Aprovasc pills 5mg+150mg 28pcs

Composition

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of 1 tab. amlodipine bezylate 7 mg, which corresponds to the content of amlodipine 5 mg, irbesartan 150 mg

Auxiliary substances:

microcrystalline cellulose 50 microns – 66 mg,

croscarmellose sodium-12 mg,

hypromellose 6 MPa * s-5 mg,

microcrystalline cellulose 100 microns-5 mg,

colloidal silicon dioxide-2.5 mg,

magnesium stearate-2.5 mg.

Composition of the film shell:

 opadray white (hypromellose-62.5%, titanium dioxide (E 171) – 31.25%, macrogol 400-6.25%) – 10 mg

Pharmacological action

Combined antihypertensive drug. 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 compared to that 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 intake into the cell and reducing the vasoconstrictor effect caused by angiotensin II are complementary mechanisms.

Irbesartan

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

Irbesartan blocks the strong vasoconstrictor and aldosterone-secreting effects of angiotensin II due to selective antagonism to angiotensin II receptors (subtype-AT1) located in vascular smooth muscle cells and the adrenal cortex. Irbesartan has no agonistic activity against AT1 receptors. Its affinity for AT1 receptors is 8500 times greater than for AT2 receptors (receptors that have not been shown to be associated with maintaining balance [homeostasis] of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), and also does not affect other hormone receptors or ion channels in the cardiovascular system involved in the regulation of blood pressure and sodium ion homeostasis. Irbesartan blockade of AT1 receptors 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 decreases, but when using the drug at the recommended doses, there are no significant changes in the serum potassium content (the average increase in serum potassium content 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 uric acid excretion by the kidneys.

The antihypertensive effect of irbesartan develops after 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 150-300 mg / day resulted in a greater reduction in systolic (SBP)/diastolic (DBP) blood pressure (24 hours after the dose) in the supine or sitting position (an average of 8-13 / 5-8 mm Hg) than that with placebo. The effect of the drug 24 hours after the dose was 60-70% of the corresponding maximum reduction in DBP and SBP. Optimal effectiveness in reducing blood pressure within 24 hours is achieved with a single dose of the drug per day.

Blood pressure decreases approximately equally when standing and lying down. Orthostatic effects are rare, and as with ACE inhibitors, they may be expected to occur 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 irbesartan monotherapy, the addition of small doses of hydrochlorothiazide (12.5 mg) to irbesartan 1 time/day leads to an additional (compared to the placebo effect) decrease in SBP/DBP, determined 24 hours after their use, by 7-10/3-6 mm Hg, 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 black race have a weaker antihypertensive effect with irbesartan monotherapy. When irbesartan is taken with small doses of hydrochlorothiazide (for example,12.5 mg / day) the antihypertensive effect in patients of the black race is close to that in patients of the Caucasian race.

After irbesartan is discontinued, blood pressure gradually returns to its original level. No withdrawal symptoms were observed when irbesartan was discontinued.

Amlodipine

Amlodipine is a slow calcium channel blocker from the group of dihydropyridine derivatives, which inhibits the transmembrane entry 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 the smooth muscles of blood vessels.

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 dilates the peripheral arterioles and thereby reduces the OPSS, the so-called afterload. Since the heart rate when taking amlodipine practically does not increase, this reduction in the load on the heart muscle reduces the energy consumption of the myocardium and its oxygen demand.

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

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

In patients with angina pectoris, a single daily dose of amlodipine during a physical activity test increases the total time of exercise, the time before the onset of an angina attack, and the time before the appearance of ST-segment depression on a 1 mm deep ECG. In addition, taking the drug reduces the daily number of angina attacks and the daily need for taking nitroglycerin tablets.

No adverse metabolic effects or changes in blood lipid concentrations were observed when taking amlodipine. Amlodipine can be used in patients with asthma, diabetes mellitus, and gout.

Clinical evidence for the effectiveness of a fixed-dose combination of irbesartan and amlodipine was obtained in two multicenter, prospective, open-label parallel group studies with blind evaluation of efficacy indicators: 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 to amlodipine monotherapy or irbesartan monotherapy.

Indications

Arterial hypertension (if irbesartan or amlodipine monotherapy is ineffective).

Contraindications

— hypersensitivity to irbesartan, amlodipine and other dihydropyridine derivatives, as well as auxiliary substances of the drug;

— cardiogenic shock;

— clinically significant aortic stenosis;

— unstable angina (with the exception of prinzmetals angina);

— pregnancy;

— the period of breastfeeding;

— children’s and teenage age up to 18 years (efficacy and safety not established);

— simultaneous use with drugs containing aliskiren in patients with diabetes or moderate-to-severe renal insufficiency (GFR< 60 ml/min/1.73 m 2);

— concomitant use with ACE inhibitors in patients with diabetic nephropathy.

With caution:

In patients with hypovolemia and hyponatremia that occur, for example, during intensive diuretic treatment, hemodialysis, a diet with limited salt intake, diarrhea, vomiting.

In patients whose renal function depends on the activity of the RAAS (such as patients with arterial hypertension with renal artery stenosis of one or both kidneys, patients with chronic heart failure of NYHA functional class III-IV), treatment with drugs that affect the 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 with ARA II, including irbesartan).

In patients with NYHA functional class II-IV chronic heart failure of non-ischemic etiology (due to the content of amlodipine in the composition of the drug, the use of which in such patients was associated with an increase in reports of pulmonary edema compared to placebo, despite the absence of differences in the frequency of heart failure progression).

In patients with hepatic insufficiency (risk of increased T1 / 2 of amlodipine).

In patients with renal insufficiency and after kidney transplantation (due to the content of irbesartan in the preparation, monitoring of potassium and creatinine concentrations in the blood is recommended); after a recent kidney transplant (lack of experience with clinical use of irbesartan).

In patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCMP).

In patients with CHD and / or clinically significant atherosclerosis of the cerebral vessels (with an excessive decrease in blood pressure, there is a risk of increasing ischemic disorders, up to the development of acute myocardial infarction and stroke).

In patients with SSS (due to the content of amlodipine in the drug).

Side effects

the Frequency of adverse events/reactions (AES/HP), reported in clinical studies on the use of a combination of fixed-dose irbesartan and amlodipine (I clinical trial-ADD-I-COMBINE and I-COMBO), in clinical studies on the use of irbesartan and its post-marketing use and in clinical studies on the use of amlodipine were 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 rare (< 0.01%), the frequency is unknown – according to available data it is impossible to estimate the frequency of occurrence of AES/HP.

The frequency of HP reported during post-marketing use of the drug was defined as “frequency unknown”, since information about these HP came from spontaneous reports, without specifying the number of patients taking the drug.

In clinical studies, when compared with the combination of fixed-dose irbesartan/amlodipine with irbesartan or amlodipine monotherapy, the types and frequency of treatment-related adverse events that may occur during treatment were similar to those observed in previous clinical studies or in post-marketing reports with irbesartan and amlodipine monotherapy. The most common AE 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 of irbesartan/amlodipine

General reactions: often-peripheral edema, edema; infrequently-asthenia.

Hearing disorders and labyrinth disorders: infrequently – vertigo.

From the cardiovascular system: often-palpitation, orthostatic hypotension; infrequently-sinus bradycardia, excessive decrease in blood pressure.

Nervous system disorders: often – dizziness, headache, drowsiness; infrequently-paresthesia.

From the side of the reproductive system: infrequently – erectile dysfunction.

Respiratory system disorders: infrequently-cough.

From 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.

From the side of metabolism: infrequently-hyperkalemia.

Musculoskeletal disorders: infrequently – joint stiffness, arthralgia, myalgia.

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

From the immune system: frequency unknown-hypersensitivity reactions (allergic reactions), including angioedema, urticaria.

From the side of metabolism: frequency unknown-hyperkalemia.

Hearing disorders and labyrinth disorders: often-vertigo; frequency unknown-tinnitus.

Nervous system disorders: often – dizziness, headache*; infrequently-orthostatic dizziness.

* The incidence of headache in the I-ADD, I-COMBINE, and I-COMBO studies was rated as “infrequent”.

From the cardiovascular system: infrequently-tachycardia.

Skin and subcutaneous tissue disorders: frequency unknown-leukocytoclastic vasculitis.

Respiratory system disorders: infrequently-cough.

From the digestive system: often – nausea/vomiting, upper abdominal pain, tongue disorders, glossodynia (burning sensation and soreness in the tongue); infrequently-diarrhea, dyspepsia, heartburn; frequency unknown-jaundice, increased liver function tests, hepatitis; frequency unknown-dysgeusia (taste distortion).

Liver and biliary tract disorders: frequency unknown-jaundice, increased liver function tests, hepatitis.

Skin and subcutaneous tissue disorders: infrequently – alopecia.

Allergic reactions: frequency unknown-angioedema, urticaria.

Musculoskeletal disorders: frequency unknown – myalgia.

From the urinary system: frequency unknown-impaired renal function, including isolated cases of renal failure in patients with risk factors for its development.

From the side of the reproductive system: infrequently – erectile dysfunction.

General reactions: often – increased fatigue*, edema; infrequently-chest pain; frequency unknown-asthenia.

* The incidence of increased fatigue in the I-ADD, I-COMBINE, and I-COMBO studies was rated as “infrequent”.

Injuries, intoxications, and manipulation complications: infrequently-falls.

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

From the hematopoietic system: very rarely – thrombocytopenia.

From the immune system: very rarely – allergic reactions, including angioedema, urticaria.

From the side of metabolism: very rarely – hyperglycemia.

Mental disorders: infrequently – insomnia, lability of mood.

Nervous system disorders: often – dizziness, headache*, drowsiness; infrequently-hypesthesia, paresthesia, tremor, taste distortions, syncopal states; very rarely-peripheral neuropathy.

* The incidence of headache in the I-ADD, I-COMBINE, and I-COMVO studies was rated as “infrequent”.

From the side of the visual organ: infrequently-visual disorders.

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

From the cardiovascular system: often – palpitations, hot flushes of blood to the skin, redness of the skin*; very rarely-myocardial infarction, cardiac arrhythmias, ventricular tachycardia and atrial fibrillation( atrial fibrillation), vasculitis.

* The incidence of skin redness in the I-ADD, I-COMBINE, and I-COMBO studies was rated as “infrequent”.

Respiratory system disorders: often – cough; infrequently-shortness of breath, rhinitis; very rarely-coughing.

From the digestive system: often – nausea, abdominal pain, glossodynia, glossitis; infrequently-dyspepsia, vomiting, changes in the rhythm of defecation, dryness of the oral mucosa; very rarely-pancreatitis, gastritis, gum hyperplasia.

Liver and biliary tract disorders: very rarely – hepatitis, jaundice and increased activity of liver enzymes (mainly associated with cholestasis).

Skin and subcutaneous tissue disorders: often-contact dermatitis; infrequently – skin rash, itching, purpura, increased sweating, changes in skin pigmentation (the appearance of discolored skin areas), alopecia; very rarely – erythema multiforme.

Musculoskeletal disorders: infrequently – arthralgia, muscle cramps, myalgia, back pain.

From the urinary system: infrequently – increased frequency of urination, painful urge to urinate, nocturia.

From the side of the reproductive system: infrequently – impotence, gynecomastia.

General reactions: often-increased fatigue, edema*, peripheral edema; infrequently-chest pain, asthenia, feeling unwell, pain; rarely-facial edema.

* According to the I-ADD, I-COMBINE, and I-COMBO studies, the incidence of edema is “infrequent”.

Laboratory and instrumental data: infrequently – weight gain, weight loss.

Interaction

Combination of irbesartan and amlodipine

Based on pharmacokinetic studies in which irbesartan and amlodipine were taken separately or in combination, there was no pharmacokinetic interaction between irbesartan and amlodipine.

No studies have been conducted on the drug interaction of Aprovask® with other drugs.

Irbesartan

Based on data from in vitro studies, no interaction should be expected with drugs that are metabolized with the participation of isoenzymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.

Irbesartan is primarily metabolized by the CYP2C9 isoenzyme, but no significant pharmacokinetic interaction was observed during clinical interaction studies when irbesartan was administered simultaneously with warfarin, which is metabolized by the CYP2C9 isoenzyme.

The pharmacokinetic parameters of irbesartan do not change when it is co-administered 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 Aprovasc with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or moderate to severe renal insufficiency (GFR).

The use of Aprovasc® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended for other patients.

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

In elderly patients, patients with hypovolemia (due to diuretics) or with impaired renal function, concomitant use of NSAIDs, including selective COX-2 inhibitors together with ARA II, including irbesartan, may lead to deterioration of renal function, including the development of acute renal failure. These effects are usually reversible. Renal function should be monitored periodically in patients taking concomitant ARA II and NSAIDs, including selective COX-2 inhibitors.

An increase in the concentration of lithium in the blood plasma and the toxic effect of lithium were described against the background of the combined use of irbesartan with lithium preparations. Plasma lithium concentrations should be monitored in patients taking irbesartan together with lithium preparations.

Amlodipine

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

Data from in vitro studies with human blood plasma showed that amlodipine does not affect the binding to plasma proteins of digoxin, phenytoin, warfarin or Indometacin.

Concomitant use of amlodipine and cimetidine did not affect the pharmacokinetics of amlodipine.

Concomitant use of 250 mg grapefruit juice with a single dose of 10 mg amlodipine in 20 healthy volunteers did not significantly affect the pharmacokinetics of amlodipine.

When combined with amlodipine and sildenafil, each of the drugs independently showed its own blood pressure-lowering effect.

Simultaneous course use 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 achieving Css.

Concomitant use of amlodipine with digoxin did not alter serum digoxin concentrations or renal digoxin clearance in healthy volunteers.

Simultaneous use of amlodipine and did not change the prothrombin time when taking warfarin.

Pharmacokinetic studies with cyclosporine have shown that amlodipine does not significantly affect the pharmacokinetics of cyclosporine.

Concomitant use of tacrolimus and amlodipine may increase the concentration of tacrolimus in blood plasma. It is necessary to monitor the concentration of tacrolimus in the blood plasma and, if necessary, adjust its dose.

Concomitant use of amlodipine with simvastatin may increase exposure to simvastatin compared to simvastatin therapy. When simvastatin and amlodipine are used concomitantly, the daily dose of simvastatin should be limited to 20 mg.

How to take, course of use and dosage

The drug is taken orally. The tablet is swallowed with water. Aprovasc®can be taken both simultaneously with a meal and on an empty stomach (i. e., regardless of the time of the meal).

Usually, the initial and maintenance dose of Aprovasc® is 1 tab. /day. Aprovasc should be used in patients who are unable to achieve the target blood pressure values with irbesartan or amlodipine monotherapy, or for continuing treatment of patients who are already taking irbesartan and amlodipine as separate tablets. Doses should be selected individually, first using separate irbesartan and amlodipine medications. Doses are selected depending on the response of blood pressure to therapy and the target value of blood pressure. The maximum recommended dose of 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).

As a rule, no dose reduction is required in elderly patients and in patients with impaired renal function.

In patients with hepatic impairment, Aprovasc should be used with caution due to the presence of amlodipine in the drug.

Overdose

Symptoms: when taking irbesartan in doses up to 900 mg/day in adults, no toxicity was found.

Available data for amlodipine suggest that severe overdose may lead to severe peripheral vasodilation and possibly to the development of reflex tachycardia. Severe and prolonged excessive BP reduction, up to fatal shock, has been reported.

Treatment: the patient should be under close medical supervision. Treatment should be symptomatic and supportive of the body’s essential vital functions.

There is no specific information on the treatment of irbesartan overdose. Suggested measures for overdose of Aprovasc include gastric lavage. use of activated charcoal to healthy volunteers immediately after or 2 hours after oral use of 10 mg of amlodipine showed a slight decrease in amlodipine absorption.

Due to the fact that amlodipine is characterized by a high degree of binding to blood proteins, and irbesartan is not eliminated from the body by hemodialysis, it is unlikely that an overdose can be useful hemodialysis.

In case of severe overdose, active monitoring of heart activity and respiration should be initiated. Frequent blood pressure measurement is necessary. A clinically significant reduction in blood pressure due to an overdose of amlodipine requires active maintenance of cardiovascular activity, including giving an elevated position to the limbs. BCC and diuresis should be monitored. Vasoconstrictor medications may be required to restore vascular tone and blood pressure (if there are no contraindications to their use). Intravenous use of calcium gluconate may be useful in eliminating the effects of calcium channel blockage.

Special instructions

Excessive lowering of blood pressure: patients with hypovolemia and hyponatremia

Irbesartan rarely caused an excessive decrease in blood pressure in patients with arterial hypertension without other comorbidities. As with ACE inhibitors, an excessive decrease in blood pressure with appropriate symptoms may be expected in patients with hypovolemia and hyponatremia, which include patients undergoing intensive diuretic therapy, and/or patients with restrictions in the intake of table salt or patients on hemodialysis. Hyponatremia and hypovolemia should be corrected before starting treatment with Aprovasc, or consideration should be given to using the drug at lower initial doses.

Patients with chronic heart failure

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

Liver failure

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

Hypertensive crisis

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

Effects on kidney function

Due to the inhibition of RAAS, changes in renal function can be expected in predisposed patients. In patients whose renal function depends on the activity of the RAAS (patients with arterial hypertension with renal artery stenosis of one or both kidneys or patients with chronic heart failure of functional class III-IV [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 with the use of ARA II, including irbesartan.

Double blockade of the RAAS in combination with Aprovasc® with drugs containing aliskiren and an ACE inhibitor

Double blockade of the RAAS when using a combination of Aprovasc® with an ACE inhibitor or with aliskiren is not recommended, since there is an increased risk of a sharp decrease in blood pressure, hyperkalemia and impaired renal function.

In patients with diabetes mellitus or moderate to severe renal insufficiency (with GFR

Patients with diabetic nephropathy should not be treated with Aprovasc® in combination with ACE inhibitors.

Use in elderly patients

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

Use in pediatrics

Safety and efficacy in children have not yet been established.

Influence on the ability to drive motor vehicles and manage mechanisms

Effect of Aprovasc® The ability to drive vehicles or engage in other potentially dangerous activities that require increased attention has not been studied. However, based on the pharmacodynamic properties, the effect of Aprovasc® this ability is unlikely. In case of dizziness, vertigo, or weakness, it is not recommended to drive vehicles or engage in other potentially dangerous activities.

Form of production

White film-coated tablets, oval, biconvex, with the inscription “150/5” on one side.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C.

Shelf

life is 3 years.

Active ingredient

Amlodipine, Irbesartan

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Hypertension