Each tablet contains:

active ingredient: enalapril maleate – 10 mg, hydrochlorothiazide – 25 mg;

excipients: microcrystalline cellulose, lactose monohydrate, povidone, maize starch, sodium starch glycolate, magnesium stearate, calcium hydrogen phosphate.

Combined antihypertensive drugs; C09BA02.

Enalapril

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolysed to enalaprilat, which inhibits ACE, which leads to increased plasma renin activity (due to removal of negative feedback on renin release), and decreased aldosterone secretion.

ACE is identical to kininase II. Thus enalapril may also block the degradation of bradykinin, a potential vasodepressor peptide. However, the role that this plays in the therapeutic effects of enalapril remains to be elucidated. While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, which plays a major role in the regulation of blood pressure, enalapril is antihypertensive even in patients with low-renin hypertension.

Enalapril – Hydrochlorothiazide

Hydrochlorothiazide is a diuretic and antihypertensive agent which increases plasma renin activity. Although enalapril alone is antihypertensive even in patients with low-renin hypertension, concomitant administration of hydrochlorothiazide in these patients leads to greater reduction of blood pressure.

Enalapril

Enalapril acts as a prodrug of the diacid enalaprilat, its active form, which is poorly absorbed by mouth. About 60% of an oral dose of enalapril is absorbed from the gastrointestinal tract and peak plasma concentrations are achieved within about 1 hour. Enalapril is extensively hydrolysed in the liver to enalaprilat; peak plasma concentrations of enalaprilat are achieved 3 to 4 hours after an oral dose of enalapril. Enalaprilat is 50 to 60% bound to plasma proteins. After an oral dose, enalapril is excreted in the urine and in faeces, as enalaprilat and unchanged drug, with the urinary route predominating; 100% of an intravenous dose of enalaprilat is excreted in the urine. The elimination of enalaprilat is multiphasic but the effective half-life for accumulation after multiple doses of enalapril is reported to be about 11 hours in patients with normal renal function. Enalaprilat is removed by haemodialysis and by peritoneal dialysis.

Enalaprilat crosses the placental barrier and is distributed into breast milk.

Enalaprilat may be removed from general circulation by hemodialysis and peritoneal dialysis

Hydrochlorothiazide

Hydrochlorothiazide is fairly rapidly absorbed from the gastrointestinal tract. It is reported to have a bioavailability of about 65 to 70%. Onset of hydrochlorothiazide’s diuretic effect occurs within two hours. It has been estimated to have a plasma half-life of between about 5 and 15 hours and appears to be preferentially bound to red blood cells.

Hydrochlorothiazide is 40% bound to plasma proteins. Hydrochlorothiazide is eliminated rapidly by the kidney and excreted unchanged (> 95%) and about 4% as an inactive metabolite in the urine. Hydrochlorothiazide crosses the placental barrier and is distributed into breast milk.

Pharmacokinetics in special clinical cases

Renal impairment: The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml/min) steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance LESS-THAN OR EQUAL TO (8804)30 ml/min), AUC was increased approximately 8-fold. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency and time to steady state is delayed (See Section 4.2). Enalaprilat may be removed from the general circulation by haemodialysis. The dialysis clearance is 62 ml/min.

In patients with hepatic insufficiency the metabolism of enalapril may be slowed without damage to its farmakodinamičeskogo effect.

In patients with heart failure and metabolic intake englaprilata slows down, It also reduces the V(d). Because. in these patients is kidney failure, they may slow down the removal of enalapril.

Older patients may vary, enalapril pharmacokinetics more due to associated diseases, older than.

The simultaneous use of enalapril and hydrochlorothiazide does not affect the farmakokinetik of each.

• Hypertension
• Symptomatic heart failure
• Prevention of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction.

Administration

Treatment of hypertension should not begin with a combination of medicines. The original must be defined with adequate doses of the individual components. The dose should always be selected individually for each patient.

You should regularly take the drug at the same time (preferably in the morning). Pills alone during or after a meal, squeezed small amount of liquid.

Adults

Hypertension, used alone, initially 5 mg (1/2 tablet) once daily; if used in renal impairment, lower initial doses may be required; usual maintenance dose 20 mg (2 tablets) once daily; max. 40 mg (4 tablets) once daily

Heart failure (adjunct), asymptomatic left ventricular dysfunction, initially 2.5 mg (1/4 tablet) once daily under close medical supervision (see notes above), increased gradually over 2–4 weeks to 10–20 mg (1-2 tablets) twice daily.

Prior diuretic therapy: symptomatic hypotension may occur following the initial dose of Enalapril-H; this is more likely in patients who are volume and/or salt depleted as a result of prior diuretic therapy. The diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with Enalapril-H.

Dosage in renal insufficiency

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency).

In patients with creatinine clearance of >30 and

In patients with moderate renal impairment, the recommended initial dose of enalapril is 2.5 mg.

Symptoms: increased diuresis, expressed lower ad with bradycardia or other disturbances of heart rhythm, cramps, paresis, paralytic ileus, human consciousness (including to whom), kidney failure, violation of acid-base balance, violation of electrolyte balance blood.

Treatment: Treatment is symptomatic and supportive. Treatment with Enalapril maleate/Hydrochlorothiazide should be discontinued and the patient should be carefully monitored. Recommended measures include administration of activated charcoal and administration of a laxative and/or gastric lavage if the tablets were taken recently. You need to monitor the blood pressure, pulse rate, respiratory function, levels of urea, creatinine, and electrolytes in the blood serum. Any dehydration, disturbances in the electrolyte balance and hypotension should be treated in an appropriate manner. If hypotension develops , so should be given 0.9% solution of sodium chloride Enalaprilat can be eliminated from blood circulation via haemodialysis. The extent to which hydrochlorothiazide is removed is not established.

• Severe renal impairment (creatinine clearance ≤30 ml/min).

• History of angioneurotic edema associated with previous ACE-inhibitor therapy.

• Hypersensitivity to sulfonamide-derived drugs.

• Resistant hypokalemia, hyponatremia, hypercalcemia.

• Symptomatic hyperuricemia.

• Addison’s disease.

• Pregnancy, lactation.

• Children under 18 years of age (efficacy and safety have not been established).

Metabolic and nutrition disorders: hypoglycemia.

Nervous system disorders: depression,ataxia,anxiety, dysesthesia, somnolence, insomnia, nervousness, paraesthesia, , sleep disorders.

From the sensory organs very common: blurred vision, disturbance of taste and smell, tinnitus, conjunctivitis, dryness of the conjunctiva, lacrimation.

Cardiac and vascular disorders: hypotension, myocardial infarction or cerebrovascular accident, rhythm disorders, angina pectoris,cardiac arrest, orthostatic hypotension, palpitations, Raynaud’s syndrome.

Respiratory, thoracic and mediastinal disorders: pulmonary embolism, hoarseness, bronchospasm, asthma, pneumonia, pulmonary infiltrates,sinusitis, pharyngitis, rhinitis, eosinophilic pneumoniapulmonary infarction, pulmonary edema, respiratory distress,including pneumonitis and pulmonary edema.

Gastrointestinal disorders: nausea, diarrhoea, abdominal pain, ileus, pancreatitis, vomiting, constipation, anorexia, intestinal colics, dry mouth, salivary glands inflammation, meteorism, stomatitis, glossitis.

Hepatobiliary disorders: hepatic failure, hepatitis – either hepatocellular or cholestatic, hepatitis including necrosis, elevated liver enzymes, hyperbilirubinemia, jaundice, мmelena, cholestasis (including jaundice).

Skin and subcutaneous tissue disorders and allergic reactions: rash, photosensitivity, hypersensitivity, angioneurotic oedema (angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported), pruritus, urticaria, alopecia, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, anaphylactic reactions.

Renal and urinary disorders: renal dysfunction, renal failure, interstitial nephritis, oliguria.

Reproductive system and breast disorders: impotence, gynaecomastia.

Investigations: hyperkalaemia, hyponatraemia, hypochloremic alkalosis, hyperglycemia, glycosuria, hyperuricemia, hypercholesterolemia, hypertriglyceridemia.

Others: increased sweating, tinea, lupus-like syndrome (fever, myalgia, and arthralgia, serositis, vasculitis, increased erythrocyte sedimentation rate, leukocytosis and eosinophilia, skin rash, a positive test for antinuclear antibodies), fever, weakness, thrombocytopenic purpura, necrotizing vasculitis.

Food does not affect absorption of Enalapril- H.

Simultaneous application Enalapril-H with other antigipertenzivei means, tricyclic antidepressants, fenotiazinom and with ethanol, enhances the antihypertensive activity Enalapril-H.

Analgesics and NSAIDS, a large amount of salt in diet, simultaneous reception cholestyramine and colestipol reduce the effect Enalapril-H.

If possible, you should avoid simultaneous application Enalapril-H and drugs lithium, since the development of lithium intoxication due to reduced excretion of lithium.

Potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene vs amiloride), potassium supplements or potassium-containing salt substitutes may lead to a significant increase in serum potassium. If concomitant use is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring serum potassium.

Allopurinol, cytostatics, immunosuppressant or systemic corticosteroids can cause leukopenia, anemia or pancytopenia, therefore requires periodic monitoring of hemogram.

Concomitant treatment with cyclosporine may increase the risk of kidney failure.

Concomitant treatment with sulfonamides or sulfonylurea antidiabetic drugs may cause allergic reactions (may be cross-allergy).

Digitalis glycosides:Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.

Corticosteroids: Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

Muscle Relaxants and general anesthesia: enhanced hypotensive effect.

In cases of renal impairment (creatinine clearance 30 – 80 ml/min) the initial enalapril dosage should be adjusted according to the patient’s creatinine clearance and then as a function of the patient’s response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients.

Some hypertensive patients, with no apparent pre-existing renal disease have developed increases in blood urea and creatinine when enalapril has been given concurrently with a diuretic. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required. This situation should raise the possibility of underlying renal artery stenosis.

Allopurinol, cytostatics, immunosuppressant or systemic corticosteroids can cause leukopenia, anemia or pancytopenia, therefore requires periodic monitoring of hemogram.

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should closely be

monitored during the first month of treatment with an ACE inhibitor.

In patients with severe heart failure and hyponatremia, severe renal insufficiency, hypertrophy or dysfunction of left ventricular, and especially in patients in a state of hypovolemia caused by diuretics, salt-free diet, diarrhea, vomiting, or hemodialysis, after taking the first tablets Enalapril-H may develop hypotension. If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of 0.9% solution of sodium chloride.

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and /or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Enalapril-H. This may occur at any time during treatment. In such cases, Enalapril-H should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history or airway surgery.Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3ml to 0.5ml) and/or measures to ensure a patent airway, should be administered promptly.

Hypokalaemia caused by Enalapril-H, can bring to hepatic coma in patients with liver disease and ventricular arrhythmias, as well as increased toxic effects of digitalis drugs in patients with heart disease.

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage should be adjusted accordingly. Treatment should be discontinued before carrying out tests for parathyroid function.

Enalapril should be used with care in patients with severe aortic stenosis or idiopathic hypertrophic cardiomyopathy and generalized atherosclerosis.

The antihypertensive effect of Enalapril-H can be exacerbated after simpatotomia. Due to the increased risk of anaphylactic reactions Enalapril-H should not be given to patients on hemodialysis using polyacrylonitrile membranes with dextran sulfate apheresis treatment and immediately before desensitization of wasp or bee venom.

Care should be taken in patients receiving sulfonamides or anti-diabetic drugs of sulfonylureas.

During the treatment the concentration of electrolytes, urea, serum creatinine, activity of hepatic transaminases and protein in the urine should be monitored periodically in these patients.

Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine, because 1 tablet of Enalapril-H content 25 mg lactose monohydrate.

Enalapril H is contraindicated during pregnancy and breastfeeding.

White biconvex scored odorless tablets.

2 blister packets with 10 tablets in the cardboard box.

3 years. Do not use after the expiration date.

Store at a room temperature (15-25⁰C), in a dry place, out of the reach of children. Protect from light.