Sinopril (Tablets) Instructions for Use

Marketing Authorization Holder

Eczacibasi Ilac Sanayi ve Ticaret, A.S. (Turkey)

Packaged By

PharmFirma Sotex, ZAO (Russia)

ATC Code

C09AA03 (Lisinopril)

Active Substance

Lisinopril (Rec.INN registered by WHO)

Dosage Forms

	Sinopril	Tablets 5 mg: 20, 30, 10000, 25000 or 120000 pcs.
		Tablets 10 mg: 30 pcs.
		Tablets 20 mg: 20, 30, 10000, 25000 or 120000 pcs.

Dosage Form, Packaging, and Composition

Tablets white, round, flat, with a score on one side; white on the break.

Excipients: corn starch, mannitol, calcium hydrogen phosphate dihydrate, gelatinized starch, magnesium stearate.

10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

Tablets pink, flat, with a score on one side.

10 pcs. – blisters (2) – cardboard packs.

Tablets light pink, round, biconvex, with a score on one side; light pink on the break.

Excipients: corn starch, mannitol, lactose (monohydrate), gelatinized starch, red iron oxide, yellow iron oxide, magnesium stearate.

10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE blocker

Pharmacological Action

Long-acting ACE inhibitor, reduces the formation of angiotensin II from angiotensin I, which leads to a direct reduction in aldosterone secretion.

It reduces the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces total peripheral resistance, blood pressure, preload, pulmonary capillary pressure, causes an increase in cardiac output and an increase in myocardial tolerance to stress in patients with chronic heart failure. It dilates arteries to a greater extent 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 arteries. It improves blood supply to the ischemic myocardium. ACE inhibitors prolong the life expectancy of patients with chronic heart failure, slow the progression of left ventricular dysfunction in patients who have had myocardial infarction without clinical manifestations of heart failure.

The antihypertensive effect begins approximately after 6 hours and persists for 24 hours. The duration of the effect also depends on the dose. The onset of action is within 1 hour. The maximum effect is determined after 6-7 hours. In arterial hypertension, the effect is noted in the first days after the start of treatment, a stable effect develops after 1-2 months.

No marked increase in blood pressure was observed upon abrupt withdrawal of the drug.

In addition to lowering blood pressure, Lisinopril reduces albuminuria. In patients with hyperglycemia, Lisinopril promotes the normalization of the function of damaged glomerular endothelium. Lisinopril does not affect blood glucose concentration in patients with diabetes mellitus and does not lead to an increased incidence of hypoglycemia.

Pharmacokinetics

Absorption and Distribution

Absorption from the gastrointestinal tract is about 30%. Bioavailability is about 29%; food intake does not affect the bioavailability of the drug. After oral administration, C_max of lisinopril in plasma is reached within 6 hours. At a dose of 10 mg/day, C_max is 32-38 ng/ml.

Lisinopril is almost not bound to plasma proteins, binds exclusively to ACE. It enters the systemic circulation unchanged.

Metabolism and Excretion

It is almost not metabolized, excreted by the kidneys unchanged. The fraction bound to ACE is excreted slowly. T_1/2 is 12.6 hours.

Permeability through the blood-brain and placental barriers is low.

Indications

• Arterial hypertension (as monotherapy or in combination with other antihypertensive agents);
• Chronic heart failure (as part of combination therapy for the treatment of patients taking digitalis preparations and/or diuretics).

ICD codes

Dosage Regimen

The drug should be taken orally once a day, regardless of meals, at approximately the same time of day.

For the treatment of arterial hypertension, the recommended initial dose of Sinopril is 10 mg/day (for patients not receiving other antihypertensive drugs). The daily maintenance dose is 20 mg, which can be increased to a maximum of 40 mg/day depending on blood pressure dynamics.

If a satisfactory therapeutic effect is not achieved, another antihypertensive drug should be additionally prescribed. A 2-4 week course of treatment may be required for the full development of the hypotensive effect, which should be taken into account when increasing the dose.

Patients with arterial hypertension receiving diuretics should discontinue their use 2-3 days before starting Sinopril. If their withdrawal is not possible, Sinopril is prescribed at an initial dose not exceeding 5 mg/day. In this case, medical supervision is recommended for several hours after taking the first dose (maximum effect is reached in about 6 hours), as a marked decrease in blood pressure may occur.

In the treatment of renovascular hypertension or other conditions with increased activity of the renin-angiotensin-aldosterone system, it is advisable to also prescribe a low initial dose of 2.5-5 mg/day under enhanced medical supervision (blood pressure, renal function, serum potassium concentration). The maintenance dose, continuing strict medical supervision, should be determined depending on blood pressure dynamics.

In the treatment of arterial hypertension in patients with renal impairment, since Sinopril is excreted by the kidneys, the initial dose should be determined depending on creatinine clearance, then, according to the response, the maintenance dose should be established under conditions of monitoring renal function, serum potassium and sodium levels.

In the treatment of chronic heart failure, the recommended initial dose is 2.5 mg/day. It can be gradually increased to a maintenance daily dose of 5-20 mg/day. The maximum daily dose is 20 mg/day.

Adverse Reactions

Most common: dizziness, headache (5-6% of patients), weakness, diarrhea, dry cough (3% of patients), nausea, vomiting, orthostatic arterial hypotension, skin rash, chest pain (1-3% of patients).

Rare side effects occur in <1% of patients.

From the cardiovascular system: marked decrease in blood pressure, orthostatic arterial hypotension, impaired renal function; rarely – palpitations; tachycardia; myocardial infarction; cerebrovascular stroke in patients at increased risk of the disease, due to a marked decrease in blood pressure.

From the digestive system rarely – dry mouth, anorexia, dyspepsia, taste changes, abdominal pain, pancreatitis, hepatocellular or cholestatic jaundice, hepatitis.

From the central and peripheral nervous system increased fatigue, drowsiness, convulsive twitching of the muscles of the limbs and lips; rarely – asthenic syndrome, mood lability, confusion, impotence.

From the hematopoietic system leukopenia, neutropenia, agranulocytosis, thrombocytopenia are possible; with long-term treatment – a slight decrease in hemoglobin and hematocrit, erythrocytopenia.

From the urinary system rarely – impaired renal function, oliguria, anuria, acute renal failure, uremia, proteinuria.

From metabolism hyperkalemia, azotemia, hyperuricemia, hyperbilirubinemia, increased activity of liver transaminases (especially in patients with a history of kidney disease, diabetes mellitus and renovascular hypertension).

Dermatological reactions urticaria, increased sweating, skin itching, alopecia.

Allergic reactions 0.1% – angioedema (face, upper and lower extremities, lips, tongue, larynx or epiglottis); rarely – a syndrome including accelerated ESR, arthralgia and the appearance of antinuclear antibodies.

Other rarely – myalgia, fever, impaired fetal development.

Contraindications

• History of angioedema (including after the use of ACE inhibitors);
• Hereditary angioedema;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to lisinopril or other ACE inhibitors.

Use with caution in severe renal impairment, bilateral renal artery stenosis or stenosis of the artery of a single kidney, renal failure, azotemia, hyperkalemia, aortic stenosis, hypertrophic obstructive cardiomyopathy, primary hyperaldosteronism, arterial hypotension, cerebrovascular diseases (including cerebrovascular insufficiency), coronary artery disease, coronary insufficiency, autoimmune systemic connective tissue diseases (including scleroderma, systemic lupus erythematosus), bone marrow depression, sodium-restricted diet, hypovolemic conditions (including diarrhea, vomiting), in elderly patients.

Use in Pregnancy and Lactation

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

If pregnancy is established, the use of Sinopril should be discontinued as soon as possible.

There are no data on the negative effect of the drug on the fetus in case of use in the first trimester of pregnancy. The use of the drug in the second and third trimester of pregnancy may have an adverse effect on the fetus: marked decrease in blood pressure, renal failure, hyperkalemia, skull hypoplasia, intrauterine death.

Newborns and infants who have been exposed to ACE inhibitors in utero should be closely monitored for the timely detection of marked decrease in blood pressure, oliguria, hyperkalemia.

Lisinopril crosses the placental barrier. There are no data on the excretion of lisinopril in breast milk. If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Renal Impairment

In patients with impaired renal function, the dose is set depending on the CC values.

* doses are adjusted according to treatment results.

Special Precautions

Symptomatic hypotension

Most often, a marked decrease in blood pressure occurs with a decrease in fluid volume caused by diuretic therapy, reduced salt in the diet, dialysis, diarrhea or vomiting. In patients with chronic heart failure (with or without concomitant renal failure), a marked decrease in blood pressure is possible. It is more often detected in patients with severe heart failure due to the use of large doses of diuretics, hyponatremia or impaired renal function. In such patients, treatment should be started under strict medical supervision (carefully titrate the dose of the drug and diuretics).

Similar rules should be followed when prescribing Sinopril to patients with coronary artery disease, cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke.

A transient hypotensive reaction is not a contraindication for taking the next dose of the drug.

When using Sinopril in some patients with chronic heart failure but with normal or low blood pressure, a decrease in blood pressure may be noted, which is usually not a reason to discontinue treatment.

Before starting treatment with Sinopril, the sodium concentration should be normalized and/or the lost fluid volume should be replenished, and the effect of the initial dose of Sinopril on the patient’s blood pressure should be carefully monitored.

In the case of renal artery stenosis (especially with bilateral stenosis or with stenosis of the artery of a single kidney), as well as in circulatory failure due to sodium and/or fluid deficiency, the use of Sinopril may lead to impaired renal function, acute renal failure, which is usually reversible after discontinuation of the drug.

In acute myocardial infarction

The use of standard therapy (thrombolytics, acetylsalicylic acid, beta-blockers) is indicated. Sinopril can be used in combination with intravenous administration or the use of transdermal nitroglycerin systems.

Surgical intervention/general anesthesia

During extensive surgical interventions, as well as when using other drugs that cause a decrease in blood pressure, Lisinopril, by blocking the formation of angiotensin II, can cause a marked unpredictable decrease in blood pressure.

In elderly patients, the same dose leads to a higher concentration of the drug in the blood, so special caution is required when determining the dose, despite the fact that no differences in the antihypertensive effect of Sinopril between the elderly and young people have been identified.

Since the potential risk of agranulocytosis cannot be excluded, periodic monitoring of the blood picture is required.

When using the drug during dialysis with a polyacrylonitrile membrane, anaphylactic shock may occur, so another type of dialysis membrane is recommended or other antihypertensive drugs are prescribed.

Effect on the ability to drive vehicles and mechanisms

There are no data on the effect of lisinopril, used in therapeutic doses, on the ability to drive vehicles and mechanisms, however, it must be taken into account that dizziness may occur, so caution should be exercised.

Overdose

Symptoms marked decrease in blood pressure.

Treatment symptomatic therapy, intravenous fluid administration, blood pressure control, normalization of water and electrolyte balance. Sinopril can be removed from the body by hemodialysis.

Drug Interactions

Particular caution is required when using the drug concomitantly with potassium-sparing diuretics (including spironolactone, triamterene, amiloride), potassium, salt substitutes containing potassium, since the risk of hyperkalemia increases (especially with impaired renal function). Concomitant administration is possible only on the basis of an individual decision of the attending physician with regular monitoring of serum potassium levels and renal function.

With the simultaneous use of Sinopril with diuretics, other antihypertensive agents, an additive antihypertensive effect is possible – the risk of a marked decrease in blood pressure.

With the simultaneous use of Sinopril with NSAIDs (including indomethacin), estrogens, adrenergic stimulants, a decrease in the antihypertensive effect of lisinopril is possible.

With the simultaneous use of Sinopril with lithium, the excretion of lithium may decrease, so the concentration of lithium in the blood serum should be regularly monitored.

With the simultaneous use of Sinopril with antacids and cholestyramine, the latter reduce absorption in the gastrointestinal tract.

Sinopril may enhance the effect of ethanol.

Sinopril reduces the excretion of potassium from the body during treatment with diuretics.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 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.