Diroton Plus, 1.5 mg+5 mg 28 pcs

Pharmacotherapeutic group: combined hypotensive agent (diuretic + ACE inhibitor).

ATC code: C09BA03
Pharmacological properties

Pharmacodynamics

Diroton® Plus is a combination drug with fixed doses of lisinopril and indapamide.

Indapamide

Indapamide is a sulfonamide derivative containing an indole ring. According to its pharmacological properties, indapamide is close to thiazide-like diuretics, which inhibit reabsorption of sodium ions in the cortical segment of the Genle loop. This is accompanied by increased excretion of sodium, chloride and potassium ions and, to a lesser extent, magnesium ions, which leads to increased diuresis and antihypertensive effect. In phase II and III clinical trials, the use of indapamide as monotherapy in doses that do not cause a pronounced diuretic effect caused a 24-hour antihypertensive effect.

The antihypertensive activity of indapamide leads to improvement of elasticity index of large arteries and to reduction of total peripheral and arteriolar resistance.

Indapamide reduces left ventricular hypertrophy.

In certain doses, the optimal therapeutic effect of thiazide and thiazide-like diuretics is achieved; however, further increasing the dose increases the frequency of side effects. Therefore, the dose should not be increased if the therapeutic effect is not achieved with the use of the drug at the recommended therapeutic doses.

In short-, medium-, and long-term studies in which patients with arterial hypertension have participated, it has been shown that indapamide:

• does not affect lipid metabolism, including triglyceride, cholesterol, low-density lipoprotein and high-density lipoprotein concentrations.
• does not affect carbohydrate metabolism, including in patients with diabetes.

Lisinopril

It is an inhibitor of angiotensin-converting enzyme ACE, which inhibits the conversion of angiotensin I to angiotensin II. A decrease in angiotensin II concentration leads to a direct decrease in aldosterone secretion. Lisinopril suppresses bradykinin degradation and increases prostaglandin synthesis.

Liminopril reduces total peripheral vascular resistance, blood pressure, preload and pulmonary capillary pressure. In patients with chronic heart failure, lisinopril increases the minute blood volume and increases myocardial tolerance to stress. It dilates arteries more than veins. Some effects are attributed to the effect on tissue reninangiotensin systems. Long-term use reduces myocardial hypertrophy and resistive arterial wall hypertrophy.

Lisinopril improves the blood supply to the ischemic myocardium.

In patients with chronic heart failure, ACE inhibitors increase life expectancy; in patients with a history of myocardial infarction without clinical manifestations of heart failure, lisinopril slows the progression of left ventricular dysfunction.

Lisinopril takes effect within 1 hour after oral administration.

The maximum effect is achieved within 6-7 hours; the duration of effect is 24 hours. In patients with arterial hypertension, the effect is seen within the first days of treatment; stable effect occurs within 1-2 months of treatment. No cases of significant increase in blood pressure (BP) after abrupt withdrawal of the drug have been reported. Lisinopril reduces both BP and albuminuria. In patients with hyperglycemia, lisinopril helps to restore impaired glomerular endothelial function. In patients with diabetes mellitus, lisinopril has no effect on plasma glucose concentration; the drug is not associated with increased risk of hypoglycemia.

Pharmacokinetics

Indapamide

The active ingredient is deposited on a special carrier matrix which allows slow controlled release of indapamide in the gastrointestinal tract.

Absorption: The released indapamide is quickly and completely absorbed in the gastrointestinal tract. Food intake slightly prolongs absorption time of indapamide, while it does not affect the amount of absorption. Cmax of indapamide is reached 12 hours after a single dose. When taking the drug repeatedly the changes in plasma concentration of the drug between doses are smoothed.

Individual variability in absorption is noted.

Distribution and protein binding: approximately 79% of the drug is bound to plasma proteins. The half-life (T½) is 14-24 hours (on average, 18 hours). Equilibrium concentrations are reached 7 days after initiation of therapy. Multiple administration does not lead to cumulation of the drug.

Elimation: indapamide is excreted mainly as inactive metabolite by urine (70% of the dose taken) and through the intestine (22%).

High-risk patients: pharmacokinetics of indapamide is not altered in patients with renal insufficiency.

Lisinopril

Absorption: When lisinopril is taken orally about 25% of the drug is absorbed in the gastrointestinal tract. Food intake has no effect on absorption. Mean absorption is 30%; bioavailability is 29%.

Distribution and binding to plasma proteins: maximum concentration in plasma (Cmax) is reached 6-8 hours after oral administration. The degree of binding to plasma proteins is low. Lisinopril poorly penetrates through the blood-brain barrier.

Metabolism: lisinopril is not biotransformed in human body.

Elimination: half-life (T½) is 12 hours.

Indications

Active ingredient

Composition

Active ingredients:

indapamide – 1.500 mg,

lisinopril dihydrate – 5.444 mg (equivalent to lisinopril – 5.000 mg).

Auxiliary substances:

Lactose monohydrate – 84.000 mg,

calcium hydrophosphate dihydrate – 58.566 mg,

Hypromellose (type 2208) – 49.500 mg,

Mannitol – 16.670 mg,

Corn starch – 12.150 mg,

Microcrystalline cellulose, type 102 – 9,000 mg,

croscarmellose sodium – 3,000 mg,

talc – 2,500 mg,

magnesium stearate – 2.420 mg,

colloidal silica – 0.750 mg,

opadray II white – 4.500 mg (contains: polyvinyl alcohol – 40.0%, titanium dioxide – 25.0%, macrogol-3350 – 20.20%, talc 14.80%),

hard gelatin capsule – 76 mg (contains: iron oxide red dye – 0.1180%, titanium dioxide – 2.2263%, gelatin – 83.1600%, water – 14.5000%).

How to take, the dosage

Interaction

Interactions with indapamide

Induatable drug combinations

Lithium preparations

The combined use of indapamide and lithium preparations may increase plasma lithium content by reducing excretion, leading to intoxication. Combined use of diuretics and lithium preparations is possible if required; however, the dose of preparations should be carefully selected and plasma lithium levels should be monitored regularly.

Combinations of drugs requiring special attention

Drugs that can cause pirouette-type arrhythmias:

Non-steroidal anti-inflammatory drugs (when used systemically), including selective COX-2 inhibitors, salicylates in high doses (>3 g/day).

The antihypertensive effect of indapamide may be reduced.

In case of significant fluid loss, acute renal failure may develop (due to decreased glomerular filtration). Fluid replacement and careful monitoring of renal function at the beginning of treatment is indicated.

Angiotensin-converting enzyme inhibitors

The use of ACE inhibitors in patients with decreased plasma sodium content (especially in patients with renal artery stenosis) leads to severe arterial hypotension and/or acute renal failure. Patients with arterial hypertension and possible reduction of plasma sodium content due to the administration of diuretics is indicated:

Increased risk of hypokalemia (additive effect).

The regular monitoring of plasma potassium is indicated and, if necessary, its correction. Patients receiving cardiac glycosides require special attention. The use of laxatives that do not stimulate intestinal motility is recommended.

Baclofen

An increase in antihypertensive effect has been reported.

Patients should have fluid replacement and monitoring of renal function at the start of treatment.

Cardiac glycosides:

Hypokalemia increases the toxic effects of cardiac glycosides.

In combined use of indapamide and cardiac glycosides, plasma potassium and ECG monitoring are indicated. Correction of therapy should be made if necessary.

Combinations of drugs requiring attention

Caliberating diuretics (amiloride, spironolactone, triamterene)

The combined use of potassium-saving diuretics and indapamide is effective in some patients. Despite this, the risk of hypokalemia (especially in patients with diabetes mellitus and renal insufficiency) or hyperkalemia should not be ignored.

Potassium monitoring and, if necessary, correction of plasma potassium and ECG monitoring are indicated.

Metformin

Functional renal insufficiency, which can occur with diuretics, especially loop diuretics, increases the risk of lactic acidosis when metformin is used concomitantly.

Do not use metformin when creatinine concentrations are greater than 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodine-containing radiopaque agents

Dehydration when diuretics are used may increase the risk of acute renal failure, especially when iodine-containing agents are used in high doses.

Liquid loss should be replenished prior to administration of iodine-containing radiopaque agents.

Tricyclic antidepressants, antipsychotics (neuroleptics)

The drugs in this class enhance the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect).

Calcium salts

The combined use increases the risk of hypercalcemia due to reduced renal calcium excretion.

Cyclosporine, tacrolimus

Possible increase in plasma creatinine concentration with unchanged circulating cyclosporine concentration, even with normal circulating blood volume and plasma sodium content.

Corticosteroid drugs, tetracosactide (when used systemically)

Decrease antihypertensive effect (fluid and sodium retention caused by corticosteroids).

Interactions with lisinopril

Potassium preparations, potassium-saving diuretics, or potassium-containing salt substitutes

Concomitant use of lisinopril with potassium-saving diuretics (spironolactone, triamterene, amiloride), potassium preparations, and potassium-containing salt substitutes is associated with an increased risk of hyperkalemia, especially in patients with impaired renal function.

Diuretics

Simultaneous use with other diuretics leads to a significant reduction

Other hypotensive drugs

The combined use with other hypotensive drugs leads to an additive effect.

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at a dose of >3 g/day

Combination with non-steroidal anti-inflammatory drugs (indomethacin, etc.etc), estrogens and adrenal stimulants leads to decreased antihypertensive effect of lisinopril.

Lithium

Continuous use with lithium preparations contributes to delayed excretion of lithium.

Antacids and cholestyramine

Concomitant use with antacids and cholestyramine leads to suppression of gastrointestinal absorption.

Ethanol

Ethanol increases the effect of lisinopril.

Double blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin II receptor antagonists, ACE inhibitors or aliskiren

. Dual RAAS blockade with combined treatment with ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been shown in clinical studies to increase the incidence of side effects such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure) compared to the use of the RAAS-acting drug alone.

Special Instructions

Hepatic impairment

When prescribing thiazide and thiazide-like diuretics to patients with impaired hepatic function, hepatic encephalopathy may develop, especially in the presence of electrolyte imbalance. In this case the use of diuretics should be stopped.

Photosensitization

Photosensitization cases have been reported with thiazide and thiazide-like diuretics (see section “Side effects”). If photosensitization develops with therapy, withdrawal of these drugs is indicated. If it is necessary to continue treatment it is recommended to protect the skin from sunlight or artificial UV radiation.

Water-electrolyte balance

Pasma sodium content

Plasma sodium content must be determined before the start of treatment. Regular monitoring of this parameter is indicated for the duration of therapy. All diuretics may cause hyponatremia, which can sometimes have very serious consequences. Continuous monitoring of sodium content in blood plasma is necessary, since at the beginning of therapy this decrease may not be accompanied by the appearance of pathological symptoms. Monitoring of sodium content should be conducted especially carefully in patients with cirrhosis and in elderly patients (see sections “Side effects” and “Overdose”).

Plasma potassium

With thiazide and thiazide-like diuretics therapy, plasma potassium may decrease rapidly, and hypokalemia may develop. It is necessary to minimize the risk of hypokalemia (<3.4 mmol/l) in the following groups of patients: elderly patients, weakened patients, patients receiving combined therapy with other progival agents and drugs that may prolong QT interval, patients with liver cirrhosis, peripheral edema and ascites, coronary insufficiency, heart failure. In such patients, hypokalemia increases the toxic effects of cardiac glycosides and increases the risk of arrhythmias. In addition, patients with prolonged QT interval should be classified as high-risk, regardless of the presence of the above conditions or the effect of medical drugs.

Hypokalemia, as well as bradycardia, is a condition that contributes to severe arrhythmias and, in particular, cardiac arrhythmias that can be fatal. Regular monitoring of plasma potassium in these groups of patients is indicated, starting from the first week of treatment. In case of hypokalemia prescription of appropriate therapy is indicated.

Plasma calcium content

It has been reported that thiazide and thiazide-like diuretics decrease renal calcium excretion that leads to a slight temporary increase of plasma calcium content. Hypercalcemia with clinical manifestations may be the result of previously undiagnosed hyperparathyroidism. In this case it is necessary to cancel diuretics before investigation of parathyroid function.

Plasma glucose

Control of glucose concentration in patients with diabetes mellitus is indicated, especially in the presence of hypokalemia.

Uracilic acid

In gout sufferers, an increase in the frequency of attacks or aggravation of the course of gout is possible.

Diuretics and renal function

Thiazide and thiazide-like diuretics are most effective in patients with normal or slightly reduced renal function (adult blood plasma creatinine <25 mg/L or 220 μmol/L). Creatinine concentration in plasma in elderly patients is estimated depending on the age, body weight and sex.

In the beginning of treatment decrease of glomerular filtration rate is observed due to hypovolemia that may be connected with water and sodium ion loss because of diuretics action. Due to this, the concentration of uric acid and creatinine in blood plasma may increase. In the absence of renal dysfunction, such transient functional renal failure usually goes without complications, but the general condition of patients may worsen in the presence of renal failure.

Athletes

Because indapamide is a part of the drug Diroton® Plus, it is possible that athletes may test positive for doping.

Lactose

The drug contains lactose, so it should not be taken in patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Lisinopril-related

Symptomatic arterial hypotension

The most common significant BP decrease is associated with hypovolemia caused by diuretics, decreased salt in food, dialysis, diarrhea, or vomiting. In patients with chronic heart failure, regardless of whether it is associated with renal failure, arterial hypotension may develop. It has been found that in patients with severe heart failure this condition occurs more often due to the prescription of high doses of diuretics, hyponatremia or impaired renal function. In such patients, close medical supervision is required (careful dosage selection of lisinopril and diuretics is indicated). The same indications apply to patients with coronary heart disease and cerebrovascular insufficiency, in whom a sharp decrease of BP may lead to myocardial infarction or stroke.

If there is a significant decrease in BP, the patient should be in horizontal position; intravenous infusion of 0.9% sodium chloride solution is possible.

Transient hypotensive reactions are not contraindications for administration of the next dose of lisinopril.

In patients with chronic heart failure with normal or reduced BP, use of lisinopril may result in lower BP; this is usually not a reason to discontinue the drug. If hypotension is accompanied by clinical manifestations, a dose reduction or discontinuation of lisinopril should be considered.

In patients at risk of symptomatic arterial hypotension (with low-salt or no-salt diet), regardless of the presence of hyponatremia, as well as in patients receiving high-dose diuretics, compensation of these conditions (hypovolemia or sodium deficiency) should be achieved before initiating treatment. The effect of the initial dose of lisinopril on blood pressure is indicated.

Acute myocardial infarction

The standard treatment (thrombolytics, acetylsalicylic acid, beta-adrenoblockers) is recommended.

Lisinopril may be used in combination with intravenous nitroglycerin or transdermal nitroglycerin.

In patients with acute myocardial infarction and risk of further deterioration of hemodynamics and worsening of symptoms after administration of vasodilators, therapy with lisinopril should not be started. Such patients include patients with systolic BP <100 mm Hg and patients with cardiogenic shock. In patients with systolic BP <120 mm Hg, dose reduction is indicated during the first three days after myocardial infarction. In patients with systolic BP <100 mm Hg, the maintenance dose should be reduced to 5 mg (or temporarily to 2.5 mg). In patients with persistent arterial hypotension (systolic BP <90 mm Hg for 1 hour or more) lisinopril withdrawal is indicated.

Kidney function impairment

In patients with chronic heart failure, a significant decrease in BP with ACE inhibitors may worsen renal function impairment. There have been recorded cases of acute renal failure.

In patients with bilateral renal artery stenosis or renal artery stenosis of the only kidney, increase in serum urea and creatinine concentration during ACE inhibitors administration has been noted; usually these disorders were temporary and subsided after therapy withdrawal. They occurred more frequently in patients with renal insufficiency.

Patients with acute myocardial infarction and severe renal dysfunction (serum creatinine concentration >177 μmol/l and/or proteinuria >500 mg/day) lisinopril is contraindicated. If renal function abnormalities develop during treatment (serum creatinine concentration >265 μmol/l or doubling of baseline), lisinopril should be stopped.

Allergic reactions, Quincke’s edema

In rare cases, angioedema of the face, extremities, lips, tongue, epiglottis and/or larynx have been reported during use of ACE inhibitors, including lisinopril. In such cases, immediate discontinuation of lisinopril is required; patients should be monitored until the symptoms are completely resolved. Angioneurotic edema of the face and lips is usually temporary and does not require treatment; however, antihistamines may be prescribed.

Laryngeal angioedema may cause death. Swelling of the tongue, epiglottis or larynx may lead to secondary airway obstruction. If this occurs, 0.3-0.5 ml of 1:1000 adrenaline solution should be given immediately subcutaneously and the airway should be secured.
It has been reported that patients receiving ACE inhibitors of the Negro race were more likely to have Quincke’s edema than patients in other ethnic groups.

Patients with a history of Quincke’s edema unrelated to ACE inhibitor use have a higher risk of developing angioedema when using ACE inhibitors.

Anaphylactic reactions associated with desensitization by Hymenoptera venom

. In very rare cases, patients taking ACE inhibitors may develop life-threatening anaphylactic reactions during desensitization with Hymenoptera venom, so ACE inhibitors should be temporarily stopped before desensitization.

Patients on hemodialysis

Anaphylactic reactions have also occurred in patients undergoing hemodialysis e using high permeability dialysis membranes (e.g., AN69) with concomitant use of ACE inhibitors. Other dialysis membranes or other hypotensive medications are indicated in these patients.

Cough

Therapy with ACE inhibitors may cause cough, which should be considered in the differential diagnosis. Prolonged dry cough usually stops after withdrawal of ACE inhibitors.

Surgical interventions/general anesthesia

The use of hypotensive drugs during major surgical intervention or during general anesthesia may lead to inhibition of angiotensin II formation due to compensatory renin secretion. The significant decrease in BP associated with this effect can be prevented by increasing circulating blood volume.

Patients taking ACE inhibitors should inform their surgeon/anesthesiologist prior to surgical intervention (including dental procedures).

Plasma potassium

Cases of hyperkalemia have been reported.

Risk factors for hyperkalemia include renal insufficiency, diabetes mellitus, therapy with potassium-saving diuretics (spironolactone, triamterene and amiloride), use of potassium preparations and potassium-based salt substitutes, especially in patients with impaired renal function.

When combined use of lisinopril and these drugs is necessary, regular monitoring of plasma potassium is indicated.

Double RAAS blockade

The simultaneous administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure). Thus, it is not recommended to prescribe ACE inhibitors, angiotensin II receptor blockers or aliskiren for dual RAAS blockade.

If there are absolute indications for dual RAAS blockade, it should be performed under close supervision of a specialist with frequent monitoring of BP, renal function and electrolyte content.

The ACE inhibitors and angiotensin II receptor blockers should not be used simultaneously in patients with diabetic nephropathy.

Impact on driving and operating machinery

There are no data on the effect of lisinopril on driving and operating machinery. However, the possibility of dizziness should be considered. In this regard, caution should be exercised when driving vehicles and operating machinery.

Indapamide does not cause impairment of psychomotor functions, but in some patients with blood pressure decrease various individual reactions may occur, especially at the beginning of therapy or when prescribing additional hypotensive drug to the basic scheme of treatment. In this case, the ability to drive vehicles and operate machinery may be reduced.

Contraindications

Aortic stenosis, hypertrophic obstructive cardiomyopathy, cerebrovascular disease (including cerebrovascular insufficiency), coronary heart disease, coronary artery disease, severe autoimmune systemic connective tissue disease (including systemic lupus erythematosus, scleroderma), myelosuppression, diabetes, hyperkalemia, bilateral renal artery stenosis, renal artery stenosis in patients with a single kidney, conditions after renal transplantation, renal failure, azotemia, primary aldosteronism, salt restricted diet, conditions associated with decreased circulating blood volume (including vomiting and diarrhea), elderly patients, liver failure.
Weakened patients or patients receiving combined therapy with other antiarrhythmic drugs (see section “Interaction with other drugs”); water-electrolyte balance disorders; prolongation of QT interval on ECG; high serum concentration of uric acid; hyperparathyroidism.

Side effects

Most adverse reactions (laboratory and clinical changes) are dose-dependent.

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

Nervous system disorders: rarely – asthenia, headache, paresthesia, dizziness; frequency is unknown – fainting.

Cardiovascular system disorders: very rare – arrhythmia, significant arterial hypotension; frequency unknown – ventricular tachycardia type “pirouette” (life-threatening condition) (see sections “Interaction with other medicinal products” and “Cautions”).

Gastrointestinal disorders: infrequent – vomiting; rare – nausea, constipation, dry mouth; very rare – pancreatitis.

Hepatic and biliary tract disorders: very rare – liver function abnormality; frequency is unknown – in case of hepatic insufficiency liver encephalopathy may develop (see “Contraindications”). “Contraindications and Special Indications); hepatitis.

Skin and subcutaneous tissue disorders: hypersensitivity reactions, mainly dermatological, in patients with predisposition to allergic and asthmatic reactions.

Frequently – maculopapular rash; infrequently – hemorrhagic vasculitis; very rarely – angioedema and/or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome; frequency is unknown – possible deterioration in patients with acute systemic lupus erythematosus. Cases of photosensitivity reactions have been reported (see sections “Special Precautions” and “Interaction with other medicinal products”).

Impact on the results of laboratory and instrumental studies: frequency is unknown – QT interval prolongation on ECG (see section “Indications”). ); increase of concentration of uric acid and glucose – in patients with gout and diabetes mellitus treatment with thiazide and thiazide-like diuretics should be performed with caution; increase of “liver” enzymes activity. In clinical trials hypokalemia was observed in 10% of patients (potassium content in plasma less than 3.4 mmol/l) and in 4% of patients – 3.2 mmol/l after 4-6 weeks of treatment. In 12 weeks plasma potassium content decreased, on the average, by 0.23 mmol/l; very rarely – hypercalcemia; frequency is unknown – decrease of potassium content and development of hypokalemia, especially significant for risk group patients (see “Special indications”); hyponatremia accompanied with hypovolemia, dehydration and orthostatic hypotension. Concomitant reduction of chloride may lead to compensatory metabolic alkalosis, but its frequency and severity are insignificant.

Lisinopril-related

The most common adverse reactions include dizziness, headache, fatigue, diarrhea, dry cough, and nausea.

Blood and lymphatic system disorders: rare – decrease in hemoglobin and hematocrit; very rare – leukopenia, neutropenia, agranulocytosis, thrombocytopenia, anemia; frequency is unknown – erythrocytopenia.

Intrinsic system disorders: infrequent – skin rash, itching; rare – angioedema of facial area, angioedema of extremities, lips, tongue, epiglottis and/or larynx; very rare – interstitial angioedema; frequency unknown – fever, positive test for antinuclear antibodies, increased erythrocyte sedimentation rate, eosinophilia, leukocytosis.

Psychiatric disorders: infrequent – emotional lability; rare – mental confusion.

Nervous system disorders: infrequent – paresthesia, somnolence; rare – asthenic syndrome; frequency of unknown – twitching of muscles of extremities and face.

Chronic disorders: infrequent – pain in the chest; rarely – tachycardia, bradycardia, increasing symptoms of heart failure, atrioventricular conduction disorders, myocardial infarction, palpitations.

Vascular disorders: frequently – marked BP decrease; rarely – orthostatic hypotension; frequency unknown – vasculitis.

Respiratory system, thoracic markers and mediastinum disorders: very rare – bronchospasm; frequency unknown – dyspnea.

Gastrointestinal disorders: infrequent – dyspepsia, dysgeusia, abdominal pain; rare – dry mouth; very rare – pancreatitis; frequency unknown – decreased appetite.

Liver and biliary tract disorders: very rare – hepatic-cell and cholestatic jaundice, hepatitis.

Skin and subcutaneous tissue disorders: infrequent – skin itching; rare – urticaria, alopecia; very rare – sweating; frequency unknown – photosensitization.

Muscular and connective tissue disorders: frequency unknown – myalgia, arthralgia/arthritis.

Renal and urinary tract disorders: frequent – renal dysfunction; rare – acute renal failure, uremia; very rare – oliguria, anuria; frequency unknown – proteinuria.

Gender and mammary gland disorders: infrequent – decreased potency.

Impact on the results of laboratory and instrumental studies: infrequent – hyperkalemia, hyponatremia; rare – increased liver enzymes activity, hyperbilirubinemia, increased concentration of creatinine and urea.

If any of the side effects mentioned in the instructions worsen, or if you notice any other side effects not specified in the instructions, inform your physician.

Overdose

Pregnancy use