Aprovask, 5 mg+150 mg 28 pcs.

A combined antihypertensive drug. The pharmacodynamic properties of each of the active ingredients in Aprovask®, irbesartan and amlodipine contribute to their additive antihypertensive effect when used in combination compared to when each drug is used alone. Both angiotensin II receptor antagonists (ARA II) and slow calcium channel blockers decrease BP by reducing peripheral vascular resistance, and the blockade of calcium entry into the cell and the reduction of angiotensin II-induced vasoconstrictor action are complementary mechanisms.

Irbesartan

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

Irbesartan blocks the strong vasoconstrictor and aldosterone-secreting actions of angiotensin II through selective antagonism to angiotensin II receptors (subtype-AT1) located in vascular smooth muscle cells and adrenal cortex. Irbesartan has no agonist activity for AT1 receptors. Its affinity for AT1 receptors is 8,500 times greater than that for AT2 receptors (receptors that have not been shown to be associated with cardiovascular equilibrium [homeostasis] maintenance).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE) and does not affect other hormone receptors or ion channels in the cardiovascular system involved in the regulation of BP and sodium ion homeostasis. Blockade of AT1 receptors by irbesartan breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II. Irbesartan decreases plasma concentrations of aldosterone, but there are no significant changes in serum potassium when using the drug at the recommended doses (average increase in serum potassium is less than 0.1 mEq/L). Irbesartan has no significant effect on serum triglyceride, cholesterol or glucose concentrations. Irbesartan has no effect on serum concentrations of uric acid or renal excretion of uric acid.

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

Single administration of irbesartan in doses up to 900 mg/day caused a dose-dependent decrease in BP. A single dose of irbesartan 150-300 mg/day resulted in greater systolic (SBP)/diastolic (BP) decrease (24 hours after the dose) in the supine or sitting position (on average 8-13/5-8 mmHg) than placebo. The drug effect 24 h after the dose was 60-70% of the corresponding maximum reduction of BP and BP. Optimal efficacy with respect to 24-hour BP reduction is achieved with a single daily dose of the drug.

The BP decreases approximately equally in standing and lying position. Orthostatic effect is rare, and as with ACE inhibitors, its occurrence may be expected in patients with hyponatremia or hypovolemia.

The antihypertensive effects of irbesartan and thiazide diuretics are additive. In patients who do not achieve target BP values with irbesartan monotherapy, adding small doses of hydrochlorothiazide (12.5 mg) once daily to irbesartan causes an additional (compared to the effect of adding placebo) 7-10/3-6 mm Hg decrease in BP/DP, 24 hours after administration, respectively.

Age and gender have no effect on the efficacy of irbesartan. As with treatment with other drugs that affect the RAAS, a weaker antihypertensive effect is observed in non-Hispanic patients on irbesartan monotherapy. When irbesartan is taken with low-dose hydrochlorothiazide (e.g., 12.5 mg/day), the antihypertensive effect in non-Hispanic patients is similar to that in Caucasian patients.

After discontinuation of irbesartan, BP gradually returns to baseline. No withdrawal syndrome has been observed with discontinuation of irbesartan.

Amlodipine

Amlodipine is a slow calcium channel blocker from the group of dihydropyridine derivatives, which inhibits transmembrane entry of calcium ions into myocardial and vascular smooth muscle cells. The mechanism of antihypertensive action of amlodipine is associated with direct relaxant action 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 following two effects.

1) Amlodipine dilates the peripheral arterioles and thereby reduces ROS, the so-called afterload. Because heart rate does not increase significantly when taking amlodipine, this decrease in cardiac output reduces myocardial energy expenditure and myocardial oxygen demand.

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

In patients with arterial hypertension, administration of amlodipine once daily provides clinically significant reduction of BP in lying and standing position for 24 hours. Because of its slow onset of action, amlodipine is not indicated for the management of hypertensive crises.

In patients with angina pectoris, once daily administration of amlodipine during exercise testing increases total time to exercise, time to onset of angina attack and time to ST-segment depression of 1 mm on ECG. In addition, taking the drug reduces the daily number of angina attacks and the daily requirement for taking nitroglycerin tablets.

There have been no adverse metabolic effects or changes in blood lipid concentrations when taking amlodipine. Amlodipine can be administered to patients with bronchial asthma, diabetes mellitus and gout.

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

Indications

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

Active ingredient

Composition

1 tablet amlodipine besylate 7 mg, corresponding to amlodipine 5 mg, irbesartan 150 mg

Excipients:

Microcrystalline cellulose 50 µm – 66 mg,

croscarmellose sodium – 12 mg,

Hypromellose 6 mPa-c – 5 mg,

100 µm microcrystalline cellulose – 5 mg,

colloidal silicon dioxide – 2.5 mg,

magnesium stearate – 2.5 mg.

Composition of the film coating:

Opadray white (hypromellose – 62.5%, titanium dioxide (E171) – 31.25%, macrogol 400 – 6.25%) – 10 mg.

How to take, the dosage

The drug is taken orally. The tablet is swallowed with water. Aprovasc® can be taken with or on an empty stomach (i.e., regardless of the time of eating).

The usual starting and maintenance dose of Aprovask® is 1 tablet/day. Aprovasc® should be used in patients failing to achieve target BP values with irbesartan monotherapy or amlodipine monotherapy or to continue treatment of patients already taking irbesartan and amlodipine as single tablets. Doses should be adjusted individually, initially with separate preparations of irbesartan and amlodipine. Doses are selected depending on BP response to therapy and target BP. The maximum recommended dose of Aprovask® 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).

In elderly patients and patients with impaired renal function, there is generally no need to decrease the dose.

Patients with hepatic impairment should use Aprovasc® with caution due to the presence of amlodipine.

Interaction

Combination of irbesartan and amlodipine

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

There have been no studies of drug interactions of Aprovasc® with other medicinal products.

Irbesartan

Based on these in vitro studies, no interaction with drugs whose metabolism is mediated by isoenzymes should be expected: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.

Irbesartan is primarily metabolized with the CYP2C9 isoenzyme, but no significant pharmacokinetic interaction was observed in clinical interaction studies when irbesartan was taken concomitantly with warfarin, which is metabolized with the CYP2C9 isoenzyme.

The pharmacokinetic parameters of irbesartan do not change when used concomitantly with nifedipine and hydrochlorothiazide.

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

The combination of the drug Aprovasc® with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal insufficiency (GFR < 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

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-saving diuretics or other drugs that can increase plasma potassium (heparin) can sometimes significantly increase the serum potassium concentration, which requires careful monitoring of plasma potassium in patients during treatment.

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

An increase in plasma lithium concentrations and toxic effects of lithium have been described when irbesartan is coadministered with lithium preparations. Plasma lithium concentrations should be monitored in patients taking irbesartan concomitantly with lithium preparations.

Amlodipine

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

In vitro studies with human plasma have shown that amlodipine does not affect the binding to plasma proteins of digoxin, phenytoin, warfarin or indomethacin.

The concomitant administration of amlodipine and cimetidine did not interfere with the pharmacokinetics of amlodipine.

Concomitant ingestion of 250 mg grapefruit juice with a single 10 mg dose of amlodipine in 20 healthy volunteers had no significant effect on amlodipine pharmacokinetics.

When amlodipine and sildenafil were administered in combination, each drug had an independent BP-lowering effect.

Concomitant administration of amlodipine 10 mg and atorvastatin 80 mg resulted in non-significant changes in pharmacokinetic parameters of atorvastatin in the Css reach state.

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

Concomitant administration of amlodipine and did not alter prothrombin time with warfarin.

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

Concomitant use of tacrolimus and amlodipine may increase tacrolimus plasma concentrations. Plasma concentrations of tacrolimus should be monitored and the dose should be adjusted if necessary.

The concomitant use of amlodipine with simvastatin may increase the exposure of simvastatin compared to simvastatin therapy. When concomitant use of simvastatin and amlodipine it is necessary to limit the daily dose of simvastatin to 20 mg.

Special Instructions

Excessive BP decrease: patients with hypovolemia and hyponatremia

Irbesartan has rarely caused excessive BP decrease in patients with arterial hypertension without other comorbidities. As with ACE inhibitors, excessive BP reduction with associated symptoms may be expected in patients with hypovolemia and hyponatremia, which include patients receiving intensive diuretic therapy and/or patients with restrictions on table salt intake or patients on hemodialysis. Hyponatremia and hypovolemia should be corrected before initiating treatment with Aprovasc® or the use of the drug in lower initial doses should be considered.

Patients with chronic heart failure

. In a long-term placebo-controlled trial (PRAISE-2) of amlodipine in patients with chronic heart failure of functional class III-IV (NYHA classification) nonischemic etiology, amlodipine was associated with increased reports of pulmonary edema, despite no significant difference in the rate of heart failure progression compared with placebo.

Hepatic impairment

As with other slow calcium channel blockers, the T1/2 of amlodipine is increased in patients with impaired liver function, and no dosing regimen recommendations for impaired liver function have been established. Therefore, Aprovasc® should be used with caution in these patients.

Hypertensive crisis

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

Impact on renal function

Inhibition of the RAAS may be expected to result in changes in renal function in predisposed patients. In patients whose renal function depends on RAAS activity (patients with arterial hypertension with renal artery stenosis of one or both kidneys or patients with chronic heart failure of III-IV functional class [according to NYHA classification]), treatment with other drugs that affect RAAS has been associated with the development of oliguria and/or progressive azotemia and rarely with renal failure and/or death. The possibility of this effect occurring with the use of ARA II, including irbesartan, cannot be excluded.

Double RAAS blockade when combining Aprovask® with drugs containing aliskiren and with an ACE inhibitor

Double RAAS blockade when combining Aprovask® with an ACE inhibitor or with aliskiren is not recommended because of the increased risk of acute coronary events.There is an increased risk of hypertension, hyperkalemia and renal dysfunction.

In patients with diabetes mellitus or moderate to severe renal impairment (FFR < 60 ml/min/1.73 m2 body surface area), Aprovasc® in combination with aliskiren is contraindicated.

Patients with diabetic nephropathy are contraindicated in combination with ACE inhibitors.

The use in elderly patients

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

Pediatric use

The safety and effectiveness in children have not been established at this time.

The effect of Aprovask® on the ability to drive and operate machinery

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

Contraindications

– hypersensitivity to irbesartan, amlodipine and other dihydropyridine derivatives and excipients of the drug;

– cardiogenic shock;

– clinically significant aortic stenosis;

– unstable angina (except for Prinzmetal angina);

– pregnancy;

– period of breastfeeding;

– childhood and adolescence under 18 years of age (efficacy and safety not established);

– concomitant use with drugs containing aliskiren in patients with diabetes or moderate to severe renal impairment (GFR< 60 ml/min/1.73 m2);

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

With caution:

In patients with hypovolemia and hyponatremia, occurring, for example, during intensive treatment with diuretics, hemodialysis, adherence to a diet with restriction of table salt intake, diarrhea, vomiting.

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

In patients with chronic heart failure of NYHA functional class II-IV nonischemic etiology (due to amlodipine content of the drug, the use of which in these patients was associated with increased reports of pulmonary edema compared to placebo administration, despite no difference in the rate of heart failure progression).

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

In patients with renal insufficiency and after renal transplantation (due to irbesartan in the drug, monitoring of potassium and blood creatinine concentrations is recommended); after recent renal transplantation (no experience in 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 cerebral vessels (with excessive BP reduction there is a risk of increased ischemic disorders, up to the development of acute myocardial infarction and stroke).

In patients with CHD (because of the content of amlodipine in the drug).

Side effects

The frequency of adverse events/reactions (AEs/NRs) reported in clinical trials of fixed-dose combination irbesartan and amlodipine (I-ADD, I-SOMVINE, and I-COMBO clinical trials), in clinical trials of irbesartan and its postmarketing use, and in clinical trials of amlodipine were determined by WHO classification as follows: Very common (≥10%); common (≥1% and < 10%); infrequent (≥0.1% and < 1%); infrequent (≥ 0.01% and < 0.1%); very rare (< 0.01%), frequency unknown – the incidence of HP/NR cannot be estimated from the available data.

The incidence of HP reported during postmarketing use of the drug was defined as “incidence unknown” because information on these HPs came from spontaneous reports, with no indication of the number of patients taking the drug.

In clinical trials comparing fixed-dose combination irbesartan/amlodipine with irbesartan or amlodipine monotherapy, the types and frequency of adverse events occurring during treatment, possibly related to the treatment studied, were similar to those observed in previous clinical trials or in postmarketing reports for irbesartan and amlodipine monotherapy. Peripheral edema, mainly associated with amlodipine, was the most common NIH.

An adverse event observed during treatment and possibly related to the study drug in clinical trials of irbesartan/amlodipine (I-ADD, I-COMBINE, and I-COMBO)

Fixed irbesartan/amlodipine combination

General reactions: Frequent – peripheral edema, edema; infrequent – asthenia.

Hearing and labyrinth disorders: infrequent – vertigo.

Cardiovascular system disorders: frequently – palpitations, orthostatic hypotension; infrequently – sinus bradycardia, excessive BP decrease.

Nervous system disorders: frequently – dizziness, headache, somnolence; infrequently – paresthesia.

As to the sexual system: infrequent – erectile dysfunction.

Respiratory system: infrequent – cough.

Gastrointestinal system: often – swollen gums; infrequent – nausea, upper abdominal pain, constipation.

Urinary system: often – proteinuria; infrequent – azotemia, hypercreatinemia.

Metabolism: infrequent – hyperkalemia.

Muscular system: infrequent – joint stiffness, arthralgia, myalgia.

Irbesartan adverse events observed with irbesartan in clinical studies (including I-ADD, I-COMBINE and I-COMBO clinical studies) and in its post-marketing use

Immune system disorders: frequency unknown – hypersensitivity reactions (allergic reactions), including angioedema, urticaria.

Metabolic disorders: frequency unknown – hyperkalemia.

Hearing and labyrinth disorders: frequent – vertigo; frequency unknown – tinnitus.

Nervous system disorders: frequent – dizziness, headache*; infrequent – orthostatic vertigo.

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

Cardiovascular system disorders: infrequent – tachycardia.

Skin and subcutaneous tissue: frequency unknown – leukocytoclastic vasculitis.

Respiratory system: infrequent – cough.

The digestive system: frequently – nausea/vomiting, upper abdominal pain, tongue disorders, glossodynia (burning sensation and pain in the tongue); infrequently – diarrhea, dyspepsia, heartburn; frequently unknown – jaundice, increased liver function test scores, hepatitis; frequently unknown – dysgeusia (perversion of taste).

Hepatic and biliary tract disorders: frequency unknown – jaundice, increased liver function tests, hepatitis.

Skin and subcutaneous tissue: infrequent – alopecia.

Allergic reactions: frequency unknown – angioedema, urticaria.

Muscular system: frequency unknown – myalgia.

Muscular system disorders: frequency unknown – renal dysfunction, including individual cases of renal failure in patients with risk factors for its development.

In the sexual system: infrequent – erectile dysfunction.

General reactions: frequent – fatigue*, edema; infrequent – 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 complications of manipulation: infrequent falls.

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

Hematopoietic system: very rare – thrombocytopenia.

The immune system: very rare – allergic reactions, including angioedema, urticaria.

Metabolism disorders: very rare – hyperglycemia.

Psychiatric disorders: infrequent – insomnia, mood swings.

Nervous system disorders: frequently – dizziness, headache*, somnolence; infrequently – hypoesthesia, paresthesia, tremor, distortion of taste, syncopal conditions; very rarely – peripheral neuropathy.

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

Visual organs: infrequent visual disturbances.

Hearing organ and labyrinth disorders: infrequent – tinnitus, vertigo.

Cardiovascular system: frequently – palpitations, “rushes” of blood to the skin with a feeling of heat, redness of the skin*; very rarely – myocardial infarction, cardiac rhythm disorders, 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: frequent – cough; infrequent – shortness of breath, rhinitis; very rare – coughing.

The digestive system: frequently – nausea, abdominal pain, glossodynia, glossitis; infrequently – dyspepsia, vomiting, altered defecation rhythm, dry mucous membranes of the mouth; very rarely – pancreatitis, gastritis, gum hyperplasia.

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

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

Muscular system disorders: infrequent – arthralgia, muscle cramps, myalgia, back pain.

Urinary system disorders: infrequent increased frequency of urination, painful urge to urinate, nicturia.

Perior genital system disorders: infrequent impotence, gynecomastia.

General reactions: frequently – fatigue, edema*, peripheral edema; infrequently – chest pain, asthenia, malaise, pain; rarely – facial edema.

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

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

.

Overdose

Symptoms: no toxicity has been established in adults taking irbesartan at doses up to 900 mg/day.

The available data for amlodipine suggest that severe overdose may result in marked peripheral vasodilation and possibly development of reflex tachycardia. The development of severe and prolonged excessive BP reduction, up to the development of shock with fatal outcome, has been reported.

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

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

Because amlodipine has a high degree of binding to blood proteins and irbesartan is not excreted by hemodialysis, it is unlikely that hemodialysis may be beneficial in overdose.

In severe overdose, active cardiac and respiratory monitoring should be initiated. Frequent BP measurement is necessary. Clinically significant BP decrease due to amlodipine overdose requires active cardiovascular support, including elevation of limbs. CPR and diuresis should be monitored. It may be necessary to administer vasoconstrictors to restore vascular tone and BP (provided there are no contraindications for their administration). Intravenous injection of calcium gluconate may be useful in eliminating the effects of calcium channel blockade.