drug Aprovasc - 1 tab. / Day.
Aprovasc should be used in patients in whom it is not possible to achieve the target values ​​of blood pressure in monotherapy with irbesartan or amlodipine monotherapy, or to continue treatment of patients already taking irbesartan and amlodipine in the form of individual tablets. Doses should be selected individually, first with the use of individual drugs irbesartan and amlodipine. Doses are selected depending on the response of blood pressure to the therapy and the target value of blood pressure.
The maximum recommended dose of the drug Aprovasc is 150 mg / 10 mg or 300 mg / 10 mg per day (due to the fact that the maximum daily dose of amlodipine is 10 mg).
The safety and efficacy of Aprovasc in children have not been established.
Elderly patients and patients with impaired renal function dose adjustment is not required.
In patients with impaired liver function, Aprovasc should be used with caution, due to the presence of amlodipine in the formulation.

Side effects of Aprovasc tablets

The frequency of adverse events / reactions (AE / HP) reported in clinical studies on the use of a combination with fixed doses of irbesartan and amlodipine (clinical studies I-ADD, I-COMBINE and I-COMBO), in clinical studies on the use of irbesartan and its post-marketing use, as well as 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%); rarely (≥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 AE / HP.
The frequency of HP, which was reported in the post-marketing use of Aprovasc, was defined as "frequency unknown" because information about these HPs came from spontaneous reports, without specifying the number of patients taking the drug.
In clinical studies, compared with fixed doses of irbesartan / amlodipine with irbesartan or amlodipine monotherapy, the types and frequency of adverse events that occurred during treatment, possibly related to the treatment being studied, were similar to those seen in previous clinical studies or in post-marketing messages monotherapy with irbesartan and amlodipine. The most common AEs were peripheral edema, mainly associated with amlodipine.
Adverse events observed during treatment and possibly associated with the study drug in clinical studies of irbesartan / amlodipine (I-ADD, I-COMBINE and I-COMBO)
Irbesartan / Amlodipine Fixed Combination
General reactions: often - peripheral edema, edema; infrequently - asthenia.
On the part of the organ of hearing and labyrinth disorders: infrequently - vertigo.
Since the cardiovascular system: often - a feeling of palpitations, orthostatic hypotension; infrequently - sinus bradycardia, excessive decrease in blood pressure.
On the part of the nervous system: often - dizziness, headache, drowsiness; infrequently - paresthesia.
On the part of the respiratory system: Infrequently - cough.
On the part of the digestive system: often - swelling of the gums; infrequently - nausea, pain in the upper abdomen, constipation.
From the urinary system: often - proteinuria; infrequently - azotemia, hypercreatinemia.
On the part of the reproductive system: infrequently - erectile dysfunction.
From the side of metabolism: infrequently - hyperkalemia.
On the part of the musculoskeletal system: infrequently - joint stiffness, arthralgia, myalgia.
Adverse events observed with the use of irbesartan in clinical studies (including clinical studies I-ADD, I-COMBINE and I-COMBO) and during its post-marketing use
On the part of the immune system: the frequency is unknown - hypersensitivity reactions (allergic reactions).
On the part of metabolism: the frequency is unknown - hyperkalemia.
On the part of the organ of hearing and labyrinth disturbances: often - vertigo; frequency unknown - tinnitus.
From the nervous system: often - dizziness, headache *; infrequently - orthostatic dizziness.
* The incidence of headache in the I-ADD, I-COMBINE and I-COMBO studies was rated “infrequently”.
Since the cardiovascular system: infrequently - tachycardia.
On the part of the respiratory system: Infrequently - cough.
On the part of the skin and subcutaneous tissues: infrequently - alopecia; frequency is unknown - leukocytoclastic vasculitis.
On the part of the digestive system: often - nausea / vomiting, pain in the upper abdomen, language disturbances, glossy (burning sensation and soreness in the tongue); infrequently - diarrhea, dyspepsia, heartburn; frequency is unknown - dysgeusia (taste perversion).
On the part of the liver and biliary tract: the frequency is unknown - jaundice, increased functional liver function tests, hepatitis.
On the part of the musculoskeletal system: the frequency is unknown - myalgia.
On the part of the urinary system: the frequency is unknown - impaired renal function, including individual cases of renal failure in patients with risk factors for its development.
On the part of the reproductive system: infrequently - erectile dysfunction.
General reactions: often - increased fatigue *, edema; infrequently - chest pain; frequency is unknown - asthenia.
* The incidence of fatigue in the I-ADD, I-COMBINE, and I-COMBO studies was rated as “infrequent”.
Injuries, intoxication and complications of manipulations: infrequently - falls.
Adverse events observed with amlodipine in clinical trials (including clinical studies I-ADD, I-COMBINE and I-COMBO)
From the hematopoietic system: very rarely - thrombocytopenia.
On the part of the immune system: very rarely - allergic reactions.
On the part of metabolism: very rarely - hyperglycemia.
Mental Disorders: Infrequently - insomnia, mood lability.
On the part of the nervous system: often - dizziness, headache *, drowsiness; infrequently - hypoesthesia, paresthesia, tremor, taste perversions, syncopal states; very rarely, peripheral neuropathy.
* The incidence of headache in I-ADD, I-COMBINE and I-COMVO was assessed as “infrequent”.
On the part of the organ of vision: infrequently - visual disorders.
On the part of the organ of hearing and labyrinth disorders: infrequently - ringing in the ears, vertigo.
From the side of the cardiovascular system: often - a sensation of heartbeat, "flush" of blood to the skin with a feeling of heat, redness of the skin *; infrequently - excessive decrease in blood pressure; very rarely - myocardial infarction, cardiac arrhythmias, ventricular tachycardia and atrial fibrillation (atrial fibrillation), vasculitis.
* The incidence of reddening of the skin in the I-ADD, I-COMBINE and I-COMBO studies was rated as “infrequent”.
On the part of the respiratory system: often - cough; infrequently - shortness of breath, rhinitis; very rarely - coughing.
On the part of the digestive system: often - nausea, abdominal pain, glossy, glossitis; infrequently - dyspepsia, vomiting, changes in the rhythm of defecation, dry mucous membranes of the oral cavity; very rarely - pancreatitis, gastritis, gum hyperplasia.
On the part of the liver and biliary tract: very rarely - hepatitis, jaundice and increased activity of liver enzymes (mainly associated with cholestasis).
From the skin and subcutaneous tissues: often - contact dermatitis; infrequently - skin rash, itching, purpura, increased sweating, changes in skin pigmentation (the appearance of discolored skin), alopecia; very rarely - angioedema, erythema multiforme, urticaria.
From the musculoskeletal system: infrequently - arthralgia, muscle cramps, myalgia, back pain.
From the urinary system: infrequently - an increase in the frequency of urination, painful urge to urinate, nocturia.
On the part of the reproductive system: infrequently - impotence, gynecomastia.
General reactions: often - fatigue, edema *, peripheral edema; infrequently - chest pain, asthenia, malaise, pain; rarely - swelling of the face.
* According to I-ADD, I-COMBINE and I-COMBO studies, the frequency of occurrence of edema is "infrequent."
Laboratory and instrumental data: infrequently - weight gain, weight loss.

Overdose

Symptoms: when adults take irbesartan in doses up to 900 mg / day, no toxicity is established.
Available data for amlodipine suggest that severe overdose may lead to severe peripheral vasodilation and, possibly, to the development of reflex tachycardia. It was reported about the development of pronounced and prolonged excessive reduction of blood pressure, up to the development of shock with a fatal outcome.
Treatment: The patient must be under close medical supervision. Treatment should be symptomatic and maintain the basic vital functions of the body.
There is no specific information for the treatment of irbesartan overdose. Proposed measures for overdose of the drug Aprovasc include gastric lavage. The intake of activated carbon by healthy volunteers immediately after or 2 hours after ingestion of 10 mg of amlodipine showed a slight decrease in the absorption of amlodipine.
Due to the fact that amlodipine is characterized by a high degree of binding to blood proteins, and irbesartan is not excreted from the body through hemodialysis, it is unlikely that hemodialysis may be useful in overdose.
In severe overdose, active monitoring of cardiac activity and respiration should begin. Frequent blood pressure measurement is necessary. A clinically significant reduction in blood pressure due to an overdose of amlodipine requires the active maintenance of cardiovascular activity, including giving an elevated position to the extremities. BCC and diuresis should be monitored. May require the introduction of vasoconstrictor drugs to restore vascular tone and blood pressure (provided there are no contraindications to their introduction). In / in the introduction of calcium gluconate may be useful in eliminating the effects of calcium channel blockade.

Drug interaction

Combination of irbesartan and amlodipine

Based on pharmacokinetic studies in which irbesartan and amlodipine were taken separately and in combination, there was no pharmacokinetic interaction between irbesartan and amlodipine.
No studies have been conducted on drug interaction of the drug Aprovasc with other drugs.

Irbesartan

Based on in vitro research, one should not expect any interaction with drugs whose metabolism is carried out with the participation of isoenzymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.
Irbesartan is predominantly metabolized with the participation of CYP2C9 isoenzyme, but during clinical interaction studies, when irbesartan was administered simultaneously with warfarin, which is metabolized by the CYP2C9 isoenzyme, no significant pharmacokinetic interaction was observed.
The pharmacokinetic parameters of irbesartan do not change when used simultaneously with nifedipine and hydrochlorothiazide.
Irbesartan does not alter the pharmacokinetics of simvastatin, which is metabolized by the isoenzyme CYP3A4, or digoxin (a substrate of P-glycoprotein).
The combination of the drug Aprovasc with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or moderate and severe renal insufficiency (GFR <60 ml / min / 1.73 m2 of body surface) and is not recommended in other patients.
ACE inhibitors: use of the drug Aprovasc in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended for other patients.
Based on the experience of using other drugs that affect the RAAS, the simultaneous use of irbesartan with potassium preparations; potassium-containing salt substitutes; potassium-sparing diuretics or other drugs that can increase the content of potassium in the blood plasma (heparin) can sometimes significantly increase the serum concentration of potassium, which requires careful monitoring of the content of potassium in the blood plasma of patients during treatment.
In elderly patients, patients with hypovolemia (due to diuretic administration) or with impaired renal function, simultaneous use of NSAIDs, including selective COX-2 inhibitors in conjunction with ARA II, including irbesartan, can lead to deterioration of renal function, including the development of acute renal failure. These effects are usually reversible. Kidney function should be periodically monitored in patients who simultaneously take ARA II and NSAIDs, including selective COX-2 inhibitors.
Lithium: against the background of the combined use of irbesartan with lithium preparations, an increase in the plasma concentration of lithium and the toxic effect of lithium have been described. In patients taking irbesartan in conjunction with lithium preparations, plasma concentrations of lithium should be monitored.

Amlodipine

Amlodipine was 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 plasma proteins of digoxin, phenytoin, warfarin or indomethacin.
Cimetidine: simultaneous administration of amlodipine and cimetidine did not violate the pharmacokinetics of amlodipine.
Grapefruit juice: the simultaneous intake of 240 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.
Sildenafil: with the simultaneous use of amlodipine and sildenafil, each of the drugs independently showed its effect of reducing blood pressure.
Atorvastatin: simultaneous course administration of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg resulted in unreliable changes in the pharmacokinetic parameters of atorvastatin in the state of attaining Css.
Digoxin: co-administration of amlodipine with digoxin did not change the concentration of digoxin in the blood serum or the renal clearance of digoxin in healthy volunteers.
Warfarin: simultaneous use of amlodipine did not change the prothrombin time while taking warfarin.
Cyclosporine: pharmacokinetic studies with cyclosporine have demonstrated that amlodipine does not have a significant effect on cyclosporine pharmacokinetics.
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 control the concentration of tacrolimus in the blood plasma and, if necessary, to adjust its dose.
Simvastatin: the simultaneous use of amlodipine with simvastatin may increase the exposure of simvastatin compared with simvastatin therapy. With simultaneous use of simvastatin and amlodipine, it is necessary to limit the daily dose of simvastatin to 20 mg.

special instructions

Excessive reduction in blood pressure: patients with hypovolemia and hyponatremia

Irbesartan rarely caused an excessive decrease in blood pressure in patients with arterial hypertension without another concomitant pathology. As with the use of ACE inhibitors, an excessive decrease in blood pressure with appropriate symptoms in patients with hypovolemia and hyponatremia, which include patients undergoing intensive diuretic therapy, and / or patients with restrictions on the consumption of salt or hemodialysis patients can be expected. Hyponatremia and hypovolemia should be adjusted before starting treatment with Aprovasc, or the use of Aprovasc in lower initial doses should be considered.

Patients with chronic heart failure

In a long-term placebo-controlled study (PRAISE-2) of amlodipine in patients with chronic heart failure of the III-IV functional class (according to NYHA classification) of non-ischemic etiology, amlodipine was associated with an increase in reports of pulmonary edema, despite the absence of a significant difference in the rate of progression of heart failure compared to placebo.

Liver failure

As with other slow calcium channel blockers, T1 / 2 amlodipine is increased in patients with impaired liver function, and recommendations for its dosing regimen for impaired liver function have not been established. Therefore, the drug Aprovasc should be used with caution in these patients.

Hypertensive crisis

The safety and efficacy of Aprovasc in hypertensive crises have not been established.

Impact on kidney function

Due to inhibition of the RAAS, changes in renal function can be expected in susceptible patients. In patients whose kidney function depends on the activity of the RAAS (patients with arterial hypertension with stenosis of the renal artery of one or both kidneys or patients with chronic heart failure of the III-IV functional class [according to the NYHA classification]), treatment with other drugs that affect the RAAS , has been associated with the development of oliguria and / or progressive azotemia, and rarely with renal failure and / or death. It is impossible to exclude the possibility of such an effect when using APA II, including irbesartan.
Double blockade of RAAS with the combination of the drug Aprovasc with drugs containing aliskiren, and with an ACE inhibitor
Double blocking of the RAAS when using the Aprovasc combination with an ACE inhibitor or aliskiren is not recommended, because there is an increased risk of developing a sharp decrease in blood pressure, hyperkalemia and impaired renal function.
In patients with diabetes or renal failure of moderate and severe (with GFR <60 ml / min / 1.73 m2 of body surface), the use of the drug Aprovasc in combination with aliskiren is contraindicated.
The use of the drug Aprovasc in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy.

Use in elderly patients

In clinical studies, there was no difference in the efficacy or safety of irbesartan in elderly patients (65 years and older) compared with younger patients.

Use in Pediatrics

Safety and efficacy in children have not yet been established.

Influence on ability to drive vehicles and mechanisms

The effect of the drug Aprovasc on the ability to drive vehicles or engage in other potentially hazardous activities requiring increased attention has not been studied. However, based on the pharmacodynamic properties, the effect of the drug Aprovasc on this ability is unlikely. In the event of dizziness, vertigo, weakness, it is not recommended to drive vehicles or engage in other potentially hazardous activities.

Pregnancy and lactation

Pregnancy

There are not enough and well-controlled studies of the use of the drug Aprovasc in pregnant women. The effect on the fetus of ACE inhibitors, which were taken by pregnant women in the second and third trimesters of pregnancy, caused damage and death of the developing fetus. Like any other drugs that directly affect the RAAS, Aprovasc is contraindicated during pregnancy.
Aprovasc should not be used in women of childbearing age who do not use effective methods of contraception. If pregnancy is detected during treatment with Aprovasc, it should be discontinued as soon as possible.
In preclinical studies when orally administered to pregnant rats from day 0 to day 20 of gestation, irbesartan in doses ≥50 mg / kg body weight / day (which, in terms of kg of body weight, is approximately equivalent to the maximum recommended dose of irbesartan in humans [MRDICH] of 300 mg / day) transient effects were observed in the fetuses of rats (slight or moderate expansion of the renal pelvis, hydroureter and / or absence of the renal papillae). Oral administration of irbesartan in doses of ≥180 mg / kg body weight / day (approximately equivalent to 4 × MRDICH in terms of kg of body weight) pregnant rats developed a subcutaneous edema from day 20 to day 20 of gestation. Since these developmental disorders were not observed with 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 days of gestation, they appear to be the late gestational effects of irbesartan. In rabbits, the use of irbesartan at a dose of 30 mg / kg body weight / day was associated with maternal mortality and abortion. Surviving females who received a dose equivalent to 1.5 × MRDIC when 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. Irbesartan was found to penetrate the placental barrier in rats and rabbits. In rats and rabbits no teratogenic effect of amlodipine was detected.

Breastfeeding period

Aprovasc is contraindicated during breastfeeding.

Use in childhood

Contraindicated in children under the age of 18 years (efficacy and safety have not been established);

In case of impaired renal function

Due to inhibition of the RAAS, changes in renal function can be expected in susceptible patients. In patients whose kidney function depends on the activity of the RAAS (patients with arterial hypertension with stenosis of the renal artery of one or both kidneys or patients with chronic heart failure of the III-IV functional class [according to the NYHA classification]), treatment with other drugs that affect the RAAS , has been associated with the development of oliguria and / or progressive azotemia, and rarely with renal failure and / or death. It is impossible to exclude the possibility of such an effect when using APA II, including irbesartan.

With abnormal liver function

As with the use of other blockers of “slow” calcium channels, T1 / 2 of amlodipine is increased in patients with impaired liver function, and recommendations for its dosing schedule for impaired liver function have not been established. Therefore, the drug Aprovasc should be used with caution in these patients.

Use in old age

In patients who took irbesartan in clinical studies, there was no difference in the efficacy or safety of irbesartan in older patients (65 years and older) compared with younger patients.

Pharmacy sales terms

You can buy Aprovasc without a prescription.

Terms and conditions of storage

Aprovasc should be stored out of the reach of children at a temperature not higher than 30 ° C. Shelf life - 3 years.