Inhibace^® (Tablets) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

F. Hoffmann-La Roche, Ltd (Switzerland)

Or

Roche Farma S.A. (Spain)

Packaging and Quality Control Release

MAKIZ-PHARMA, LLC (Russia)

ATC Code

C09AA08 (Cilazapril)

Active Substance

Cilazapril (Rec.INN registered by WHO)

Dosage Forms

	Inhibace®	Film-coated tablets, 1 mg: 15, 28, 30, 50, 98 or 100 pcs.
		Film-coated tablets, 2.5 mg: 15, 28, 30, 50, 98 or 100 pcs.
		Film-coated tablets, 5 mg: 15, 28, 30, 50, 98 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pale yellow, oval, biconvex; engraved with “CIL 1” on one side and a score on the other side.

Excipients: lactose, corn starch, hypromellose, talc, sodium stearyl fumarate, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172).

7 pcs. – blisters (4) – cartons.
7 pcs. – blisters (14) – cartons.
10 pcs. – blisters (3) – cartons.
15 pcs. – dark glass bottles (1) – cartons.
30 pcs. – dark glass bottles (1) – cartons.
50 pcs. – dark glass bottles (1) – cartons.
100 pcs. – dark glass bottles (1) – cartons.

Film-coated tablets dull red, oval, biconvex; engraved with “CIL 2.5” on one side and a score on the other side.

Excipients: lactose, corn starch, hypromellose, talc, sodium stearyl fumarate, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172).

7 pcs. – blisters (4) – cartons.
7 pcs. – blisters (14) – cartons.
10 pcs. – blisters (3) – cartons.
15 pcs. – dark glass bottles (1) – cartons.
30 pcs. – dark glass bottles (1) – cartons.
50 pcs. – dark glass bottles (1) – cartons.
100 pcs. – dark glass bottles (1) – cartons.

Film-coated tablets from reddish-brown to brown, oval, biconvex; engraved with “CIL 5” on one side and a score on the other side.

Excipients: lactose, corn starch, hypromellose, talc, sodium stearyl fumarate, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172).

7 pcs. – blisters (4) – cartons.
7 pcs. – blisters (14) – cartons.
10 pcs. – blisters (3) – cartons.
15 pcs. – dark glass bottles (1) – cartons.
30 pcs. – dark glass bottles (1) – cartons.
50 pcs. – dark glass bottles (1) – cartons.
100 pcs. – dark glass bottles (1) – cartons.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE blocker

Pharmacological Action

Inhibace^® is a long-acting ACE inhibitor. It suppresses the renin-angiotensin-aldosterone system and thereby the conversion of inactive angiotensin I to angiotensin II, which has a strong vasoconstrictive effect. In recommended doses, the effect of Inhibace^® in patients with arterial hypertension and in patients with chronic heart failure lasts for 24 hours.

In patients with normal renal function, serum potassium concentration usually remains within the normal range during treatment with Inhibace^®. In patients concurrently taking potassium-sparing diuretics, an increase in potassium levels is possible.

Arterial hypertension

Inhibace^® reduces systolic and diastolic blood pressure both in the upright and supine positions, usually without orthostatic reactions. The drug is effective at all stages of arterial hypertension, as well as in renal hypertension. The antihypertensive effect of Inhibace^® usually appears within the first hour after oral administration and reaches a maximum after 3-7 hours. Reflex tachycardia does not occur, although minor changes in heart rate of no clinical significance may be observed. In some patients, the reduction in blood pressure may decrease by the time of the next dose.

During long-term treatment, the antihypertensive effect of Inhibace^® is maintained. After sudden withdrawal of the drug, a rapid increase in blood pressure does not occur.

In patients with arterial hypertension who have moderate or severe renal failure, the glomerular filtration rate and renal blood flow during treatment with Inhibace^® generally do not change, despite a clinically significant decrease in blood pressure.

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

Chronic heart failure

In chronic heart failure, the activity of the renin-angiotensin-aldosterone system, as well as the sympathetic nervous system, is usually increased, leading to increased systemic vasoconstriction and enhanced sodium and water retention in the body. In patients receiving diuretics and/or digitalis preparations, Inhibace^®, by suppressing the renin-angiotensin-aldosterone system, reduces the load on the heart by decreasing systemic vascular resistance (afterload) and pressure in the pulmonary capillaries (preload). Furthermore, in these patients, exercise tolerance is significantly improved, which enhances their quality of life. Hemodynamic and clinical effects are achieved quickly and are maintained for a long time.

Pharmacokinetics

Absorption

After oral administration, Cilazapril is well absorbed and rapidly converted to its active form, cilazaprilat. Taking food immediately before drug intake somewhat delays and reduces absorption, which is not of therapeutic significance. After oral administration of cilazapril, the bioavailability of cilazaprilat is about 60%, based on results of its determination in urine. C_max in plasma is reached within 2 hours after administration and is directly proportional to the dose.

Elimination

Cilazaprilat is excreted unchanged by the kidneys. T_1/2 after oral administration once daily is 9 hours.

Pharmacokinetics in special clinical cases

In patients with renal failure, plasma concentrations of cilazaprilat are higher than in patients with normal renal function, because the clearance of the drug decreases with low creatinine clearance. In patients with end-stage renal failure, elimination is absent altogether; however, 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 pharmacokinetic changes are observed in patients with moderate or severe liver cirrhosis.

In patients with chronic heart failure, the clearance of cilazaprilat correlates with creatinine clearance. Therefore, no additional dose adjustment, other than that recommended for patients with renal impairment, is required.

Indications

• Arterial hypertension (including renovascular);
• As an adjunct in chronic heart failure (in combination with cardiac glycosides and/or diuretics).

ICD codes

Dosage Regimen

Inhibace^® should be taken once daily. Since food intake does not have a clinically significant effect on absorption, the drug can be taken before or after meals, always at approximately the same time of day.

For arterial hypertension the recommended initial dose is 1-1.25 mg once daily. The dose should be individually adjusted based on blood pressure dynamics. The standard dose range of Inhibace^® is from 2.5 to 5 mg once daily. If blood pressure reduction is insufficient at a dose of 5 mg once daily, a potassium-excreting diuretic in a low dose can be prescribed simultaneously to enhance the hypotensive effect.

For renovascular hypertension treatment with Inhibace^® should be started at a dose of 500 mcg or less once daily, since in these patients ACE inhibitors can cause a more pronounced decrease in blood pressure than in patients with arterial hypertension of other origins. The maintenance dose is selected individually.

Patients with arterial hypertension receiving diuretics: to reduce the likelihood of symptomatic hypotension, the diuretic should be discontinued 2-3 days before starting treatment with Inhibace^®. If necessary, its use can be resumed later. The recommended initial dose for these patients is 500 mcg once daily.

Chronic heart failure: treatment with Inhibace^® should be started at a dose of 500 mcg once daily under careful medical supervision. Depending on drug tolerance and clinical condition, the dose is increased to the lowest maintenance dose of 1 mg per day. Further dose selection within the usual maintenance dose of 1-2.5 mg/day is based on the patient’s response to treatment, their clinical condition, and drug tolerance. The maximum dose is 5 mg once daily.

Results of clinical studies have shown that the clearance of cilazaprilat in patients with chronic heart failure correlates with creatinine clearance. Therefore, when treating patients with chronic heart failure and impaired renal function, the dosage regimen should be adjusted in accordance with the recommendations below.

Patients with renal impairment may require a dose reduction depending on creatinine clearance. The recommended dosage regimen is given in the table.

If in exceptional cases patients with liver cirrhosis require treatment with cilazapril, the drug should be prescribed with caution at an initial dose of 250-500 mcg once daily, as marked arterial hypotension may develop.

For arterial hypertensionin elderly patients the initial dose of Inhibace^® is from 0.5-1.25 mg/day. The maintenance dose is selected individually based on drug tolerance, the patient’s response to treatment, and their clinical condition.

For chronic heart failure in elderly patients taking high doses of diuretics, the recommended initial dose of 500 mcg should be strictly adhered to when prescribing the drug.

Adverse Reactions

From the CNS most frequently – headache and dizziness.

From the cardiovascular system: less than 2% – weakness, arterial hypotension. During treatment with ACE inhibitors, there are isolated reports of symptomatic arterial hypotension, especially in patients with hyponatremia and hypovolemia caused by vomiting, diarrhea, prior treatment with diuretics, a salt-free diet, or dialysis.

From the digestive system less than 2% – dyspepsia. As with the use of other ACE inhibitors, isolated cases of pancreatitis, sometimes fatal, have been described during treatment with Inhibace^®.

Allergic reactions as with treatment with other ACE inhibitors, cases of angioedema, although rare, have been described. If edema spreads to the face, lips, tongue, glottis, and/or larynx, Inhibace^® should be discontinued and appropriate treatment immediately prescribed.

Other less than 2% – rash and cough.

From laboratory parameters rarely – a slight, often reversible, increase in serum creatinine and urea content (such changes occur mainly in patients with renal artery stenosis or with renal failure, but sometimes in patients with normal renal function, especially those concurrently receiving diuretics).

In patients whose renal function depends mainly on the renin-angiotensin-aldosterone system, for example, in severe circulatory failure, renal artery stenosis and other kidney diseases, treatment with Inhibace^®, as with other ACE inhibitors, may lead to an increase in blood urea nitrogen and serum creatinine concentrations. Although these changes are usually reversible after discontinuation of Inhibace^® and/or diuretics, cases of severe renal impairment and, rarely, acute renal failure have been reported.

A decrease in hemoglobin, hematocrit and/or leukocyte levels was sometimes observed, but a causal relationship of these changes with the intake of Inhibace^® has not been established.

In most cases, adverse reactions are mild or moderate in severity, are transient and do not require discontinuation of treatment.

Contraindications

• 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 polyacrylonitrile methallyl sulfonate membranes (e.g., AN69), hemofiltration or LDL apheresis;
• Hypersensitivity to cilazapril or other ACE inhibitors.

With caution the drug should be used in chronic renal failure (proteinuria more than 1 g/day), in severe circulatory failure, severe autoimmune diseases (including systemic lupus erythematosus, scleroderma), in arterial hypotension, mitral stenosis, aortic stenosis, in coronary artery disease, bone marrow depression, condition after kidney transplantation, in patients on hemodialysis, in diabetes mellitus, gout, hyperuricemia, against the background of a salt-restricted diet, in liver cirrhosis, conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), in obstructive lung diseases, in children and adolescents under 18 years of age (safety and efficacy of use have not been studied).

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies on the safety of the drug use during pregnancy have not been conducted. The use of other ACE inhibitors in pregnant women has been associated with cases of oligohydramnios, hypotension in newborns and/or anuria.

In experimental studies in animals, ACE inhibitors had a toxic effect on the fetus. Although relevant data for Inhibace^® are lacking, pregnant women should be informed of the potential risk to the fetus.

It is not known whether Cilazapril is excreted in human breast milk, but since studies have shown its presence in rat milk, Inhibace^® should not be prescribed to nursing mothers.

Use in Hepatic Impairment

The drug should be used with caution in liver cirrhosis.

Use in Renal Impairment

With caution the drug should be used in chronic renal failure (proteinuria more than 1 g/ day), condition after kidney transplantation.

In patients with renal impairment, plasma concentrations of cilazaprilat are higher than in patients with normal renal function, because the clearance of the drug decreases with low creatinine clearance. In patients with end-stage renal failure, elimination is absent altogether; however, hemodialysis can to some extent reduce the concentrations of both cilazapril and cilazaprilat.

The use of the drug is contraindicated in bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Special Precautions

Like other ACE inhibitors, Inhibace^® should be prescribed with caution to patients with aortic stenosis.

In case of acute arterial hypotension, the patient should be placed in a horizontal position; they may require an infusion of saline or a drug that increases circulating blood volume. After circulating blood volume replenishment, treatment with Inhibace^® can be continued. However, if symptoms do not disappear, the dose should be reduced or the drug discontinued.

In patients with chronic circulatory failure receiving ACE inhibitors, a significant decrease in blood pressure is possible. However, in clinical studies where patients with chronic circulatory failure took Inhibace^® at a dose of 500 mcg, symptoms of arterial hypotension did not occur.

Arterial hypotension can be caused by the use of ACE inhibitors during surgical interventions in combination with anesthetics that also have a hypotensive effect. In such cases, the patient may be shown an increase in circulating blood volume by intravenous infusion or – if this measure does not help – an infusion of angiotensin II.

In renal failure, as well as in severe heart failure, renal function should be monitored during the first weeks of therapy.

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

Hemodialysis using high-flux polyacrylonitrile methallyl sulfonate membranes (e.g., AN 69), hemofiltration or LDL apheresis can 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 should be avoided in such patients.

Anaphylactic reactions may occur in patients undergoing hyposensitization with wasp or bee venom and simultaneously receiving an ACE inhibitor. Therefore, the use of Inhibace^® should be discontinued before starting hyposensitization. Furthermore, in this situation, Inhibace^® should not be replaced with beta-blockers.

The use of ACE inhibitors in patients with diabetes mellitus may potentiate the hypoglycemic effect of oral hypoglycemic drugs.

Use in pediatrics

The tolerability and efficacy of Inhibace^® in children have not been established; therefore, the use of the drug in pediatrics is not recommended.

Overdose

Symptoms there is very little data on drug overdose in patients. In healthy volunteers who took single doses of up to 160 mg, no undesirable effect on blood pressure was noted. The most likely symptom is a pronounced decrease in blood pressure.

Treatment for a pronounced decrease in blood pressure involves measures aimed at increasing the circulating blood volume. If indicated, cilazaprilat can be partially removed from the body by hemodialysis.

Drug Interactions

If Inhibace^® is used in combination with other antihypertensive agents, an additive effect may be observed, and the risk of developing arterial hypotension increases.

Inhibace^® has been used concomitantly with digoxin, nitrates, furosemide, thiazides, coumarin anticoagulants, and histamine H₂-receptor blockers. No increase in digoxin plasma concentration or other clinically significant or pharmacokinetic interaction was observed.

Concomitant use of potassium-sparing diuretics with Inhibace^® may lead to an increase in serum potassium levels, especially in patients with renal failure.

Concomitant use with NSAIDs may reduce the hypotensive effect of Inhibace^®, as with other ACE inhibitors. This is not observed in patients who received Inhibace^® before the prescription of NSAIDs.

Storage Conditions

List B. The drug 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.

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.