PROTEKON FAST

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IZICARD^®A (IZICARD^®A)

Composition:

Active substances: telmisartan, amlodipine;

1 tablet contains 80 mg of telmisartan and 13.870 mg of amlodipine besylate, equivalent to 10 mg of amlodipine

or

1 tablet contains 80 mg of telmisartan and 6.935 mg of amlodipine besylate, equivalent to 5 mg of amlodipine

or

1 tablet contains 40 mg of telmisartan and 13.870 mg of amlodipine besylate, equivalent to 10 mg of amlodipine

or

1 tablet contains 40 mg of telmisartan and 6.935 mg of amlodipine besylate, equivalent to 5 mg of amlodipine

Excipients: mannitol (E 421), povidone, sodium hydroxide, meglumine, magnesium stearate, anhydrous citric acid, blue diamond FCF dye (E 133).

Pharmaceutical form.

Tablets.

Main physical and chemical properties:

80 mg/10 mg tablets: two-layer tablets of prolonged shape without a shell, one layer of white or almost white color with an imprint of "C9" on one side, the second layer of blue color on the other side;

80 mg/5 mg tablets: two-layer tablets of prolonged shape without a shell, one layer of white or almost white color with an imprint of "C8" on one side, the second layer of blue color on the other side;

40 mg/10 mg tablets: two-layer tablets of prolonged shape without a shell, one layer of white or almost white color with an imprint of "C7" on one side, the second layer of blue color on the other side;

40 mg/5 mg tablets: two-layer tablets of prolonged shape without a shell, one layer of white or almost white color with an imprint of "C6" on one side, the second layer of blue color on the other side.

Pharmacotherapeutic group.

Combination products that act on the renin-angiotensin system, angiotensin II antagonists, and calcium channel blockers. ATC code C09D B04.

Pharmacological properties.

Pharmacodynamics.

The drug Izikard^®A is a combination drug that contains two antihypertensive components with complementary effects, allowing blood pressure control in patients with arterial (essential) hypertension - angiotensin II receptor antagonist (ARA II) telmisartan and calcium channel blocker (CCB), dihydropyridine derivative amlodipine. The combination of these components has an additive antihypertensive effect, reducing blood pressure to a greater extent than each component separately. Taking the drug Izikard^®A once daily provides effective and sustained blood pressure reduction over 24 hours.

Telmisartan.

Telmisartan is an effective and specific ARA II (type AT1). Telmisartan, due to its higher affinity, replaces angiotensin II at its binding sites on AT1 receptors, which are responsible for the known effects of angiotensin II. Telmisartan does not exhibit any partial agonistic effect on the AT1 receptor. Telmisartan selectively binds to the AT1 receptor. The binding is long-lasting. Telmisartan does not exhibit affinity for other receptors, including AT2 and other less studied AT receptors. The functional role of these receptors is unknown, as is the effect of their possible "overstimulation" by angiotensin II, the level of which increases under the influence of telmisartan. Telmisartan reduces aldosterone levels in plasma, does not inhibit renin in human plasma, and does not block ion channels. Also, telmisartan does not inhibit angiotensin-converting enzyme (ACE) - kininase II, an enzyme that breaks down bradykinin. Therefore, it should not be expected to potentiate side effects mediated by bradykinin.

In humans, telmisartan at a dose of 80 mg almost completely blocks the increase in blood pressure caused by angiotensin II. The therapeutic effect lasts for 24 hours and is observed up to 48 hours. After the first application, the hypotensive effect of the drug develops gradually within 3 hours. Maximum blood pressure reduction is usually achieved within 4-8 weeks after starting treatment with telmisartan and is maintained during long-term therapy.

The antihypertensive effect is consistently maintained over 24 hours after taking one dose of the drug, including the last 4 hours before the next dose, as confirmed by ambulatory blood pressure monitoring. The ratio of the decrease in blood pressure before taking the next dose to the maximum decrease in blood pressure is more than 80% after taking 40 mg or 80 mg, as established in placebo-controlled clinical trials. A dose-dependent effect on systolic blood pressure was noted, but the data on diastolic pressure are contradictory. In patients with arterial hypertension, telmisartan reduces both systolic and diastolic pressure without affecting heart rate. The effect of the diuretic and natriuretic effect of the drug on its hypotensive effect is still being determined.

In studies with other classes of antihypertensive drugs (amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril), the equivalent antihypertensive efficacy of telmisartan was demonstrated.

When telmisartan treatment is abruptly stopped, blood pressure returns to pre-treatment levels over several days without the risk of withdrawal syndrome.

Clinical trials have shown that cases of dry cough occur significantly less frequently with telmisartan treatment than with ACE inhibitors.

Amlodipine.

Amlodipine, a dihydropyridine derivative, inhibits the transmembrane transition of calcium ions (slow calcium channel blocker or calcium ion antagonist); it also blocks the transmembrane flow of calcium ions in myocardial cells and smooth muscle cells of blood vessels. The mechanism of amlodipine's antihypertensive action is due to its direct relaxing effect on vascular smooth muscle, which leads to a decrease in peripheral vascular resistance and a reduction in blood pressure. Amlodipine is relatively vascular-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Experimental data confirm that amlodipine binds to dihydropyridine and non-dihydropyridine binding sites. Contractile processes of cardiac and vascular smooth muscle depend on the passage of extracellular calcium into these cells through specific ion channels.

After administration of therapeutic doses to patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure in both lying and standing positions. This decrease in blood pressure is not accompanied by significant changes in heart rate or catecholamine levels in the blood during long-term use.

The effect correlates with concentrations in the blood plasma of young patients and elderly patients.

As with other calcium channel blockers, measurements of cardiac hemodynamics at rest and during exercise (or walking) in patients with normal ventricular function treated with amlodipine generally showed a slight increase in cardiac index without significant effects on dP/dt, or on end-diastolic pressure, or left ventricular volume. In hemodynamic studies, amlodipine did not exhibit a negative inotropic effect when used in therapeutic doses in intact animals and humans, even when combined with beta-blockers in humans.

Amlodipine does not affect the function of the sinoatrial node or atrioventricular conduction in healthy animals or humans. In clinical trials where amlodipine was used in combination with beta-blockers in patients with arterial hypertension or angina pectoris, no changes in electrocardiogram parameters were observed.

Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and ischemic heart disease confirmed by angiography.

Hemodynamic studies and exercise-based controlled clinical trials involving patients with heart failure (NYHA class II-IV) showed that amlodipine did not lead to clinical deterioration, as determined by exercise tolerance, left ventricular ejection fraction, and clinical symptoms.

Due to the slow onset of action, acute arterial hypotension is not characteristic when taking amlodipine.

In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine lead to a decrease in renal vascular resistance, an increase in glomerular filtration rate, and effective plasma flow in the kidneys without changing the filtration fraction or proteinuria.

Amlodipine is not associated with any adverse metabolic effects or changes in blood lipids, making it suitable for patients with asthma, diabetes, and gout.

Telmisartan/Amlodipine.

Available data from an 8-week, multicenter, randomized, double-blind, placebo-controlled, factorial study with parallel groups involving 1461 patients with arterial hypertension (mean diastolic blood pressure ≥ 95 and ≤ 119 mmHg) showed that treatment with a combination of monotherapy doses corresponding to each dosage of the drug Izikard^®A resulted in significantly greater reductions in systolic and diastolic blood pressure and better blood pressure control (in percentage) compared to monotherapy with the corresponding components.

A dose-dependent reduction in systolic/diastolic blood pressure was also noted across the entire range of therapeutic doses: -21.8/-16.5 mmHg (40 mg/5 mg), -22.1/-18.2 mmHg (80 mg/5 mg), -24.7/-20.2 mmHg (40 mg/10 mg), and -26.4/-20.1 mmHg (80 mg/10 mg). A diastolic blood pressure reduction below 90 mmHg was achieved in 71.6%, 74.8%, 82.1%, and 85.3% of patients, respectively. Age, sex, and the presence or absence of diabetes in patients did not affect the antihypertensive effect of the combination.

Studies of this combination in patient populations other than those with arterial hypertension have not been conducted. Telmisartan has been studied in patients at high risk of cardiovascular disease. Amlodipine has been studied in patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.

Pharmacokinetics.

Pharmacokinetics of the fixed combination.

The rate and extent of absorption of the drug Izikard^®A are equivalent to the bioavailability of telmisartan and amlodipine when administered as separate tablets.

Linearity. It is not expected that a small decrease in the area under the concentration-time curve (AUC) for telmisartan will result in a decrease in therapeutic efficacy. There is no linear relationship between doses and plasma levels. Cmax and, to a lesser extent, AUC increase disproportionately at doses above 40 mg.

Amlodipine has linear pharmacokinetics.

Absorption. After oral administration in therapeutic doses, telmisartan is rapidly absorbed in the gastrointestinal tract. The mean absolute bioavailability of telmisartan is approximately 50%. When telmisartan is taken with food, the AUC for telmisartan decreases from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). Three hours after administration, the plasma concentration is the same regardless of whether telmisartan is taken on an empty stomach or with food.

After oral administration of therapeutic doses, amlodipine is well absorbed from the gastrointestinal tract, with maximum blood levels achieved within 6-12 hours after administration. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect the bioavailability of amlodipine.

Distribution. Telmisartan is actively bound to plasma proteins (>99.5%), mainly to albumin and alpha-1 acid glycoprotein. The volume of distribution is approximately 500 liters. In vitro studies have shown that approximately 97.5% of circulating amlodipine in the systemic circulation is bound to plasma proteins. The volume of distribution of amlodipine is approximately 21 L/kg.

Metabolism. Telmisartan is metabolized by conjugation to glucuronide of the primary substance. The pharmacological activity of the conjugate has not been established.

Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.

Elimination. Telmisartan is characterized by bi-exponential pharmacokinetics with a terminal half-life of more than 20 hours. Cmax and AUC increase disproportionately with dose. No clinically significant accumulation of telmisartan is expected when used at recommended doses. Plasma concentrations are higher in women than in men, without significant effects on efficacy. After oral administration, telmisartan is almost completely excreted in the feces, mainly as an unchanged compound. Cumulative renal excretion is less than 1% of the dose. Total clearance from plasma is high (approximately 1000 mL/min) compared to hepatic blood flow (approximately 1500 mL/min).

The elimination of amlodipine from plasma is biphasic, with a terminal half-life of approximately 30-50 hours, which corresponds to once-daily dosing. Steady-state plasma levels are reached after repeated administration for 7-8 days. 10% of unchanged amlodipine and 60% of amlodipine metabolites are excreted in the urine.

Special patient populations.

Children.

Data on the pharmacokinetics of telmisartan in children are not available.

According to some studies on the pharmacokinetics of amlodipine, significant interindividual variability was observed. Data on children under 6 years of age are limited.

Sex.

A difference in plasma concentrations of telmisartan was observed depending on sex. Cmax and AUC are 2-3 times higher in women compared to men.

Elderly patients.

The pharmacokinetics of telmisartan in young patients and elderly patients do not differ.

The time to reach maximum plasma concentration of amlodipine is the same in young patients and elderly patients. However, in elderly patients, the clearance of amlodipine is reduced, resulting in increased AUC and half-life. Increased AUC and half-life are also observed in patients with congestive heart failure.

Patients with impaired renal function.

Telmisartan is bound to plasma proteins and is not removed by hemodialysis in patients with renal failure. Also, lower plasma concentrations of telmisartan are observed, and the half-life does not change.

The pharmacokinetics of amlodipine in patients with impaired renal function do not change significantly.

Patients with impaired liver function.

A study of pharmacokinetics in patients with impaired liver function found an increase in the absolute bioavailability of telmisartan to approximately 100%. The half-life of telmisartan does not change.

There are limited clinical data on the use of amlodipine in patients with impaired liver function. Patients with liver failure have reduced creatinine clearance, resulting in increased AUC by approximately 40-60% and prolonged amlodipine half-life.

Clinical characteristics.

Indications.

- Essential hypertension in adult patients with blood pressure adequately controlled by a combination of amlodipine and telmisartan, which are used as two separate drugs.

- Essential hypertension in adult patients whose blood pressure is not regulated by monotherapy with amlodipine or telmisartan.

Contraindications.

- Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any excipient.

- Obstructive biliary disorders.

- Severe liver dysfunction.

- Severe arterial hypotension.

- Obstruction of the left ventricular outflow tract (including high-grade aortic stenosis).

- Hemodynamically unstable heart failure after myocardial infarction.

- Shock (including cardiogenic shock).

- Concurrent use with aliskiren in patients with diabetes and/or impaired renal function (GFR <60 mL/min/1.73 m²).

- Pregnancy.

- Breastfeeding.

- Children under 18 years of age.

Interactions with other medicinal products and other forms of interaction.

Interactions inherent to the combination.

Interactions between the two active components of the drug Izikard^®A were not found in clinical trials. Special studies on the interaction of the drug Izikard^®A with other medicinal products have not been conducted.

To be considered when used concomitantly.

Other antihypertensive medicinal products.

The blood pressure-lowering effect of the drug Izikard^®A may be enhanced by concomitant use of other antihypertensive medicinal products.

Medicinal products with potential to lower blood pressure.

Based on pharmacological properties, it can be expected that some medicinal products may enhance the hypotensive effects of all antihypertensive drugs, including Izikard^®A, such as baclofen, amifostine, neuroleptics, or antidepressants. Furthermore, orthostatic hypotension may be enhanced by alcohol consumption.

Corticosteroids (systemic use).

Possible decrease in antihypertensive effect.

Telmisartan.

As with other drugs that affect the RAAS, telmisartan may cause hyperkalemia. This risk may increase when combined with other drugs that can also provoke hyperkalemia (potassium-sparing diuretics, potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, heparin, and immunosuppressants (cyclosporine or tacrolimus)).

The frequency of hyperkalemia depends on associated risk factors. The risk increases with the use of the above-mentioned therapeutic combinations. This risk is particularly high when combined with potassium-sparing diuretics and potassium supplements. The combination with, for example, ACE inhibitors or NSAIDs creates a smaller risk, provided that precautions are taken when used.

Concomitant use is contraindicated.

The combination of telmisartan and aliskiren is contraindicated for patients with diabetes and impaired renal function (GFR <60 mL/min/1.73 m²) and is not recommended for other patients.

Potassium-sparing diuretics and potassium supplements.

Potassium-sparing diuretics, such as spironolactone, eplerenone, triamterene, or amiloride, potassium supplements, or salt substitutes containing potassium may lead to significant increases in potassium levels in the blood serum. If concomitant use is indicated due to confirmed hypokalemia, they should be taken with caution and with regular monitoring of potassium levels in the blood serum.

Lithium.

Known cases of reversible increases in lithium levels in blood serum and increased toxicity have been reported during concomitant use of lithium with ACE inhibitors and ARBs, including telmisartan. If the use of this combination is considered necessary, careful monitoring of lithium levels in blood serum is required.

Concomitant use requires caution.

Nonsteroidal anti-inflammatory drugs.

Therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), particularly acetylsalicylic acid in anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs, may reduce the antihypertensive effect of ARBs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with impaired renal function), concomitant use of ARBs and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such a combination should be used with caution, especially in elderly patients. Patients should receive adequate fluid intake, and the possibility of monitoring renal function after starting concomitant treatment and periodically after its completion should be considered.

Diuretics (thiazide or loop diuretics).

Prior treatment with high doses of such diuretics as furosemide (loop diuretic) and hydrochlorothiazide (thiazide diuretic) may lead to dehydration and increased risk of developing arterial hypotension at the start of telmisartan treatment.

Ramipril.

In a clinical study, when taking a combination of telmisartan and ramipril, an increase in AUC0-24 and maximum plasma concentration (Cmax) of ramipril and ramiprilat by 2.5 times was observed. The clinical significance of this phenomenon is not established.

Other drugs

No clinically significant interaction was found with digoxin, warfarin, hydrochlorothiazide, glibenclamide, simvastatin, ibuprofen, paracetamol, and amlodipine. An increase in the average digoxin concentration in plasma by 49% and minimum concentrations by 20% was observed. When telmisartan and digoxin are used concomitantly, monitoring of digoxin levels in plasma is recommended to maintain them within the therapeutic range.

Amlodipine.

Concomitant use that requires caution.

Grapefruit or grapefruit juice.

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase bioavailability in some patients, leading to increased antihypertensive effect.

CYP3A4 inhibitors.

Concomitant use of amlodipine with potent or moderate CYP3A4 inhibitors (protease inhibitors, antifungal drugs of the azole group, macrolides; e.g., erythromycin or clarithromycin, verapamil or diltiazem) may result in significant increases in amlodipine concentrations. Clinical manifestations of these pharmacokinetic effects may be more pronounced in elderly patients. In this case, monitoring of clinical status and adjustment of the drug dose may be necessary.

CYP3A4 inducers. Amlodipine plasma concentrations may change after concomitant use of known CYP3A4 inducers.

Therefore, blood pressure monitoring and dose adjustment should be performed when concomitantly using these medicinal products, both during and after concomitant treatment, especially with strong CYP3A4 inducers (e.g., rifampicin, St. John's wort preparations).

Dantrolene.

In laboratory animals, cases of ventricular fibrillation and cardiovascular failure with lethal outcome and collapse were observed when using verapamil and intravenous dantrolene. Due to the risk of hyperkalemia, concomitant use of dantrolene and calcium channel blockers, including amlodipine, should be avoided in patients prone to malignant hyperthermia and during the treatment of malignant hyperthermia.

Simvastatin.

Concomitant use of amlodipine with simvastatin at a dose of 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin monotherapy. Therefore, in patients using amlodipine, the dose of simvastatin should be limited to 20 mg per day.

Immunosuppressants.

When using amlodipine concomitantly, it may increase the systemic exposure of cyclosporine or tacrolimus. In such cases, monitoring of cyclosporine or tacrolimus levels in the blood and adjustment of the dose as needed is recommended.

Concomitant use that should be considered.

It has been established that the concomitant use of amlodipine with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin (used sublingually), nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents is safe. When amlodipine and sildenafil were used concomitantly, each drug had an independent antihypertensive effect.

Special warnings and precautions for use.

Pregnancy.

No special studies of the drug Izikard^®A during pregnancy or breastfeeding have been conducted. The effects of the individual components of the drug should be considered.

The use of ARA II is contraindicated during pregnancy. If pregnancy is diagnosed, the drug should be discontinued immediately. If necessary, alternative therapy should be prescribed (see "Use during pregnancy or breastfeeding").

Impaired liver function.

Telmisartan is mainly excreted in the bile. In patients with obstructive biliary disorders or liver failure, it can be expected that the clearance of telmisartan will decrease; therefore, telmisartan should not be prescribed to patients with cholestasis, obstructive biliary disorders, or severe liver failure (see "Contraindications"). The drug should be used with caution in patients with mild to moderate liver dysfunction. As with all calcium channel blockers, the half-life of amlodipine is prolonged in patients with impaired liver function. Dosing recommendations have not been developed. Therefore, patients with liver dysfunction, in the absence of obstructive biliary disorders, should take the drug Izikard^®A with caution.

Angioedema of the intestine.

There have been reports of angioedema of the intestine in patients taking angiotensin II receptor blockers (see "Adverse reactions"). In these patients, abdominal pain, nausea, vomiting, and diarrhea were observed. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If angioedema of the intestine is diagnosed, telmisartan treatment should be discontinued, and appropriate monitoring should be initiated until complete resolution of symptoms.

Renovascular hypertension.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, who are taking drugs that affect the RAAS, there is an increased risk of developing pronounced hypotension and renal failure.

Renal failure and kidney transplantation.

Experience with the use of the drug Izikard^®A in patients after kidney transplantation is lacking. Amlodipine and telmisartan are not removed from the body during hemodialysis. Patients with impaired renal function are recommended to have periodic monitoring of potassium and creatinine levels in the blood serum.

Reduced circulating blood volume (CBV) and/or hyponatremia.

Due to limited salt intake, intensive diuretic therapy, diarrhea, or vomiting, symptomatic arterial hypotension may develop, especially after taking the first dose of the drug. Such conditions require correction before using the drug Izikard^®A.

Dual blockade of the RAAS.

In some patients, due to the suppression of the RAAS, especially when using a combination of agents that affect this system (e.g., adding ACE inhibitors or aliskiren, a direct renin inhibitor, to an ARB), renal function may be impaired (including acute renal failure). Therapy involving such dual blockade of the RAAS is not recommended and should be limited to individual cases under close monitoring of renal function.

The combination of telmisartan and aliskiren is contraindicated for patients with diabetes and impaired renal function (GFR <60 mL/min/1.73 m²).

Other conditions that require stimulation of the RAAS.

In patients whose vascular tone and renal function depend mainly on the activity of the RAAS (e.g., patients with chronic heart failure or kidney disease, including renal artery stenosis), treatment with drugs that affect this system may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria, and, in some cases, acute renal failure.

Primary hyperaldosteronism.

In patients with primary aldosteronism, antihypertensive drugs whose mechanism of action is based on the inhibition of the RAAS are generally ineffective. Therefore, the use of telmisartan in such cases is not recommended.

Aortic stenosis and mitral stenosis, obstructive hypertrophic cardiomyopathy.

In patients with aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy, the use of the drug Izikard^®A, as well as other vasodilators, requires special caution. In the presence of high-grade aortic stenosis, the drug is contraindicated.

Unstable angina, acute myocardial infarction.

There are no data on the use of the drug Izikard^®A in unstable angina and during and within one month after myocardial infarction.

As with the use of other antihypertensive drugs, significant blood pressure reduction in patients with ischemic heart disease or ischemic heart disease may lead to myocardial infarction or stroke.

Heart failure.

In a clinical study, it was found that the use of amlodipine in patients with heart failure of non-ischemic etiology (NYHA class III and IV) was accompanied by more frequent development of pulmonary edema, despite the absence of significant differences in the frequency of worsening heart failure compared to placebo.

Patients with diabetes who are treated with insulin or oral hypoglycemic agents.

During treatment with telmisartan, hypoglycemia may develop in such patients. Therefore, in these patients, blood glucose levels should be monitored, and this should be taken into account when adjusting the dose of insulin or oral hypoglycemic agents.

Hyperkalemia.

During treatment with drugs that affect the RAAS, especially in the presence of renal dysfunction and/or heart failure, hyperkalemia may occur. Hyperkalemia can be fatal in elderly patients, patients with renal failure, diabetic patients, patients taking other drugs that can increase potassium levels in the blood, and/or patients with intercurrent diseases.

Before considering the use of drugs that suppress the RAAS, the ratio of benefit to risk should be weighed.

The main risk factors for the development of hyperkalemia that should be taken into account:

- Diabetes, renal failure, age over 70 years;

- Combination therapy with one or more other drugs that affect the RAAS, and/or dietary supplements containing potassium. The drugs or therapeutic groups of drugs that can provoke hyperkalemia include potassium-sparing diuretics, potassium supplements, ACE inhibitors, ARBs, NSAIDs (including selective COX-2 inhibitors), heparin, and immunosuppressants (cyclosporine or tacrolimus) and trimethoprim;

- Intercurrent conditions, especially dehydration, acute cardiac decompensation, metabolic acidosis, worsening renal function, sudden deterioration of kidney function (e.g., infectious diseases), cell lysis (e.g., acute limb ischemia, acute muscle necrosis, extensive trauma).

Patients at risk should undergo careful monitoring of potassium levels in the blood serum.

Simvastatin.

Available data indicate that concomitant use of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin monotherapy. Therefore, in patients using amlodipine, the dose of simvastatin should be limited to 20 mg per day.

Ethnic differences.

As with all ARBs, telmisartan is clearly less effective in lowering blood pressure in black patients than in patients of other races. This may be explained by the greater prevalence of low-renin states in black patients with arterial hypertension.

Use during pregnancy or breastfeeding.

Pregnancy.

Telmisartan.

The use of ARA II is contraindicated during pregnancy. If pregnancy is diagnosed, the drug should be discontinued immediately. If necessary, alternative therapy should be prescribed.

Preclinical studies of telmisartan did not reveal teratogenic properties, but established the presence of fetotoxicity.

It is known that the use of ARA II during the II and III trimesters of pregnancy has a fetotoxic effect (reduced renal function, oligohydramnios, delayed ossification of the fetal skull), as well as neonatal toxicity (renal failure, arterial hypotension, and hyperkalemia).

In patients planning pregnancy, ARA II should be replaced with other antihypertensive agents that have an established safety profile during pregnancy.

Amlodipine.

The safety of amlodipine for use in pregnant women has not been established. Limited data on the use of amlodipine during pregnancy do not indicate that amlodipine or other calcium channel blockers have a harmful effect on fetal health. However, there may be a risk of prolonged labor.

Breastfeeding.

Amlodipine is excreted in breast milk. The ratio of the dose received by the newborn from the mother, in the interquartile range, is estimated to be 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Due to the lack of information on the use of telmisartan during breastfeeding, this drug is not recommended for use in breastfeeding women. Preference is given to alternative therapy with a better-established safety profile, especially during breastfeeding of a newborn or premature infant.

Given the potential adverse reactions, the use of the drug Izikard^®A is not recommended. Alternative therapy with a better-established safety profile should be used.

Fertility.

Data on the effect of the fixed combination or individual components of the drug on human fertility are not available. The effect of the drug Izikard^®A on human fertility has not been studied.

Ability to affect reaction speed when driving vehicles or operating other mechanisms.

Studies on the effect on reaction speed when driving vehicles or operating other mechanisms have not been conducted. However, it should be taken into account that during treatment, undesirable effects such as drowsiness, dizziness, or fainting may occur, so patients should exercise caution when driving vehicles or operating mechanisms. If patients experience these effects, they should avoid driving vehicles or operating mechanisms.

Method of administration and dosage.

The drug Izikard^®A is intended for long-term treatment.

Patients whose blood pressure is not adequately controlled by monotherapy with amlodipine or telmisartan may be switched to combination therapy with the drug Izikard^®A. The recommended dose is 1 tablet per day.

Izikard^®A tablets can be taken regardless of food intake, and it is recommended to take them with a small amount of liquid.

Patients who are taking amlodipine and telmisartan separately can be switched to Izikard^®A, which contains the same doses of the components. Before switching to a combination of fixed doses, individual dose selection of the components (i.e., amlodipine and telmisartan) is recommended. If clinically necessary, the possibility of direct replacement of monotherapy with a combination of fixed doses can be considered.

The daily dose is 1 tablet of Izikard^®A per day in the prescribed dosage (80/10, 80/5, 40/10, or 40/5).

The maximum permissible doses of the components of the drug are 80 mg of telmisartan and 10 mg of amlodipine per day.

Dosing for specific patient groups

Elderly patients (65 years of age and older)

For elderly patients, the usual dosing regimens are recommended.

Caution should be exercised when increasing the dose of the drug in elderly patients. There is limited information on the use of the drug in elderly patients.

Patients with impaired renal function.

In patients with impaired renal function, including those on hemodialysis, dose adjustment of the drug is not required. Amlodipine and telmisartan are not removed from the body during hemodialysis. Concomitant use of telmisartan and aliskiren is contraindicated in patients with impaired renal function (GFR <60 mL/min/1.73 m²) (see "Special warnings and precautions for use").

Impaired liver function

Patients with mild or moderate liver dysfunction can use the drug Izikard^®A with caution. The dose of telmisartan should not exceed 40 mg once daily. The drug Izikard^®A is contraindicated in patients with severe liver dysfunction.

Children.

The drug should not be used in pediatric practice.

The safety and efficacy of the drug Izikard^®A for children under 18 years of age have not been studied.

Overdose.

Symptoms.

Experience with overdose of the drug Izikard^®A is not available. Possible symptoms of overdose consist of symptoms from individual components of the drug.

Telmisartan - tachycardia, possibly bradycardia, dizziness, increased creatinine levels in the blood serum, acute renal failure.

Amlodipine - pronounced decrease in blood pressure with possible development of reflex tachycardia and symptoms of excessive peripheral vasodilation (risk of developing severe and persistent hypotension, including shock and fatal outcome).

Treatment.

Therapeutic measures depend on the time of administration and the severity of symptoms.

Patient monitoring. Therapy should be symptomatic and supportive. Proposed measures include inducing vomiting and/or gastric lavage. Activated charcoal may be useful in overdose with both telmisartan and amlodipine. It is necessary to place the patient in a position with elevated legs and start administering plasma substitutes in case of pronounced decrease in blood pressure.

In order to counteract calcium channel blockade, intravenous administration of calcium gluconate may be useful. Hemodialysis is not effective.

Adverse reactions.

Adverse reactions previously identified for one of the components of the drug (telmisartan or amlodipine) may be potential adverse reactions to the drug Izikard^®A.

The overall frequency of adverse reactions in patients with arterial hypertension in controlled clinical trials when taking telmisartan was generally comparable to that with placebo (41.4% versus 43.9%). The frequency of adverse reactions did not depend on the dose, was not related to the patient's sex, age, or race. The safety profile of telmisartan in patients treated for cardiovascular disease prevention was consistent with the safety profile obtained in the treatment of patients with arterial hypertension.

The following adverse reactions were classified by organ system and frequency according to MedDRA terminology.

Cardiac disorders: bradycardia, tachycardia, arrhythmia, atrial fibrillation, myocardial infarction.

Vascular disorders: arterial hypotension, orthostatic hypotension, flushing, vasculitis.

Nervous system disorders: drowsiness, dizziness, syncope, migraine, headache, paresthesia, peripheral neuropathy, hypesthesia, dysgeusia, extrapyramidal syndrome.

Psychiatric disorders: insomnia, mood changes, depression, anxiety, confusion.

Blood and lymphatic system disorders: anemia, eosinophilia, thrombocytopenia, leukopenia.

Immune system disorders: hypersensitivity reactions, including anaphylactic reactions, angioedema (including fatal outcome).

Eye disorders: vision disturbances.

Ear and labyrinth disorders: vertigo, tinnitus.

Respiratory, thoracic, and mediastinal disorders: rhinitis, dyspnea, cough, respiratory infections (including pharyngitis and sinusitis), sepsis (including fatal outcome).

Gastrointestinal disorders: abdominal pain, diarrhea, dyspepsia, nausea, vomiting, dry mouth, discomfort in the stomach area, dysgeusia, gastritis, intestinal motility disorders, flatulence, pancreatitis, gingival hyperplasia.

Hepatobiliary disorders: liver function disorders/liver damage, hepatitis, jaundice, elevated liver enzyme levels (in most cases corresponding to cholestasis).

Skin and subcutaneous tissue disorders: alopecia, pruritus, increased sweating, rash, erythema, polymorphic erythema, medicinal dermatitis, toxic dermatitis, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity, alopecia, purpura, skin discoloration, exanthema, toxic epidermal necrolysis (Lyell's syndrome) - this adverse reaction was observed with an unknown frequency when using amlodipine.

Musculoskeletal and connective tissue disorders: back pain (e.g., sciatica), muscle spasms, myalgia, arthralgia, limb pain, tendon pain (symptoms similar to tendinitis).

Renal and urinary disorders: urinary disorders, increased frequency of urination, nocturia, renal function disorders, including acute renal failure.

Reproductive system and breast disorders: gynecomastia, erectile dysfunction.

Infections and infestations: urinary tract infections (including cystitis), upper respiratory tract infections (including pharyngitis and sinusitis), sepsis (including fatal outcome).

Metabolic and nutritional disorders: hyperglycemia, hyperkalemia; hypoglycemia (in diabetic patients).

General disorders: chest pain, asthenia (weakness), symptoms similar to flu, peripheral edema, fatigue, weakness.

Investigations: increased creatinine levels in the blood, decreased hemoglobin levels, increased uric acid levels in the blood, increased creatine phosphokinase levels in the blood, weight gain, weight loss.

Description of individual adverse reactions

Sepsis. In the PRoFESS study, a higher incidence of sepsis was observed in patients taking telmisartan compared to those receiving placebo. This may be either coincidental or a sign of an unknown process.

Liver function disorders. According to post-marketing data, most cases of liver function disorders were observed in patients of Japanese nationality. Patients of Japanese nationality are more prone to these adverse reactions.

Interstitial lung disease. Cases of interstitial lung disease have been reported temporarily with telmisartan use in post-marketing observations. However, a causal relationship has not been established.

Hypotension. This adverse reaction was frequently observed in patients with controlled blood pressure who were treated with telmisartan to reduce cardiovascular disease in addition to standard therapy.

Angioedema of the intestine. There have been reports of angioedema of the intestine after the use of angiotensin II receptor blockers (see "Special warnings and precautions for use").

Reporting of adverse reactions after registration of a medicinal product is important. This allows for the monitoring of the benefit-risk ratio of this medicinal product. Healthcare professionals, as well as patients or their authorized representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the automated information system for pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Store in a place inaccessible to children.

Packaging.

7 tablets in an aluminum blister, 2 or 4 blisters in a cardboard box.

Release category.

By prescription.

Manufacturer.

Evertogen Life Sciences Limited.

Manufacturer's location and address of the place of business.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.