Diroton^® Plus (Capsules) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter, Plc. (Hungary)

Labeled By

GEDEON RICHTER, Plc. (Hungary)

Or

GEDEON RICHTER ROMANIA, S.A. (Romania)

Or

GEDEON RICHTER-RUS, AO (Russia)

Quality Control Release

GEDEON RICHTER, Plc. (Hungary)

Or

GEDEON RICHTER-RUS, AO (Russia)

Contact Information

GEDEON RICHTER OJSC (Hungary)

ATC Code

C09BA03 (Lisinopril and diuretics)

Active Substances

Indapamide (Rec.INN registered by WHO)

Lisinopril (Rec.INN registered by WHO)

Dosage Forms

	Diroton® Plus	Modified-release capsules 1.5 mg+5 mg: 14, 28, 56 or 112 pcs.
		Modified-release capsules 1.5 mg+10 mg: 14, 28, 56 or 112 pcs.
		Modified-release capsules 1.5 mg+20 mg: 14, 28, 56 or 112 pcs.

Dosage Form, Packaging, and Composition

Modified-release capsules hard gelatin, light pink, size No.1; capsule contents – 1 oval, biconvex, film-coated tablet, white (contains Indapamide) with engraving “CP3” on one side and a score on the other and 1 round, biconvex white tablet (contains lisinopril) with engraving “CN3” on one side.

Excipients : lactose monohydrate, calcium hydrogen phosphate dihydrate, hypromellose (type 2208), mannitol, corn starch, microcrystalline cellulose (type 102), croscarmellose sodium, talc, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry II 85F18422 white, containing: partially hydrolyzed polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol-3350 (E1521), talc (E553b); hard gelatin capsule, containing: iron oxide red (E172), titanium dioxide (E171), gelatin, water.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
14 pcs. – blisters (8) – cardboard packs.

Modified-release capsules hard gelatin, pink, size No.1; capsule contents – 1 oval, biconvex, film-coated tablet, white (contains Indapamide) with engraving “CP3” on one side and a score on the other and 1 round, biconvex white tablet (contains lisinopril) with engraving “CN4” on one side.

Excipients : lactose monohydrate, calcium hydrogen phosphate dihydrate, hypromellose (type 2208), mannitol, corn starch, microcrystalline cellulose (type 102), croscarmellose sodium, talc, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry II 85F18422 white, containing: partially hydrolyzed polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol-3350 (E1521), talc (E553b); hard gelatin capsule, containing: Ponceau 4R (E124), titanium dioxide (E171), gelatin, water.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
14 pcs. – blisters (8) – cardboard packs.

Modified-release capsules hard gelatin, red-brown, size No.1; capsule contents – 1 oval, biconvex, film-coated tablet, white (contains Indapamide) with engraving “CP3” on one side and a score on the other and 2 round, biconvex white tablets (contain lisinopril) with engraving “CN4” on one side.

Excipients : lactose monohydrate, calcium hydrogen phosphate dihydrate, hypromellose (type 2208), mannitol, corn starch, microcrystalline cellulose (type 102), croscarmellose sodium, talc, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry II 85F18422 white, containing: partially hydrolyzed polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol-3350 (E1521), talc (E553b); hard gelatin capsule, containing: iron oxide red (E172), Ponceau 4R (E124), titanium dioxide (E171), gelatin, water.

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
14 pcs. – blisters (8) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive combination drug (diuretic + ACE inhibitor)

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin-converting enzyme (ACE) inhibitors, combinations; ACE inhibitors and diuretics

Pharmacological Action

Diroton^® Plus is a fixed-dose combination drug of lisinopril and indapamide.

Indapamide

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

The antihypertensive activity of indapamide leads to an improvement in the elasticity index of large arteries and a decrease in total peripheral and arteriolar resistance.

Indapamide reduces left ventricular hypertrophy.

At certain doses, the optimal therapeutic effect of thiazide and thiazide-like diuretics is achieved; however, with a further increase in dose, the frequency of side effects increases. Thus, the dose should not be increased if the therapeutic effect is not achieved when using the drug in recommended therapeutic doses.

In short-term, medium-term and long-term studies involving patients with arterial hypertension, it was shown that Indapamide

• Does not affect lipid metabolism, including the concentration of triglycerides, cholesterol, LDL and HDL;
• Does not affect carbohydrate metabolism, including in patients with diabetes mellitus.

Lisinopril

It is an ACE inhibitor that suppresses the conversion of angiotensin I to angiotensin II. The decrease in angiotensin II concentration leads to a direct decrease in aldosterone secretion. Lisinopril inhibits the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces total peripheral resistance, preload and pulmonary capillary pressure. In patients with chronic heart failure, lisinopril increases cardiac output and improves myocardial tolerance to stress. It dilates arteries more than veins. Some effects are explained by the impact on tissue renin-angiotensin systems. With long-term use, it reduces hypertrophy of the myocardium and walls of resistive-type arteries.

Lisinopril improves 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 begins to act within 1 hour after oral administration. The maximum effect is achieved within 6-7 hours; the duration of the effect is 24 hours. In patients with arterial hypertension, the effect appears within the first days after the start of treatment; a stable effect occurs within 1-2 months of treatment. Cases of a marked increase in blood pressure after abrupt withdrawal of the drug have not been registered. Lisinopril reduces both blood pressure and albuminuria. In patients with hyperglycemia, lisinopril promotes the restoration of impaired glomerular endothelial function. In patients with diabetes mellitus, lisinopril does not affect the concentration of blood plasma glucose; taking the drug is not associated with an increased risk of hypoglycemia.

Pharmacokinetics

Indapamide

The active substance is applied to a special matrix carrier, which ensures slow controlled release of indapamide in the gastrointestinal tract.

Absorption

Released Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Food intake slightly increases the absorption time of indapamide, without affecting the extent of absorption. C_max of indapamide is reached 12 hours after a single dose. With repeated administration of the drug, fluctuations in the plasma concentration of the drug between doses are smoothed out.

Individual variability in the absorption parameters of the drug is noted.

Distribution

Plasma protein binding is approximately 79%. C_ss is reached 7 days after the start of therapy. Repeated administration does not lead to accumulation of the drug.

Elimination

T_1/2 is 14-24 hours (average 18 hours). Indapamide is excreted mainly as an inactive metabolite by the kidneys (70% of the dose taken) and through the intestines (22%).

Pharmacokinetics in special patient groups

Renal impairment. The pharmacokinetics of indapamide does not change in patients with renal impairment.

Lisinopril

Absorption

When lisinopril is taken orally, about 25% of the drug is absorbed from the gastrointestinal tract. Food intake does not affect absorption. The average absorption level is 30%; bioavailability is 29%.

Distribution

C_max in plasma is reached 6-8 hours after oral administration. The degree of binding to plasma proteins is low. Lisinopril poorly penetrates the blood-brain barrier.

Metabolism

Lisinopril is not biotransformed in the human body.

Elimination

T_1/2 is 12 hours.

Pharmacokinetics in special patient groups

Patients with chronic heart failure. In patients with CHF, the absorption and clearance of lisinopril are reduced. In this category of patients, the absolute bioavailability of lisinopril decreases by approximately 16%.

Patients with renal impairment. Impaired renal function leads to an increase in the AUC and T_1/2 of lisinopril, but these changes become clinically significant only when GFR falls below 30 ml/min/1.73 m² of body surface area. In mild to moderate renal impairment (CC from 30 to 80 ml/min), the mean AUC increases by 13%, while in severe renal impairment (CC from 5 to 30 ml/min), the mean AUC increases 4.5-fold.

Patients with hepatic impairment. In patients with liver cirrhosis, the absorption of lisinopril is reduced (by approximately 30%), but the exposure to the drug increases (by approximately 50%) compared to healthy volunteers due to reduced clearance.

Elderly patients (over 65 years). In elderly patients, the plasma concentration of lisinopril and AUC values are 2 times higher than in young patients.

Indications

Adults aged 18 years and over

• Essential arterial hypertension (patients requiring combination therapy).

ICD codes

Dosage Regimen

As a rule, fixed-dose combination drugs should not be used for initial therapy. The drug Diroton^® Plus is prescribed to adult patients who have achieved adequate control of arterial hypertension while taking lisinopril and indapamide, which the patient takes simultaneously in the same doses as in the combination drug.

The recommended dose is 1 capsule/day. The maximum daily dose is 1 capsule.

If symptomatic arterial hypotension develops at the beginning of treatment with Diroton^® Plus, the patient should lie on their back, suspend taking the drug and consult a doctor. Transient arterial hypotension usually does not require discontinuation of the drug, but the need to reduce the dose should be assessed.

If dose titration is necessary, the drugs Indapamide and lisinopril should be used separately.

Missed dose

If a capsule of Diroton^® Plus is missed, the next dose should be taken at the usual time. It is not allowed to take two capsules of the drug at the same time to make up for a missed dose.

Special patient groups

Elderly patients

This drug should be used with caution in elderly patients. It is necessary to monitor plasma creatinine concentration and assess its correspondence to age, weight and sex.

Patients with impaired renal function

During therapy with Diroton^® Plus, renal function, as well as plasma potassium and sodium levels, should be monitored. If renal function deteriorates, Diroton^® Plus should be discontinued and replaced with individually selected drugs.

Children

The safety and efficacy of Diroton^® Plus in children from 0 to 18 years have not been established. Data are not available.

Method of administration

Orally, regardless of meals, preferably in the morning, at the same time every day.

Adverse Reactions

Summary of the safety profile

The frequency of adverse reactions is presented separately for lisinopril and indapamide.

Associated with indapamide

The most common adverse reactions reported were hypokalemia, hypersensitivity reactions, mainly dermatological, in patients with a predisposition to allergic and asthmatic reactions, as well as maculopapular rash. Most adverse reactions (laboratory and clinical changes) are dose-dependent. The following adverse drug reactions have been reported with the isolated use of lisinopril and indapamide.

Associated with lisinopril

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

Tabulated summary of adverse reactions

The following adverse drug reactions have been reported with the isolated use of lisinopril and indapamide.

The adverse reactions presented below are listed according to the affected organs and organ systems and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Description of selected adverse reactions

Associated with indapamide

Within the framework of phase II and III studies comparing Indapamide at doses of 1.5 mg and 2.5 mg, a dose-dependent effect of indapamide on plasma potassium levels was revealed

• Indapamide 1.5 mg: plasma potassium concentration less than 3.4 mmol/l was observed in 10% of patients and plasma potassium concentration less than 3.2 mmol/l was observed in 4% of patients 4-6 weeks after the start of therapy. After 12 weeks of therapy, the mean decrease in plasma potassium concentration was 0.23 mmol/l.
• Indapamide 2.5 mg: plasma potassium concentration less than 3.4 mmol/l was observed in 25% of patients and plasma potassium concentration less than 3.2 mmol/l was observed in 10% of patients 4-6 weeks after the start of therapy. After 12 weeks of therapy, the mean decrease in plasma potassium concentration was 0.41 mmol/l.

Associated with lisinopril

Benign lymphadenosis of the skin

A symptom complex has been reported that may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody (ANA) test, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, skin rash, photosensitivity or other skin changes.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to lisinopril (or other ACE inhibitors), indapamide (or other sulfonamide derivatives) or to any of the excipients of the drug;

• History of angioedema, including Quincke’s edema, associated with the use of ACE inhibitors;
• Hereditary or idiopathic angioedema;
• Severe renal failure (creatinine clearance <30 ml/min);
• Hepatic encephalopathy or severe liver dysfunction;
• Hypokalemia;
• Concomitant use of the drug Diroton^® Plus and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR <60 ml/min/1.73 m² body surface area);
• Concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy);
• Concomitant use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of angioedema;
• Pregnancy;
• Breastfeeding period.

With caution

Aortic stenosis, hypertrophic obstructive cardiomyopathy, cerebrovascular diseases (including cerebral circulatory insufficiency), coronary artery disease, coronary insufficiency, severe autoimmune systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), myelosuppression, diabetes mellitus, hyperkalemia, bilateral renal artery stenosis, renal artery stenosis in patients with a single kidney, status after kidney transplantation, renal failure, azotemia, primary aldosteronism, salt-restricted diet, conditions associated with reduced circulating blood volume (including vomiting and diarrhea), elderly patients, hepatic insufficiency.

Debilitated patients or patients receiving combined therapy with other antiarrhythmic drugs and drugs that can cause QT interval prolongation, as well as polymorphic ventricular tachycardia of the “torsades de pointes” type (see section “Drug Interactions”); concomitant use with drugs containing aliskiren, or ARA II (increased risk of arterial hypotension, hyperkalemia and renal failure with dual blockade of the RAAS); water-electrolyte balance disorders; QT interval prolongation on ECG; hemodialysis using high-flux membranes or desensitization, before LDL apheresis procedure; high serum uric acid concentration; hyperparathyroidism; in patients of the Black race; athletes (possible positive reaction in doping control).

Use in Pregnancy and Lactation

Pregnancy

The use of the drug Diroton^® Plus during pregnancy is contraindicated.

Adequately controlled clinical studies on the use of the drug Diroton^® Plus in pregnant women have not been conducted. If pregnancy occurs, it is necessary to immediately stop taking the drug Diroton^® Plus. Patients planning pregnancy should stop taking the drug Diroton^® Plus and consult a doctor to select another antihypertensive drug with an established safety profile during pregnancy.

Indapamide

Currently, there is insufficient data on the use of indapamide during pregnancy (less than 300 cases described). Long-term use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and a decrease in uteroplacental blood flow, leading to fetoplacental ischemia and fetal growth retardation. As a precaution, it is recommended to avoid the use of indapamide during pregnancy.

Lisinopril

Taking ACE inhibitors by pregnant women in the II and III trimester can lead to fetal or neonatal death. Careful monitoring of the condition of newborns and infants whose mothers took ACE inhibitors in the prenatal period is indicated to identify possible significant decrease in blood pressure, oliguria and hyperkalemia. The development of oligohydramnios, as well as hypoplasia of the facial bones, deformation of the facial and skull bones, pulmonary hypoplasia and impaired kidney development in newborns is possible.

Lisinopril can cross the placental barrier. Women of childbearing age should use reliable methods of contraception. Treatment with lisinopril should not be started during pregnancy.

Breastfeeding period

The use of the drug Diroton^® Plus is contraindicated during breastfeeding.

Indapamide

It is not known whether Indapamide or its metabolites are excreted in breast milk. The newborn may develop hypersensitivity to sulfonamide derivatives and hypokalemia. In this regard, the risk to the newborn/infant cannot be excluded. Indapamide is close to thiazide diuretics, the intake of which causes a decrease in the amount of breast milk or even suppression of lactation. Indapamide should not be used during breastfeeding.

Lisinopril

There are no data on the penetration of lisinopril into breast milk. Breastfeeding should be discontinued during treatment with lisinopril.

Use in Hepatic Impairment

Contraindication: hepatic encephalopathy or severe liver dysfunction.

Use in Renal Impairment

Contraindication: severe renal failure (creatinine clearance <30 ml/min).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

In case of hospitalization, the patient must inform the attending physician that he is taking the drug Diroton^® Plus.

When using the drug Diroton^® Plus, special instructions regarding individual components of the drug must be taken into account.

Related to indapamide

Liver dysfunction

When prescribing thiazide and thiazide-like diuretics to patients with impaired liver function, the development of hepatic encephalopathy is possible, especially in the presence of electrolyte imbalance. In this case, it is necessary to stop the use of diuretics.

Photosensitivity

Cases of photosensitivity have been reported with the use of thiazide and thiazide-like diuretics (see section “Adverse Reactions”). If photosensitivity develops during therapy, these drugs should be discontinued. If it is necessary to continue treatment, protection of the skin from sunlight or artificial UV radiation is recommended.

Water-electrolyte balance

• Plasma sodium content

Plasma sodium content should be determined before starting treatment. Regular monitoring of this parameter is indicated throughout the entire duration of therapy. Constant monitoring of plasma sodium content is necessary, because at the beginning of therapy, such a decrease may not be accompanied by the appearance of pathological symptoms. Monitoring of sodium content should be carried out especially carefully in patients with liver cirrhosis and in elderly patients (see sections “Adverse Effects” and “Overdose”).

All diuretic drugs can cause hyponatremia, sometimes leading to extremely serious consequences. Hyponatremia and hypovolemia can lead to dehydration and orthostatic hypotension. A concomitant decrease in chloride ions can lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are insignificant.

• Plasma potassium content

During therapy with thiazide and thiazide-like diuretics, a sharp decrease in plasma potassium content, as well as the development of hypokalemia, is possible. It is necessary to minimize the risk of hypokalemia (<3.4 mmol/l) in the following groups of patients: elderly patients, debilitated patients, patients receiving combined drug therapy, patients with liver cirrhosis, peripheral edema and ascites, coronary artery disease, heart failure. In such patients, hypokalemia enhances the toxic effects of cardiac glycosides and increases the risk of arrhythmias. In addition, patients with a prolonged QT interval, both congenital and drug-induced, are at high risk.

Hypokalemia, as well as bradycardia, is a condition that contributes to the development of severe arrhythmias and, in particular, polymorphic ventricular tachycardia of the “torsades de pointes” type, which can be fatal. Regular monitoring of plasma potassium content is indicated in these groups of patients, starting from the first week of treatment. If hypokalemia is detected, appropriate therapy should be prescribed.

Hypokalemia detected in combination with low plasma magnesium concentration may be resistant to treatment if the plasma magnesium concentration is not corrected.

• Plasma magnesium content

Thiazide and thiazide-like diuretics, including Indapamide, have been shown to increase urinary magnesium excretion, which can lead to hypomagnesemia (see sections “Drug Interactions” and “Adverse Reactions”).

• Plasma calcium content

Thiazide and thiazide-like diuretics reduce the renal excretion of calcium, leading to a slight temporary increase in plasma calcium content. Hypercalcemia with clinical manifestations may be the result of previously undiagnosed hyperparathyroidism. In this case, it is necessary to discontinue diuretics before examining parathyroid function.

• Blood plasma glucose

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

• Uric acid

In patients with gout, an increase in the frequency of attacks or exacerbation of gout may occur.

Diuretics and kidney function

Thiazide and thiazide-like diuretics are most effective in patients with normal or slightly reduced kidney function (plasma creatinine in adults <25 mg/l or 220 µmol/l). Plasma creatinine concentration in elderly patients is assessed depending on age, weight and sex.

At the beginning of treatment, patients experience a decrease in glomerular filtration rate due to hypovolemia, which may be associated with the loss of water and sodium ions due to the action of diuretics. In this regard, an increase in the concentration of uric acid and creatinine in the blood plasma is possible. In the absence of impaired renal function, such transient functional renal failure usually resolves without complications, but the general condition of patients may worsen in the presence of renal failure.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma

Sulfonamides or sulfonamide derivatives can cause idiosyncratic reactions leading to the development of choroidal effusion with visual field defect, acute transient myopia and acute angle-closure glaucoma. Symptoms include decreased visual acuity or eye pain, which usually occur within several hours or weeks after starting the drug. If left untreated, acute angle-closure glaucoma can lead to irreversible vision loss. If symptoms appear, the drug should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of acute angle-closure glaucoma may be a history of allergic reactions to sulfonamides or penicillin.

Athletes

Indapamide may give a positive result in a doping test in athletes.

Related to lisinopril

Symptomatic arterial hypotension

Most often, a significant decrease in blood pressure is associated with hypovolemia caused by the use of diuretics, a decrease in salt in the diet, dialysis, diarrhea or vomiting (see sections “Adverse Reactions” and “Drug Interactions”). In patients with chronic heart failure, regardless of whether it is associated with renal failure, the development of arterial hypotension is possible. It has been found that in patients with severe heart failure, this condition occurs more often in connection with the prescription of high doses of diuretics, hyponatremia or impaired renal function. Such patients require careful medical supervision (careful selection of doses of lisinopril and diuretics is indicated). The same instructions apply to patients with coronary artery disease and cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke.

With a significant decrease in blood pressure, the patient must take a horizontal position; intravenous administration of 0.9% sodium chloride solution is possible.

Transient hypotensive reactions are not a contraindication to the use of the next dose of lisinopril.

In patients with chronic heart failure with normal or low blood pressure, the use of lisinopril may lead to a decrease in blood pressure; this usually does not serve as a reason for drug withdrawal. If arterial hypotension is accompanied by clinical manifestations, the issue of reducing the dose or discontinuing lisinopril should be considered.

In patients at risk of developing symptomatic arterial hypotension (with a low-salt or salt-free diet), regardless of the presence of hyponatremia, as well as in patients receiving diuretics in high doses, it is necessary to compensate for hypovolemia or sodium deficiency before starting treatment.

Blood pressure should be monitored when taking the first dose of lisinopril.

Acute myocardial infarction

Standard treatment is recommended (thrombolytics, acetylsalicylic acid, beta-blockers). Lisinopril can be used in combination with intravenous nitroglycerin or with the use of a transdermal form of nitroglycerin.

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

Renal dysfunction

In patients with chronic heart failure, a significant decrease in blood pressure during the administration of ACE inhibitors can lead to worsening of renal dysfunction. Cases of acute renal failure have been reported.
In patients with bilateral renal artery stenosis or stenosis of the renal artery of a single kidney during the use of ACE inhibitors, an increase in the concentration of urea and serum creatinine was noted; usually such disorders were temporary and stopped after discontinuation of therapy. They occurred more often in patients with renal failure.

Lisinopril is contraindicated in patients with acute myocardial infarction and severe renal impairment (serum creatinine concentration >177 µmol/l and/or proteinuria >500 mg/day). If renal dysfunction develops during treatment (serum creatinine concentration >265 µmol/l or doubling compared to the initial value), lisinopril should be discontinued.

Hypersensitivity, angioedema

In rare cases, during the use of ACE inhibitors, including lisinopril, the development of angioedema of the face, extremities, lips, tongue, epiglottis and/or larynx has been reported. In such cases, immediate withdrawal of lisinopril is required; monitoring of the patient’s condition until the symptoms are completely resolved is indicated. Usually, angioedema of the face and lips is temporary and does not require treatment; nevertheless, the appointment of antihistamines is possible.

Laryngeal angioedema can be fatal. Edema of the tongue, epiglottis or larynx can lead to secondary airway obstruction. In this case, it is necessary to immediately inject 0.3-0.5 ml of 1:1000 adrenaline solution subcutaneously, as well as ensure airway patency.

In rare cases, intestinal angioedema developed during therapy with ACE inhibitors. In this case, patients experienced abdominal pain as an isolated symptom or in combination with nausea or vomiting, in some cases without preceding facial angioedema and with a normal level of C1-esterase. The diagnosis was established using computed tomography of the abdominal organs, ultrasound or during surgery. Symptoms disappeared after discontinuation of ACE inhibitors.

Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

In patients with a history of angioedema not associated with the use of ACE inhibitors, the risk of its development when using ACE inhibitors is higher (see “Contraindications”).

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Treatment with sacubitril/valsartan should not be started earlier than 36 hours after the last dose of lisinopril. Treatment with lisinopril should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see section “Drug Interactions”).

An increased risk of angioedema (swelling of the airways or tongue, with or without respiratory distress) has been observed in patients simultaneously taking ACE inhibitors and drugs such as racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) and vildagliptin (see section “Drug Interactions”).

Caution should be exercised when starting treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) and vildagliptin in patients already taking ACE inhibitors.

Anaphylactic reactions associated with desensitization with hymenoptera venom

In very rare cases, in patients taking ACE inhibitors, life-threatening anaphylactic reactions may develop during desensitization with hymenoptera venom, so it is necessary to temporarily discontinue ACE inhibitors before desensitization.

Patients on hemodialysis

Anaphylactic reactions have also occurred in patients undergoing hemodialysis using high-permeability dialysis membranes (e.g., AN69) with concomitant use of ACE inhibitors. In such patients, the use of other dialysis membranes or other antihypertensive drugs is indicated.

Cough

ACE inhibitor therapy may cause cough, which should be considered in the differential diagnosis. A prolonged dry cough usually stops after discontinuation of ACE inhibitors.

Surgical interventions/general anesthesia

The use of antihypertensive drugs during major surgery or during general anesthesia can lead to inhibition of angiotensin II formation due to compensatory renin secretion. A significant decrease in blood pressure associated with this effect can be prevented by increasing the circulating blood volume.

Patients taking ACE inhibitors should inform the surgeon/anesthesiologist before undergoing surgery (including dental procedures).

Hyperkalemia

ACE inhibitors may cause hyperkalemia as they inhibit the release of aldosterone. In patients with normal renal function, the effect is usually minor; however, in patients with impaired renal function, diabetes mellitus, and/or in patients taking potassium-containing dietary supplements (including potassium-containing salt substitutes), potassium-sparing diuretics (spironolactone, triamterene, amiloride) or other drugs leading to increased serum potassium levels (heparin, trimethoprim or co-trimoxazole (trimethoprim + sulfamethoxazole)), and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may occur. Hyperkalemia can cause serious, sometimes fatal, arrhythmias.

If the use of the drugs listed above during treatment with an ACE inhibitor is deemed necessary, regular monitoring of renal function and serum potassium levels is recommended (see the “Drug Interactions” section).

Dual blockade of the RAAS

Concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been proven to increase the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, the combined use of ACE inhibitors, ARBs, or aliskiren for dual blockade of the RAAS is not recommended.

If there are absolute indications for dual blockade of the RAAS, it should be carried out under the close supervision of a specialist with frequent monitoring of blood pressure, renal function, and electrolyte levels.

Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² of body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Neutropenia, agranulocytosis, thrombocytopenia, and anemia may occur during treatment with ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia is rare. Diroton^® Plus should be prescribed with particular caution to patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol, or procainamide, or with a combination of these risk factors, especially patients with impaired renal function. Severe infections have occurred in some patients, in some cases resistant to intensive antibiotic therapy. When prescribing Diroton^® Plus to such patients, periodic monitoring of the white blood cell count in the blood plasma is recommended. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Mitral stenosis/aortic stenosis/hypertrophic cardiomyopathy

ACE inhibitors should be prescribed with caution to patients with mitral stenosis, as well as to patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic cardiomyopathy).

Hepatic insufficiency

Very rarely, cholestatic jaundice occurs during treatment with ACE inhibitors. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in liver enzyme activity occurs during treatment with ACE inhibitors, Diroton^® Plus should be discontinued and the patient carefully monitored.

Ethnic differences

Angioedema occurs more frequently in Black patients than in other races during treatment with ACE inhibitors. ACE inhibitors may have a less pronounced antihypertensive effect in Black patients compared to other races. This difference may be due to the fact that Black patients with arterial hypertension more often have low renin activity.

Excipients

The drug contains lactose monohydrate. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Diroton^® Plus, 1.5 mg+10 mg, modified-release capsules, and Diroton^® Plus, 1.5 mg+20 mg, modified-release capsules, contain the dye Ponceau 4R (E124). It may cause allergic reactions.

Effect on the ability to drive vehicles and operate machinery

There are no data on the effect of Diroton^® Plus on the ability to drive vehicles and operate machinery. Given the possibility of excessive blood pressure reduction, the risk of dizziness, drowsiness, and similar side effects, patients should exercise caution when performing potentially hazardous activities requiring special attention and quick reactions.

Overdose

Indapamide overdose

Toxic effects of indapamide have not been observed with overdose even at very high doses (up to 40 mg, i.e., 27 times the therapeutic dose).

Symptoms of acute drug intoxication depend primarily on water-electrolyte imbalance (hyponatremia, hypokalemia). Clinical manifestations of overdose may include nausea, vomiting, decreased blood pressure, convulsions, dizziness, drowsiness, confusion, polyuria or oliguria leading to anuria (due to hypovolemia).

Treatment emergency measures include removal of the drug from the body, gastric lavage and/or intake of activated charcoal with restoration of water-electrolyte balance.

Lisinopril overdose

Symptoms marked decrease in blood pressure, dry mouth, drowsiness, urinary retention, constipation, anxiety, irritability.

Treatment symptomatic therapy, intravenous administration of 0.9% sodium chloride solution and vasopressors (if no contraindications), blood pressure control, water-electrolyte balance control. Hemodialysis may be performed (see “Special Instructions”).

Drug Interactions

Interactions with indapamide

Combinations not recommended for use

Lithium preparations

With the combined use of indapamide and lithium preparations, as well as with a salt-free diet, an increase in the lithium content in the blood plasma is possible due to reduced excretion, leading to intoxication. If combined use of diuretics with lithium preparations is necessary, careful dose selection of the drugs and regular monitoring of lithium levels in the blood plasma are required.

Combinations requiring precautions

Drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type

• Class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide) and class IC (flecainide);
• Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide, bretylium, dronedarone);
• Some antipsychotic drugs: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other antipsychotic drugs (pimozide, sertindole);
• Antidepressants: tricyclic antidepressants, selective serotonin reuptake inhibitors (citalopram, escitalopram);
• Antibacterial agents: fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin); macrolides (erythromycin with intravenous administration, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole;
• Azole antifungal agents (voriconazole, itraconazole, ketoconazole, fluconazole);
• Antimalarial agents (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);
• Antianginal agents (ranolazine, bepridil);
• Antineoplastic drugs and immunosuppressants (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus, anagrelide);
• Antiemetic agents (ondansetron);
• Agents affecting gastrointestinal motility (cisapride, domperidone);
• Antihistamines (astemizole, terfenadine, mizolastine);
• Others: pentamidine, diphemanil, vincamine (with intravenous administration), vasopressin, terlipressin, ketanserin, probucol, propofol, sevoflurane, terodiline, cilostazol, methadone.

Increased risk of ventricular arrhythmia, in particular, cardiac rhythm disturbances – torsades de pointes arrhythmia (risk factor – hypokalemia).

Determination of potassium levels in the blood plasma and, if necessary, its correction before starting combined use of indapamide and the above drugs is indicated. Monitoring of the patient’s clinical condition, plasma electrolyte levels, and ECG is necessary.

Patients with hypokalemia should take drugs that do not cause polymorphic ventricular tachycardia of the “torsades de pointes” type.

NSAIDs (with systemic use), including selective COX-2 inhibitors, salicylates in high doses (≥3 g/day)

A decrease in the antihypertensive effect of indapamide is possible.

With 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 are indicated.

ACE inhibitors

The use of ACE inhibitors in patients with reduced plasma sodium levels (especially in patients with renal artery stenosis) is associated with the risk of sudden arterial hypotension and/or acute renal failure. Patients with arterial hypertension and possible decreased plasma sodium levels due to diuretic use are indicated

• Discontinuation of diuretics three days before prescribing ACE inhibitors. Subsequently, if necessary, resumption of a non-potassium-sparing diuretic is possible;
• Or starting therapy with an ACE inhibitor at low doses with a gradual increase in dose if necessary.

In case of chronic heart failure, treatment with ACE inhibitors should be started at the lowest possible doses with a possible preliminary reduction in the dose of diuretics. In all cases, monitoring of renal function in the first weeks after prescribing an ACE inhibitor (plasma creatinine concentration) is indicated.

Other drugs that can cause hypokalemia: amphotericin B (IV), gluco- and mineralocorticoids (with systemic use), tetracosactide, laxatives stimulating intestinal motility

Increased risk of hypokalemia (additive effect).

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

Baclofen

Enhancement of the antihypertensive effect has been reported.

Patients require fluid replacement and monitoring of renal function at the beginning of treatment.

Cardiac glycosides

Hypokalemia enhances the toxic effects of cardiac glycosides.

With the combined use of indapamide and cardiac glycosides, monitoring of plasma potassium levels, as well as ECG, is indicated. Therapy correction should be carried out if necessary.

Drug combinations requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene, eplerenone)

Combined prescription of potassium-sparing diuretics and indapamide is effective in some patients. Nevertheless, the risk of developing hypokalemia or hyperkalemia cannot be ignored (especially in patients with diabetes mellitus and renal failure).

Monitoring and, if necessary, correction of plasma potassium levels, as well as ECG monitoring, are indicated.

Metformin

Functional renal failure, which may occur with the use of diuretics, especially “loop” diuretics, increases the risk of lactic acidosis with the combined use of metformin.

Metformin should not be used at a creatinine concentration of more than 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodine-containing X-ray contrast agents

Dehydration during diuretic use may increase the risk of acute renal failure, especially when using iodine-containing drugs in high doses.

Fluid loss must be replenished before prescribing iodine-containing X-ray contrast agents.

Tricyclic antidepressants, antipsychotic drugs (neuroleptics)

Drugs of these classes enhance the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect).

Calcium salts

With combined use, the risk of hypercalcemia increases due to reduced renal excretion of calcium ions.

Cyclosporine, tacrolimus

An increase in plasma creatinine concentration may occur with an unchanged concentration of circulating cyclosporine, even with normal circulating blood volume and plasma sodium levels.

Corticosteroid drugs, tetracosactide (with systemic use)

Reduction of the antihypertensive effect (fluid and sodium retention caused by corticosteroids).

Interactions with lisinopril

Contraindicated drug combinations

Aliskiren

Concomitant use of ACE inhibitors with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² of body surface area) is contraindicated.

Prescription of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy.

Not recommended drug combinations

Angiotensin II receptor antagonists (ARBs)

The literature has reported that in patients with established atherosclerotic disease, chronic heart failure, or diabetes mellitus with target organ damage, simultaneous therapy with an ACE inhibitor and an ARB is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to the use of only one drug affecting the RAAS. Dual blockade (e.g., combining an ACE inhibitor with an ARB) should be limited to individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

Potassium preparations, potassium-sparing diuretics or potassium-containing salt substitutes and other drugs that can increase serum potassium levels

Although serum potassium levels usually remain within the normal range, some patients receiving lisinopril may develop hyperkalemia. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or salt substitutes containing potassium can lead to a significant increase in serum potassium levels, especially in patients with impaired renal function. Caution should also be exercised when using lisinopril concomitantly with other drugs that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act like amiloride as a potassium-sparing diuretic. Therefore, the combination of lisinopril with the aforementioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium levels (see the “Special Instructions” section).

Cyclosporine

Hyperkalemia may develop with the concomitant use of ACE inhibitors with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin

Hyperkalemia may develop with the concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium levels is recommended.

Lithium preparations

With the concomitant use of lithium preparations and ACE inhibitors, a reversible increase in serum lithium concentration and related toxic effects may be noted. Concomitant use of lisinopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of serum lithium concentration should be performed.

Drug combinations requiring special caution during use

Insulin and oral hypoglycemic agents

Epidemiological studies have shown that the concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may enhance their hypoglycemic effect up to the development of hypoglycemia. This effect is most likely to be observed during the first weeks of simultaneous therapy, as well as in patients with impaired renal function.

Baclofen

Enhances the antihypertensive effect of ACE inhibitors. Blood pressure levels should be carefully monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.

Diuretics

In patients taking diuretics, especially those that remove fluid and/or salts, a significant decrease in blood pressure may be observed at the beginning of therapy with an ACE inhibitor. The risk of developing antihypertensive effects can be reduced by discontinuing the diuretic, replenishing fluid or salt loss before starting therapy with ACE inhibitors. In arterial hypertension in patients with prior diuretic therapy that may have led to excessive fluid and/or salt loss, diuretics should be discontinued before starting Diroton^® Plus.

Renal function (creatinine concentration) should be monitored during the first weeks of using Diroton^® Plus.

NSAIDs, including acetylsalicylic acid at a dose of ≥3 g/day

Concomitant use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose that has an anti-inflammatory effect, COX-2 inhibitors, and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may lead to worsening of renal function, including the development of acute renal failure and an increase in serum potassium levels, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients need to compensate for fluid loss and carefully monitor renal function both at the beginning of treatment and during treatment.

Drugs that may increase the risk of angioedema

Concomitant use of ACE inhibitors with the combination sacubitril/valsartan is contraindicated, as it increases the risk of angioedema (see sections “Contraindications” and “Special Instructions”).

Concomitant use of ACE inhibitors with mTOR inhibitors (sirolimus, everolimus, temsirolimus) or neutral endopeptidase inhibitors (racecadotril), tissue plasminogen activator, or vildagliptin may lead to an increased risk of angioedema (see “Special Instructions” section).

Estramustine, mTOR inhibitors (sirolimus, everolimus, temsirolimus)

Concomitant use of estramustine with ACE inhibitors is associated with an increased risk of angioedema.

Neutral endopeptidase inhibitors

An increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor).

Concomitant use of ACE inhibitors with medicinal products containing sacubitril (a neprilysin inhibitor) increases the risk of angioedema, therefore the concomitant use of these drugs is contraindicated. ACE inhibitors should be administered no earlier than 36 hours after discontinuing drugs containing sacubitril. The administration of drugs containing sacubitril is contraindicated in patients taking ACE inhibitors, as well as within 36 hours after discontinuing ACE inhibitors.

DPP-4 inhibitors (gliptins)

Linagliptin, saxagliptin, sitagliptin, vildagliptin – when used concomitantly with ACE inhibitors, the risk of angioedema increases due to the suppression of dipeptidyl peptidase-4 (DPP-4) activity by the gliptin.

Drug combinations requiring caution during use

Other antihypertensive agents (e.g., beta-blockers, slow calcium channel blockers, diuretics) and vasodilators

Enhancement of the antihypertensive effect of the drug is possible. Caution should be exercised when co-administering with nitroglycerin, other nitrates, or other vasodilators, as this may lead to an additional decrease in blood pressure.

Antacids and cholestyramine

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

Tricyclic antidepressants, antipsychotics, general anesthetics, barbiturates, phenothiazine, ethanol

Concomitant use may enhance the effect of lisinopril.

Sympathomimetics

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

Muscle relaxants

Concomitant use of muscle relaxants with ACE inhibitors may lead to a pronounced decrease in blood pressure.

Gold preparations

Rare cases of nitritoid reactions (a symptom complex including facial skin flushing, nausea, arterial hypotension, which can be very severe) have been described in patients receiving ACE inhibitors, including lisinopril, who were administered an intravenous gold preparation (sodium aurothiomalate); these reactions were reported more frequently in patients receiving treatment with ACE inhibitors.

Co-trimoxazole (sulfamethoxazole and trimethoprim)

Increased risk of hyperkalemia.

Selective serotonin reuptake inhibitors (SSRIs: escitalopram, paroxetine, fluoxetine, sertraline)

Concomitant use with SSRIs may lead to severe hyponatremia.

Allopurinol, procainamide, cytostatics (5-fluorouracil, vincristine, docetaxel)

Leukopenia may develop.

Tissue plasminogen activators

Observational studies have revealed an increased incidence of angioedema in patients taking ACE inhibitors after the use of alteplase for thrombolytic therapy of ischemic stroke.

Storage Conditions

Capsules 1.5 mg+5 mg should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Capsules 1.5 mg+10 mg and capsules 1.5 mg+20 mg should be stored out of the reach of children at a temperature not exceeding 30°C (86°F). The shelf life is 3 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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