Renitec^® (Tablets) Instructions for Use

Marketing Authorization Holder

Organon, LLC (Russia)

Manufactured By

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Or

Merck Sharp & Dohme (United Kingdom)

Packaging and Quality Control Release

MERCK SHARP & DOHME, B.V. (Netherlands)

ATC Code

C09AA02 (Enalapril)

Active Substance

Enalapril (Rec.INN registered by WHO)

Dosage Forms

	Renitec®	Tablets 5 mg: 7, 14 or 28 pcs.
		Tablets 10 mg: 7, 14, 28 or 100 pcs.
		Tablets 20 mg: 7, 14, 28 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets white, triangular in shape, with an engraving “MSD 712” on one side and a score on the other.

Excipients: sodium bicarbonate, lactose monohydrate, corn starch, pregelatinized starch, magnesium stearate.

7 pcs. – blisters (1) – cardboard boxes.
7 pcs. – blisters (2) – cardboard boxes.
7 pcs. – blisters (4) – cardboard boxes.

Tablets pink, with inclusions, triangular in shape, with an engraving “MSD 713” on one side and a score on the other.

Excipients: sodium bicarbonate, lactose monohydrate, corn starch, pregelatinized corn starch, magnesium stearate, iron oxide red (E172).

7 pcs. – blisters (1) – cardboard boxes.
7 pcs. – blisters (2) – cardboard boxes.
7 pcs. – blisters (4) – cardboard boxes.
100 pcs. – dark glass bottles (1) – cardboard boxes.

Tablets light pink with a yellowish tint, triangular in shape, with an engraving “MSD 714” on one side and a score on the other.

Excipients: sodium bicarbonate, lactose monohydrate, corn starch, pregelatinized corn starch, magnesium stearate, iron oxide red (E172), iron oxide yellow (E172).

7 pcs. – blisters (1) – cardboard boxes.
7 pcs. – blisters (2) – cardboard boxes.
7 pcs. – blisters (4) – cardboard boxes.
100 pcs. – dark glass bottles (1) – cardboard boxes.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE blocker

Pharmacological Action

Renitec^® (enalapril maleate) belongs to agents affecting the renin-angiotensin system – ACE inhibitors and is a highly specific, long-acting, non-sulfhydryl group-containing ACE inhibitor.

Renitec^®(enalapril maleate) is a derivative of two amino acids: L-alanine and L-proline. Enalapril is an ACE inhibitor that catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, orally administered Enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which results in an increase in plasma renin activity (due to the elimination of the negative feedback on renin production changes) and a decrease in aldosterone secretion.

ACE is identical to the enzyme kininase II, so Enalapril can also block the degradation of bradykinin, a peptide with vasodilatory action. The significance of this effect in the therapeutic action of enalapril requires clarification. It is currently believed that the mechanism by which Enalapril reduces blood pressure is the suppression of the renin-angiotensin-aldosterone system, which plays an important role in blood pressure regulation. Enalapril exhibits an antihypertensive effect even in patients with low renin concentration. The decrease in blood pressure is accompanied by a decrease in total peripheral vascular resistance, an increase in cardiac output, and no change or minor changes in heart rate. As a result of taking enalapril, renal blood flow increases, but the glomerular filtration rate remains unchanged. However, in patients with initially reduced glomerular filtration, its level usually increases.

Antihypertensive therapy with enalapril leads to significant regression of left ventricular hypertrophy and preservation of its systolic function.

Therapy with enalapril is accompanied by a favorable effect on the lipoprotein fraction ratio and no effect or a favorable effect on total cholesterol concentration.

Taking enalapril by patients with arterial hypertension leads to a decrease in blood pressure regardless of body position: both in standing and lying positions without a significant increase in heart rate.

Symptomatic postural hypotension rarely develops. In some patients, achieving optimal blood pressure reduction may require several weeks of therapy. Interruption of enalapril therapy does not cause a sharp increase in blood pressure.

Effective inhibition of ACE activity usually develops 2-4 hours after a single oral dose of enalapril. The onset of the hypotensive action occurs within 1 hour, and the maximum decrease in blood pressure is observed 4-6 hours after taking the drug. The duration of action depends on the dose. However, when using the recommended doses, the antihypertensive action and hemodynamic effects are maintained for 24 hours.

Enalapril reduces the loss of potassium ions caused by the use of hydrochlorothiazide.

Pharmacokinetics

After oral administration, Enalapril is rapidly absorbed, C_max of enalapril in the blood serum is reached within 1 hour after oral administration. The absorption extent of enalapril maleate upon oral administration is approximately 60%. Food intake does not affect the absorption of enalapril.

After absorption, Enalapril is rapidly hydrolyzed to form the active substance enalaprilat, a potent ACE inhibitor. C_max of enalaprilat in the blood serum is observed 3-4 hours after taking a dose of enalapril orally. The absorption and hydrolysis duration of enalapril is similar for various recommended therapeutic doses.

Enalapril is excreted primarily through the kidneys. The main metabolites detected in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged Enalapril. There is no data on other metabolites of enalapril. The plasma concentration profile of enalaprilat has a long terminal phase, apparently due to the release of ACE-bound enalaprilat. In individuals with normal renal function, a steady-state concentration of enalaprilat is reached on the 4th day from the start of enalapril intake. T_1/2 of enalapril during course oral administration of the drug is 11 hours.

Indications

• Essential hypertension;
• Renovascular hypertension;
• Heart failure of any stage.

In patients with clinical manifestations of heart failure, the drug is also indicated for:

• Increasing patient survival;
• Slowing the progression of heart failure;
• Reducing the frequency of hospitalizations for heart failure.

Prevention of clinically manifest heart failure

In patients without clinical symptoms of heart failure with impaired left ventricular function, the drug is indicated for

• Slowing the development of clinical manifestations of heart failure;
• Reducing the frequency of hospitalizations for heart failure.

Prevention of coronary ischemia

In patients with left ventricular dysfunction, the drug is indicated for

• Reducing the incidence of myocardial infarction;
• Reducing the frequency of hospitalizations for unstable angina.

ICD codes

Dosage Regimen

Orally, regardless of food intake, since tablet absorption does not depend on food intake.

Arterial hypertension

The initial dose is 10-20 mg depending on the severity of arterial hypertension and is prescribed once a day. For mild arterial hypertension, the recommended initial dose is 10 mg/day. For other degrees of arterial hypertension, the initial dose is 20 mg/day as a single dose. The maintenance dose is 1 tab. 20 mg once a day. The dosage is selected individually for each patient, but the dose should not exceed 40 mg/day.

Renovascular hypertension

Since in patients of this group, blood pressure and renal function may be particularly sensitive to ACE inhibition, therapy is started with a low initial dose – 5 mg or less. Then the dose is selected according to the patient’s needs. A dose of 20 mg/day with daily intake is usually effective. Caution should be exercised when treating patients who have recently received diuretic treatment.

Concomitant treatment of arterial hypertension with diuretics

Arterial hypotension may develop after the first dose of Renitec^®. This effect is most likely in patients who are receiving diuretic treatment. The drug is recommended to be prescribed with caution, as such patients may have fluid or sodium deficiency. Diuretic treatment should be discontinued 2-3 days before starting treatment with Renitec^®. If this is not possible, the initial dose of Renitec^® should be reduced (to 5 mg or less) to determine the primary effect of the drug. Further, the dosage should be selected taking into account the patient’s condition.

Dosage in renal failure

The interval between Renitec^® doses should be increased and/or the dose reduced.

*Enalapril is subject to hemodialysis. Dose adjustment on days when hemodialysis is not performed should be based on the blood pressure level.

Heart failure/asymptomatic left ventricular dysfunction

The initial dose of Renitec^® in patients with heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, and the drug should be prescribed under strict medical supervision to establish the primary effect of the drug on blood pressure. Renitec^® can be used to treat heart failure with severe clinical manifestations, usually in combination with diuretics and, when necessary, with cardiac glycosides. In the absence of symptomatic hypotension (resulting from Renitec^® treatment) or after its appropriate correction, the dose should be gradually increased to the usual maintenance dose of 20 mg, which is prescribed either as a single dose or divided into 2 doses depending on the patient’s tolerance to the drug. Dose titration can be carried out over 2-4 weeks or in a shorter period if there are residual signs and symptoms of heart failure. This therapeutic regimen effectively reduces mortality rates in patients with clinically manifest heart failure.

Both before and after starting Renitec^® treatment, careful monitoring of blood pressure and renal function should be carried out in patients with heart failure, as there have been reports of the development of arterial hypotension as a result of taking the drug, followed (much less frequently) by the occurrence of renal failure. In patients receiving diuretics, the diuretic dose should be reduced if possible before starting Renitec^® treatment. The development of arterial hypotension after the first dose of Renitec^® does not mean that arterial hypotension will persist during long-term treatment and does not indicate the need to discontinue the drug. During Renitec^® treatment, serum potassium levels should also be monitored.

Adverse Reactions

In general, the drug is well tolerated. The overall frequency of side effects with the use of Renitec^® does not exceed that with placebo. In most cases, side effects are minor, temporary, and do not require discontinuation of therapy.

The following side effects are observed when prescribing the drug: dizziness and headache are most common. Increased fatigue and asthenia are observed in 2-3% of patients. Other side effects (arterial hypotension, orthostatic hypotension, syncope, nausea, diarrhea, muscle cramps, skin rash, and cough) occur in less than 2% of patients. There are rare reports of impaired renal function, renal failure, oliguria, and proteinuria.

Hypersensitivity/Angioedema

In rare cases, angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been observed; very rarely, intestinal angioedema.

In very rare cases, the following side effects occur:

From the cardiovascular system myocardial infarction or stroke, possibly secondary to severe arterial hypotension in patients at risk, chest pain, palpitations, arrhythmia, angina, Raynaud’s syndrome.

From the digestive system intestinal obstruction, pancreatitis, liver failure, hepatitis (hepatocellular or cholestatic), jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis, dry mouth.

Metabolic disorders hypoglycemia in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin.

From the CNS depression, confusion, drowsiness, insomnia, increased nervousness, paresthesia, dizziness, sleep disturbances, anxiety.

From the respiratory system pulmonary infiltrates, bronchospasm/bronchial asthma, dyspnea, rhinorrhea, sore throat, hoarseness.

Skin increased sweating, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, pruritus, urticaria, alopecia.

Other impotence, flushing, taste disturbance, tinnitus, glossitis, blurred vision.

Development of a complex symptom complex has been reported, which may include all or some of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive test for antinuclear antibodies, increased erythrocyte sedimentation rate (ESR), eosinophilia, and leukocytosis. Rash, photosensitivity, and other skin reactions may also occur as side effects.

Laboratory parameters clinically significant changes in standard laboratory parameters are rarely associated with the use of Renitec^®. An increase in blood urea, serum creatinine, increased activity of liver enzymes and/or serum bilirubin is possible. These changes are usually reversible and normalize after discontinuation of Renitec^®. Hyperkalemia and hyponatremia are sometimes encountered.

There are reports of a decrease in hemoglobin and hematocrit concentrations. There are reports of isolated cases of neutropenia, thrombocytopenia, bone marrow function suppression, and agranulocytosis, in which a connection with the use of Renitec^® cannot be excluded.

The following side effects have been identified during post-marketing surveillance, but a causal relationship with the use of the drug Renitec^® has not been established: pneumonia, urinary tract infection, upper respiratory tract infection, bronchitis, cardiac arrest, atrial fibrillation, herpes zoster, melena, ataxia, pulmonary embolism, hemolytic anemia, including cases of hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.

Contraindications

• History of angioedema associated with previous administration of ACE inhibitors;
• Hereditary or idiopathic angioedema;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to any component of the drug.

Use in Pregnancy and Lactation

Use of the drug during pregnancy is not recommended. If pregnancy occurs, Renitec^® should be discontinued immediately. ACE inhibitors can cause disease or death of the fetus or newborn when administered to pregnant women during the II and III trimesters of pregnancy. The use of ACE inhibitors during these periods was accompanied by a negative impact on the fetus and newborn, including the development of arterial hypotension, renal failure, hyperkalemia, and/or skull hypoplasia in the newborn. The development of oligohydramnios is possible, apparently due to a decrease in fetal renal function. This complication can lead to limb contractures, skull deformities, including its facial part, and lung hypoplasia. When prescribing Renitec^®, the patient should be informed about the potential risk to the fetus.

These adverse effects on the embryo and fetus do not appear to be the result of intrauterine exposure to ACE inhibitors during the first trimester of pregnancy.

Newborns whose mothers took Renitec^® should be carefully observed for the detection of decreased blood pressure, oliguria, and hyperkalemia. Enalapril, which crosses the placenta, can be partially removed from the newborn’s circulation by peritoneal dialysis; theoretically, it can be removed by exchange transfusion.

Enalapril and enalaprilat are detected in breast milk in trace concentrations. If the use of the drug is necessary, the patient should stop breastfeeding.

Use in Hepatic Impairment

With caution in patients with hepatic insufficiency.

Use in Renal Impairment

In some patients, arterial hypotension developing after the initiation of treatment with ACE inhibitors may lead to a deterioration of renal function. In some cases, the development of acute renal failure, usually reversible, has been reported.

In patients with renal impairment, a reduction in the dose and/or frequency of administration of the drug may be necessary. In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, an increase in blood urea and serum creatinine was observed. The changes were usually reversible and the values returned to normal after discontinuation of treatment. Such changes are most likely in patients with renal impairment. In some patients who had no evidence of renal disease prior to treatment, Renitec^® in combination with diuretics usually caused a slight and transient increase in blood urea and serum creatinine. In such cases, a reduction in the dose and/or discontinuation of the diuretic and/or Renitec^® may be required. The interval between doses of Renitec^® should be increased and/or the dose reduced.

**Enalapril is subject to hemodialysis. Dose adjustment on days when hemodialysis is not performed should be based on the level of blood pressure.

Pediatric Use

Age under 18 years (efficacy and safety not established).

Geriatric Use

Use with caution in patients over 65 years of age.

Special Precautions

Renitec^® should be used with caution in the treatment of patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, with primary hyperaldosteronism, hyperkalemia, status after kidney transplantation; aortic stenosis, mitral stenosis (with hemodynamic impairment), idiopathic hypertrophic subaortic stenosis; systemic connective tissue diseases; coronary artery disease; cerebrovascular diseases; diabetes mellitus; renal failure (proteinuria – more than 1 g/day); hepatic failure; in patients on a salt-restricted diet or on hemodialysis; with simultaneous use with immunosuppressants and diuretics, elderly patients (over 65 years of age), bone marrow depression; conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting).

Clinically significant arterial hypotension

Clinically significant arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving Renitec^®, arterial hypotension develops more often against the background of hypovolemia, occurring, for example, as a result of diuretic therapy, salt intake restriction, in patients on hemodialysis, as well as those suffering from diarrhea or vomiting. Clinically significant arterial hypotension has also been observed in patients with heart failure, with or without renal impairment. Arterial hypotension is observed more often in patients with more severe forms of heart failure, who use higher doses of loop diuretics, with hyponatremia or impaired renal function. In such patients, treatment with Renitec^® should be initiated under medical supervision, which should be particularly careful when changing the dose of Renitec^® and/or the diuretic. Similarly, patients with coronary artery disease, as well as cerebrovascular disease, in whom a sharp decrease in blood pressure may lead to myocardial infarction or stroke, should be monitored. If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, intravenous physiological sodium chloride solution should be administered.

Transient arterial hypotension when taking Renitec^® is not a contraindication to further treatment with the drug, which can be continued after volume replenishment and normalization of blood pressure. In some patients with heart failure and normal or low blood pressure, Renitec^® may cause an additional decrease in blood pressure. Such a reaction to the drug can be expected and should not be considered a reason to discontinue treatment. In cases where arterial hypotension becomes stable, the dose should be reduced and/or treatment with the diuretic and/or Renitec^® should be discontinued.

Aortic stenosis/Hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be prescribed with caution to patients with obstruction of the left ventricular aortic outlet.

Impaired renal function

In some patients, arterial hypotension developing after the initiation of treatment with ACE inhibitors may lead to a deterioration of renal function. In some cases, the development of acute renal failure, usually reversible, has been reported.

In patients with renal impairment, a reduction in the dose and/or frequency of administration of the drug may be necessary. In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, an increase in blood urea and serum creatinine was observed. The changes were usually reversible and the values returned to normal after discontinuation of treatment. Such changes are most likely in patients with renal impairment. In some patients who had no evidence of renal disease prior to treatment, Renitec^® in combination with diuretics usually caused a slight and transient increase in blood urea and serum creatinine. In such cases, a reduction in the dose and/or discontinuation of the diuretic and/or Renitec^® may be required.

Hypersensitivity/Angioedema

Rare cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx, occurring at different periods of treatment, have been described with the prescription of ACE inhibitors, including Renitec^®. In such cases, treatment with Renitec^® should be discontinued immediately and the patient should be monitored continuously to ensure complete resolution of symptoms. Even in cases where only swallowing difficulty occurs without respiratory impairment, patients should be under medical supervision for a long time, as therapy with antihistamines and corticosteroids may be insufficient. Angioedema of the larynx or tongue can be fatal. In cases where the edema is localized in the area of the tongue, glottis or larynx and may cause airway obstruction, appropriate therapy should be started quickly, which may include subcutaneous administration of 0.1% epinephrine (adrenaline) solution (0.3-0.5 ml) and/or urgent measures to ensure airway patency.

Patients with a history of angioedema not associated with the use of ACE inhibitors may have an increased risk of its occurrence when treated with an ACE inhibitor. In patients of the Black race, the frequency of angioedema when taking ACE inhibitors is higher than in other races.

Anaphylactic reactions during desensitization with hymenoptera venom allergen

In rare cases, patients receiving ACE inhibitors during desensitization with hymenoptera venom allergen developed anaphylactic reactions that were life-threatening to the patients. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting desensitization.

Patients on hemodialysis

In patients undergoing dialysis using high-flux membranes (e.g., AN69^®) and simultaneously receiving an ACE inhibitor, anaphylactic reactions have developed in some cases. Therefore, for such patients, the use of a different type of dialysis membrane or an antihypertensive agent of another group is recommended.

Cough

There are reports of cough occurring during treatment with ACE inhibitors. The cough is usually non-productive, persistent, and resolves after discontinuation of the drug. Cough due to ACE inhibitor treatment should be considered in the differential diagnosis of cough.

Surgery/General anesthesia

During major surgery or during general anesthesia using agents that cause a hypotensive effect, Enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If a marked decrease in blood pressure develops, explained by such a mechanism, it can be corrected by increasing the volume of fluid administered.

Hyperkalemia

Risk factors for the development of hyperkalemia are renal failure, diabetes mellitus, simultaneous administration of potassium-sparing diuretics (spironolactone, triamterene or amiloride), as well as the use of potassium-containing supplements and salts.

The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salts, especially in patients with renal impairment, can lead to a significant increase in serum potassium levels. Hyperkalemia can cause serious, sometimes fatal, cardiac arrhythmias.

If concomitant administration of the above-mentioned potassium-containing or potassium-elevating drugs is necessary, caution should be exercised and serum potassium levels should be regularly monitored.

Hypoglycemia

Patients with diabetes mellitus receiving oral hypoglycemic agents or insulin should be informed of the need for careful monitoring of blood glucose levels (hypoglycemia) before starting ACE inhibitors, especially during the first month of concomitant use of these drugs.

Use in elderly patients

Clinical studies of the efficacy and tolerability of enalapril were similar in elderly and younger patients.

Effect on ability to drive and/or operate machinery

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions (dizziness is possible, especially after taking the initial dose of an ACE inhibitor in patients taking diuretic medications).

Overdose

Information on overdose is limited.

Symptoms: marked decrease in blood pressure, starting approximately 6 hours after taking the drug, and stupor. Plasma concentrations of enalaprilat exceeding 100-200 times the concentrations observed with therapeutic doses occurred after ingestion of 300 and 440 mg of enalapril, respectively.

Treatment: intravenous infusion of isotonic sodium chloride solution, if possible – infusion of angiotensin II; induction of vomiting. Enalaprilat can be removed by hemodialysis.

Drug Interactions

When Renitec^® is prescribed in combination with other antihypertensive agents, an additive effect may be observed.

Serum potassium concentration usually remains within normal limits. In patients with arterial hypertension treated with Renitec^® for more than 48 weeks, an increase in serum potassium of up to 0.2 mEq/L is observed.

When Renitec^® is used concomitantly with potassium-losing diuretics, hypokalemia caused by the action of diuretics is generally attenuated due to the effect of enalapril.

Risk factors for the development of hyperkalemia are renal failure, diabetes mellitus, simultaneous administration of potassium-sparing diuretics (spironolactone, triamterene or amiloride), as well as the use of potassium-containing supplements and salts. The use of potassium supplements, potassium-sparing diuretics or potassium-containing salts, especially in patients with renal impairment, can lead to a significant increase in serum potassium levels. If concomitant administration of the above-mentioned potassium-containing or potassium-elevating drugs is necessary, caution should be exercised and serum potassium levels should be regularly monitored.

Concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect of the latter with the risk of hypoglycemia. This phenomenon has generally been most frequently noted during the first weeks of their concomitant use, as well as in patients with renal impairment. In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose levels should be carefully monitored, especially during the first month of concomitant use with ACE inhibitors.

ACE inhibitors reduce the renal excretion of lithium and increase the risk of lithium intoxication. If it is necessary to prescribe lithium salts, the level of lithium in the blood serum should be monitored.

NSAIDs, including selective COX-2 inhibitors, may reduce the effect of diuretics and other antihypertensive agents. Thus, the antihypertensive effect of ACE inhibitors may be attenuated by NSAIDs, including COX-2 inhibitors.

In some patients with impaired renal function and taking NSAIDs, including COX-2 inhibitors, concomitant use of ACE inhibitors may lead to further deterioration of renal function. These changes are usually reversible.

A symptom complex including facial flushing, nausea, vomiting and arterial hypotension has been described in rare cases with the concomitant use of parenteral gold preparations (sodium aurothiomalate) and ACE inhibitors (Enalapril).

Storage Conditions

Store in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years 6 months.

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.