Enap N tablets 10mg/25mg 20 pcs.

Pharmacodynamics. The drug is a combination of an ACE inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).

Enalapril maleate. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a decrease in plasma angiotensin II levels, which leads to an increase in plasma renin activity (due to inhibition of negative feedback on renin release) and a decrease in aldosterone secretion.

ACE is identical to kininase II. Enalapril can also block the breakdown of bradykinin, which is a potent vasodepressor peptide. However, the role of this fact in the therapeutic effects of enalapril remains unknown. While the mechanism of blood pressure lowering by enalapril is primarily associated with inhibition of the renin-angiotensin-aldosterone system, which plays a major role in blood pressure regulation, enalapril may have an antihypertensive effect even in patients with low-renin hypertension.

Hydrochlorothiazide is a diuretic and antihypertensive agent that increases renin activity in blood plasma.

Enalapril maleate/hydrochlorothiazide. The antihypertensive effects of the two components are additive and generally last for 24 hours. Although enalapril alone has a hypotensive effect even in patients with low-renin hypertension, concomitant use with hydrochlorothiazide in such patients results in a more pronounced reduction in blood pressure. Enalapril in the composition of the drug generally reduces the potassium excretion caused by hydrochlorothiazide.

Pharmacokinetics.

Enalapril maleate. After oral administration, enalapril is rapidly absorbed, reaching C _max in plasma within 1 hour. Based on urinary excretion, the absorption of enalapril after oral administration is about 60-70%.

After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. C _max of enalaprilat in plasma is reached 3-4 hours after oral administration of enalapril maleate. Enalapril is excreted mainly by the kidneys. The main substance in the urine is enalaprilat – about 40% of the dose, and enalapril in unchanged form. With the exception of conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The plasma concentration profile of enalaprilat is characterized by a prolonged terminal phase, which is probably due to binding of ACE. In individuals with normal renal function, the equilibrium concentration of enalaprilat in plasma is achieved on the 4th day of oral administration of enalapril. The effective T _½ of enalaprilat after multiple oral administration of enalapril is 11 hours. Food intake does not affect the absorption of enalapril from the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar when taking different doses within the recommended therapeutic range.

Hydrochlorothiazide. When monitoring plasma levels for at least 24 hours, T _½ from plasma was 5.6-14.8 hours. Hydrochlorothiazide is not metabolized, but is rapidly excreted by the kidneys. When administered orally, at least 61% of the dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier and does not cross the blood-brain barrier.

Enalapril/hydrochlorothiazide. Multiple simultaneous administration of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of these substances. A tablet containing a combination of two substances that is bioequivalent to its individual components when administered simultaneously.

Arterial hypertension in patients for whom combination therapy is indicated.

Arterial hypertension. Tablets with a fixed combination of enalapril maleate and hydrochlorothiazide are prescribed to patients whose blood pressure is not adequately controlled with enalapril alone.

The use of a fixed combination of enalapril maleate and hydrochlorothiazide is not suitable for initial therapy and is usually recommended after titration of the individual components. If clinically appropriate, direct transfer from monotherapy to the fixed combination may be possible.

The dosage regimen is set individually depending on the patient’s condition and the severity of hypertension. Treatment begins with low doses of the drug with a gradual increase in dosage. The drug is used orally, regardless of meals. The established daily dose should be taken in the morning, washed down with plenty of liquid.

The usual dose is 1 tablet taken once a day. If necessary, the dose may be increased to 2 tablets per day in one dose.

The fixed combination tablets 10 mg/25 mg and 20 mg/12.5 mg can replace therapy consisting of taking 10 or 20 mg of enalapril and 25 or 12.5 mg of enalapril separately, respectively, in patients whose condition is stabilized on treatment with the individual components.

Previous diuretic therapy: symptomatic hypotension may occur at the beginning of therapy with the drug. Most often it is observed in patients in whom previous diuretic therapy caused a violation of water and electrolyte balance. Diuretic therapy should be discontinued 2-3 days before the start of therapy with Enap-H, Enap-HL and Enap-20 HL.

Dosage in renal impairment. Creatinine clearance 30 ml/min. For patients with renal impairment with creatinine clearance ≥30 ml/min, enalapril dose adjustment by titration is necessary before switching to a fixed combination. For such patients, loop diuretics are more acceptable than thiazides. The dose of enalapril and hydrochlorothiazide should be kept as low as possible. Periodic monitoring of potassium and creatinine is necessary, for example, every 2 months when the patient’s condition is stabilized.

Creatinine clearance 30 ml/min. Use of the drug is contraindicated.

Special Populations: For patients with electrolyte/fluid depletion, the starting dose of enalapril is ≤5 mg and titration of monocomponents is recommended.

Dosage for elderly patients. The drug is used in elderly patients in the same dose as in young patients. In case of physiological renal failure, the dose of enalapril should be adjusted by titration before switching to a fixed combination.

There is no time limit on the duration of treatment.

The most common adverse reactions were dizziness and fatigue, which usually resolved with dose reduction and rarely required drug discontinuation.

Other adverse reactions (1-2%) were muscle cramps, nausea, asthenia, orthostatic effects including hypotension; headache, cough and impotence.

Adverse reactions reported with enalapril or hydrochlorothiazide alone, either during clinical trials or after the drug was marketed, are included.

Cardiovascular system: orthostatic hypotension, palpitations, tachycardia, chest pain.

Gastrointestinal: pancreatitis, diarrhea, vomiting, dyspepsia, abdominal pain, peptic ulcers, flatulence, constipation, dry mouth, aphthous ulcers.

Nervous system/psychiatric: fainting, insomnia, drowsiness, paresthesia, dizziness, fatigue, malaise, nervousness, paresis (due to hypokalemia).

Respiratory system: shortness of breath, allergic alveolitis.

Skin: Stevens-Johnson syndrome, rash, itching, increased sweating, hyperhidrosis, photosensitivity or other dermatological reactions.

On the part of the blood: a decrease in hemoglobin, hematocrit, as well as a decrease in the number of platelets and leukocytes, rarely – neutropenia, thrombocytopenia, bone marrow suppression.

Renal and urinary disorders: renal dysfunction, renal failure, proteinuria.

From the reproductive system: decreased libido.

Metabolic disorders: gout.

From the side of the organs of hearing and vestibular apparatus: tinnitus.

Others. A symptom complex has been reported that may include some or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis and arthralgia/arthritis, positive antinuclear antibody (ANA) test, increased ESR, eosinophilia, leukocytosis.

Hypersensitivity reactions: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely (see Precautions). Intestinal angioedema has been reported very rarely with the use of ACE inhibitors, including enalapril.

Changes in laboratory parameters: hyperglycemia, hyperuricemia, hypokalemia. Increased levels of nitrogen, urea and creatinine in the blood serum, increased levels of liver enzymes and / or bilirubin in the blood serum have been noted. These symptoms are usually reversible upon discontinuation of the drug. Cases of hyperkalemia, hypochloremic alkalosis, hypomagnesemia, hypercalcemia, increased levels of cholesterol and triglycerides in the blood have been noted.

Impact on the results of the following laboratory parameters:

• the drug may reduce the level of protein-bound iodine in blood plasma;
• the drug is able to increase the concentration of free bilirubin in the blood serum;
• Due to their effect on calcium metabolism, thiazides may affect the results of parathyroid function tests, so treatment should be discontinued before testing for parathyroid function.

Additional adverse reactions that have been observed with the use of individual components of the drug and may be potential side effects of the drug Enap-N, Enap-NL or Enap-20NL.

enalapril

On the part of the digestive system: ileus, anorexia, change in taste, stomatitis, glossitis, nausea.

From the hepatobiliary system: hepatic failure, hepatitis (hepatocellular or cholestatic), cholecystitis, hepatic necrosis, cholestasis.

Nervous system/psychiatric: depression, confusion, sleep disorders, abnormal dreams, asthenia.

Respiratory: pulmonary infiltrates, bronchospasm/asthma, sore throat and hoarseness, rhinorrhea.

Cardiovascular system: cardiac arrhythmias, angina pectoris, orthostatic hypotension, myocardial infarction or stroke (possibly due to excessive hypotension in high-risk patients), Raynaud’s phenomenon.

Skin and mucous membranes: photosensitivity, alopecia, erythroderma, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, pemphigus.

On the part of the blood: aplastic and hemolytic anemia, hyponatremia.

On the part of the immune system: urticaria, anaphylactic shock, autoimmune disorders.

Metabolic disorders: hypoglycemia.

Others: blurred vision, lymphadenopathy, oliguria, syndrome of inappropriate ADH secretion, muscle cramps.

Hydrochlorothiazide

Cardiovascular system: arrhythmia.

From the hepatobiliary system: jaundice (intrahepatic, cholestatic), hepatic necrosis, cholestasis, cholecystitis.

On the part of the digestive system: anorexia, gastric irritation, sialadenitis, change in taste sensations, nausea.

Metabolic disorders: glycosuria, hypochloremic alkalosis (which can induce hepatic encephalopathy or hepatic coma), hyperuricemia (which can provoke gout attacks in patients with asymptomatic disease), hypoglycemia, decreased glucose tolerance (which can cause manifestation of latent diabetes mellitus).

On the part of the blood: leukopenia, agranulocytosis, thrombocytopenia, aplastic and hemolytic anemia.

Immune system disorders: anaphylactic reactions, urticaria.

Skin and mucous membranes: photosensitivity, necrotizing angiitis (vasculitis), toxic epidermal necrolysis.

On the part of the organ of vision: xanthopsia, transient visual impairment.

Respiratory: respiratory distress (including pneumonia and pulmonary edema).

Nervous system/psychiatric: anxiety, disorientation, mood changes, exhaustion.

Changes in laboratory parameters: electrolyte imbalance (including hyponatremia).

Others: fever, interstitial nephritis, muscle spasms, convulsions, thirst, sexual disorders.

Enalapril and hydrochlorothiazide

Hypotension and electrolyte imbalance. Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. In patients with hypertension who use the drug, hypotension develops more often in cases of electrolyte/fluid depletion, for example, due to diuretic therapy, salt restriction, dialysis, diarrhea or vomiting. Regular monitoring of plasma electrolyte levels is necessary in such patients. Symptomatic hypotension has developed more often in patients with severe heart failure who have used maximum doses of loop diuretics, with hyponatremia or impaired renal function. In such patients, treatment with the drug should be started under the supervision of a physician.

Patients should be monitored for clinical signs of fluid and electrolyte imbalance, such as dehydration, hyponatremia, hypochloremic alkalosis, which may induce hepatic encephalopathy or hepatic coma; hypomagnesemia or hypokalemia, which may occur as a result of diarrhea or vomiting. Serum electrolyte levels should be monitored periodically in such patients.

The approach to treating patients with ischemic heart disease or cerebrovascular disease should be particularly careful, since excessive lowering of blood pressure can lead to myocardial infarction or stroke.

If hypotension develops, the patient should be placed on his back and, if necessary, 0.9% sodium chloride solution should be administered intravenously. Transient hypotension during treatment is not a contraindication to treatment, which can be continued after normalization of blood pressure and restoration of fluid volume.

In some patients with heart failure and normal or low blood pressure, the drug may further reduce blood pressure. This reaction to the drug is to be expected and should not be considered a reason for discontinuation of treatment. In cases where arterial hypotension is resistant to treatment, the dose should be reduced and / or treatment with the diuretic and / or Enap-H, Enap-HL and Enap-20HL should be discontinued.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to isolated cases with careful monitoring of blood pressure, renal function, and electrolytes. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual RAAS blockade is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a single RAAS-acting agent. Enalapril should not be used with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate 60 ml/min/1.73 m2 ⁾ (see Adverse Reactions or Precautions).

Renal impairment: Renal impairment has been reported with enalapril, particularly in patients with severe heart failure or renal disease, including renal artery stenosis. If diagnosed promptly and treated appropriately, renal impairment associated with enalapril therapy may be reversible.

Some patients with hypertension without pre-existing renal insufficiency have experienced increases in plasma urea and creatinine when enalapril is given with a diuretic. A reduction in the dose of enalapril and/or discontinuation of the diuretic may be necessary. In such cases, the possibility of renal artery stenosis should be considered.

Hyperkalemia. When using the combination of enalapril and a diuretic in low doses, hyperkalemia may occur.

Lithium. Concomitant use of enalapril and lithium is generally not recommended.

Elderly patients: The efficacy and tolerability of enalapril maleate and hydrochlorothiazide when co-administered are similar to those in young adult patients with hypertension.

Use in children. The safety and effectiveness of the drug in children have not been established.

enalapril

Aortic or mitral stenosis/hypertrophic cardiomyopathy: As with all vasodilators, ACE inhibitors should be used with caution in patients with mitral valve stenosis and left ventricular outflow obstruction. Their use should be avoided in patients with cardiogenic shock and left ventricular outflow obstruction.

Renovascular hypertension. Patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney who are taking ACE inhibitors are at increased risk of developing hypotension. Even with minor changes in plasma creatinine, renal function may deteriorate. In these patients, treatment should be initiated under close medical supervision, with low doses and with careful dose titration and monitoring of renal function.

Patients on hemodialysis. Anaphylactoid reactions have been reported in some patients on dialysis with high-flux membranes (e.g. AN 69) and concomitant treatment with ACE inhibitors. Therefore, the use of a different type of dialysis membrane or a different class of antihypertensive agent is recommended in such patients.

Kidney transplantation. There is no experience in patients with a recent kidney transplant. Therefore, treatment with the drug is not recommended for them.

Hepatic impairment. Very rarely, a syndrome that begins with cholestatic jaundice and progresses to hepatic necrosis, sometimes fatal, has been associated with the use of ACE inhibitors. The mechanism of this syndrome is unknown. In patients receiving ACE inhibitors, if jaundice develops or if liver enzymes become significantly elevated, the ACE inhibitors should be discontinued and appropriate treatment initiated.

Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and without specific risk factors. Enalapril should be used with great caution in patients with collagen vascular disease, immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of the above risk factors, especially in patients with pre-existing renal impairment. Some of these patients have developed severe infections, sometimes resistant to intensive antibiotic therapy.

When using enalapril in such patients, periodic monitoring of leukocyte counts is recommended, and the patient should be warned to inform the physician of any signs of infection.

Hyperkalemia. Some patients taking ACE inhibitors, including enalapril, have experienced increases in plasma potassium. Risk factors for hyperkalemia include renal insufficiency or decreased renal function, age (over 70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or other drugs that increase plasma potassium levels (e.g., heparin). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in plasma potassium. Hyperkalemia may cause serious, sometimes fatal arrhythmias. With simultaneous use of the drug and any of the above agents, the level of potassium in the blood plasma should be regularly monitored (see Interactions with other drugs).

Hypoglycemia: In patients with diabetes mellitus taking oral antidiabetic agents or insulin, careful glycemic control is necessary, especially during the first month of treatment with ACE inhibitors.

Hypersensitivity/angioedema. In patients taking ACE inhibitors, including Enap-N, Enap-NL or Enap 20 NL, in some cases angioedema of the face, extremities, lips, tongue, larynx, glottis narrowing has occurred. It can occur at any time during treatment. In such a case, the use of the drug should be discontinued immediately and the patient should be monitored closely until the symptoms disappear. Even if only swelling of the tongue is noted in the absence of respiratory distress syndrome, the patient may require prolonged observation, since treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal angioedema of the larynx or tongue has been reported. If swelling of the tongue, larynx, or glottis occurs, airway obstruction is likely, especially in patients who have undergone respiratory surgery. In these cases, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 (0.3-0.5 ml) and/or measures to maintain a patent airway.

Angioedema was more common in black patients treated with ACE inhibitors than in patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitors are at increased risk of developing angioedema when taking ACE inhibitors.

Anaphylactoid reactions during desensitization therapy. Occasionally, patients receiving ACE inhibitors during desensitization with an allergen from the venom of hymenoptera insects have developed anaphylactoid reactions, which can be life-threatening. Such reactions can be avoided by temporarily stopping the ACE inhibitor before the start of desensitization.

Anaphylactoid reactions during low-density lipoprotein apheresis. Rarely, life-threatening anaphylactoid reactions may occur during low-density lipoprotein apheresis with dextran sulfate in patients receiving ACE inhibitors. Such reactions can be avoided by temporarily withdrawing ACE inhibitor therapy before each apheresis.

Cough: Cough has been reported with ACE inhibitors. The cough is usually non-productive, persistent, and resolves after discontinuation of the drug. Cough associated with ACE inhibitors should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: During major surgery or anesthesia with drugs that cause hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. If hypotension develops, which can be explained by these mechanisms of interaction, it is corrected by increasing the volume of fluid.

Race: As has been reported for other ACE inhibitors, enalapril may be less effective in lowering blood pressure in black patients with hypertension than in non-black patients, possibly because of the lower renin status of these patients.

Hydrochlorothiazide

Renal impairment: Thiazides may not be effective diuretics in patients with renal impairment or when creatinine clearance is ≤30 mL/min (i.e., moderate to severe renal impairment).

Enap-N, Enap-HL or Enap 20 HL should not be prescribed to patients with renal insufficiency (creatinine clearance 80 ml/min) until the appropriateness of the doses contained in the combination drug has been proven by titration of the doses of the individual components.

Hepatic impairment: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since even minor disturbances of fluid and electrolyte balance may lead to hepatic coma.

Metabolic and endocrine effects: Thiazide therapy may alter glucose tolerance. Dose adjustment of antidiabetic drugs, including insulin, may be necessary.

Thiazides can reduce plasma sodium, magnesium, and potassium levels.

Elevations in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, minimal or no effect has been reported at low doses (12.5 mg).

Thiazides may reduce urinary calcium excretion and cause occasional slight increases in plasma calcium levels.

Marked hypercalcemia may be a manifestation of latent hyperparathyroidism. Thiazides should be discontinued before thyroid function tests are performed.

Thiazide therapy may cause hyperuricemia and/or exacerbation of gout in some patients. However, enalapril may increase urinary uric acid levels and thus may attenuate the hyperuricemic effect of hydrochlorothiazide.

Despite the lack of data from controlled clinical studies in patients taking Enap H, Enap HL, Enap 20 HL, as well as in patients taking diuretics, plasma electrolyte levels should be regularly monitored at certain intervals.

Thiazides (including hydrochlorothiazide) may cause fluid and electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Dangerous signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargic sleep, drowsiness, fatigue, muscle pain or cramps, muscle weakness, hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting).

Although hypokalemia may occur during thiazide diuretic therapy, concomitant therapy with enalapril may reduce diuretic-induced hypokalemia. The risk of hypokalemia may be increased in patients with cirrhosis of the liver, increased diuresis, inadequate electrolyte intake, and in those receiving concomitant corticosteroid or ACTH therapy.

In hot weather, hyponatremia may occur in patients prone to edema. Chloride deficiency is usually mild and does not require treatment.

Thiazides increase urinary magnesium excretion, which may lead to hypomagnesemia.

The drug may affect the results of the following laboratory tests:

• the drug may reduce the level of protein-bound iodine in blood plasma;
• Treatment should be discontinued before laboratory testing to assess parathyroid function.
• the drug is able to increase the concentration of free bilirubin in the blood serum;
• hydrochlorothiazide, which can give a positive result in an anti-doping test.

Hypersensitivity: Patients with a predisposition to allergies or a history of bronchial asthma may experience hypersensitivity reactions to hydrochlorothiazide.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Special warnings regarding inactive ingredients. The drug contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.

Pregnancy and breast-feeding. ACE inhibitors are contraindicated in pregnant women and women planning to become pregnant (see Adverse Reactions).

Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if possible, alternative therapy should be started.

Epidemiological findings regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy are mixed; however, some increase in risk cannot be excluded. It is known that the use of ACE inhibitors during the second and third trimesters of pregnancy can cause fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

When prescribing the drug, the patient must be informed about the potential harm to the fetus.

If ACE inhibitors are used during pregnancy, periodic ultrasound examinations should be performed to assess the intraamniotic space. However, the physician and patient should be aware that oligoamnios may develop after irreversible fetal damage has occurred.

When using ACE inhibitors in the second trimester of pregnancy, it is recommended to perform an ultrasound of the kidneys and skull of the embryo.

Neonates whose mothers have taken ACE inhibitors should be carefully observed for hypotension, oliguria, and hyperkalemia. Enalapril crosses the placenta but can be partially removed from the neonate by peritoneal dialysis; theoretically, it can be removed by exchange transfusion, although there is no experience with the latter procedure.

Hydrochlorothiazide. Experience with hydrochlorothiazide during pregnancy, especially in the first trimester, is limited. Animal studies are insufficient. Hydrochlorothiazide crosses the placental barrier. When used in the II and III trimesters of pregnancy, hydrochlorothiazide may impair fetoplacental circulation and cause jaundice in the fetus or newborn, electrolyte imbalance and thrombocytopenia.

Hydrochlorothiazide should not be used to treat edema, hypertension, or preeclampsia in pregnant women, because instead of having a beneficial effect on the course of the disease, it increases the risk of decreased blood plasma volume and impairs placental blood supply.

Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women.

Hydrochlorothiazide should not be used during pregnancy.

Breastfeeding

Enalapril. Limited pharmacokinetic data indicate very low concentrations in breast milk (see Pharmacokinetics). Although these concentrations are considered clinically insignificant, the use of Enap-N or Enap-NL is not recommended during breastfeeding because of the hypothetical risk of cardiovascular and renal effects and because of insufficient experience with such use.

Hydrochlorothiazide. Hydrochlorothiazide passes into breast milk; its use during breastfeeding is contraindicated. If its use is absolutely necessary, breastfeeding should be discontinued.

Children: The safety and efficacy of the drug in children have not been established.

Ability to influence the reaction rate when driving or operating other mechanisms. When driving or operating other mechanisms, the possibility of side effects from the nervous system, such as dizziness or drowsiness, should be taken into account.

Enalapril maleate and hydrochlorothiazide

Other antihypertensive drugs. Concomitant use of β-adrenergic blockers, methyldopa, calcium channel blockers may increase the hypotensive effect of the drug. Concomitant use of nitroglycerin and other nitrates or vasodilators may further reduce blood pressure.

Ganglio- or beta-blockers, when used concomitantly with enalapril, should only be administered under close supervision of the patient.

Lithium. Concomitant use of lithium and ACE inhibitors has been shown to reversibly increase plasma lithium concentrations and toxicity. Concomitant use with thiazide diuretics may further increase lithium levels and the risk of ACE inhibitor-induced lithium toxicity. Co-administration with lithium is not recommended, but careful monitoring of plasma lithium concentrations is recommended if co-administration is warranted.

NSAIDs, including selective COX-2 inhibitors, may reduce the effect of diuretics and other antihypertensive agents. Thus, the antihypertensive effect of angiotensin II antagonists, ACE inhibitors and diuretics may be reduced.

Concomitant use of NSAIDs, including selective inhibitors, and angiotensin II antagonists or ACE inhibitors has been associated with additional increases in plasma potassium levels and possible deterioration of renal function. These effects are usually reversible.

Rarely, acute renal failure may occur, especially in patients with impaired renal function. Such effects are usually reversible. Therefore, the drug should be used with caution in patients with impaired renal function. Patients should drink sufficient fluids and be closely monitored for renal function at the beginning of concomitant therapy and periodically during such treatment.

enalapril

Potassium-sparing diuretics and potassium supplements. ACE inhibitors reduce potassium excretion. Potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salts may lead to significant increases in plasma potassium levels. If concomitant use is necessary for established hypokalaemia, they should be used with caution and regular monitoring of plasma potassium levels should be performed (see Precautions).

Diuretics (thiazide or loop diuretics). Previous treatment with high doses of diuretics may lead to a decrease in BCC and the risk of developing arterial hypotension at the beginning of therapy with enalapril (see Features of use). The hypotensive effect can be reduced by discontinuing the diuretic, increasing BCC or salt intake, or starting treatment with low doses of the drug.

Tricyclic antidepressants/antipsychotics/narcotics: Concomitant use of anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may result in further reduction in blood pressure.

Gold preparations: Isolated reactions similar to those to nitrites (symptoms of vasodilation, including flushing, facial edema, dizziness, nausea, vomiting, and hypotension) have been reported in patients receiving injectable gold preparations (sodium aurothiomalate) in combination with an ACE inhibitor, including enalapril.

Sympathomimetics: Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Alcohol: Alcohol potentiates the hypotensive effect of ACE inhibitors.

Antidiabetic agents: Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may lead to an increased hypoglycaemic effect with a risk of hypoglycaemia. This effect is most likely to occur during the first weeks of concomitant use and in patients with renal impairment.

Acetylsalicylic acid, thrombolytics, β-adrenergic blockers. Enalapril can be used with caution simultaneously with acetylsalicylic acid (when used as a thrombolytic agent), thrombolytics and β-adrenergic blockers.

Concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist. In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor antagonist has been reported to be associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of an angiotensin receptor antagonist alone. Dual blockade (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) should be limited to individual cases and accompanied by close monitoring of renal function, potassium, and blood pressure.

Hydrochlorothiazide: The following drugs may interact with thiazide diuretics when used concomitantly.

Non-depolarizing muscle relaxants: Thiazides may enhance the effect of tubocurarine.

Alcohol, barbiturates, narcotic analgesics: Potentiation of orthostatic hypotension may occur.

Antidiabetic agents (oral antidiabetic agents and insulin). Glucose tolerance may be impaired during thiazide therapy. Dose adjustment may be required. Metformin should be used with caution due to the risk of lactic acidosis due to possible renal failure associated with hydrochlorothiazide.

Cholestyramine and colestipol resins. Anion exchange resins may reduce the absorption of hydrochlorothiazide. Single administration of cholestyramine or colestipol resins reduces the absorption of hydrochlorothiazide from the gastrointestinal tract by 85 and 43%, respectively.

QT prolongation (e.g. procainamide, amiodarone, sotalol). Increased risk of torsades de pointes.

Cardiac glycosides: Hypokalemia may increase the sensitivity or clinical response of the heart to digitalis toxicity (e.g., increased ventricular excitability).

Amphotericin B, corticosteroids, ACTH, laxatives or glycyrrhizin. Hydrochlorothiazide may exacerbate electrolyte imbalances, particularly hypokalemia.

Potassium-sparing diuretics (e.g. furosemide), carbenoxolone or laxative abuse. Hydrochlorothiazide may cause increased excretion of potassium and/or magnesium.

Pressor amines (e.g. adrenaline): Thiazides may reduce the response to vasopressor amines, but not enough to preclude concomitant use.

Cytotoxic drugs (e.g. cyclophosphamide, methotrexate). Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic drugs and enhance their myelosuppressive effects.

Prostaglandin synthetase inhibitors. In some patients, their use may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.

Medicines used to treat gout (probenecid, sulfinpyrazone and allopurinol). Dose adjustment of medicines that promote the excretion of uric acid may be necessary, as hydrochlorothiazide may increase serum uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased. Concomitant use of thiazides may increase the incidence of hypersensitivity to allopurinol.

Salicylates. When taking high doses of salicylates, hydrochlorothiazide may enhance their toxic effect on the central nervous system.

Methyldopa: There have been isolated reports of hemolytic anemia with the concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine. Concomitant use of cyclosporine may exacerbate hyperuricemia and increase the risk of complications such as gout.

Anticholinergics (e.g. atropine, biperiden) increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Alcohol (ethanol), barbiturates, narcotics or antidepressants. May lead to increased orthostatic hypotension.

Other antihypertensive agents. Additive effect.

Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may precipitate digitalis glycoside-induced cardiac arrhythmias.

Medicinal products affected by changes in serum potassium. Periodic monitoring of plasma potassium and ECG is recommended when losartan/hydrochlorothiazide is administered concomitantly with medicinal products affected by changes in serum potassium (e.g. digitalis glycosides and antiarrhythmics) and with the following medicinal products (including antiarrhythmics) that induce torsades de pointes, hypokalaemia being a predisposing factor for torsades de pointes (ventricular tachycardia):

• Class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide);
• some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, triflupyrazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• other drugs (e.g. bepridil, cisapride, diphemanil, erythromycin for intravenous administration, halofantrine, mizolastine, pentamidine, terfenadine, vincomycin for intravenous administration).

Calcium salts. Thiazides may increase the calcium content in the blood plasma due to a decrease in its excretion. If it is necessary to prescribe calcium preparations, the dose should be selected under the control of the calcium content in the blood plasma.

Laboratory Test Effects: Due to their effects on calcium metabolism, thiazides may interfere with parathyroid function tests (see Precautions).

Carbamazepine: Due to the risk of symptomatic hyponatremia, clinical and biological monitoring is necessary.

Iodinated contrast media: Diuretic-induced dehydration increases the risk of acute renal failure, especially with high doses of contrast media. Patients should be rehydrated prior to administration of iodinated contrast media.

NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid 3 g/day and non-selective NSAIDs. When used concomitantly, NSAIDs may reduce the antihypertensive effect of hydrochlorothiazide and increase the effect of hydrochlorothiazide on serum potassium levels.

Beta-blockers and diazoxide: Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazides, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.

Amantadine: Thiazides, including hydrochlorothiazide, may increase the risk of side effects of amantadine.

Treatment is symptomatic and supportive. The drug should be discontinued and the patient carefully monitored. Suggested measures include: induction of vomiting if the drug has been ingested recently, and correction of dehydration, electrolyte imbalance, and hypotension by standard measures.

Enalapril maleate. The main manifestation of overdose is pronounced hypotension, which occurs within 6 hours after taking the drug and is accompanied by blockade of the renin-angiotensin system and stupor. Symptoms associated with overdose with ACE inhibitors may include circulatory shock, electrolyte imbalance, hyperventilation, tachycardia, palpitations, dizziness, anxiety and cough. Plasma levels of enalapril, which are 100 and 200 times higher than the maximum levels achieved with therapeutic doses, have been reported after taking 300 mg and 440 mg of enalaprilat, respectively. If hypotension occurs, the need for angiotensin II infusions and / or administration of catecholamines may be considered.

The recommended treatment for overdose is the administration of 0.9% sodium chloride solution. Enalapril can be removed from the systemic circulation by hemodialysis.

For bradycardia that is resistant to therapeutic agents, pacemaker therapy is indicated.

Hydrochlorothiazide. Common signs and symptoms include hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis. If digitalis is also used, hypokalemia may exacerbate cardiac arrhythmias. Overdose may also include tachycardia, hypotension, shock, weakness, confusion, dizziness, muscle spasms, paresthesias, exhaustion, impaired consciousness, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, increased blood urea nitrogen (mainly renal failure).

Vital signs, electrolyte concentrations, and serum creatinine levels should be monitored continuously.

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