Aprovasc^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Pasteur, S.A. de C.V. (Mexico)

Manufactured By

Sanofi-Aventis de Mexico, S.A. de C.V. (Mexico)

Packaging and Quality Control Release

SANOFI-AVENTIS de Mexico, S.A. de C.V. (Mexico)

Or

ORTAT, JSC (Russia)

Contact Information

SANOFI

ATC Code

C09DB05 (Irbesartan and amlodipine)

Active Substances

Irbesartan (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Dosage Forms

	Aprovasc®	Film-coated tablets, 5 mg+150 mg: 14, 28 or 56 pcs.
		Film-coated tablets, 5 mg+300 mg: 14, 28 or 56 pcs.
		Film-coated tablets, 10 mg+150 mg: 14, 28 or 56 pcs.
		Film-coated tablets, 10 mg+300 mg: 14, 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oval, biconvex, engraved with “150/5” on one side.

Excipients: microcrystalline cellulose 50 µm, croscarmellose sodium, hypromellose 6 mPa.s, microcrystalline cellulose 100 µm, colloidal silicon dioxide, magnesium stearate.

Coating composition: Opadry white*.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Film-coated tablets pink, oval, biconvex, engraved with “150/10” on one side.

Excipients: microcrystalline cellulose 50 µm, croscarmellose sodium, hypromellose 6 mPa.s, microcrystalline cellulose 100 µm, colloidal silicon dioxide, magnesium stearate.

Coating composition: Opadry pink**.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Film-coated tablets yellow, oval, biconvex, engraved with “300/5” on one side.

Excipients: microcrystalline cellulose 50 µm, croscarmellose sodium, hypromellose 6 mPa.s, microcrystalline cellulose 100 µm, colloidal silicon dioxide, magnesium stearate.

Coating composition: Opadry yellow***.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Film-coated tablets white, oval, biconvex, with a score and bevel to the score on one side.

Excipients: microcrystalline cellulose 50 µm, croscarmellose sodium, hypromellose 6 mPa.s, microcrystalline cellulose 100 µm, colloidal silicon dioxide, magnesium stearate.

Coating composition: Opadry white*.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

* Opadry white contains hypromellose, titanium dioxide (E171), macrogol-400.
** Opadry pink contains hypromellose, titanium dioxide (E171), macrogol-400, macrogol-8000, iron oxide red dye (E172).
*** Opadry yellow contains hypromellose, titanium dioxide (E171), macrogol-400, macrogol-8000, iron oxide yellow dye (E172).

Clinical-Pharmacological Group

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

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists, combinations; angiotensin II receptor antagonists and calcium channel blockers

Pharmacological Action

The pharmacodynamic properties of each of the active substances included in the drug Aprovasc^®, amlodipine and irbesartan, contribute to their additive antihypertensive effect when used in combination compared to the use of each of these drugs separately.

Both angiotensin II receptor antagonists (ARAs) and slow calcium channel blockers (CCBs) reduce blood pressure by reducing peripheral vascular resistance; however, blocking calcium entry into the cell and reducing the vasoconstrictive action mediated by angiotensin II are complementary mechanisms.

Amlodipine

Amlodipine is a slow calcium channel blocker from the dihydropyridine derivative group that inhibits the transmembrane transport of calcium ions into myocardial cells and vascular smooth muscle.

The mechanism of the antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle.

Amlodipine dilates peripheral arterioles and thereby reduces total peripheral vascular resistance, the so-called afterload.

Since the heart rate practically does not increase when taking amlodipine, this reduction in the load on the heart muscle reduces myocardial energy expenditure and its oxygen demand.

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure in the supine and standing positions over 24 hours.

Due to its slow onset of action, amlodipine is not intended for the relief of hypertensive crises.

In patients with angina pectoris, a single daily dose of amlodipine during exercise testing increases total exercise time, time to onset of angina, and time to 1 mm ST-segment depression on ECG.

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

No undesirable metabolic effects or changes in blood lipid concentrations were observed when taking amlodipine.

Amlodipine can be prescribed to patients with bronchial asthma, diabetes mellitus, and gout.

Clinical study data

Use of amlodipine in patients with arterial hypertension

A randomized double-blind morbidity and mortality trial “Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial” (ALLHAT) was conducted to compare new drug therapies: amlodipine at a dose of 2.5-10 mg/day (calcium channel blocker) or lisinopril at a dose of 10-40 mg/day (ACE inhibitor) for mild to moderate arterial hypertension as first-line therapy compared with the thiazide diuretic chlorthalidone at a dose of 12.5-25 mg/day.

A total of 33,357 patients with arterial hypertension aged 55 years and older were randomized to treatment groups and followed for an average of 4.9 years.

The primary endpoint was a combination of fatal coronary heart disease or nonfatal myocardial infarction.

The primary endpoints for amlodipine therapy and chlorthalidone therapy did not differ.

Among the secondary endpoints, the incidence of heart failure was statistically significantly higher in the amlodipine group compared to the chlorthalidone group.

However, no statistically significant difference was found in all-cause mortality rates between the amlodipine and chlorthalidone treatment groups.

Use of amlodipine in patients with heart failure

In hemodynamic studies and controlled clinical trials that assessed exercise capacity in patients with heart failure of functional class (FC) II-IV according to the NYHA classification, the use of amlodipine did not lead to clinically significant deterioration in exercise tolerance, left ventricular ejection fraction, and clinical manifestations.

The results of a placebo-controlled study, the design of which involved assessing the condition of patients with heart failure FC III-IV according to the NYHA classification receiving digoxin, diuretics and ACE inhibitors, showed that the use of amlodipine did not lead to an increased risk of death or the overall rate of mortality and morbidity in heart failure.

In an observational long-term placebo-controlled study (PRA1SE-2) of amlodipine in patients with heart failure FC III and IV according to the NYHA classification without clinical manifestations or objective pathology indicating the presence of coronary artery disease, which used constant doses of ACE inhibitors, digoxin and diuretics, the use of amlodipine had no effect on the overall mortality rate due to cardiovascular diseases.

In the same population, it was noted that the use of amlodipine was associated with an increased number of reports of pulmonary edema development.

Use of amlodipine in children

In a study involving 268 children aged 6 to 17 years with predominantly secondary arterial hypertension, the results of comparing the use of 2.5 mg and 5 mg of amlodipine and placebo showed that both doses of the drug reduced systolic blood pressure statistically significantly more than placebo.

The difference between these two doses was not statistically significant.

The long-term effect of amlodipine on growth, puberty and overall development has not been studied.

The long-term efficacy of amlodipine in reducing cardiovascular morbidity in children and mortality in adulthood has also not been established.

Irbesartan

Irbesartan is a selective, potent ARA II (subtype AT₁).

Angiotensin II is an important component of the RAAS involved in the pathophysiology of arterial hypertension and in sodium ion homeostasis.

The action of irbesartan does not require metabolic activation.

Irbesartan blocks the strong vasoconstrictive and aldosterone-secreting actions of angiotensin II through selective antagonism to angiotensin II receptors (subtype AT₁) located in vascular smooth muscle cells and the adrenal cortex.

Irbesartan has no agonistic activity towards AT₁ receptors.

Its affinity for AT₁ receptors is 8500 times greater than for AT₂ receptors (receptors for which no connection with the maintenance of cardiovascular system homeostasis has been shown).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE), nor does it affect other hormonal receptors or ion channels in the cardiovascular system involved in the regulation of blood pressure and sodium ion homeostasis.

Blockade of AT₁ receptors by irbesartan interrupts the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II.

When irbesartan is used, the plasma concentration of aldosterone decreases; however, when the drug is used in recommended doses, no significant changes in serum potassium levels occur (the average increase in serum potassium is less than 0.1 mEq/L).

Irbesartan does not have a significant effect on serum triglyceride, cholesterol, or glucose concentrations.

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

The antihypertensive effect of irbesartan is noted after the first dose with significant development of the therapeutic effect 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 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 reduction in systolic (SBP)/diastolic (DBP) blood pressure (24 hours after dose) in the supine or sitting position (on average by 8-13/5-8 mm Hg) than with placebo.

The effect of the drug 24 hours after administration was 60-70% of the corresponding maximum reduction in DBP and SBP.

Optimal efficacy in reducing blood pressure over 24 hours is achieved with a single daily dose of the drug.

Blood pressure decreases approximately equally in the standing and lying positions.

Orthostatic effect occurs rarely, 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 target blood pressure values with irbesartan monotherapy, adding small doses of hydrochlorothiazide (12.5 mg) to once-daily irbesartan leads to an additional (compared to the effect of adding placebo) reduction in SBP/DBP, determined 24 hours after their intake, by 7-10/3-6 mm Hg, respectively.

Age and sex do not affect the efficacy of irbesartan.

As with treatment with other drugs affecting the RAAS, a weaker antihypertensive effect is observed in Black patients with irbesartan monotherapy.

When Irbesartan is taken with small doses of hydrochlorothiazide (e.g., 12.5 mg/day), the antihypertensive effect in Black patients approaches that in Caucasian patients.

After discontinuation of irbesartan, blood pressure gradually returns to baseline.

No “withdrawal” syndrome was observed upon discontinuation of irbesartan.

Clinical evidence of the efficacy of the fixed-dose combination of irbesartan and amlodipine was obtained in two multicenter, prospective, open-label, parallel-group studies with blinded efficacy assessment: 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.

Pharmacokinetics

Absorption

Amlodipine and Irbesartan

Simultaneous administration of amlodipine and irbesartan in the form of a fixed-dose tablet or free combination of drugs does not affect the bioavailability of the individual components.

Three fixed-dose combinations of amlodipine and irbesartan (10 mg + 150 mg, 5 mg + 300 mg and 10 mg + 300 mg) are bioequivalent to free-dose combinations in terms of both rate and extent of absorption.

When used separately or simultaneously in doses of 10 mg and 300 mg, the median time to C_max of amlodipine and irbesartan in plasma remains unchanged, i.e., 5 h and from 0.75 to 1 h after administration, respectively.

Similarly, C_max and AUC are in the same range, contributing to a relative bioavailability of 98% for amlodipine and 95% for irbesartan when used concomitantly.

Amlodipine

After oral administration in therapeutic doses, amlodipine is well absorbed, C_max in plasma is reached 6-12 hours after administration.

Absolute bioavailability is 64-80%.

The bioavailability of amlodipine is not affected by food intake.

Irbesartan

Irbesartan is an oral drug; its activity does not require biotransformation.

After oral administration, Irbesartan is rapidly and completely absorbed.

C_max in plasma is reached 1.5-2 hours after oral administration.

The absolute bioavailability of irbesartan is 60-80%.

Food intake does not affect the bioavailability of irbesartan.

Distribution

Amlodipine

The V_d of amlodipine is approximately 21 L/kg.

In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Irbesartan

Approximately 96% of irbesartan is bound to plasma proteins; the level of binding of irbesartan to blood cellular components is insignificant.

V_d is 53-93 L/kg.

Metabolism

Amlodipine

Amlodipine is extensively converted to inactive metabolites by metabolism in the liver, with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Irbesartan

In plasma, unchanged Irbesartan accounts for 80-85% of the circulating radioactivity after oral or intravenous administration of ¹⁴C-labeled irbesartan.

Irbesartan is metabolized in the liver by oxidation and conjugation with glucuronic acid.

The main circulating metabolite in plasma is irbesartan glucuronide (approximately 6%).

Irbesartan undergoes oxidation primarily under the action of the cytochrome P450 isoenzyme CYP2C9; the isoenzyme CYP3A4 has a minor effect on it.

It is not metabolized, nor does it significantly induce or inhibit most of the isoenzymes commonly associated with drug metabolism (e.g., CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1).

Irbesartan does not induce or inhibit the CYP3A4 isoenzyme.

Excretion

Amlodipine and Irbesartan

The mean T_1/2 values for amlodipine and irbesartan, taken separately or in combination, are similar: 58.5 h compared to 52.1 h for amlodipine and 17.6 h compared to 17.7 h for irbesartan.

The excretion of amlodipine and irbesartan remains unchanged when used separately and in combination.

The pharmacokinetics of both drugs are linear over the range of simultaneously administered doses (i.e., between 5 and 10 mg for amlodipine and between 150 and 300 mg for irbesartan).

Amlodipine

The terminal T_1/2 of amlodipine is approximately 35-50 hours and is consistent with daily dosing.

Irbesartan

The terminal T_1/2 of irbesartan is 11-15 hours.

The total clearance of irbesartan after intravenous administration is 157-176 ml/min, of which 3.0-3.5 ml/min is renal clearance.

Irbesartan exhibits linear pharmacokinetics over the entire therapeutic dose range.

Steady-state plasma concentration is achieved within three days of starting once-daily administration.

Limited accumulation (<20%) is observed in plasma upon repeated single daily administration.

Irbesartan and its metabolites are excreted by both the liver (with bile) and the kidneys.

After oral administration or after intravenous administration of ¹⁴C irbesartan, about 20% of the radioactivity is found 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.

Pharmacokinetics in Special Patient Groups

Race

Irbesartan. When used in Caucasians and Blacks with normal blood pressure, the plasma AUC and T_1/2 of irbesartan were 20-25% higher in Blacks than in Caucasians; the C_max of irbesartan in blood plasma was practically equivalent.

Gender

Irbesartan. Among men and women with arterial hypertension, women have a higher (11-44%) plasma concentration of irbesartan than men, although after multiple doses there are no differences in accumulation periods and half-life between men and women. Clinical efficacy did not differ by gender.

Elderly Patients

Amlodipine. The time to reach C_max of amlodipine in plasma is the same in elderly patients and younger patients. The clearance of amlodipine tends to decrease with a subsequent increase in AUC and T_1/2 in elderly patients. The increase in AUC and T_1/2 in patients with congestive heart failure corresponded to that expected for the studied age group of patients.

Irbesartan. In elderly patients (male and female) with normal blood pressure (65-80 years), corresponding to the clinical norm of renal and hepatic function, the AUC and C_max of irbesartan in plasma are approximately 20-50% higher than in younger patients (18-40 years). T_1/2 does not differ by age. No significant differences in clinical effect related to patient age were observed.

Children

Amlodipine and Irbesartan. Information for fixed-dose combinations is not available.

Amlodipine. A population pharmacokinetic study was conducted involving 74 children with arterial hypertension aged from 12 months to 17 years (of which 34 patients were aged 6-12 years and 28 patients were 13-17 years), who received amlodipine at a dose of 1.25-20 mg once or twice daily.

In children 6-12 years and adolescents 13-17 years, the typical oral clearance (CL/F) was 22.5 and 27.4 L/h respectively in male patients and 16.4 and 21.3 L/h respectively in female patients. There was large variability in exposure between individual patients. Data for children under 6 years of age are limited.

Irbesartan. Safety and efficacy of use in children have not been established.

Hepatic Impairment

Amlodipine. There is insufficient clinical data on the use of amlodipine in patients with hepatic impairment. In patients with hepatic insufficiency, a decrease in amlodipine clearance is observed, leading to a longer T_1/2 and an increase in AUC of approximately 40-60%.

Irbesartan. In patients with mild to moderate hepatic insufficiency (due to liver cirrhosis), the pharmacokinetics of irbesartan do not change significantly.

Renal Impairment

Irbesartan. In patients with impaired renal function (regardless of degree) and in patients on hemodialysis, the pharmacokinetics of irbesartan do not change significantly. Irbesartan is not removed by hemodialysis.

Indications

• Arterial hypertension (when monotherapy with irbesartan or amlodipine is ineffective).

ICD codes

Dosage Regimen

The drug is taken orally, with water, regardless of meals.

The initial and maintenance dose of the drug Aprovasc^® is 1 tablet/day.

Aprovasc^® should be used in patients in whom target blood pressure values are not achieved with irbesartan monotherapy or amlodipine monotherapy, or to continue treatment of patients already taking Irbesartan and amlodipine as separate tablets. In the latter case, doses should be selected individually.

The maximum recommended dose of the drug Aprovasc^® is 10 mg + 150 mg or 10 mg + 300 mg per day (since the maximum daily dose of amlodipine is 10 mg).

If a change in the dose of one of the active substances in the drug is required (for example, due to a newly diagnosed disease, change in the patient’s condition, or drug interaction), an individual selection of doses of the individual components is necessary.

Use of the drug in pediatric patients is contraindicated; the safety and efficacy of the drug Aprovasc^® have not been established.

In elderly patients and patients with impaired renal function, dose adjustment is not required.

In patients with impaired hepatic function, Aprovasc^® should be used with caution due to the presence of amlodipine in the drug.

In elderly patients with impaired hepatic function, it is necessary to reduce the initial dose of the drug Aprovasc^® to the one containing the lowest dose of amlodipine (1 tablet 5 mg + 150 mg or 5 mg + 300 mg).

Adverse Reactions

The frequency of adverse reactions was determined in accordance with the WHO classification: very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10000 and <1/1000); very rare (<1/10000), frequency unknown (cannot be calculated from the available data).

Below are the adverse reactions reported in clinical studies on the use of fixed-dose combinations of irbesartan and amlodipine (I-ADD, I-COMBINE and I-COMBO clinical studies), in clinical studies on the use of irbesartan and amlodipine monotherapy and their post-registration use (Table 1).

The frequency of adverse reactions reported during post-registration use of the drug was determined as “frequency unknown”, because information about these adverse reactions came from spontaneous reports, without specifying the number of patients taking the drug.

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

Table 1

Contraindications

• Hypersensitivity to irbesartan, amlodipine and other dihydropyridine derivatives, as well as to the excipients of the drug;
• Shock (including cardiogenic shock);
• Obstruction of the left ventricular outflow tract (including severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Severe arterial hypotension (systolic blood pressure less than 90 mm Hg);
• Severe hepatic insufficiency (functional class C or more than 9 points on the Child-Pugh scale);
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Concomitant use with drugs containing aliskiren in patients with diabetes mellitus and/or with moderate and severe renal failure (GFR <60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy.

With caution

• In hypovolemia and hyponatremia, occurring, for example, during intensive diuretic therapy, hemodialysis, adherence to a salt-restricted diet, diarrhea, vomiting;
• In patients with renal function dependent on the activity of the RAAS (such as patients with arterial hypertension with bilateral or unilateral renal artery stenosis, patients with chronic heart failure class III-IV [according to NYHA classification]), treatment with drugs affecting the RAAS; is 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 even when taking angiotensin II receptor antagonists, including Irbesartan);
• In patients with chronic heart failure of non-ischemic etiology class II-IV according to the NYHA classification (due to the presence of amlodipine in the drug, the use of which in such patients is associated with an increase in reports of pulmonary edema development compared with placebo, despite the absence of differences in the frequency of heart failure progression);
• In patients with hepatic insufficiency (risk of increased T_1/2 of amlodipine);
• In patients with renal insufficiency (due to the presence of irbesartan in the drug, monitoring of potassium levels and serum creatinine concentration is recommended), after recent kidney transplantation (no clinical experience with irbesartan);
• In patients with aortic and mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM);
• In patients with coronary artery disease and/or clinically significant cerebral atherosclerosis (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 acute myocardial infarction (and within 1 month after it);
• In patients with sick sinus syndrome (due to the presence of amlodipine in the drug);
• In patients with psoriasis (including history) due to the possible exacerbation of psoriasis;
• With simultaneous use with inhibitors or inducers of the CYP3A4 isoenzyme;
• With simultaneous use of NSAIDs, including COX-2 inhibitors (increased risk of renal function impairment, including the possibility of acute renal failure and increased serum potassium, especially in elderly patients, patients with hypovolemia (including patients taking diuretics) or patients with impaired renal function;
• When used in combination with ACE inhibitors or aliskiren, as compared with monotherapy, dual blockade of the RAAS is associated with an increased risk of excessive blood pressure reduction, hyperkalemia, and impaired renal function.

Use in Pregnancy and Lactation

Use of the drug Aprovasc^® is contraindicated during pregnancy and breastfeeding.

Appropriate strictly controlled studies on the use of the drug in pregnant women have not been conducted. The drug Aprovasc^® should not be used in women of childbearing potential who are not using effective methods of contraception. If pregnancy is detected, the drug Aprovasc^® should be discontinued as soon as possible.

Pregnancy

Amlodipine

The safety of amlodipine during pregnancy has not been established. In preclinical animal studies, signs of reproductive toxicity were observed at high doses of amlodipine.

Irbesartan

There are no sufficient and well-controlled studies of irbesartan use in pregnant women. Fetal exposure to ACE inhibitors, taken by pregnant women during the second and third trimesters, led to damage and death of the developing fetus. Like any other drugs that directly affect the RAAS, Irbesartan is contraindicated during pregnancy.

Breastfeeding period

Amlodipine

It passes into breast milk in an amount of 3-7% of the maternal dose (up to 15% maximum). The effect of amlodipine on newborns is unknown. When treating nursing women, preference should be given to alternative drugs with a better-studied safety profile during breastfeeding, especially when feeding a newborn or premature infant. A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the need for its use for the mother.

Irbesartan

It is excreted in the milk of lactating rats. It is not known whether Irbesartan/its metabolites can be excreted in human breast milk. During breastfeeding, irbesartan is contraindicated. After assessing the ratio of the intended benefit of the drug for the mother and the potential risk to the child, either breastfeeding or irbesartan should be discontinued.

Fertility

Amlodipine

Clinical data on the potential effect of amlodipine on fertility are insufficient. In one study in rats, adverse events on male fertility were found.

When using CCBs, biochemical changes in the sperm head were observed in some patients. The volume of clinical data on the potential effect of amlodipine on fertility is insufficient.

Irbesartan

In studies in male and female rats, Irbesartan did not affect fertility and reproductive function even at doses that had some toxic effects on the parents (up to 650 mg/kg/day). No significant effect on the number of corpora lutea, implanted embryos, or live fetuses was observed. Irbesartan did not affect the survival, development, or reproduction of offspring.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency (class C or more than 9 points on the Child-Pugh scale).

The drug should be prescribed with caution to patients with hepatic insufficiency (risk of increased amlodipine T_1/2).

Use in Renal Impairment

In patients with impaired renal function, dose adjustment is not required.

The drug should be prescribed with caution to patients with renal insufficiency (due to the presence of irbesartan in the drug, monitoring of potassium and serum creatinine levels is recommended), after recent kidney transplantation (lack of clinical experience with irbesartan).

Pediatric Use

Use of the drug is contraindicated under the age of 18 years.

Geriatric Use

In elderly patients, dose adjustment is not required.

Special Precautions

Amlodipine

Patients with chronic heart failure

In a long-term placebo-controlled study (PRAISE-2) of amlodipine in patients with chronic heart failure of NYHA class III-IV of non-ischemic etiology, an increased incidence of pulmonary edema was noted, despite the absence of a significant difference in the frequency of heart failure progression compared with placebo. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular complications and mortality.

Hepatic insufficiency

As with other slow calcium channel blockers, in patients with impaired liver function, the T_1/2 and AUC of amlodipine increase; recommendations for its dosing regimen in case of impaired liver function are not defined. It is recommended to start treatment with the minimum doses of amlodipine, which should be taken with caution both at the beginning of treatment and when increasing the dose in such patients. Patients with severe liver dysfunction may require slow dose titration and careful monitoring.

Elderly patients

In elderly patients, the dose should be increased with caution.

Patients with impaired renal function

In patients with impaired renal function, amlodipine can be used in standard doses. Changes in plasma amlodipine concentration are not associated with the degree of renal impairment. Amlodipine is not removed by dialysis.

Hypertensive crisis

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

Withdrawal syndrome

Although CCBs do not have a withdrawal syndrome, it is desirable to discontinue amlodipine treatment by gradually reducing the dose of the drug.

Peripheral edema

Mild or moderate peripheral edema was the most common adverse event of amlodipine in clinical studies. The incidence of peripheral edema increases with increasing dose (when using amlodipine at doses of 2.5, 5, 10 mg/day, edema occurred in 1.8%, 3% and 10.8% of patients, respectively). Peripheral edema associated with the use of amlodipine should be carefully differentiated from the symptoms of progressive left ventricular heart failure.

Other

Dental hygiene and dental supervision should be maintained (to prevent soreness, bleeding and gingival hyperplasia).

Irbesartan

Excessive BP reduction in patients with hypovolemia and hyponatremia

Irbesartan rarely caused excessive BP reduction in patients with hypertension without other concomitant pathology. As with the use of ACE inhibitors, excessive BP reduction with corresponding symptoms can be expected in patients with hypovolemia/hyponatremia (for example, as a result of intensive diuretic therapy, diarrhea, vomiting, a salt-restricted diet), as well as in patients on hemodialysis. Hyponatremia and/or hypovolemia should be corrected before starting treatment with Aprovasc^®, or the use of lower initial doses should be considered.

Hypoglycemia

The use of irbesartan may lead to the development of hypoglycemia, especially in patients with hypertension receiving drugs for the treatment of diabetes mellitus. Therefore, dose adjustment of drugs for the treatment of diabetes mellitus, such as repaglinide or insulin, may be required.

Fetal/neonatal morbidity and mortality

Although there is no experience with the use of irbesartan in pregnant women, it has been reported that in utero exposure to ACE inhibitors, when taken by pregnant women in the second and third trimesters, can lead to impaired development and fetal death. The drug Aprovasc^® is contraindicated for use during pregnancy, like any other drug that has a direct effect on the RAAS. If pregnancy is detected during treatment, the use of the drug Aprovasc^® should be discontinued as soon as possible (see sections “Contraindications”, “Pregnancy and Lactation”).

Effect on renal function

Due to the inhibition of the RAAS, changes in renal function can be expected in predisposed patients. In patients with renal function dependent on RAAS activity (patients with hypertension with bilateral or unilateral renal artery stenosis or patients with chronic heart failure NYHA class III-IV), treatment with other drugs that affect the RAAS has been associated with the development of oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. The possibility of such an effect when using ARBs II, including Irbesartan, cannot be excluded.

Kidney transplantation

There are no clinical data on the use of the drug Aprovasc^® in patients who have recently undergone kidney transplantation.

Hyperkalemia

As with the use of other drugs that affect the RAAS, hyperkalemia may develop during treatment with the drug Aprovasc^®, especially in the presence of renal insufficiency and/or heart disease. In such patients, it is recommended to monitor serum potassium levels.

Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy

As with the use of other vasodilators, caution should be exercised when taking the drug Aprovasc^® in patients with aortic or mitral stenosis or with hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting through inhibition of the RAAS, so the use of the drug Aprovasc^® in such cases is not advisable.

Patients with coronary artery disease and/or clinically significant cerebral atherosclerosis

As with the use of other antihypertensive drugs, a significant decrease in blood pressure in patients with coronary artery disease and/or severe cerebral atherosclerosis can lead to the development of myocardial infarction or stroke. Treatment of such patients should be carried out under strict blood pressure control.

Dual blockade of the RAAS with simultaneous use of irbesartan with ACE inhibitors or with aliskiren

Dual blockade of the RAAS with the use of a combination of irbesartan with ACE inhibitors or aliskiren is not recommended, as there is an increased risk of a sharp decrease in blood pressure, hyperkalemia and impaired renal function.

Simultaneous use of ARBs II, including irbesartan, which is part of the drug Aprovasc^®, with drugs containing aliskiren, is contraindicated in patients with diabetes mellitus and/or moderate or severe renal insufficiency (with GFR <60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Simultaneous use of ARBs II, including irbesartan, which is part of the drug Aprovasc^®, with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Psoriasis

In patients with psoriasis (including history), the decision to use the drug should be made only after a careful assessment of the risk/benefit ratio due to the possible exacerbation of psoriasis.

Use in elderly patients (65 years and older)

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

Use in children and adolescents under 18 years of age

Safety and efficacy in children and adolescents under 18 years of age have not been established to date.

Effect on the ability to drive vehicles and mechanisms

Amlodipine . Amlodipine may have a slight or moderate effect on the ability to drive a car or operate machinery. If a patient receiving amlodipine experiences dizziness, headache, weakness, or nausea, their reaction speed may be slowed down. It is recommended to exercise particular caution at the beginning of treatment.

Irbesartan . Studies of the effect of irbesartan on the ability to drive vehicles and operate machinery have not been conducted. According to the pharmacodynamic properties of irbesartan, an effect on this ability is unlikely. When driving vehicles or operating machinery, the possibility of dizziness or a feeling of fatigue during the treatment of arterial hypertension should be taken into account.

Overdose

Symptoms: no toxicity was established when irbesartan was taken by adults at doses up to 900 mg/day.

Available data for amlodipine suggest that severe overdose may lead to marked peripheral vasodilation and possibly the development of reflex tachycardia. Marked and prolonged excessive decrease in blood pressure, up to the development of shock with a fatal outcome, has been reported.

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

There is no specific information on the treatment of irbesartan overdose. Proposed measures for an overdose of the drug Aprovasc^® include gastric lavage. Administration of activated charcoal to healthy volunteers immediately after or 2 hours after oral administration of 10 mg of amlodipine showed a slight reduction in the absorption of amlodipine.

Since amlodipine is characterized by a high degree of binding to blood proteins, and Irbesartan is not removed from the body by hemodialysis, it is unlikely that hemodialysis will be useful in case of overdose.

In case of severe overdose, active monitoring of cardiac activity and respiration should be initiated. Blood pressure should be measured frequently. Clinically significant hypotension due to amlodipine overdose requires active support of cardiovascular activity, including elevation of the limbs. Blood volume and diuresis should be monitored. Administration of vasoconstrictor drugs may be required to restore vascular tone and blood pressure (provided there are no contraindications to their administration). Intravenous administration of calcium gluconate may be useful in eliminating the effects of calcium channel blockade.

Drug Interactions

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 drug interaction studies of the drug Aprovasc^® with other drugs have been conducted.

Amlodipine

Pharmacodynamic interaction

Other antihypertensive and antianginal drugs

Amlodipine can be safely used to treat arterial hypertension together with thiazide diuretics, beta-blockers or ACE inhibitors.

In patients with stable angina, amlodipine can be used in combination with other antianginal agents, for example, long-acting or short-acting nitrates, beta-blockers.

Enhancement of the antianginal and antihypertensive effects of CCBs is possible with simultaneous use with thiazide and “loop” diuretics, ACE inhibitors, beta-blockers and nitrates.

Ethanol, barbiturates, neuroleptics, antidepressants, narcotic analgesics, general anesthetics

Enhancement of the antihypertensive effect of dihydropyridine derivatives and an increased risk of orthostatic hypotension are possible.

Other drugs that can lower blood pressure

Some drugs (for example, baclofen and aminophen) can be expected to enhance the antihypertensive effect of amlodipine due to their pharmacological properties. Blood pressure and renal function should be monitored, and the dose of amlodipine should be adjusted if necessary.

Corticosteroids (mineralo- and glucocorticoids), tetracosactide

Reduction of the antihypertensive effect of amlodipine (due to fluid and sodium ion retention as a result of the action of corticosteroids).

Calcium preparations may reduce the effect of CCBs.

Dantrolene (with intravenous administration)

In animal studies, after administration of verapamil and dantrolene (IV), cases of fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia were observed. Given the risk of hyperkalemia, simultaneous use of CCBs (including amlodipine) and dantrolene should be avoided in patients with malignant hyperthermia or prone to its development.

Pharmacokinetic interaction

Effect of other drugs on the pharmacokinetics of amlodipine

Inhibitors of the CYP3A4 isoenzyme. Simultaneous use of amlodipine with potent or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors [ritonavir], azole antifungals [ketoconazole, itraconazole], macrolides [erythromycin, clarithromycin], verapamil or diltiazem) may increase the plasma concentration of amlodipine and increase the risk of hypotension. Amlodipine should be used with caution simultaneously with inhibitors of the CYP3A4 isoenzyme (especially in elderly patients), careful medical supervision is recommended and, if necessary, dose adjustment.

Inducers of the CYP3A4 isoenzyme. When used simultaneously with inducers of the CYP3A4 isoenzyme, the concentration of amlodipine may vary. Blood pressure should be monitored, and the possibility of adjusting the dose of amlodipine during and after simultaneous administration, especially with potent inducers of the CYP3A4 isoenzyme (for example, rifampicin and preparations of St. John’s wort), should be considered.

Grapefruit/grapefruit juice . The use of amlodipine together with grapefruit or grapefruit juice is not recommended, as an increase in the bioavailability of amlodipine and, consequently, an enhancement of its antihypertensive effect is possible in some patients.

Aluminum- or magnesium-containing antacids . With a single simultaneous administration, they do not have a significant effect on the pharmacokinetics of amlodipine.

Sildenafil . When used simultaneously, amlodipine and sildenafil independently showed their antihypertensive effect.

Cimetidine . Cimetidine does not affect the pharmacokinetics of amlodipine.

Effect of amlodipine on the pharmacokinetics of other drugs

Simvastatin . Simultaneous multiple administration of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in simvastatin exposure by 77%. In such cases, the simvastatin dose should be limited to 20 mg.

Atorvastatin. Concurrent multiple administration of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetic parameters AUC (increase by an average of 18%), C_max and T_max of atorvastatin.

Cyclosporine. Studies on the concurrent use of amlodipine and cyclosporine in healthy volunteers and all patient groups have not been conducted, except for patients after kidney transplantation, in whom a variable increase in cyclosporine concentration (on average from 0 to 40%) was observed. These data should be taken into account and cyclosporine concentration should be monitored in this group of patients during concurrent use of cyclosporine and amlodipine, and the dose of cyclosporine should be reduced if necessary.

Tacrolimus. When used concurrently with amlodipine, there is a risk of increased plasma concentration of tacrolimus. To avoid tacrolimus toxicity during concurrent use with amlodipine, plasma tacrolimus concentration should be monitored and its dose adjusted if necessary.

mTOR inhibitors (mammalian Target of Rapamycin). mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) are substrates of the CYP3A4 isoenzyme. Since amlodipine is a weak inhibitor of the CYP3A4 isoenzyme, concurrent use may increase the exposure of mTOR inhibitors.

Ethanol. Amlodipine, when administered as a single dose or repeatedly at a dose of 10 mg, does not affect the pharmacokinetics of ethanol.

Digoxin. Amlodipine does not affect the serum concentration of digoxin or its renal clearance in healthy volunteers. In in vitro studies, amlodipine did not affect the binding of digoxin to plasma proteins.

Warfarin. Amlodipine does not have a significant effect on the action of warfarin (prothrombin time). In in vitro studies, amlodipine did not affect the binding of warfarin to plasma proteins.

Phenytoin. In in vitro studies, amlodipine did not affect the binding of phenytoin to plasma proteins.

Other interactions

Amlodipine can be safely used concurrently with antibiotics and oral hypoglycemic agents.

Unlike other CCBs, no clinically significant interaction of amlodipine with NSAIDs, including indomethacin, has been detected. In in vitro studies, amlodipine did not affect the binding of indomethacin to plasma proteins.

Although a negative inotropic effect is usually not observed with amlodipine studies, some CCBs may enhance the negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (e.g., amiodarone and quinidine).

Irbesartan

Based on in vitro data, no interactions are expected to occur with drugs whose metabolism is mediated by the following cytochrome P450 isoenzymes: 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 concurrently with warfarin, which is metabolized by the CYP2C9 isoenzyme, no significant pharmacokinetic interaction was observed. The pharmacokinetic parameters of irbesartan are not impaired when used concurrently 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).

Medicinal products containing aliskiren

Concurrent use of ARBs, including irbesartan contained in the drug Aprovasc^®, with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (with GFR <60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

ACE inhibitors

Concurrent use of ARBs, including irbesartan contained in the drug Aprovasc^®, with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Repaglinide

Irbesartan may inhibit the OATP1B1 transporter. During a clinical study, it was reported that administration of irbesartan 1 hour before repaglinide increased the C_max and AUC of repaglinide (an OATP1B1 substrate) by 1.8 and 1.3 times, respectively. In another study, no significant pharmacokinetic interaction was reported with concurrent use of irbesartan and repaglinide. Therefore, a dose adjustment of repaglinide for the treatment of diabetes mellitus may be required.

Potassium preparations and potassium-sparing diuretics, heparin

Based on experience with other drugs affecting the RAAS, concurrent use of irbesartan with potassium preparations; salt substitutes containing potassium; potassium-sparing diuretics or other drugs that can increase plasma potassium levels (heparin) may lead to an increase in plasma potassium levels (sometimes severe), which requires careful monitoring of plasma potassium levels in patients during treatment.

NSAIDs, including selective COX-2 inhibitors

In elderly patients, patients with hypovolemia (due to diuretic use) or with impaired renal function, concurrent use of NSAIDs, including selective COX-2 inhibitors, with ARBs, 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 concurrently taking ARBs and NSAIDs, including selective COX-2 inhibitors. The antihypertensive effect of ARBs, including Irbesartan, may be attenuated by the use of NSAIDs, including selective COX-2 inhibitors.

Lithium preparations

Increased serum lithium concentrations and enhanced lithium toxicity have been reported with concurrent use with irbesartan. In patients taking Irbesartan concurrently with lithium preparations, plasma lithium concentrations should be monitored.

Diuretics and other antihypertensive agents

Enhancement of the antihypertensive effect is possible. Irbesartan can be used with other antihypertensive agents, such as beta-blockers, long-acting CCBs, and thiazide diuretics.

Prior treatment with high doses of diuretics may lead to hypovolemia and increase the risk of excessive blood pressure reduction at the beginning of treatment with irbesartan.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years. Do not use the drug after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.