Tenзocard: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TENSOCARD (TENSOCARD)

Composition:

Active substances: amlodipine, indapamide;

1 capsule contains:

6.935 mg of amlodipine besylate equivalent to 5 mg of amlodipine, and 1.5 mg of indapamide,

or 13.870 mg of amlodipine besylate equivalent to 10 mg of amlodipine, and 1.5 mg of indapamide;

Excipients:

for amlodipine tablets: lactose monohydrate; microcrystalline cellulose; crospovidone; magnesium stearate; colloidal anhydrous silicon dioxide;

for indapamide tablets: lactose monohydrate; hypromellose K4M; povidone; hypromellose E6; titanium dioxide (E 171); magnesium stearate; polyethylene glycol 6000 (macrogol 6000); iron oxide (E 172); colloidal anhydrous silicon dioxide;

Capsule (body and cap): gelatin; water; titanium dioxide (E 171).

Pharmaceutical form. Modified-release solid hard capsules.

Main physicochemical properties: opaque, solid hard gelatin capsules of white or almost white color, containing two white or almost white amlodipine tablets and one film-coated indapamide tablet of yellow-brown color.

Pharmacotherapeutic group.

Calcium channel blockers and diuretics. Amlodipine and diuretics. ATC code C08GA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics, acting by inhibiting sodium reabsorption in the cortical segment of the kidneys. This increases urinary excretion of sodium and chloride, and to a lesser extent – potassium and magnesium, thereby increasing diuresis and providing antihypertensive effect.

Amlodipine is a dihydropyridine-type calcium influx inhibitor (slow calcium channel blocker or calcium ion antagonist) that prevents transmembrane calcium ion influx into vascular smooth muscle and myocardium. The mechanism of amlodipine's antihypertensive action is based on its ability to relax vascular smooth muscle.

Pharmacodynamic effects

Phase II and III clinical studies have demonstrated that when indapamide is used as monotherapy, the antihypertensive effect lasts for 24 hours. This effect occurs at doses where diuretic properties are minimal. The antihypertensive action of indapamide is associated with improved arterial elasticity, reduced arteriolar resistance, and decreased total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.

When the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the number of adverse reactions increases. If there is no treatment response, the dose should not be increased.

Additionally, short-, medium-, and long-term studies involving patients with arterial hypertension have shown that indapamide:

does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins);
does not affect carbohydrate metabolism, even in patients with diabetes mellitus and arterial hypertension.

In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant reduction of arterial blood pressure over 24 hours, both in supine and standing positions. Due to amlodipine's slow onset of action, its use does not lead to acute hypotension. Amlodipine administration has not been associated with any metabolic adverse reactions or changes in plasma lipid levels, making it suitable for patients with asthma, gout, or diabetes mellitus.

Pharmacokinetics.

Concomitant administration of indapamide and amlodipine does not alter their pharmacokinetic properties compared to their individual use.

Indapamide

Indapamide 1.5 mg is formulated as a prolonged-release dosage form, enabled by a matrix system in which the active substance is dispersed, allowing for uniform, prolonged release of indapamide.

Absorption

Indapamide released from the tablet is rapidly and completely absorbed in the gastrointestinal tract. Food intake slightly increases the rate of absorption but does not affect the total amount of absorbed active substance. Maximum plasma concentration is reached approximately 12 hours after a single oral dose. Repeated administration reduces fluctuations in plasma indapamide levels between doses. There is inter-individual variability.

Distribution

Plasma protein binding of indapamide is 79%. The elimination half-life ranges from 14 to 24 hours (on average, 18 hours). Steady-state concentration is achieved within 7 days. Repeated administration does not lead to accumulation.

Excretion

Excretion occurs primarily via urine (70% of dose) and feces (22%) as inactive metabolites.

High-risk patients

Pharmacokinetic parameters are not altered in patients with renal impairment.

Amlodipine

Amlodipine is formulated as an immediate-release dosage form.

Absorption, distribution, plasma protein binding

After oral administration at therapeutic doses, amlodipine is well absorbed, with peak blood concentration reached within 6–12 hours. Absolute bioavailability is 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins. Food intake does not affect amlodipine bioavailability.

Biological transformation/excretion

The elimination half-life of amlodipine in plasma is approximately 35–50 hours, consistent with once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites, excreted unchanged in urine (10%) and as metabolites (60%).

Use in patients with hepatic impairment

Clinical data on amlodipine use in patients with hepatic impairment are limited. In patients with liver dysfunction, amlodipine clearance is reduced, leading to an increase in elimination half-life and area under the plasma concentration-time curve (AUC) by approximately 40–60%.

Use in elderly patients

Time to reach maximum plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, resulting in increased AUC and elimination half-life. Increased AUC and half-life in patients with congestive heart failure were consistent with the age group studied.

Clinical characteristics.

Indications.

Treatment of essential hypertension in patients requiring therapy with indapamide and amlodipine in doses available in fixed combinations.

Contraindications.

Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, or to any of the excipients of the medicinal product;
severe renal impairment (creatinine clearance < 30 mL/min);
hepatic encephalopathy or severe hepatic dysfunction;
hypokalemia;
breastfeeding period;
severe hypotension;
shock (including cardiogenic);
left ventricular outflow obstruction (e.g., severe aortic stenosis);
heart failure with unstable hemodynamics following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Interactions related to indapamide

Combinations not recommended

Lithium

Possible increase in plasma lithium concentration, leading to symptoms of lithium toxicity similar to those observed during salt-free diet (reduced urinary lithium excretion). However, if diuretic therapy is truly necessary, plasma lithium levels should be closely monitored and the diuretic dose adjusted accordingly.

Combinations requiring precautions

Medicinal products that may induce torsades de pointes ventricular tachycardia:

Class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide);
Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide, bretylium);
certain antipsychotics:
- phenothiazines (chlorpromazine, thiopropazin, levomepromazine, thioridazine, trifluoperazine);
- benzamides (amisulpride, sulpiride, sultopride, tiapride);
- butyrophenones (droperidol, haloperidol);
- other antipsychotics (e.g., pimozide);
other medicinal products: bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine.

Increased risk of ventricular arrhythmias, including torsades de pointes ventricular tachycardia (hypokalemia is a risk factor). Before prescribing such combinations, hypokalemia should be ruled out and potassium levels corrected if necessary. Clinical status, plasma electrolyte levels, and ECG monitoring should be performed. In the presence of hypokalemia, drugs not associated with torsades de pointes should be used.

Non-steroidal anti-inflammatory drugs (NSAIDs) (systemic use), including selective cyclooxygenase-2 inhibitors and high-dose acetylsalicylic acid (≥ 3 g/day)

Concomitant use may reduce the antihypertensive effect of indapamide. In dehydrated patients, the risk of acute renal failure increases (due to decreased glomerular filtration rate). Fluid balance should be restored and renal function assessed before initiating treatment.

Angiotensin-converting enzyme (ACE) inhibitors

In patients with sodium deficiency, treatment with ACE inhibitors may lead to sudden arterial hypotension and/or acute renal failure (especially in patients with renal artery stenosis).

For patients with arterial hypertension in whom prior diuretic therapy has led to sodium deficiency, it is necessary to:

discontinue diuretic therapy 3 days before initiating ACE inhibitor treatment and, if needed, restart diuretic therapy afterward;
or initiate ACE inhibitor therapy with a low starting dose, gradually increasing it.

For patients with congestive heart failure, ACE inhibitor therapy should be initiated at the lowest possible dose, possibly after reducing the dose of potassium-wasting diuretics.

In all cases, renal function (plasma creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.

Other compounds that may cause hypokalemia: intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic use), tetracosactide, stimulant laxatives

Increased risk of hypokalemia (additive effect). Plasma potassium levels should be monitored and corrected as needed. This is particularly important when treating concomitantly with cardiac glycosides. Non-stimulant laxatives are recommended.

Cardiac glycosides

Reduced blood potassium levels may enhance the toxic effects of cardiac glycosides. Plasma potassium levels and ECG should be monitored, and therapy reviewed if necessary.

Baclofen

Enhanced antihypertensive effect. At the beginning of treatment, fluid balance should be restored and renal function monitored.

Allopurinol

Concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.

Combinations requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

Although this combination may be rational in certain patients, both hypokalemia and hyperkalemia may occur (especially in patients with renal impairment or diabetes mellitus). Plasma potassium levels should be monitored, ECG monitoring performed, and therapy reviewed if necessary.

Metformin

Increased risk of metformin-associated lactic acidosis due to possible development of functional renal impairment associated with diuretic use, particularly loop diuretics. Metformin should not be prescribed if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents

In patients with dehydration caused by diuretic use, the risk of acute renal failure increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored before administering iodinated contrast agents.

Tricyclic antidepressants, neuroleptics

Enhanced antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

Calcium (salts)

Possible development of hypercalcemia due to reduced urinary calcium excretion.

Cyclosporine, tacrolimus

Possible increase in plasma creatinine levels without changes in circulating cyclosporine levels, even in the absence of water and sodium deficiency.

Corticosteroids, systemic tetracosactide

Possible reduction in antihypertensive effect (due to water and sodium retention caused by corticosteroids).

Interactions related to amlodipine

Dantrolene (infusion)

Animal studies have shown ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia after intravenous administration of verapamil and dantrolene. In patients predisposed to malignant hyperthermia or undergoing its treatment, concomitant use of calcium channel blockers such as amlodipine should be avoided due to the risk of hyperkalemia.

Grapefruit or grapefruit juice

Amlodipine should not be taken with grapefruit or grapefruit juice, as in some patients bioavailability may increase, leading to enhanced hypotensive effect.

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine concentration. These pharmacokinetic changes are more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary. There is an increased risk of arterial hypotension in patients receiving clarithromycin in combination with amlodipine. Close monitoring is recommended for such patients.

CYP3A4 inducers

When used concomitantly with known CYP3A4 inducers, amlodipine plasma concentration may change. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, particularly strong CYP3A4 inducers (e.g., rifampicin, St. John's wort (Hypericum perforatum)).

Effect of amlodipine on other medicinal products

Amlodipine's hypotensive effects may potentiate the hypotensive action of other medicinal products with antihypertensive properties (additive effect). Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Tacrolimus

There is a risk of increased blood tacrolimus levels when used concomitantly with amlodipine. To avoid tacrolimus toxicity, blood levels should be monitored and dose adjusted if necessary.

mTOR inhibitors (mechanistic target of rapamycin inhibitors)

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use with mTOR inhibitors may enhance their effects.

Cyclosporine

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other patient groups, except in kidney transplant patients, where an increase in cyclosporine trough concentration (on average from 0 to 40%) was observed. In kidney transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and its dose reduced if necessary.

Simvastatin

Administration of amlodipine at doses greater than 10 mg in combination with 80 mg simvastatin resulted in a 77% increase in simvastatin concentration compared to simvastatin monotherapy. Patients taking amlodipine should limit the dose of simvastatin to 20 mg per day.

Special precautions for use.

Special warnings

Hepatic encephalopathy

In patients with impaired liver function, the use of thiazide-like diuretics may precipitate hepatic encephalopathy, which may progress to hepatic coma, particularly in the presence of electrolyte imbalance. In such cases, the use of the medicinal product TENSOCARD should be immediately discontinued due to the presence of indapamide in its composition.

Photosensitivity

Photosensitivity reactions have been reported during treatment with thiazide and thiazide-like diuretics (see section "Adverse reactions"). If a photosensitivity reaction occurs during treatment, use of the medicinal product is recommended to be discontinued. If re-initiation of treatment is necessary, protection of exposed areas from sunlight or artificial ultraviolet sources is recommended.

Precautions for use

Hypertensive crisis

Specific safety and efficacy studies of amlodipine in hypertensive crisis have not been conducted.

Water and electrolyte balance:

Plasma sodium levels

Plasma sodium levels should be determined before starting treatment and at regular intervals thereafter. Decreased plasma sodium levels may initially be asymptomatic, thus monitoring is required. Monitoring should be performed more frequently in elderly patients and in those with hepatic cirrhosis (see sections "Overdose" and "Adverse reactions"). Any diuretic therapy may lead to hyponatremia, sometimes with very serious consequences. Hyponatremia in combination with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are minor.

Plasma potassium levels

Reduction in plasma potassium levels leading to hypokalemia is the main risk associated with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis, predominantly with severe hypokalemia, have been reported. Hypokalemia (< 3.4 mmol/L) should be prevented in patients at high risk, such as elderly patients, poorly nourished patients and/or those taking multiple medications, patients with cirrhosis accompanied by edema and ascites, patients with ischemic heart disease (IHD) and heart failure. In such patients, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias. Patients with congenital or drug-induced prolonged QT interval also belong to the risk group. In these patients, hypokalemia and bradycardia may lead to the development of severe arrhythmias, including torsade de pointes ventricular tachycardia, which may be fatal. More frequent monitoring of plasma potassium levels is required in all the above-mentioned cases. The first determination of plasma potassium levels should be performed within the first week of treatment. If hypokalemia is detected, correction of plasma potassium levels is necessary. Hypokalemia associated with low serum magnesium concentration may be refractory to treatment unless serum magnesium levels are also corrected.

Magnesium in plasma

Thiazides and related diuretics, including indapamide, have been shown to increase urinary excretion of magnesium, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Plasma calcium levels

Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and lead to a slight and transient increase in plasma calcium levels. The occurrence of hypercalcemia may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be evaluated.

Plasma glucose levels

Due to the presence of indapamide in the medicinal product, monitoring of plasma glucose levels is important in patients with diabetes mellitus, particularly in the presence of hypokalemia.

Heart failure

TENSOCARD should be administered with caution in patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher with amlodipine than 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 events and death.

Renal function

Thiazide and thiazide-like diuretics are most effective when renal function is normal or only slightly impaired (plasma creatinine < 25 mg/L, i.e., 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and gender. Hypovolemia caused by loss of water and sodium due to diuretic use at the beginning of treatment is associated with reduced glomerular filtration rate. This may lead to increased plasma urea and creatinine levels. This transient functional renal impairment has no consequences in patients with normal renal function, but may exacerbate pre-existing renal insufficiency.

Amlodipine can be used in standard doses in patients with renal impairment. Fluctuations in amlodipine plasma concentrations are independent of the severity of renal impairment. Amlodipine is not dialyzable. Studies evaluating the efficacy of the amlodipine/indapamide combination in patients with renal dysfunction have not been conducted. In patients with impaired renal function, the dose of the medicinal product should be adjusted according to the dosing recommendations for each individual component when used as monotherapy.

Plasma uric acid levels

In patients with a history of gout, there is a possibility of increased frequency of gout attacks due to elevated plasma uric acid levels caused by the presence of indapamide in the formulation.

Patients with impaired liver function

In patients with impaired liver function, the elimination half-life of amlodipine is prolonged and AUC is increased; however, dosing recommendations are lacking. Therefore, treatment with amlodipine should be initiated at the lowest dose. The medicinal product should be used with caution at the beginning of treatment and when increasing the dose. Targeted studies evaluating the efficacy of the amlodipine/indapamide combination in patients with impaired liver function have not been conducted. Due to the properties of indapamide and amlodipine, the medicinal product TENSOCARD is contraindicated in patients with severe hepatic impairment. TENSOCARD should be used with caution in patients with mild to moderate hepatic impairment.

Elderly patients

TENSOCARD should be administered to elderly patients with consideration of renal function (see sections "Pharmacokinetics" and "Dosage and administration").

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms, including acute onset of decreased visual acuity or eye pain, usually occur within hours or weeks after starting the medicinal product. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical interventions may be necessary. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Sportsmen

Athletes should be aware that the product contains an active substance that may lead to a positive doping test.

Excipients

Since the medicinal product TENSOCARD contains lactose, it should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Due to the effects of the components of the combined medicinal product TENSOCARD on pregnancy and breastfeeding:

use of the medicinal product during pregnancy is not recommended;
the medicinal product is contraindicated during breastfeeding.

Pregnancy

Warnings related to indapamide

Data on the use of indapamide in pregnant women are lacking or limited (less than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may result in reduced circulating blood volume (CBV) in the pregnant woman and uteroplacental hypoperfusion, potentially leading to fetoplacental ischemia and delayed fetal development. In rare cases, neonates have shown hypoglycemia and thrombocytopenia. Animal studies did not reveal any direct or indirect toxic effects on reproductive function.

Warnings related to amlodipine

Safety studies of amlodipine use in pregnant women have not been conducted. Animal studies using high doses showed toxic effects on reproductive function.

Breastfeeding

Warnings related to indapamide

Data on the passage of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, whose use during breastfeeding is associated with reduced or even suppressed lactation.

Warnings related to amlodipine

Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant has been estimated as an interquartile range of 3–7% with a maximum of 15%. The effect of amlodipine on infants is unknown.

Fertility

Warnings related to indapamide

Reproductive toxicity studies showed no effect on fertility in male and female rats. An effect on human fertility is not expected.

Warnings related to amlodipine

In some patients, calcium channel blockers have been associated with reversible biochemical changes in the sperm head. Clinical data on the potential effect of amlodipine on fertility are limited. In one animal study, adverse effects affecting male fertility were observed.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product TENSOCARD has a minor or moderate influence on the ability to drive vehicles and operate machinery.

Indapamide

Indapamide does not affect alertness, but various reactions related to decreased blood pressure may occur, particularly at the beginning of treatment or when used concomitantly with other antihypertensive agents. As a result, the ability to drive vehicles or operate machinery may be impaired.

Amlodipine

Amlodipine may have a minor or moderate influence on the ability to drive vehicles and operate machinery. If patients taking amlodipine experience adverse reactions such as dizziness, headache, fatigue, or nausea, their reaction ability may be reduced. Caution is recommended, especially at the beginning of treatment.

Method of Administration and Dosage

The medicinal product TENSOCARD is intended for oral administration.

The recommended dose is 1 capsule once daily, preferably in the morning before food. The capsule should be swallowed whole with water. The maximum daily dose is 1 capsule (10 mg/1.5 mg).

Fixed-dose combination therapy is not indicated for initiation of treatment.

If dose adjustment is required, individual titration of each component of the combination should be performed.

Special Patient Groups

Patients with Renal Impairment (see sections "Contraindications" and "Special Warnings and Precautions for Use")

TENSOCARD is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Dose adjustment is not required in patients with mild to moderate renal impairment.

Elderly Patients (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")

TENSOCARD should be used in elderly patients with consideration of renal function.

Patients with Hepatic Impairment (see sections "Contraindications" and "Special Warnings and Precautions for Use")

Treatment with TENSOCARD is contraindicated in patients with severe hepatic impairment. For patients with mild to moderate hepatic impairment, dosage recommendations for amlodipine have not been established; therefore, the dose should be carefully adjusted, starting with the lowest dose (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Children

Safety and efficacy of the amlodipine/indapamide combination in children have not been established. Data are lacking.

Overdose

There is no human experience with overdose of the amlodipine/indapamide combination.

Overdose with Indapamide

Symptoms

No toxic effects were observed following indapamide doses up to 40 mg, which is 27 times the therapeutic dose. Symptoms of acute poisoning are primarily related to disturbances in water and electrolyte balance (hyponatremia, hypokalemia). Clinically, nausea, vomiting, arterial hypotension, seizures, vertigo, drowsiness, confusion, polyuria, or oliguria may occur, potentially leading to anuria (due to hypovolemia).

Treatment

Emergency measures include rapid removal of the ingested substance by gastric lavage and/or administration of activated charcoal, followed by correction of water and electrolyte imbalances under hospital conditions.

Overdose with Amlodipine

Data on intentional overdose in humans are limited.

Symptoms

Available data suggest that ingestion of very high doses may lead to excessive peripheral vasodilation and reflex tachycardia. Profound, possibly prolonged systemic hypotension has been reported, leading to shock and fatal outcomes. Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, which may develop with delay (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors may include early resuscitation measures (including fluid overload) aimed at supporting perfusion and cardiac output.

Treatment

Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with legs elevated, and monitoring of blood volume and urine output. Administration of vasopressors may be beneficial to restore vascular tone and blood pressure, provided there are no contraindications. Intravenous administration of calcium gluconate may help counteract the effects of calcium channel blockade. In some cases, gastric lavage may be beneficial. Administration of activated charcoal within 2 hours after ingestion of 10 mg amlodipine reduces its absorption rate. Due to the high protein binding of amlodipine, hemodialysis is unlikely to be effective.

Adverse Reactions

The most commonly reported adverse reactions during separate administration of indapamide and amlodipine include hypokalemia, somnolence, dizziness, headache, visual disturbances, diplopia, palpitations, flushing, dyspnea, abdominal pain, nausea, dyspepsia, altered defecation rhythm, diarrhea, constipation, maculopapular rash, ankle edema, muscle cramps, edema, fatigue, and asthenia.

During treatment with indapamide and amlodipine, adverse reactions have been reported with the following frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (≤ 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations: rhinitis (uncommon – amlodipine).

Blood and lymphatic system disorders: leukopenia (very rare – indapamide, amlodipine), thrombocytopenia (very rare – indapamide, amlodipine), agranulocytosis (very rare – indapamide), aplastic anemia (very rare – indapamide), hemolytic anemia (very rare – indapamide).

Immune system disorders: hypersensitivity (very rare – amlodipine).

Metabolism and nutrition disorders: hypokalemia (common – indapamide (in clinical trials, hypokalemia (plasma potassium level < 3.4 mmol/L) was observed in 10% of patients, and plasma potassium levels < 3.2 mmol/L in 4% of patients after 4–6 weeks of treatment; after 12 weeks of therapy, the mean decrease in plasma potassium level was 0.23 mmol/L (see section "Special precautions for use")), hyperglycemia (very rare – amlodipine), hypercalcemia (very rare – indapamide), hyponatremia with hypovolemia* (uncommon – indapamide); hypochloremia (rare – indapamide); hypomagnesemia (rare – indapamide).

Psychiatric disorders: insomnia (uncommon – amlodipine), mood changes (including anxiety) (uncommon – amlodipine), depression (uncommon – amlodipine), confusion (rare – amlodipine).

Nervous system disorders: somnolence (common – amlodipine (especially at the beginning of treatment)), dizziness (common – amlodipine (especially at the beginning of treatment)), headache (rare – indapamide, common – amlodipine (especially at the beginning of treatment)), tremor (uncommon – amlodipine), dysgeusia (uncommon – amlodipine), loss of consciousness (frequency not known – indapamide, uncommon – amlodipine), hypesthesia (uncommon – amlodipine), paresthesia (rare – indapamide, uncommon – amlodipine), hypertonia (very rare – amlodipine), peripheral neuropathy (very rare – amlodipine), extrapyramidal disorders (extrapyramidal syndrome) (frequency not known – amlodipine), hepatic encephalopathy may occur in case of liver insufficiency (see sections "Contraindications" and "Special precautions for use") (frequency not known – indapamide).

Eye disorders: visual disturbances (frequency not known – indapamide, common – amlodipine), diplopia (common – amlodipine), myopia (frequency not known – indapamide), acute angle-closure glaucoma (frequency not known – indapamide), blurred vision (frequency not known – indapamide), choroidal effusion (frequency not known – indapamide).

Ear and labyrinth disorders: tinnitus (uncommon – amlodipine), vertigo (rare – indapamide).

Cardiac disorders: palpitations (common – amlodipine), myocardial infarction (very rare – amlodipine), arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) (very rare – indapamide, uncommon – amlodipine), torsades de pointes (potentially fatal) (frequency not known – indapamide (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction")).

Vascular disorders: flushing (common – amlodipine), arterial hypotension (very rare – indapamide, uncommon – amlodipine), vasculitis (very rare – amlodipine).

Respiratory, thoracic and mediastinal disorders: dyspnea (common – amlodipine), cough (uncommon – amlodipine).

Gastrointestinal disorders: abdominal pain (common – amlodipine), nausea (rare – indapamide, common – amlodipine), vomiting (uncommon – indapamide, amlodipine), dyspepsia (common – amlodipine), altered defecation rhythm (common – amlodipine), dry mouth (rare – indapamide, uncommon – amlodipine), pancreatitis (very rare – indapamide, amlodipine), gastritis (very rare – amlodipine), gingival hyperplasia (very rare – amlodipine), diarrhea (common – amlodipine), constipation (rare – indapamide, common – amlodipine).

Hepatobiliary disorders: hepatitis (frequency not known – indapamide, very rare – amlodipine), jaundice (very rare – amlodipine), liver function abnormalities (very rare – indapamide).

Skin and subcutaneous tissue disorders: maculopapular rash (common – indapamide), purpura (uncommon – indapamide, amlodipine), alopecia (uncommon – amlodipine), skin discoloration (uncommon – amlodipine), hyperhidrosis (uncommon – amlodipine), pruritus (uncommon – amlodipine), rash (uncommon – amlodipine), exanthema (uncommon – amlodipine), angioedema (very rare – indapamide, amlodipine), urticaria (very rare – indapamide, uncommon – amlodipine), toxic epidermal necrolysis (very rare – indapamide, frequency not known – amlodipine), Stevens-Johnson syndrome (very rare – indapamide, amlodipine), erythema multiforme (very rare – amlodipine), exfoliative dermatitis (very rare – amlodipine), Quincke's edema (very rare – amlodipine), photosensitivity reactions (see section "Special precautions for use") (cases of photosensitivity reactions have been reported – indapamide, very rare – amlodipine).

Musculoskeletal and connective tissue disorders: ankle edema (common – amlodipine), arthralgia (uncommon – amlodipine), myalgia (uncommon – amlodipine), muscle cramps (common – amlodipine), muscle weakness (frequency not known – indapamide); rhabdomyolysis (frequency not known – indapamide), back pain (uncommon – amlodipine), possible exacerbation of pre-existing systemic lupus erythematosus (frequency not known – indapamide).

Renal and urinary disorders: micturition disorders (uncommon – amlodipine), nocturia (uncommon – amlodipine), polyuria (uncommon – amlodipine), renal failure (very rare – indapamide).

Reproductive system and breast disorders: erectile dysfunction (uncommon – amlodipine), gynecomastia (uncommon – amlodipine).

General disorders and administration site conditions: edema (very rare – amlodipine), fatigue (rare – indapamide, common – amlodipine), chest pain (uncommon – amlodipine), asthenia (common – amlodipine), pain (uncommon – amlodipine), malaise (uncommon – amlodipine).

Investigations: weight increased (uncommon – amlodipine), weight decreased (uncommon – amlodipine), QT interval prolongation on ECG (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction") (frequency not known – indapamide), increased blood glucose levels (the appropriateness of prescribing these diuretics should be carefully considered before administration to patients with gout or diabetes mellitus) (frequency not known – indapamide), increased blood uric acid levels (the appropriateness of prescribing these diuretics should be carefully considered before administration to patients with gout or diabetes mellitus) (frequency not known – indapamide), increased liver enzymes (frequency not known – indapamide, very rare** – amlodipine).

*May lead to dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory alkalosis; the frequency and severity of this effect are low.

**Mostly due to cholestasis.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 capsules per blister, 3 blisters per cardboard pack.

Or 30 capsules in a bottle, 1 bottle per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

NVF "MIKROKHM" LLC (responsible for batch release, excluding batch control/testing).

JSC "Farmak" (responsible for manufacturing and batch control/testing, excluding batch release).

Manufacturer's address and location of business activity.

Ukraine, 01013, Kyiv, Budynsturiyi St., 5.

Ukraine, 04080, Kyiv, Kyrylivska St., 74.

INSTRUCTION

for medical use of medicinal product

TENSOCARD

(TENSOCARD)

Composition:

Active substances: amlodipine, indapamide;

1 capsule contains:

6.935 mg amlodipine besylate equivalent to 5 mg amlodipine, and 1.5 mg indapamide,

or 13.870 mg amlodipine besylate equivalent to 10 mg amlodipine, and 1.5 mg indapamide;

Excipients:

for amlodipine tablets: lactose monohydrate; microcrystalline cellulose; crospovidone; magnesium stearate; colloidal anhydrous silicon dioxide;

Capsule (body and cap): gelatin; water; titanium dioxide (E 171).

Pharmaceutical form. Modified-release hard capsules.

Main physicochemical characteristics: opaque, hard gelatin capsules, white or almost white, containing two amlodipine tablets, white or almost white, and one film-coated indapamide tablet, yellowish-brown in colour.

Pharmacotherapeutic group.

Calcium channel blockers and diuretics. Amlodipine and diuretics. ATC code C08GA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics, acting by inhibiting sodium reabsorption in the cortical segment of the kidneys. This increases urinary excretion of sodium and chloride, and to a lesser extent potassium and magnesium, thereby increasing diuresis and providing antihypertensive effect.

Amlodipine is a dihydropyridine calcium channel blocker (inhibitor of calcium ion influx or calcium channel antagonist) that prevents transmembrane influx of calcium ions into vascular smooth muscle and myocardial cells. The antihypertensive mechanism of amlodipine is based on its ability to relax vascular smooth muscle.

Pharmacodynamic effects

Phase II and III clinical studies have demonstrated that when used as monotherapy, the antihypertensive effect of indapamide lasts for 24 hours. This effect occurs at doses where diuretic activity is minimal. The antihypertensive action of indapamide is associated with improved arterial elasticity, reduced arteriolar resistance, and decreased total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.

When the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the incidence of adverse reactions increases. If treatment is ineffective, the dose should not be increased.

In addition, short-, medium-, and long-term studies involving patients with arterial hypertension have shown that indapamide:

does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins);
does not affect carbohydrate metabolism, even in patients with diabetes mellitus and arterial hypertension.

In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant reduction in blood pressure over 24 hours, both in supine and standing positions. Due to the slow onset of action, amlodipine does not cause acute hypotension. The use of amlodipine has not been associated with any metabolic adverse reactions or changes in plasma lipid levels, making it suitable for use in patients with asthma, gout, and diabetes mellitus.

Pharmacokinetics.

Concomitant administration of indapamide and amlodipine does not alter their pharmacokinetic properties compared to their individual use.

Indapamide

Indapamide 1.5 mg is formulated as a prolonged-release dosage form, enabled by a matrix system in which the active substance is dispersed, allowing for uniform, prolonged release of indapamide.

Absorption

Indapamide released from the tablet is rapidly and completely absorbed in the gastrointestinal tract. Food intake slightly increases the rate of absorption but does not affect the total amount of absorbed active substance. Maximum plasma concentration is reached approximately 12 hours after single oral administration. Repeated dosing reduces fluctuations in plasma indapamide levels between doses. There is inter-individual variability.

Distribution

Elimination

Elimination occurs primarily via urine (70% of the dose) and feces (22%) as inactive metabolites.

High-risk patients

In patients with renal impairment, pharmacokinetic parameters are not altered.

Amlodipine

Amlodipine is formulated as an immediate-release dosage form.

Absorption, distribution, plasma protein binding

After oral administration at therapeutic doses, amlodipine is well absorbed, with peak blood concentrations reached within 6–12 hours. Absolute bioavailability is 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins. Food intake does not affect amlodipine bioavailability.

Biological transformation/elimination

The elimination half-life of amlodipine in plasma is approximately 35–50 hours, consistent with once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites and is excreted unchanged in urine (10%) and as metabolites (60%).

Use in patients with hepatic impairment

Clinical data on amlodipine use in patients with hepatic impairment are limited. In patients with liver insufficiency, amlodipine clearance is reduced, resulting in an approximately 40–60% increase in elimination half-life and area under the plasma concentration-time curve (AUC).

Use in elderly patients

Time to reach maximum plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and elimination half-life. In patients with congestive heart failure, increased AUC and half-life were consistent with the expected profile for the studied age group.

Clinical characteristics.

Indications.

Treatment of essential hypertension in patients requiring therapy with indapamide and amlodipine in doses available in fixed combinations.

Contraindications.

Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, or to any of the excipients of the medicinal product;
severe renal impairment (creatinine clearance < 30 mL/min);
hepatic encephalopathy or severe hepatic dysfunction;
hypokalemia;
breastfeeding period;
severe hypotension;
shock (including cardiogenic);
obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis);
heart failure with unstable hemodynamics following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Interactions related to indapamide

Not recommended combinations

Lithium

Combinations requiring precautions

Medicinal products that may provoke torsades de pointes ventricular tachycardia:

Class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide);
class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide, bretylium);
certain antipsychotics:
- phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine);
- benzamides (amisulpride, sulpiride, sultopride, tiapride);
- butyrophenones (droperidol, haloperidol);
- other antipsychotics (e.g., pimozide);
other medicinal products: bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine.

Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalemia is a risk factor). Before prescribing such combinations, check for hypokalemia and correct potassium levels if necessary. Monitor the patient's clinical status, plasma electrolyte levels, and perform ECG monitoring. In the presence of hypokalemia, use medicinal products that do not provoke torsades de pointes.

Non-steroidal anti-inflammatory drugs (NSAIDs) (systemic use), including selective cyclooxygenase-2 inhibitors and high-dose acetylsalicylic acid (≥ 3 g/day)

Angiotensin-converting enzyme (ACE) inhibitors

In patients with sodium deficiency, treatment with ACE inhibitors may lead to sudden arterial hypotension and/or acute renal failure (especially in patients with renal artery stenosis).

For patients with arterial hypertension in whom prior diuretic therapy has led to sodium deficiency, it is necessary to:

discontinue the diuretic 3 days before starting ACE inhibitor therapy and, if needed, resume diuretic treatment afterward;
or initiate ACE inhibitor therapy with a low starting dose and gradually increase it.

For patients with congestive heart failure, ACE inhibitor therapy should be initiated at the lowest possible dose, possibly after reducing the dose of concomitant potassium-wasting diuretics.

In all cases, renal function (plasma creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Other compounds that may cause hypokalemia: intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic use), tetracosactide, stimulant laxatives

Digitalis preparations

Reduced blood potassium levels increase the risk of toxic effects of digitalis preparations. Plasma potassium levels and ECG should be monitored, and therapy reviewed if necessary.

Baclofen

Enhanced antihypertensive effect. At the beginning of treatment, restore the patient's fluid balance and monitor renal function.

Allopurinol

Concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.

Combinations requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

Metformin

Increased risk of metformin-associated lactic acidosis due to possible development of functional renal impairment related to diuretic use, particularly loop diuretics. Metformin should not be prescribed if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents

In the presence of dehydration caused by diuretic use, the risk of acute renal failure increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored before administering iodinated contrast agents.

Tricyclic antidepressants, neuroleptics

Enhanced antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

Calcium (salts)

Possible development of hypercalcemia due to reduced urinary calcium excretion.

Cyclosporine, tacrolimus

Possible increase in plasma creatinine levels without changes in circulating cyclosporine levels, even in the absence of water and sodium deficiency.

Corticosteroids, tetracosactide (systemic action)

Possible reduction in antihypertensive effect (water and sodium retention due to corticosteroids).

Interactions related to amlodipine

Dantrolene (infusion)

Animal studies have shown ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia after intravenous administration of verapamil and dantrolene. In patients predisposed to malignant hyperthermia and during its treatment, concomitant use of calcium channel blockers such as amlodipine should be avoided due to the risk of hyperkalemia.

Grapefruit or grapefruit juice

It is not recommended to take amlodipine with grapefruit or grapefruit juice, as in some patients bioavailability may increase, leading to enhanced hypotensive effect.

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine concentration. These pharmacokinetic changes are more pronounced in elderly patients. Clinical monitoring and dose adjustment may therefore be necessary. There is an increased risk of arterial hypotension in patients taking clarithromycin in combination with amlodipine. Such patients should be closely monitored.

CYP3A4 inducers

When used concomitantly with known CYP3A4 inducers, plasma concentrations of amlodipine may change. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, particularly strong CYP3A4 inducers (e.g., rifampicin, St. John's wort (hypericum perforatum)).

Effect of amlodipine on other medicinal products

The antihypertensive effects of amlodipine potentiate the hypotensive action of other medicinal products with antihypertensive properties (additive effect). Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Tacrolimus

There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid tacrolimus toxicity when used concomitantly with amlodipine, blood levels should be monitored and the dose adjusted if necessary.

mTOR (mechanistic target of rapamycin) inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When used concomitantly with mTOR inhibitors, amlodipine may enhance their effects.

Cyclosporine

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other patient groups, except in kidney transplant patients, in whom an increase in cyclosporine trough concentration fluctuations (on average from 0 to 40%) was observed. In kidney transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and its dose reduced if necessary.

Simvastatin

The use of amlodipine at doses ≥10 mg in combination with 80 mg simvastatin resulted in a 77% increase in simvastatin concentration compared to monotherapy. Patients taking amlodipine should limit the dose of simvastatin to 20 mg daily.

Special precautions for use.

Special warnings

Hepatic encephalopathy

In patients with impaired liver function, the use of thiazide-like diuretics may precipitate hepatic encephalopathy, which may progress to hepatic coma, particularly in the presence of electrolyte imbalance. In such cases, TENZOCARD should be discontinued immediately due to the presence of indapamide in its composition.

Photosensitivity

Photosensitivity reactions have been reported with the use of thiazide and thiazide-like diuretics (see section "Adverse reactions"). If a photosensitivity reaction occurs during treatment, use of the medicinal product should be discontinued. If re-initiation of treatment is necessary, protection of exposed areas from sunlight or artificial ultraviolet sources is recommended.

Precautions for use

Hypertensive crisis

Clinical studies specifically evaluating the safety and efficacy of amlodipine in hypertensive crisis have not been conducted.

Water and electrolyte balance:

Plasma sodium levels

Plasma sodium levels should be determined before initiating treatment and at regular intervals thereafter. Decreased plasma sodium levels may initially be asymptomatic, thus monitoring is required. Monitoring should be performed more frequently in elderly patients and in those with hepatic cirrhosis (see sections "Overdose" and "Adverse reactions"). Any diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia in combination with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are low.

Plasma potassium levels

Reduction in plasma potassium levels leading to hypokalemia is a major risk associated with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis, mainly associated with severe hypokalemia, have been reported. Hypokalemia (< 3.4 mmol/L) should be prevented in high-risk patients, such as elderly patients, those who are poorly nourished and/or taking multiple medications, patients with cirrhosis accompanied by edema and ascites, and patients with ischemic heart disease (IHD) and heart failure. In such patients, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias. Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. In these patients, hypokalemia and bradycardia may lead to severe arrhythmias, including torsades de pointes-type paroxysmal ventricular tachycardia, which may be fatal. In all such cases, more frequent monitoring of plasma potassium levels is required. The first determination of plasma potassium levels should be performed within the first week of treatment. If hypokalemia is detected, correction of plasma potassium levels is necessary. Hypokalemia associated with low serum magnesium levels may be refractory to treatment unless serum magnesium levels are also corrected.

Magnesium in plasma

Plasma calcium levels

Thiazide and thiazide-like diuretics may reduce urinary excretion of calcium and lead to a slight and transient increase in plasma calcium levels. The occurrence of hypercalcemia may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be evaluated.

Plasma glucose levels

Due to the presence of indapamide in the medicinal product, monitoring of plasma glucose levels is important in patients with diabetes mellitus, especially in the presence of hypokalemia.

Heart failure

TENZOCARD should be administered with caution in patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher with amlodipine than with placebo. Calcium channel antagonists, including amlodipine, should be administered with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and death.

Renal function

Thiazide and thiazide-like diuretics are most effective when renal function is not impaired or only mildly impaired (plasma creatinine level < 25 mg/L, i.e., < 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and sex. Hypovolemia caused by loss of water and sodium due to diuretic use at the beginning of treatment is associated with reduced glomerular filtration rate. This may lead to increased plasma urea and creatinine levels. This transient functional renal insufficiency has no consequences in patients with normal renal function, but may exacerbate pre-existing renal impairment.

Amlodipine can be used in standard doses in patients with renal impairment. Plasma concentration fluctuations of amlodipine do not depend on the severity of renal impairment. Amlodipine is not dialyzable. Studies evaluating the efficacy of the amlodipine/indapamide combination in patients with renal dysfunction have not been conducted. In patients with impaired renal function, the dose of the medicinal product should be adjusted according to the dosing recommendations for each individual component when used as monotherapy.

Plasma uric acid levels

In patients with a history of gout, there is a risk of increased gout attacks due to elevated plasma uric acid levels caused by the presence of indapamide in the formulation.

Patients with impaired liver function

In patients with impaired liver function, the elimination half-life of amlodipine is prolonged and AUC is increased, but dosing recommendations are lacking. Therefore, treatment with amlodipine should be initiated at the lowest dose. The medicinal product should be used with caution at the beginning of treatment and when increasing the dose. Targeted studies evaluating the efficacy of the amlodipine/indapamide combination in patients with impaired liver function have not been conducted. Due to the properties of indapamide and amlodipine, TENZOCARD is contraindicated in patients with severe hepatic impairment. TENZOCARD should be used with caution in patients with mild to moderate hepatic impairment.

Elderly patients

TENZOCARD should be used in elderly patients with consideration of renal function (see sections "Pharmacokinetics" and "Dosage and administration").

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms, including acute onset of decreased visual acuity or eye pain, usually occur within hours or weeks after starting the medicinal product. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical intervention may be necessary. Risk factors for the development of acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Sportsmen

Athletes should be aware that the product contains an active substance that may result in a positive doping test.

Excipients

Since TENZOCARD contains lactose, it should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Due to the effects of the components of the combined medicinal product TENZOCARD on pregnancy and breastfeeding:

use of the medicinal product during pregnancy is not recommended;
the medicinal product is contraindicated during breastfeeding.

Pregnancy

Warnings related to indapamide

Data on the use of indapamide in pregnant women are lacking or limited (< 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may result in reduced circulating blood volume (CBV) in the pregnant woman and uteroplacental perfusion, potentially leading to fetoplacental ischemia and delayed fetal development. In rare cases, neonates have exhibited hypoglycemia and thrombocytopenia. Animal studies have not revealed direct or indirect toxic effects on reproductive function.

Warnings related to amlodipine

Clinical safety studies of amlodipine use in pregnant women have not been conducted. Animal studies have shown toxic effects on reproductive function when high doses were administered.

Breastfeeding

Warnings related to indapamide

Data on the passage of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. Risk to neonates/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, the use of which during breastfeeding is associated with reduced or even suppressed lactation.

Warnings related to amlodipine

Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant has been estimated as an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Fertility

Warnings related to indapamide

Reproductive toxicity studies showed no effect on fertility in male and female rats. An effect on human fertility is not expected.

Warnings related to amlodipine

In some patients, calcium channel blockers have been associated with reversible biochemical changes in the sperm head. Clinical data on the potential effect of amlodipine on fertility are insufficient. In one animal study, adverse effects affecting male fertility were observed.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product TENZOCARD has a minor or moderate effect on the ability to drive vehicles and operate machinery.

Indapamide

Amlodipine

Amlodipine may have a minor or moderate effect on the ability to drive vehicles and operate machinery. If patients taking amlodipine experience adverse reactions such as dizziness, headache, fatigue, or nausea, their reaction time may be reduced. Caution is recommended, especially at the beginning of treatment.

Dosage and Administration

The medicinal product TENSOCARD is intended for oral administration.

The recommended dose of the medicinal product is 1 capsule once daily, preferably in the morning before food. The capsule should be swallowed whole with water. The maximum daily dose is 1 capsule (10 mg/1.5 mg).

The use of this fixed combination is not indicated for initiating therapy.

If dose adjustment is necessary, individual titration of each component of the combination should be performed.

Special Patient Groups

Patients with Renal Impairment (see sections "Contraindications" and "Special Warnings and Precautions for Use")

TENSOCARD is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). No dose adjustment is required in patients with mild to moderate renal impairment.

Elderly Patients (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")

TENSOCARD should be used in elderly patients with consideration of renal function.

Patients with Hepatic Impairment (see sections "Contraindications" and "Special Warnings and Precautions for Use")

TENSOCARD is contraindicated in patients with severe hepatic impairment. For patients with mild to moderate hepatic impairment, dosage recommendations for amlodipine have not been established; therefore, the dose should be carefully titrated, starting with the lowest dose (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Children

The safety and efficacy of the amlodipine/indapamide combination in children have not been studied. Data are lacking.

Overdose

There is no human information available regarding overdose with the amlodipine/indapamide combination.

Overdose with Indapamide

Symptoms

No toxic effects were observed with indapamide doses up to 40 mg, which is 27 times higher than the therapeutic dose. Symptoms of acute poisoning are mainly related to disturbances in water and electrolyte balance (hyponatremia, hypokalemia). Clinically, nausea, vomiting, hypotension, seizures, vertigo, drowsiness, confusion, polyuria, or oliguria may occur, potentially leading to anuria (due to hypovolemia).

Treatment

Overdose with Amlodipine

Data on intentional overdose in humans are limited.

Symptoms

Available data suggest that ingestion of very high doses may lead to excessive peripheral vasodilation and possible reflex tachycardia. Profound, possibly prolonged systemic hypotension has been reported, leading to shock with fatal outcome. Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, which may develop with delay (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

Treatment

Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with legs elevated, and monitoring of circulating blood volume and urine output. Administration of a vasopressor may be beneficial to restore vascular tone and arterial pressure, provided there are no contraindications. Intravenous calcium gluconate may help counteract the effects of calcium channel blockade. In some cases, gastric lavage may be beneficial. Administration of activated charcoal within 2 hours after ingestion of 10 mg amlodipine reduces its absorption rate. Since amlodipine is highly protein-bound, hemodialysis is unlikely to be effective.

Adverse reactions

The most commonly reported adverse reactions with indapamide and amlodipine when used separately include hypokalaemia, somnolence, dizziness, headache, visual disturbances, diplopia, palpitations, flushing, dyspnoea, abdominal pain, nausea, dyspepsia, altered defecation rhythm, diarrhoea, constipation, maculopapular rash, ankle oedema, muscle cramps, oedema, fatigue, and asthenia.

During treatment with indapamide and amlodipine, adverse reactions have been reported with the following frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Infections and infestations: rhinitis (uncommon – amlodipine).

Blood and lymphatic system disorders: leucopenia (very rare – indapamide, amlodipine), thrombocytopenia (very rare – indapamide, amlodipine), agranulocytosis (very rare – indapamide), aplastic anaemia (very rare – indapamide), haemolytic anaemia (very rare – indapamide).

Immune system disorders: hypersensitivity (very rare – amlodipine).

Metabolism and nutrition disorders: hypokalaemia (common – indapamide (in clinical studies, hypokalaemia (plasma potassium level < 3.4 mmol/L) was observed in 10% of patients, plasma potassium level < 3.2 mmol/L in 4% of patients after 4–6 weeks of treatment; after 12 weeks of therapy, the mean decrease in plasma potassium level was 0.23 mmol/L (see section "Special precautions for use")), hyperglycaemia (very rare – amlodipine), hypercalcaemia (very rare – indapamide), hyponatraemia with hypovolaemia* (uncommon – indapamide); hypochloraemia (rare – indapamide); hypomagnesaemia (rare – indapamide).

Psychiatric disorders: insomnia (uncommon – amlodipine), mood changes (including anxiety) (uncommon – amlodipine), depression (uncommon – amlodipine), confusion (rare – amlodipine).

Nervous system disorders: somnolence (common – amlodipine (especially at the beginning of treatment)), dizziness (common – amlodipine (especially at the beginning of treatment)), headache (rare – indapamide, common – amlodipine (especially at the beginning of treatment)), tremor (uncommon – amlodipine), dysgeusia (uncommon – amlodipine), loss of consciousness (frequency not known – indapamide, uncommon – amlodipine), hypoesthesia (uncommon – amlodipine), paraesthesia (rare – indapamide, uncommon – amlodipine), hypertonia (very rare – amlodipine), peripheral neuropathy (very rare – amlodipine), extrapyramidal disorders (extrapyramidal syndrome) (frequency not known – amlodipine), in case of hepatic insufficiency, hepatic encephalopathy may occur (see sections "Contraindications" and "Special precautions for use") (frequency not known – indapamide).

Ear and labyrinth disorders: tinnitus (uncommon – amlodipine), vertigo (rare – indapamide).

Cardiac disorders: palpitations (common – amlodipine), myocardial infarction (very rare – amlodipine), arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) (very rare – indapamide, uncommon – amlodipine), torsade de pointes (potentially fatal) (frequency not known – indapamide (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction")).

Vascular disorders: flushing (common – amlodipine), arterial hypotension (very rare – indapamide, uncommon – amlodipine), vasculitis (very rare – amlodipine).

Respiratory, thoracic and mediastinal disorders: dyspnoea (common – amlodipine), cough (uncommon – amlodipine).

Gastrointestinal disorders: abdominal pain (common – amlodipine), nausea (rare – indapamide, common – amlodipine), vomiting (uncommon – indapamide, amlodipine), dyspepsia (common – amlodipine), altered defecation rhythm (common – amlodipine), dry mouth (rare – indapamide, uncommon – amlodipine), pancreatitis (very rare – indapamide, amlodipine), gastritis (very rare – amlodipine), gingival hyperplasia (very rare – amlodipine), diarrhoea (common – amlodipine), constipation (rare – indapamide, common – amlodipine).

Hepatobiliary disorders: hepatitis (frequency not known – indapamide, very rare – amlodipine), jaundice (very rare – amlodipine), liver function abnormalities (very rare – indapamide).

Skin and subcutaneous tissue disorders: maculopapular rash (common – indapamide), purpura (uncommon – indapamide, amlodipine), alopecia (uncommon – amlodipine), skin discoloration (uncommon – amlodipine), hyperhidrosis (uncommon – amlodipine), pruritus (uncommon – amlodipine), rash (uncommon – amlodipine), exanthema (uncommon – amlodipine), angioneurotic oedema (very rare – indapamide, amlodipine), urticaria (very rare – indapamide, uncommon – amlodipine), toxic epidermal necrolysis (very rare – indapamide, frequency not known – amlodipine), Stevens-Johnson syndrome (very rare – indapamide, amlodipine), erythema multiforme (very rare – amlodipine), exfoliative dermatitis (very rare – amlodipine), Quincke's oedema (very rare – amlodipine), photosensitivity reactions (see section "Special precautions for use") (cases of photosensitivity reactions have been reported – indapamide, very rare – amlodipine).

Musculoskeletal and connective tissue disorders: ankle oedema (common – amlodipine), arthralgia (uncommon – amlodipine), myalgia (uncommon – amlodipine), muscle cramps (common – amlodipine), muscle weakness (frequency not known – indapamide); rhabdomyolysis (frequency not known – indapamide), back pain (uncommon – amlodipine), possible exacerbation of existing systemic lupus erythematosus (frequency not known – indapamide).

Renal and urinary disorders: micturition disorders (uncommon – amlodipine), nocturia (uncommon – amlodipine), polyuria (uncommon – amlodipine), renal failure (very rare – indapamide).

Reproductive system and breast disorders: erectile dysfunction (uncommon – amlodipine), gynaecomastia (uncommon – amlodipine).

General disorders and administration site conditions: oedema (very rare – amlodipine), fatigue (rare – indapamide, common – amlodipine), chest pain (uncommon – amlodipine), asthenia (common – amlodipine), pain (uncommon – amlodipine), malaise (uncommon – amlodipine).

Investigations: weight increased (uncommon – amlodipine), weight decreased (uncommon – amlodipine), QT interval prolongation on ECG (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction") (frequency not known – indapamide), increased blood glucose level (the appropriateness of prescribing these diuretics should be carefully considered before administration to patients with gout or diabetes mellitus) (frequency not known – indapamide), increased blood uric acid level (the appropriateness of prescribing these diuretics should be carefully considered before administration to patients with gout or diabetes mellitus) (frequency not known – indapamide), increased liver enzymes (frequency not known – indapamide, very rare** – amlodipine).

*May lead to dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory alkalosis; the frequency and severity of this effect are low.

**Mostly due to cholestasis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life.

2 years.

Storage conditions.

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

Keep out of the reach and sight of children.

Packaging.

10 capsules in a blister, 3 blisters in a cardboard pack.

Or 30 capsules in a bottle, 1 bottle in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM LLC (manufacturing operations).

Manufacturer's address and place of business.

24-v Promyslova Street, Severodonetsk, Luhansk region, 93400, Ukraine