Enap-NL, tablets 12.5mg+10 mg 60 pcs

A combination drug, the action of which is due to the properties of its constituent components.

Enalapril is an ACE inhibitor and is a prodrug: its hydrolysis produces enalaprilate, which inhibits ACE.

Hydrochlorothiazide is a thiazide diuretic. It acts at the level of the distal renal tubules, increasing the excretion of sodium and chlorine ions.

In the beginning of treatment with hydrochlorothiazide, the volume of fluid in blood vessels is reduced as a result of increased sodium and fluid excretion, which leads to a decrease in BP and cardiac output.

As a consequence of hyponatremia and decreased body fluid, the RAAS is activated. Reactive increase of angiotensin II concentration partially limits BP reduction. If therapy is continued, the hypotensive effect of hydrochlorothiazide is based on the reduction of RAS. The result of activation of renin-angiotensin-aldosterone system is metabolic effects on electrolyte balance of blood, uric acid, glucose and lipids, which partially neutralizes the effectiveness of antihypertensive treatment.

Despite effective BP reduction, thiazide diuretics do not reduce structural changes in the heart and vessels. Enalapril enhances the antihypertensive effect: it inhibits the RAAS, i.e. angiotensin II production and its effects. Additionally, it reduces the production of aldosterone and enhances the effects of bradykinin and the release of prostaglandins. Since it often has its own diuretic effect, this may increase the effect of hydrochlorothiazide.

Enalapril reduces pre- and postload, which unloads the left ventricle, reduces regression of hypertrophy and collagen overgrowth, and prevents myocardial cell damage. As a result, the heart rhythm slows down and the load on the heart (in chronic heart failure) decreases, coronary blood flow improves and oxygen consumption by cardiomyocytes decreases.

In this way, the sensitivity of the heart to ischemia is reduced, and the number of dangerous ventricular arrhythmias is reduced. It has a favorable effect on the cerebral blood flow in patients with arterial hypertension and chronic cardiovascular diseases. It prevents the development of glomerulosclerosis, maintains and improves kidney function and slows down the course of chronic kidney disease even in patients who have not yet developed arterial hypertension.

The antihypertensive effect of ACE inhibitors is known to be greater in patients with hyponatremia, hypovolemia and elevated serum renin levels, whereas the effect of hydrochlorothiazide is independent of serum renin levels.

Hence, concomitant administration of enalapril and hydrochlorothiazide has an additional antihypertensive effect. In addition, enalapril prevents or attenuates the metabolic effects of diuretic therapy and has a favorable effect on structural changes in the heart and vessels.

The simultaneous administration of ACE inhibitor and hydrochlorothiazide is used when each drug separately is not sufficiently effective or monotherapy is performed using maximum doses of the drug, which increases the incidence of adverse effects. This combination allows for a better therapeutic effect with lower doses of enalapril and hydrochlorothiazide and a reduction in the development of adverse events.

The antihypertensive effect of the combination usually lasts for 24 h.

Indications

Arterial hypertension (patients who are indicated for combination therapy).

Active ingredient

Composition

Active ingredients:

Hydrochlorothiazide 12.50 mg,

Enalapril maleate 10.00 mg,

Associates:

Sodium bicarbonate* 5.10 mg,

Lactose monohydrate 130.08 mg,

corn starch 32.10 mg,

Pregelatinized starch 6.00 mg,

talc 6.00 mg,

magnesium stearate 2.00 mg

*2.68 mg CO2 and 1.10 mg H2O resulting from the chemical reaction between sodium hydrocarbonate and enalapril maleate are evaporated during the manufacturing process and are not included in the final weight of the tablet.

How to take, the dosage

Enap® NL should be taken regularly at the same time, preferably in the morning, during or after a meal, without chewing, with a small amount of liquid. The recommended dose is 1 tablet per day. If necessary, the dose may be increased to a maximum daily dose of 2 tablets, taken once a day.

In patients on therapy with diuretics it is recommended to cancel the treatment or decrease the dose of diuretics at least 3 days before treatment with Enap® NL to prevent development of symptomatic arterial hypotension.

The duration of treatment is determined by the physician.

Dose in impaired renal function

Enap®-NL in patients with renal impairment (CKR 30 ml/min) should be used only if enalapril dose titration has demonstrated adequate dose of the Enap®-NL combination drug.

Interaction

The use of potassium supplements, potassium-saving agents or potassium-containing drugs, salt substitutes, especially in patients with renal insufficiency, may lead to a significant increase in serum potassium. Loss of potassium against the background of thiazide diuretics is usually reduced by enalapril. Serum potassium content usually remains within normal limits.

When concomitant use with lithium preparations the excretion of lithium is delayed (increase of the cardiotoxic and neurotoxic effects of lithium).

Thiazide diuretics may increase the effect of tubocurarine chloride.

The simultaneous use of thiazide diuretics, opioid analgesics or phenothiazine derivatives may lead to orthostatic hypotension.

The concomitant use of beta-adrenoblockers, alpha-adrenoblockers, ganglioblockers, methyldopa, or slow calcium channel blockers with enalapril may further decrease BP.

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

The concomitant use of thiazide diuretics with GCS, calcitonin may lead to hypokalemia.

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

The concomitant use of NSAIDs (including selective COX-2 inhibitors) may weaken the antihypertensive effect of ACE inhibitors. NSAIDs and ACE inhibitors have an additive effect on the increase in serum potassium, 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 decrease the bioavailability of ACE inhibitors.

Sympathomimetics may decrease the antihypertensive effect of ACE inhibitors.

Thiazide diuretics may decrease the effect of adrenomimetics (epinephrine).

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

Epidemiological studies suggest that simultaneous use of ACE inhibitors and hypoglycemic agents may lead to hypoglycemia. More often hypoglycemia develops in the first weeks of therapy in patients with impaired renal function. Long-term and controlled clinical trials of enalapril do not confirm these data and do not limit 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 adjustment of their doses.

Single administration of colestiramine or colestipol reduces gastrointestinal absorption of hydrochlorothiazide by 85% and 43%, respectively.

When ACE inhibitors and gold drugs (sodium aurothiomalate) are administered concomitantly by IV, a symptom complex including facial hyperemia, nausea, vomiting, and arterial hypotension has been described.

Special Instructions

Arterial hypotension with all clinical consequences may be observed after the first administration 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 hypovolemic as a result of diuretic therapy, salt-free diet, diarrhea, vomiting or hemodialysis.

In case of arterial hypotension, the patient should be placed on his back with a low headboard and, if necessary, the volume of the blood circulation should be corrected by infusion of 0.9% sodium chloride solution. Arterial hypotension occurring after the first dose is not a contraindication for further treatment.

Cautions are required in patients with CHD, marked cerebrovascular disease, aortic stenosis or idiopathic hypertrophic obstructive subaortic stenosis impeding blood flow from the left ventricle, marked atherosclerosis, in elderly patients due to the risk of arterial hypotension and impaired blood supply to the heart, brain and kidneys.

The regular monitoring of serum electrolyte concentrations during treatment is necessary to detect possible imbalances and to take timely, necessary measures. Determination of serum electrolyte concentrations is mandatory in patients with prolonged diarrhea, vomiting.

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

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

With caution, use in patients with hepatic impairment or advanced liver disease because hydrochlorothiazide may cause hepatic coma even with minimal water-electrolyte imbalances. Several cases of acute hepatic failure with cholestatic jaundice, fulminant liver necrosis and death have been reported (rarely) during treatment with ACE inhibitors. In case of jaundice and elevated liver transaminase activity, treatment should be discontinued immediately and patients should be monitored.

Caution is necessary in all patients receiving treatment with oral hypoglycemic agents or insulin, as hydrochlorothiazide may impair and enalapril may potentiate their effects.

Thiazide diuretics may decrease renal calcium excretion and cause a slight and transient increase in serum calcium.

Developed hypercalcemia may be a sign of occult hyperparathyroidism. Thiazide diuretics must be discontinued before parathyroid function testing.

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

The therapy with thiazide diuretics in some patients may aggravate hyperuricemia and/or aggravate the course of gout. However, enalapril increases uric acid excretion by the kidneys, thereby counteracting the hyperuricemic effect of hydrochlorothiazide.

In case of angioedema of the face, withdrawal of therapy and administration of antihistamines to the patient is usually sufficient.

The angioedema of the tongue, pharynx, or larynx can be fatal. If angioedema of the tongue, pharynx or larynx could lead to airway obstruction, epinephrine (0.3-0.5 ml of epinephrine (adrenaline) solution p/k at a ratio of 1:1000) should be given immediately and airway patency maintained (intubation or tracheostomy).

The incidence of angioedema is higher among non-Hispanic patients receiving ACE inhibitor therapy than among patients of other racial backgrounds.

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 may develop with or without a history of allergic reactions. Worsening of the course of systemic lupus erythematosus has been reported.

Because of the increased risk of anaphylactic reactions, this combination should not be used in patients on hemodialysis using high flow polyacrylonitrile membranes (AN 69®) used for LDL apheresis with dextransulfate and immediately prior to desensitization to wasp or bee venom.

Warn the anesthesiologist about the use of ACE inhibitors before surgical procedures (including dentistry). During surgical interventions or general anesthesia with agents causing arterial hypotension, ACE inhibitors may block angiotensin II formation in response to compensatory renin release. If a marked decrease in BP develops due to this mechanism, measures should be taken to increase the RBC in order to correct it.

Cough has been noted with ACE inhibitors. The cough is dry and prolonged, and disappears after discontinuation of ACE inhibitors. In the differential diagnosis of cough, cough caused by use of ACE inhibitors must also be considered.

Impact on the ability to drive vehicles and mechanisms

In the beginning of treatment with this combination, there may be a marked decrease in BP, dizziness and somnolence, which may impair the ability to drive vehicles and other potentially dangerous activities. Therefore, at the beginning of treatment, it is not recommended to drive vehicles and engage in work requiring increased concentration and quick psychomotor reactions.

Contraindications

– Hypersensitivity to enalapril, hydrochlorothiazide (including other sulfonamide derivatives) and other drug components;

Side effects

Cardiovascular system disorders: palpitations, various heart rhythm disorders, marked BP decrease, orthostatic hypotension, cardiac arrest, myocardial infarction, cerebrovascular stroke, angina pectoris, Raynaud’s syndrome, necrotizing angiitis.

Digestive system disorders: dry mouth, glossitis, stomatitis, salivary gland inflammation, anorexia, nausea, vomiting, diarrhea, constipation, flatulence, epigastric pain, intestinal colic, ileus, pancreatitis, liver failure, hepatitis, jaundice, melena.

Respiratory system: rhinitis, sinusitis, pharyngitis, hoarseness, bronchospasm, asthma, pneumonia, pulmonary infiltrates, eosinophilic pneumonia, pulmonary embolism, pulmonary infarction, respiratory distress (including pneumonitis and pulmonary edema).

CNS and peripheral nervous system disorders: depression, ataxia, somnolence, insomnia, anxiety, nervousness, peripheral neuropathy (paresthesia, dysesthesia).

Urinary system disorders: oliguria, renal failure, renal dysfunction, interstitial nephritis.

Reproductive system disorders: gynecomastia, decreased potency.

Sensory system disorders: visual impairment, damage to taste, impaired sense of smell, tinnitus, conjunctivitis, dry conjunctivae, lacrimation.

Hematopoietic system disorders: leukocytosis, eosinophilia, neutropenia, leukopenia, agranulocytosis, anemia, hypohaemoglobinemia, pancytopenia.

Metabolism disorders: hypokalemia, hyperkalemia, hypomagnesemia, hypercalcemia, hyponatremic alkalosis, hyperglycemia, glucosuria, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, increased liver enzymes activity, hyperbilirubinemia.

Dermatological reactions: sweating, rash, shingles, alopecia.

Allergic reactions: urticaria, pruritus, skin rash, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, photosensitivity, hypersensitivity reactions (angioedema, thrombocytopenic purpura), anaphylactic reactions.

Others: weakness, fever, lupus-like syndrome described in the literature (increased body temperature, myalgia and arthralgia, serositis, vasculitis, skin rash, increased CRP, leukocytosis, eosinophilia, positive test for antinuclear antibodies).

Overdose

In case of overdose, Enap®-NL should be discontinued. Symptomatic and supportive therapy is required.

Symptoms: marked BP decrease with bradycardia or other cardiac rhythm disturbances, dizziness, cough, increased diuresis resulting in hypokalemia, hypochloremia, hyponatremia, convulsions, anxiety, consciousness disorders (including coma), acute renal failure, disorders of acid-base state and blood water-electrolyte balance.

Treatment: the patient is transferred to the horizontal position with elevated legs. In mild cases gastric lavage and ingestion of activated charcoal are indicated, in more serious cases – measures aimed at BP stabilization – intravenous administration of plasma substitutes, infusion of 0.9% sodium chloride solution. The patient’s blood pressure, heart rate, respiratory rate, serum concentrations of urea, creatinine, electrolytes and diuresis should be monitored, if necessary – hemodialysis (elimination rate of enalaprilat – 62 ml/min). If bradycardia is refractory to drug therapy, pacing should be performed.

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