Enafarm-N (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmacor Production, LLC (Russia)

ATC Code

C09BA02 (Enalapril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Enalapril (Rec.INN registered by WHO)

Dosage Form

Enafarm-N

Tablets 10 mg+25 mg: 10, 14, 20, 28, 40, 56, 7200, or 14400 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (4) – cardboard packs.
14 pcs. – blister packs (1) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
7 pcs. – blister packs (1) – cardboard packs.
7 pcs. – blister packs (2) – cardboard packs.
7 pcs. – blister packs (4) – cardboard packs.
100 pcs. – polyethylene bottles (72) – cardboard boxes.
200 pcs. – polyethylene bottles (72) – cardboard boxes.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

Combined antihypertensive drug.

Enalapril inhibits ACE, which promotes the conversion of angiotensin I to angiotensin II, reduces the concentration of aldosterone in the blood, increases renin release, improves the function of the kallikrein-kinin system, stimulates the release of prostaglandins and endothelial relaxing factor, and suppresses the sympathetic nervous system. Together, these effects eliminate spasm and dilate peripheral arteries, reduce total peripheral vascular resistance, systolic and diastolic blood pressure, and post- and preload on the myocardium. It dilates arteries to a greater extent than veins, with no noted reflex increase in heart rate. The hypotensive effect is more pronounced with high plasma renin concentration than with normal or reduced concentration. A decrease in blood pressure within therapeutic limits does not affect cerebral circulation. It improves blood supply to the ischemic myocardium. It increases renal blood flow, while the glomerular filtration rate does not change. In patients with initially reduced glomerular filtration, its rate usually increases.

The maximum effect of enalapril develops after 6-8 hours and lasts up to 24 hours.

Hydrochlorothiazide is a thiazide diuretic of medium potency. It reduces the reabsorption of sodium ions at the level of the cortical segment of the loop of Henle, without affecting its part passing through the renal medulla. It blocks carbonic anhydrase in the proximal part of the convoluted tubules, increases the renal excretion of potassium, bicarbonate, and phosphate ions. It has almost no effect on the acid-base state. It increases the excretion of magnesium ions. It retains calcium ions in the body. The diuretic effect develops after 1-2 hours, reaches a maximum after 4 hours, and lasts 10-12 hours. The action decreases with a decrease in the glomerular filtration rate and stops when it is less than 30 ml/min. It reduces blood pressure by reducing the circulating blood volume and changing the reactivity of the vascular wall.

The use of a combination of enalapril and hydrochlorothiazide leads to a more pronounced decrease in blood pressure compared to monotherapy with each of the drugs separately.

Pharmacokinetics

Enalapril

After oral administration, absorption is 60%. Food intake does not affect absorption. It is metabolized in the liver to form the active metabolite enalaprilat, which is a more effective ACE inhibitor than Enalapril. Time to reach C_max of enalapril is 1 hour, of enalaprilat is 3-4 hours. Enalaprilat easily penetrates through histohematic barriers, excluding the blood-brain barrier, a small amount penetrates the placental barrier, and is excreted in breast milk. Plasma protein binding of enalaprilat is 50-60%.

In the liver, Enalapril is hydrolyzed to the active metabolite, enalaprilat, which undergoes further metabolism. The renal clearance of enalapril and enalaprilat is 0.005 ml/s (18 L/h) and 0.00225-0.00264 ml/s (8.1-9.5 L/h), respectively. T_1/2 of enalaprilat is 11 hours. It is excreted mainly by the kidneys – 60% (20% as enalapril and 40% as enalaprilat), through the intestine – 33% (6% as enalapril and 27% as enalaprilat). It is removed by hemodialysis (rate 38-62 ml/min) and peritoneal dialysis; the serum concentration of enalaprilat after 4-hour hemodialysis decreases by 45-57%.

In patients with impaired renal function, the excretion of enalapril is slowed. In patients with hepatic insufficiency, the metabolism of enalapril may be slowed without changing its pharmacodynamic effect. In patients with chronic heart failure, the absorption and metabolism of enalaprilat are slowed, and V_d is also reduced.

Hydrochlorothiazide

Hydrochlorothiazide is absorbed mainly in the duodenum and proximal small intestine. Absorption is 70% and increases by 10% when taken with food. C_max in blood serum is reached in 1.5-5 hours. Bioavailability is 70%. V_d is about 3 L/kg. Plasma protein binding is 40%. In the therapeutic dose range, the mean AUC increases in direct proportion to the dose increase; when administered once daily, accumulation is insignificant. It penetrates the placental barrier and into breast milk. It accumulates in the amniotic fluid. The serum concentration of hydrochlorothiazide in umbilical cord blood is practically the same as in maternal blood. The concentration in the amniotic fluid exceeds that in the serum from the umbilical vein (by 19 times). Hydrochlorothiazide is not metabolized in the liver. Hydrochlorothiazide is excreted mainly in the urine – 95% unchanged and about 4% as the hydrolyzate 2-amino-4-chloro-m-benzenedisulfonamide by glomerular filtration and active tubular secretion in the proximal part of the nephron. The renal clearance of hydrochlorothiazide in healthy volunteers and patients with arterial hypertension is approximately 5.58 ml/s (335 ml/min). Hydrochlorothiazide has a biphasic excretion profile. T_1/2 in the initial phase is 2 hours, in the terminal phase (10-12 hours after administration) is about 10 hours.

In elderly patients, Hydrochlorothiazide does not have a negative effect on the pharmacokinetics of enalapril, but the serum concentration of enalaprilat is higher. When hydrochlorothiazide was administered to patients with chronic heart failure, its absorption was found to be reduced proportionally to the degree of the disease by 20-70%. T_1/2 of hydrochlorothiazide increases to 28.9 hours. Renal clearance is 0.17-3.12 ml/s (10-187 ml/min), average values 1.28 ml/s (77 ml/min). In patients who have undergone intestinal bypass surgery for obesity, the absorption of hydrochlorothiazide may be reduced by 30% and the serum concentration by 50% compared to healthy volunteers.

Indications

Arterial hypertension; chronic heart failure.

ICD codes

Dosage Regimen

Take Enafarm-N orally, once daily, regardless of meals.

The usual initial dose is one tablet (10 mg enalapril / 25 mg hydrochlorothiazide) per day.

Titrate the dose based on individual patient response. The maximum daily dose is two tablets.

For patients not adequately controlled on enalapril monotherapy, switch to this combination.

For patients on diuretic therapy, discontinue the diuretic 2-3 days before starting Enafarm-N to reduce the risk of symptomatic hypotension.

If blood pressure control is insufficient, the dose may be increased after 2-3 weeks.

In patients with a decrease in glomerular filtration rate to 30 ml/min, individual dose selection is mandatory.

For these patients, the dose should be calculated as enalapril 5-10 mg per day.

Dose adjustment may be required in patients with impaired renal function or electrolyte imbalances.

Monitor blood pressure and renal function regularly during therapy.

Adverse Reactions

Most frequently: dizziness, increased fatigue.

1-2% muscle cramps, nausea, asthenia, orthostatic hypotension, headache, cough, impotence.

From the cardiovascular system syncope, decreased blood pressure, palpitations, tachycardia, chest pain.

Allergic reactions angioedema (face, tongue, lips, vocal cords, larynx, extremities, intestine), malignant exudative erythema (Stevens-Johnson syndrome).

From the nervous system dizziness, insomnia or drowsiness, paresthesia, increased excitability.

From the respiratory system dyspnea.

From the digestive system dry mouth, dyspepsia (including nausea, vomiting, flatulence), diarrhea or constipation, abdominal pain, pancreatitis.

From the urinary system impaired renal function, renal failure, decreased libido.

From the skin skin rash, itching, sweating.

Laboratory parameters hyperglycemia, hyper- or hypokalemia, increased serum urea concentration, hypercreatininemia, hyperuricemia, increased activity of hepatic transaminases, hyperbilirubinemia, decreased Hb and hematocrit.

Other gout, tinnitus, arthralgia, lupus-like syndrome (fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive test for antinuclear antibodies, increased ESR, eosinophilia, leukocytosis, skin rash, photosensitivity).

Contraindications

Anuria; severe renal impairment (creatinine clearance <30 ml/min); history of angioedema associated with ACE inhibitor use; hereditary or idiopathic angioedema; bilateral renal artery stenosis, stenosis of the artery of a single kidney; pregnancy, lactation (breastfeeding); children under 18 years of age; hypersensitivity to the components of the combination (including other sulfonamide derivatives).

With caution

Severe aortic orifice stenosis or idiopathic hypertrophic subaortic stenosis; coronary artery disease and cerebrovascular diseases (including cerebral circulatory insufficiency), because an excessive decrease in blood pressure can lead to the development of myocardial infarction and stroke; chronic heart failure; severe atherosclerosis; severe autoimmune systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); bone marrow hematopoiesis depression; diabetes mellitus (since thiazide diuretics can reduce glucose tolerance); hyperkalemia; condition after kidney transplantation; impaired liver and/or kidney function (creatinine clearance 30-75 ml/min); conditions accompanied by a decrease in circulating blood volume (as a result of diuretic therapy, salt restriction, diarrhea and vomiting); elderly patients.

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

With caution hepatic insufficiency.

Use in Renal Impairment

In patients with a decrease in glomerular filtration rate to 30 ml/min, individual dose selection is required, calculated as Enalapril – 5-10 mg/day.

With caution renal failure, bilateral renal artery stenosis, stenosis of the artery of a single kidney, condition after kidney transplantation.

Pediatric Use

Contraindication: children under 18 years of age.

Geriatric Use

With caution elderly age.

Special Precautions

Arterial hypotension with all clinical consequences may be observed after the first dose of this combination in patients with severe heart failure and hyponatremia, severe renal failure, arterial hypertension or left ventricular dysfunction and, especially, in patients who are in a state of hypovolemia, as a result of diuretic therapy, salt-free diet, diarrhea, vomiting or hemodialysis.

In case of arterial hypotension, it is necessary to lay the patient on his back with a low headboard and, if necessary, correct the circulating blood volume by infusion of 0.9% sodium chloride solution. Arterial hypotension that occurred after the first dose is not a contraindication for further treatment.

Caution is required in patients with coronary artery disease, severe cerebrovascular diseases, aortic stenosis or idiopathic hypertrophic obstructive subaortic stenosis, which impedes the outflow of blood from the left ventricle, severe atherosclerosis, in elderly patients due to the risk of developing arterial hypotension and deterioration of blood supply to the heart, brain and kidneys.

Regular monitoring of serum electrolyte concentrations is necessary during treatment to detect possible imbalance and take timely necessary measures. Determination of serum electrolyte concentrations is mandatory for patients with prolonged diarrhea and vomiting.

When using this combination, signs of water-electrolyte imbalance should be monitored, such as dry mouth, thirst, weakness, drowsiness, increased excitability, myalgia and cramps (mainly of the calf muscles), decreased blood pressure, tachycardia, oliguria and gastrointestinal disorders (nausea, vomiting).

In patients with renal impairment (creatinine clearance 30-75 ml/min), this combination should be used only after preliminary titration of the doses of enalapril and hydrochlorothiazide separately, corresponding to the fixed doses of the combination used.

Use with caution in patients with hepatic insufficiency or progressive liver diseases, because Hydrochlorothiazide can cause hepatic coma even with minimal disturbances of water-electrolyte balance. Several cases of acute hepatic failure with cholestatic jaundice, fulminant liver necrosis and fatal outcome (rarely) have been reported during treatment with ACE inhibitors. If jaundice and increased activity of hepatic transaminases occur, treatment should be stopped immediately, and patients should be under observation.

Caution is necessary in all patients receiving treatment with oral hypoglycemic agents or insulin, because Hydrochlorothiazide can weaken, and Enalapril can enhance their effect.

Thiazide diuretics can reduce the renal excretion of calcium and cause a slight and transient increase in serum calcium levels.

Marked hypercalcemia may be a sign of latent hyperparathyroidism. Before testing parathyroid function, thiazide diuretics must be discontinued.

During treatment with thiazide diuretics, serum cholesterol and triglyceride concentrations may increase.

Thiazide diuretic therapy in some patients may exacerbate hyperuricemia and/or aggravate the course of gout. However, Enalapril enhances the renal excretion of uric acid, thereby counteracting the hyperuricemic effect of hydrochlorothiazide.

If angioedema of the face occurs, it is usually sufficient to discontinue therapy and prescribe antihistamines to the patient.

Angioedema of the tongue, pharynx, or larynx can be fatal. In case of angioedema of the tongue, pharynx, or larynx, which can lead to airway obstruction, epinephrine should be administered immediately (0.3-0.5 ml of epinephrine (adrenaline) solution s/c in a ratio of 1:1000) and airway patency should be maintained (intubation or tracheostomy).

Among patients of the Black race receiving therapy with an ACE inhibitor, the frequency of angioedema is higher than among patients of other races.

Patients with a history of angioedema not associated with ACE inhibitors have an increased risk of developing angioedema when taking any ACE inhibitor.

In patients taking thiazide diuretics, hypersensitivity reactions can develop both in the presence and absence of a history of allergic reactions. Exacerbation of systemic lupus erythematosus has been reported.

Due to the increased risk of anaphylactic reactions, this combination should not be used in patients on hemodialysis using high-flow polyacrylonitrile membranes (AN 69^®), used in LDL apheresis with dextran sulfate, and immediately before desensitization to wasp or bee venom.

Before surgery (including dentistry), the anesthesiologist must be informed about the use of ACE inhibitors. During surgery or general anesthesia using agents that cause arterial hypotension, ACE inhibitors can block the formation of angiotensin II in response to compensatory renin release. If a pronounced decrease in blood pressure develops due to this mechanism, measures should be taken to increase the circulating blood volume for correction.

Cough has been observed with the use of ACE inhibitors. The cough is dry, prolonged, and disappears after discontinuation of ACE inhibitors. When making a differential diagnosis of cough, cough caused by the use of ACE inhibitors should be taken into account.

Effect on ability to drive vehicles and mechanisms

At the beginning of treatment with this combination, pronounced decrease in blood pressure, dizziness and drowsiness are possible, which may reduce the ability to drive vehicles and engage in other potentially hazardous activities. Therefore, at the beginning of treatment, it is not recommended to drive vehicles and engage in work requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Use of potassium supplements, potassium-sparing agents or drugs containing potassium, salt substitutes, especially in patients with renal impairment, can lead to a significant increase in serum potassium levels. Potassium loss during thiazide diuretic intake is usually reduced under the influence of enalapril. Serum potassium levels usually remain within the normal range.

With simultaneous use with lithium preparations, the excretion of lithium is slowed (enhancement of the cardiotoxic and neurotoxic effects of lithium).

Thiazide diuretics may enhance the effect of tubocurarine chloride.

Simultaneous use of thiazide diuretics, opioid analgesics or phenothiazine derivatives can lead to orthostatic hypotension.

Concomitant use with enalapril of beta-blockers, alpha-blockers, ganglionic blocking agents, methyldopa or slow calcium channel blockers may additionally reduce blood pressure.

Simultaneous use of allopurinol, cytostatics and immunosuppressants with ACE inhibitors may increase the risk of leukopenia.

Concomitant use of thiazide diuretics with glucocorticosteroids, calcitonin may lead to the development of hypokalemia.

Concomitant use of cyclosporine with ACE inhibitors may increase the risk of hyperkalemia.

Concomitant use of NSAIDs (including selective COX-2 inhibitors) may reduce the antihypertensive effect of ACE inhibitors.

NSAIDs and ACE inhibitors have an additive effect on increasing serum potassium levels, which may lead to worsening of renal function, especially in patients with impaired renal function.

This effect is reversible.

NSAIDs may reduce the diuretic and antihypertensive effects of diuretics.

Antacids may reduce the bioavailability of ACE inhibitors.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Thiazide diuretics may reduce the effect of adrenergic agonists (epinephrine).

Ethanol enhances the hypotensive effect of ACE inhibitors and thiazide diuretics, which may cause orthostatic hypotension.

Epidemiological studies suggest that concomitant use of ACE inhibitors and hypoglycemic agents may lead to hypoglycemia.

Hypoglycemia occurs more frequently during the first weeks of therapy in patients with impaired renal function.

Long-term and controlled clinical studies of enalapril do not confirm these data and do not restrict the use of enalapril in patients with diabetes mellitus.

Nevertheless, such patients should be under regular medical supervision.

The use of oral hypoglycemic agents and insulin with thiazide diuretics may require dose adjustment.

A single dose of cholestyramine or colestipol reduces the absorption of hydrochlorothiazide in the gastrointestinal tract by 85% and 43%, respectively.

With the simultaneous use of ACE inhibitors and gold preparations (sodium aurothiomalate) intravenously, a symptom complex including facial flushing, nausea, vomiting, and arterial hypotension has been described.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.