Sonoprel (Tablet kit) Instructions for Use

Marketing Authorization Holder

Makiz-Pharma, LLC (Russia)

ATC Code

C09BA (ACE inhibitors in combination with diuretics)

Active Substances

Indapamide (Rec.INN registered by WHO)

Cilazapril (Rec.INN registered by WHO)

Dosage Forms

	Sonoprel	Tablet kit: 10 pcs. in a blister, 3 or 6 blisters in a pack; modified-release tablets, coated, 1.5 mg: 5 pcs.; tablets, coated, 2.5 mg: 5 pcs.
		Tablet kit: 14 pcs. in a blister, 2 or 4 blisters in a pack; modified-release tablets, coated, 1.5 mg: 7 pcs.; tablets, coated, 2.5 mg: 7 pcs.

Dosage Form, Packaging, and Composition

Tablet kit

Excipients: Methocel, lactose, colloidal silicon dioxide (aerosil), magnesium stearate.

Coating composition: Hypromellose, titanium dioxide, macrogol (polyethylene glycol 4000), magnesium hydrosilicate (talc), tropaeolin “O”.

Excipients: Lactose, corn starch, hypromellose 3 cPz, talc (sodium hydrosilicate), sodium stearyl fumarate.

Coating composition: Hypromellose 6 cPz, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide (E171).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Tablet kit

Excipients: Methocel, lactose, colloidal silicon dioxide (aerosil), magnesium stearate.

Coating composition: Hypromellose, titanium dioxide, macrogol (polyethylene glycol 4000), magnesium hydrosilicate (talc), tropaeolin “O”.

Excipients: Lactose, corn starch, hypromellose 3 cPz, talc (sodium hydrosilicate), sodium stearyl fumarate.

Coating composition: Hypromellose 6 cPz, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide (E171).

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

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

Combined antihypertensive drug.

Indapamide is a thiazide-like diuretic with moderate potency and long duration of action, a derivative of benzamides. It has a moderate saluretic and diuretic effect, which are associated with the blockade of reabsorption of sodium, chloride, hydrogen ions, and to a lesser extent, potassium ions in the proximal tubules and the cortical segment of the distal tubule of the nephron. It has a vasodilatory effect and reduces total peripheral resistance by reducing the reactivity of the vascular wall to norepinephrine and angiotensin II, increasing the synthesis of prostaglandins with vasodilatory activity, and inhibiting calcium influx into the smooth muscle of the vascular wall. It helps to reduce left ventricular hypertrophy of the heart. In therapeutic doses, it does not affect lipid and carbohydrate metabolism (including in patients with concomitant diabetes mellitus). The antihypertensive effect develops at the end of the first or beginning of the second week with continuous use of the drug and persists for 24 hours on the background of a single dose.

Cilazapril is a prodrug that is rapidly converted in the body into an active form – cilazaprilat – a specific long-acting ACE inhibitor that blocks the conversion of inactive angiotensin I to angiotensin II, which has a pronounced vasoconstrictive effect.

It reduces systolic and diastolic blood pressure, both in the standing and lying positions, usually without orthostatic reactions. Cilazapril is effective at all stages of arterial hypertension, as well as in renal hypertension. Reflex tachycardia does not occur, although slight changes in heart rate may be observed, which are of no clinical significance. In some patients, the decrease in blood pressure may decrease by the time of the next dose of the drug. With long-term treatment, the antihypertensive effect of cilazapril is maintained. After sudden withdrawal of the drug, a rapid increase in blood pressure does not occur.

In patients with arterial hypertension and concomitant moderate or severe renal failure, the glomerular filtration rate and renal blood flow during treatment with cilazapril, as a rule, do not change, despite a clinically significant decrease in blood pressure.

As with other ACE inhibitors, the antihypertensive effect of cilazapril in Black patients may be less pronounced than in patients of other races. However, if Cilazapril is used in combination with hydrochlorothiazide, no differences in the effect of the drug are observed in patients of different races.

It should be taken into account that in patients with normal renal function during treatment with cilazapril, the serum potassium concentration usually remains within the normal range. In patients simultaneously taking potassium-sparing diuretics, an increase in potassium levels is possible.

In recommended doses, the antihypertensive effect in patients with arterial hypertension and in patients with chronic heart failure lasts up to 24 hours. After oral administration, the antihypertensive effect of cilazapril usually appears within the first hour and reaches a maximum after 3-7 hours.

Pharmacokinetics

After oral administration, it is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability is high (93%). Food intake somewhat slows down the rate, but does not affect the completeness of absorption. The maximum concentration in the blood is reached 1-2 hours after oral administration. The equilibrium concentration is reached after 7 days of regular use. The drug is 70-80% bound to plasma proteins. It has a high volume of distribution, passes through histohematic (including placental) barriers, and penetrates into breast milk. It is metabolized in the liver. The half-life of indapamide averages 14-18 hours. It is excreted from the body by the kidneys (up to 80%) mainly in the form of metabolites, through the intestines – 20%. In patients with renal failure, the pharmacokinetics do not change. Does not accumulate.

Cilazapril is well absorbed and rapidly converted to the active form – cilazaprilat. Taking food immediately before taking the drug somewhat delays and reduces absorption, which, however, has no therapeutic significance. After oral administration of cilazapril, the bioavailability of cilazaprilat is about 60%, according to the results of its determination in urine. Maximum plasma concentrations are reached within 2 hours after administration and are directly proportional to the dose. Cilazaprilat is excreted unchanged through the kidneys; its half-life when taken orally once a day is 9 hours. In patients with renal failure, plasma concentrations of cilazaprilat are higher than in patients with normal renal function, as the clearance of the drug decreases with low creatinine clearance. In patients with end-stage renal failure, elimination is absent altogether, but hemodialysis can to some extent reduce the concentrations of both cilazapril and cilazaprilat. In elderly patients with renal function normal for their age, plasma concentrations of cilazaprilat may be 40% higher and clearance 20% lower than in young patients. Similar changes in pharmacokinetics are observed in patients with moderate or severe liver cirrhosis. In patients with chronic heart failure, the clearance of cilazaprilat correlates with creatinine clearance. Thus, there is no need for dose adjustment beyond what is recommended for patients with impaired renal function (see “Dosage in Special Cases”).

Indications

• Arterial hypertension.

ICD codes

Dosage Regimen

Take one modified-release indapamide 1.5 mg tablet and one-half of a cilazapril 2.5 mg tablet simultaneously each morning.

Swallow the tablets whole with a sufficient amount of water; do not crush or chew the indapamide modified-release tablet.

If blood pressure control is inadequate, the cilazapril dose may be increased.

Increase the cilazapril dose to one full 2.5 mg tablet once daily.

For a more pronounced effect, the cilazapril dose may be further increased to a maximum of two 2.5 mg tablets (5 mg total) taken once daily.

Do not exceed the maximum daily dose of one indapamide 1.5 mg tablet and two cilazapril 2.5 mg tablets.

Initiate therapy at the lower dose in patients at increased risk of hypotension, such as those who are volume-depleted, salt-restricted, or elderly.

Regularly monitor blood pressure and renal function during treatment, particularly after dose adjustments.

In patients with impaired renal function, a lower starting dose may be required; adjust dosage based on creatinine clearance.

Adverse Reactions

Indapamide

From the digestive system: nausea, anorexia, dry mouth, gastralgia, vomiting, diarrhea, constipation, pancreatitis are possible.

From the central and peripheral nervous system: asthenia, nervousness, headache, dizziness, drowsiness, vertigo, insomnia, depression; rarely – increased fatigue, general weakness, malaise, muscle spasm, tension, irritability, anxiety, paresthesia; conjunctivitis, visual impairment.

From the respiratory system: cough, pharyngitis, sinusitis; rarely – rhinitis, rhinorrhea.

From the cardiovascular system: orthostatic hypotension, ECG changes (due to hypokalemia), arrhythmia, palpitations.

From the urinary system: frequent infections, nocturia, polyuria.

From the reproductive system: decreased potency, decreased libido.

Allergic reactions: rash, urticaria, itching, hemorrhagic vasculitis.

From laboratory parameters: hyperuricemia, hyperglycemia, hypokalemia, hypochloremia, hyponatremia, hypercalcemia, increased plasma urea nitrogen, hypercreatininemia, glucosuria.

Other: flu-like syndrome, chest pain, back pain, infections, increased sweating, weight loss, exacerbation of systemic lupus erythematosus.

Cilazapril

Frequently: headache, dizziness.

Less than 2%: weakness, pronounced decrease in blood pressure, dyspepsia, skin rash, cough.

From the digestive system: in some cases – pancreatitis, sometimes with a fatal outcome.

Allergic reactions rarely – angioedema. If the edema spreads to the face, lips, tongue, vocal apparatus and/or larynx, Cilazapril should be discontinued and appropriate treatment should be prescribed immediately.

From the cardiovascular system there are isolated reports of the development of symptomatic arterial hypotension during treatment with ACE inhibitors, especially in patients with hyponatremia and hypovolemia caused by vomiting, diarrhea, previous treatment with diuretics, or in patients on a salt-free diet or dialysis.

From the hematopoietic system: sometimes – a decrease in the level of hemoglobin, hematocrit and/or leukocytes, however, a causal relationship of these changes with the intake of cilazapril has not been established.

From laboratory parameters rarely – a slight, usually reversible increase in the content of creatinine and urea in the blood serum (mainly in patients with renal artery stenosis or with renal failure, however, sometimes it is also noted in patients with normal renal function, especially in those who simultaneously receive diuretics). In patients whose renal function depends mainly on the renin-angiotensin-aldosterone system, for example, in severe heart failure, renal artery stenosis and other kidney diseases, treatment with ACE inhibitors may lead to an increase in blood urea nitrogen and serum creatinine concentrations. Although after discontinuation of cilazapril and/or diuretics these changes are usually reversible, cases of severe renal impairment and, rarely, acute renal failure have been described.

Contraindications

Indapamide

• Anuria;
• Hypokalemia;
• Severe hepatic (including with encephalopathy) and/or renal failure;
• Pregnancy;
• Lactation period (breastfeeding);
• Age under 18 years (efficacy and safety not established);
• Concomitant use of drugs that prolong the QT interval;
• Hypersensitivity to the drug and other sulfonamide derivatives.

Use with caution in decompensated diabetes mellitus, hyperuricemia (especially accompanied by gout and urate nephrolithiasis).

Cilazapril

• History of angioedema (including hereditary, idiopathic, as well as angioedema caused by the use of other ACE inhibitors);
• Bilateral renal artery stenosis or stenosis of the artery of a single kidney;
• Hyperkalemia;
• Porphyria;
• Pregnancy;
• Lactation period (breastfeeding);
• Hemodialysis using high-flux membranes (e.g., AN69), hemofiltration or LDL apheresis;
• Age under 18 years (safety and efficacy of use have not been studied);
• Hypersensitivity to cilazapril or other ACE inhibitors.

Use with caution in chronic renal failure (proteinuria more than 1 g/day), severe circulatory failure, severe autoimmune diseases (including systemic lupus erythematosus, scleroderma), arterial hypotension, mitral stenosis, aortic stenosis, coronary artery disease, bone marrow depression, condition after kidney transplantation, patients on hemodialysis, diabetes mellitus, gout, hyperuricemia, salt-restricted diet, liver cirrhosis, conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), obstructive pulmonary diseases.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Use with caution in liver cirrhosis.

Use in Renal Impairment

Use with caution in chronic renal failure (proteinuria more than 1 g/day).

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age.

Special Precautions

Indapamide

When prescribing indapamide to patients taking cardiac glycosides, laxatives, against the background of hyperaldosteronism, as well as to elderly patients, regular monitoring of potassium ions and creatinine is indicated.

During the use of indapamide, the concentration of potassium, sodium, magnesium ions in the blood plasma (since electrolyte disturbances may develop), pH, glucose concentration, uric acid and residual nitrogen should be systematically monitored.

The most thorough monitoring is indicated in patients with liver cirrhosis (especially with edema or ascites – the risk of developing metabolic alkalosis, which enhances the manifestations of hepatic encephalopathy), coronary artery disease, heart failure, as well as in elderly patients. The high-risk group also includes patients with an increased QT interval on the ECG (congenital or developed against the background of any pathological process).

The first measurement of blood potassium concentration should be carried out within the first week of treatment.

Hypercalcemia during the use of indapamide may be a consequence of previously undiagnosed hyperparathyroidism.

In patients with diabetes mellitus, it is extremely important to control blood glucose levels, especially in the presence of hypokalemia.

Significant dehydration can lead to the development of acute renal failure (decreased glomerular filtration). Patients need to compensate for water loss and carefully monitor kidney function at the beginning of treatment.

Indapamide may give a positive result during doping control.

In patients with arterial hypertension and hyponatremia (due to diuretic use), it is necessary to stop taking diuretics 3 days before starting ACE inhibitors (if necessary, diuretics can be resumed a little later), or they are prescribed initial low doses of ACE inhibitors.

Sulfonamide derivatives may exacerbate the course of systemic lupus erythematosus (must be taken into account when prescribing indapamide).

It should be taken into account that when using ACE inhibitors simultaneously with indapamide, the risk of developing arterial hypotension and/or acute renal failure increases (especially in the presence of renal artery stenosis).

Cilazapril

Like other ACE inhibitors, Cilazapril should be prescribed with caution to patients with aortic stenosis.

In case of development of acute arterial hypotension, the patient should be placed in a horizontal position; infusion of saline or drugs that increase the volume of circulating blood may be required. After replenishment of the circulating blood volume, treatment with cilazapril can be continued. However, if the symptoms do not disappear, the dose should be reduced or the drug discontinued. Blood pressure may also decrease significantly in patients with chronic circulatory failure receiving ACE inhibitors. However, in clinical studies in which patients with chronic heart failure took Cilazapril at a dose of 500 mcg, symptoms of arterial hypotension did not develop.

Arterial hypotension may develop with the use of ACE inhibitors during surgical interventions in combination with general anesthetics, which also have a hypotensive effect. In such cases, the patient may be shown an increase in the volume of circulating blood by intravenous infusion or, in the absence of effect, infusion of angiotensin II.

Patients with renal failure may require a dose reduction depending on creatinine clearance. In renal failure, as well as in severe heart failure, it is necessary to monitor renal function in the first weeks of therapy.

Concomitant use of potassium-sparing diuretics can cause an increase in serum potassium levels, especially in patients with renal failure. Therefore, if simultaneous use of these drugs is indicated, their dose should be reduced at the beginning of treatment with cilazapril, carefully monitoring serum potassium concentration and renal function.

Hemodialysis using high-flux polyacrylonitritemetalylsulfate membranes (e.g., AN69), hemofiltration, or LDL apheresis may cause anaphylaxis or anaphylactoid reactions, including life-threatening shock, in patients taking ACE inhibitors, including Cilazapril. The mechanism of this phenomenon is not precisely known. Therefore, these procedures are contraindicated in patients receiving Cilazapril.

Anaphylactic reactions may occur in patients undergoing hyposensitization with wasp or bee venom and simultaneously receiving an ACE inhibitor. For this reason, cilazapril intake should be discontinued before starting hyposensitization. Furthermore, in this situation, Cilazapril should not be replaced with beta-blockers.

The use of ACE inhibitors in diabetic patients may potentiate the hypoglycemic effect of oral hypoglycemic agents.

Overdose

Indapamide

Symptoms nausea, vomiting, weakness, gastrointestinal dysfunction, water-electrolyte imbalance, and in some cases – excessive decrease in blood pressure, respiratory depression. In patients with liver cirrhosis, hepatic coma may develop.

Treatment gastric lavage, correction of water-electrolyte balance, symptomatic therapy. There is no specific antidote.

Cilazapril

Data on cilazapril overdose are limited. In healthy volunteers who took single doses of up to 160 mg, no undesirable effects on blood pressure were noted. In case of overdose, the most likely symptom is a pronounced decrease in blood pressure, which should be managed by increasing the circulating blood volume.

Cilazaprilat can be partially removed from the body by hemodialysis.

Drug Interactions

Indapamide

Saluretics, cardiac glycosides, gluco- and mineralocorticoids, tetracosactide, amphotericin B (IV administration), laxatives when taken concomitantly with indapamide increase the risk of hypokalemia.

Concomitant use of indapamide with cardiac glycosides increases the risk of digitalis intoxication.

Concomitant use of indapamide with calcium preparations may lead to hypercalcemia.

Concomitant use of indapamide with metformin may exacerbate lactic acidosis.

Concomitant use of indapamide with lithium increases the plasma concentration of the latter (due to reduced urinary excretion), which increases the risk of nephrotoxic effects.

Concomitant use of indapamide with astemizole, erythromycin (IV administration), pentamidine, sultopride, terfenadine, vincamine, class IA antiarrhythmics (quinidine, disopyramide) and class III antiarrhythmics (amiodarone, bretylium, sotalol) may lead to torsades de pointes type arrhythmia.

Concomitant use of indapamide with NSAIDs, corticosteroids, tetracosactide, sympathomimetics reduces the antihypertensive effect.

Concomitant use of indapamide with baclofen enhances the antihypertensive effect.

The combination of indapamide with potassium-sparing diuretics may be effective in some categories of patients; however, the possibility of developing hypo- or hyperkalemia is not completely excluded, especially in patients with diabetes and renal failure.

Concomitant use of indapamide with high doses of iodine-containing contrast agents (due to dehydration) increases the risk of impaired renal function. Therefore, before using iodine-containing contrast agents, patients must restore fluid loss.

Concomitant use of indapamide with imipramine-type (tricyclic) antidepressants and antipsychotic agents (neuroleptics) enhances the antihypertensive effect and increases the risk of orthostatic hypotension.

Concomitant use of indapamide with cyclosporine increases the risk of hypercreatininemia.

Indapamide reduces the effect of indirect anticoagulants (coumarin or indandione derivatives) due to an increase in the concentration of blood clotting factors resulting from a decrease in circulating blood volume and increased production by the liver (dose adjustment may be required).

Indapamide enhances the neuromuscular blockade caused by non-depolarizing muscle relaxants.

Cilazapril

Concomitant use of cilazapril with other antihypertensive agents may result in an additive effect and increase the risk of arterial hypotension.

Cilazapril has been used concomitantly with digoxin, nitrates, furosemide, thiazides, coumarin anticoagulants, and H₂-histamine receptor blockers. No increase in plasma digoxin concentration or other clinically significant or pharmacokinetic interactions were noted.

Combined use of potassium-sparing diuretics with cilazapril may lead to an increase in serum potassium levels, especially in patients with renal failure.

Concomitant use of cilazapril with NSAIDs may attenuate the antihypertensive effect. This effect is not observed in patients receiving Cilazapril prior to NSAID administration.

Storage Conditions

List B. The drug should be stored in a dry place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

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.