Hartil-D, tablets 5 mg+25 mg 28 pcs.

Ramipril/hydrochlorothiazide tablets have antihypertensive and diuretic effects. Ramipril and hydrochlorothiazide are used alone or together in the treatment of high blood pressure (BP). The antihypertensive effects of both components complement each other, are almost additive, and the hypokalemic effect of hydrochlorothiazide is reduced by ramipril.
Ramipril

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme, kininase II). This enzyme catalyzes the conversion of angiotensin I by tissues into the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduction of angiotensin II and suppression of bradykinin breakdown leads to vasodilation.

Because angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in aldosterone release.
The use of ramipril leads to a marked decrease in peripheral vascular resistance. Usually there are no significant changes in renal blood flow rate and glomerular filtration.

The administration of ramipril tablets in patients with arterial hypertension reduces BP in standing and lying down without compensatory increase in heart rate (HR). In most patients, the antihypertensive effect appears 1-2 hours after a single dose. The degree of severity of the effect reaches its maximum 3-6 hours after administration. As a rule, the antihypertensive effect of a single dose lasts for 24 hours. During long-term treatment with ramipril maximum antihypertensive effect is usually achieved in 2-4 weeks. It has been shown that with long-term therapy the antihypertensive effect can be maintained for 2 years. Abrupt discontinuation of ramipril does not lead to a rapid and excessive increase in BP

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. It suppresses reabsorption of sodium and chlorine ions in the distal nephron. Increased renal excretion of these ions is accompanied by increased urine production (due to osmotic water binding). Excretion of potassium and magnesium ions is increased and uric acid is delayed. High doses lead to increased excretion of bicarbonate, and prolonged intake delays excretion of calcium ions. Possible mechanisms of antihypertensive action include: altering sodium balance, reducing extracellular fluid and plasma volume, altering renal vascular resistance, or reducing norepinephrine and angiotensin II responses.

The excretion of electrolytes and water begins approximately 2 hours after administration, the maximum effect is achieved in 3-6 hours and persists for 6-12 hours. Antihypertensive effect is achieved within 3-4 days of treatment and lasts for 1 week after completion of the drug. During long-term treatment, BP reduction is achieved using smaller doses than those required for the diuretic effect. Decrease of BP is accompanied by slight increase in glomerular filtration rate, renal vascular resistance and renin activity in blood plasma.

The administration of single high doses of hydrochlorothiazide leads to a decrease in plasma volume, glomerular filtration rate, renal blood flow and mean BP. With long-term administration of low doses, plasma volume remains reduced, while minute volume and glomerular filtration rate return to their baseline levels before the start of treatment. Mean BP and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with breast milk production.

Pharmacokinetics

Ramipril

Ramipril is rapidly absorbed after oral administration. Judging by the radioactivity determined in the urine after oral administration of labeled ramipril (excretion by the kidneys is only one of several routes), at least 56% of the drug is absorbed. Simultaneous intake of food has no effect on absorption.

Ramipril is a prodrug that undergoes metabolism on “first pass” through the liver, resulting in the formation (through hydrolysis, primarily in the liver) of the only active metabolite ramiprilate. In addition to conversion to the active metabolite ramiprilat, ramipril is conjugated to glucuronic acid and converted to the diketopiperazine ester of ramipril. Ramiprilat also undergoes conjugation with glucuronic acid and converts to diketopiperazine-ramiprilat (acid).

Ramipril activation/metabolism results in a bioavailability of approximately 20% after oral administration. After oral administration of 2.5-5 mg of ramipril, the bioavailability of ramipril is approximately 45% of the bioavailability reported after intravenous administration of the same doses of ramipril.

The plasma concentration of ramipril reaches its maximum value (C_max) within 1 hour after oral administration. C_max of ramiprilat in plasma is reached within 2-4 hours after oral ramipril administration. The elimination half-life (T1/2) of ramipril is approximately 1 hour. After intravenous administration, the volume of distribution of ramipril is approximately 90 L (1.2 L/kg) and of ramiprilat 500 L (6.7 L/kg). Binding to plasma proteins is approximately 73% and 56% for ramipril and ramiprilat, respectively. Experiments on lactating animals have shown that ramipril is excreted with breast milk.

The decrease in plasma concentration of ramiprilat has a multiphase pattern. The initial distribution and excretion phase is characterized by a T1/2 of approximately 3 hours. This is followed by an intermediate phase (T1/2 of approximately 15 hours) and a final phase during which plasma concentrations of ramiprilat are very low (T1/2 of 4-5 days). This final phase is due to the slow dissociation of ramiprilat from strong but saturated complexes with ACE. Despite the long elimination phase, the equilibrium concentration of ramipril is reached in approximately 4 days with daily administration of 2.5 mg or more of ramipril. The effective T1/2 (a parameter relevant to dose selection) is 13-17 hours after multiple doses.

After oral administration of 10 mg of labeled ramipril, about 40% of the radioactivity is excreted through the intestine and 60% by the kidneys. After intravenous administration of ramipril, approximately 50-60%) of the dose is detected in the urine (as ramipril and its metabolites); approximately 50% appears to be excreted bypassing the kidneys. After intravenous administration of ramiprilat about 70% of the substance and its metabolites are detected in the urine, from which it follows that about 30% of ramiprilat is excreted bypassing the kidneys. Within 24 hours after oral administration of 5 mg of ramipril in patients with catheter-derived bile excretion, equal amounts of ramipril and its metabolites were detected in the kidneys and bile. Approximately 80-90% of the metabolites excreted by the kidneys and bile were represented by ramiprilate and its further metabolized preparations. Glucuronide and the diketopiperazine derivative of ramipril accounted for approximately 10-20%, and unmetabrilized ramipril accounted for approximately 2% of total ramipril.

The pharmacokinetics of ramipril and ramiprilate in healthy volunteers are little dependent on age (no differences were found between young adults and persons aged 65 to 75 years). Renal excretion of ramiprilat is decreased in patients with impaired renal function. Renal clearance of ramiprilat is proportional to creatinine clearance (CK) and correlates with it. Because of this, plasma concentrations of ramiprilat are higher and excretion takes longer than in patients with normal renal function.

If ramipril is administered in high doses (10 mg), impaired liver function slows down the activation of ramipril (conversion to ramiprilate) and leads to an increase in its plasma concentration. Excretion of ramiprilat is delayed.
In adult patients with arterial hypertension and chronic heart failure there is no significant accumulation of ramipril and ramiprilat after oral administration of ramipril (5 mg once daily for 2 weeks).

Hydrochlorothiazide
Approximately 70%) of hydrochlorothiazide is absorbed after oral administration, and its bioavailability is also 70%. After oral administration, 12.5 mg of hydrochlorothiazide reaches maximum plasma concentration (70 ng/ml) within 1.5-4 hours; 25 mg of hydrochlorothiazide reaches maximum plasma concentration (142 ng/ml) after 2-5 hours; 50 mg of hydrochlorothiazide reaches maximum plasma concentration (260 ng/ml) after 2-4 hours. Approximately 40% of hydrochlorothiazide is bound to plasma proteins. Hydrochlorothiazide is excreted in small amounts with breast milk.

Almost completely (more than 95%)) is excreted by the kidneys unchanged. Within 24 hours after a single oral administration 50-70% is excreted).

Hydrochlorothiazide is determined in the urine as early as 60 minutes after ingestion. T1/2 of hydrochlorothiazide is within 5 to 15 hours.

In impaired renal function, excretion is reduced and T1/2 is increased. Renal clearance of hydrochlorothiazide shows a high correlation with CK. In patients with glomerular filtration rate less than 10 ml/min, only 10% of the dose taken is detected in the urine. According to recent studies, hydrochlorothiazide is partially excreted with bile. No significant changes in pharmacokinetics are observed in liver cirrhosis. Pharmacokinetics has not been studied in patients with heart failure.
Ramipril and hydrochlorothiazide

The simultaneous administration of ramipril and hydrochlorothiazide does not affect the bioavailability of either component. The fixed combination of 5 mg of ramipril and 25 mg of hydrochlorothiazide in the form of tablets of Hartil-D can be considered biologically equivalent to the combined administration of 5 mg of ramipril and 25 mg of hydrochlorothiazide.

Indications

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

Active ingredient

Composition

1 tablet contains:

acting ingredients:

5 mg ramipril and 25 mg hydrochlorothiazide.

Auxiliary substances:

Lactose monohydrate,

hypromellose,

crosspovidone,

microcrystalline cellulose,

sodium stearyl fumarate.

How to take, the dosage

Hartil-D should be taken once daily in the morning with plenty of fluid. The drug can be taken regardless of meals. The tablets are not intended to be divided into parts.

Adults:
Prescribing the combined drug Hartil-D is recommended only after individual selection of doses of each of the components. The dose may be increased at intervals of at least 3 weeks. The usual starting dose is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide. The usual maintenance dose is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide or 5 mg of ramipril and 25 mg of hydrochlorothiazide. The recommended maximum daily dose is 5 mg of ramipril and 25 mg of hydrochlorothiazide.

Elderly patients and patients with impaired renal function

In elderly patients and patients with a CK of 30 to 60 mL/min, individual doses of each component (ramipril and hydrochlorothiazide) should be carefully adjusted before switching to the combination drug Hartil-D.

The dose of Hartil-D should be as low as possible. The recommended maximum daily dose is 5 mg of ramipril and 25 mg of hydrochlorothiazide.

Hartil-D is contraindicated in patients with severe renal dysfunction, that is, when the CK is less than 30 mL/min/1.73 m2.
Impaired liver function

Patients with mild to moderate impaired liver function should adjust the dose of ramipril before switching to Hartil-D.
Patients with severe hepatic impairment and/or cholestasis should not take Hartil-D (see Contraindications).

Children and adolescents (under 18 years of age)

Hartil-D is not recommended for children and adolescents (under 18 years of age) due to lack of safety and efficacy data for this age group.

Interaction

The following are interactions of components of Hartil-D with other ACE inhibitors

AcE and drugs containing hydrochlorothiazide.

Ramipril

Diuretics

Prescribing a diuretic to a patient taking ramipril usually results in summation of the antihypertensive effect.
In patients who are already taking diuretics, especially those who are newly prescribed diuretics, the addition of ramipril may sometimes cause excessive BP reduction. The likelihood of symptoms of arterial hypotension under the influence of ramipril is reduced if the diuretic is stopped before starting ramipril treatment (see section Cautionary Instructions).

Tricyclic antidepressants/antipsychotics (neuroleptics)/anesthetics

The administration of some anesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors may increase arterial hypotension (see section Cautionary Instructions. See section Cautions).

Sympathomimetics

Sympathomimetics may weaken the hypotensive effect of ACE inhibitors, so patients need careful monitoring.
Hypoglycemic agents

Epidemiological studies have shown that concomitant use of ACE inhibitors and hypoglycemic agents (insulin and oral hypoglycemic agents) may potentiate the effects of the latter, up to and including hypoglycemia. The probability of such phenomena is especially high during the first weeks of combined treatment of patients, as well as in case of impaired renal function.
Thrombolytics and/or beta-adrenoblockers

Ramipril may be used together with thrombolytics and beta-adrenoblockers.

Other antihypertensive drugs

The simultaneous use of nitroglycerin and other organic nitrates or vasodilators may increase the hypotensive effect of ramipril.

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (3 g/day)

Ramipril can be used with acetylsalicylic acid (in small doses under medical supervision). Prolonged use of NSAIDs may weaken the hypotensive effect of ACE inhibitors. The effects of NSAIDs and ACE inhibitors on the increase in serum potassium levels are summarized, which may lead to impaired renal function. These effects are usually reversible. In rare cases, acute renal failure may be observed, especially with impaired renal function, such as in elderly or dehydrated patients.

Allopurinol

Concomitant treatment with an ACE inhibitor and allopurinol increases the risk of renal failure and may lead to an increased risk of leukopenia.

Cyclosporine

The concomitant use of ACE inhibitors and cyclosporine increases the risk of renal failure and hyperkalemia.

Lovastatin

Concomitant use of ACE inhibitors and lovastatin increases the risk of hyperkalemia.

Procainamide, cytostatics and immunosuppressants

The simultaneous use of these drugs with ACE inhibitors may increase the risk of leukopenia.

Hartil-D is not indicated in patients whose condition requires dialysis, because administration of ACE inhibitors against the background of dialysis using high current membranes is often accompanied by anaphylactoid reactions. This combination is not acceptable.

Hydrochlorothiazide
Amphotericin B (parenterally), carbenoxolone, corticosteroids, corticotropin (ACTH) or stimulant laxatives

br> Hydrochlorothiazide may cause electrolyte imbalances, especially hypokalemia.

Calcium salts
When these drugs are taken concomitantly with thiazide diuretics, decreased calcium ion excretion may increase serum calcium levels.

Heart glycosides
The risk of foxglove drug poisoning and thiazide hypokalemia is increased.

Cholestyramine resins and colestipol
These drugs may reduce or delay absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be taken at least one hour before or 4 to 6 hours after taking resin.

Nondepolarizing myorelaxants (i.e., tubocurarine chloride)
Hydrochlorothiazide may enhance the effects of these medications.

Drugs that cause pirouette tachycardia

The risk of hypokalemia necessitates caution when taking hydrochlorothiazide and drugs that cause pirouette tachycardia, such as some antipsychotics and other drugs, concurrently.

Sotalol
The risk of arrhythmia is increased with thiazide hypokalemia due to sotalol administration.

Ramipril/hydrochlorothiazide
Potassium-containing supplements, potassium-saving diuretics, or potassium-containing salt substitutes
Although serum potassium levels in clinical trials of ACE inhibitors have generally remained within normal limits, some patients have still developed hyperkalemia.

The risk of hyperkalemia has been associated with a number of factors, which include renal insufficiency, diabetes mellitus, and concurrent use of potassium-saving diuretics (such as spironolactone, triamterene or amiloride) as well as potassium-containing supplements or salt substitutes. Use of potassium-containing food supplements, potassium-saving diuretics or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels, especially in patients with impaired renal function.

When ramipril is taken against a background of potassium-containing diuretics, the hypokalemia caused by their administration may be attenuated.

Lithium

The simultaneous use of lithium and ACE inhibitors reversibly increases serum lithium levels and develops toxic effects. The use of thiazide diuretics may increase the risk of lithium intoxication and aggravate lithium intoxication if it is already caused by concomitant use of ACE inhibitors. Use of ramipril concomitantly with lithium is not recommended, but serum lithium levels should be closely monitored in those cases where such a combination is necessary.

Trimethoprim
The use of ACE inhibitors and thiazides concomitantly with trimethoprim increases the risk of hyperkalemia.

Peroral hypoglycemic agents (e.g., sulfourea derivatives and biguanidines such as metformin) and insulin
It is possible that hydrochlorothiazide weakens the hypoglycemic effect of these agents, while ramipril potentiates it.

Sodium chloride
Weakening of the antihypertensive effect of the fixed combination of ramipril and hydrochlorothiazide.

Treatment with high doses of salicylates (> 3 g/day)
Hydrochlorothiazide may increase the toxic effects of salicylates on the CNS.

Special Instructions

Ramipril

Symptoms of arterial hypotension

In patients with uncomplicated arterial hypertension, symptoms of arterial hypotension are rare. In patients with arterial hypertension taking ramipril, the likelihood of developing arterial hypotension increases with decreased circulating blood volume (e.g., as a result of diuretic treatment, restriction of salt intake with food, dialysis, diarrhea, or vomiting), and with severe forms of renin-dependent arterial hypertension.

Symptoms of arterial hypotension have been observed in patients with heart failure, regardless of whether it is combined with renal failure. This is most commonly seen in patients with more severe heart failure who are forced to take high doses of “loop” diuretics and who have hyponatremia or functional renal insufficiency. Patients at increased risk of arterial hypotension need close monitoring during the initial period of treatment and during dose adjustment.

This also applies to patients with coronary heart disease or cerebrovascular disease, in whom a significant drop in BP may lead to myocardial infarction or impaired cerebral circulation. In case of arterial hypotension, the patient should be placed on his back, legs elevated and, if necessary, an intravenous infusion of sodium chloride solution should be given. Transient hypotensive reaction is not a contraindication for subsequent administration of the drug. In some patients with heart failure who have normal or low BP, ramipril may cause an additional decrease in systolic BP. This effect is foreseeable, so it is usually not a reason to discontinue treatment. If arterial hypotension is symptomatic, it may be necessary to reduce the dose or discontinue treatment.

Aortic and mitral stenosis/hypertrophic cardiomyopathy

As with other ACE inhibitors, ramipril requires caution when administered to patients with aortic stenosis or left ventricular ejection difficulties (e.g., aortic stenosis or hypertrophic cardiomyopathy). In individual cases, the hemodynamic picture may make the fixed combination of ramipril and gidrochlothiazide unacceptable.
Primary aldosteronism (Conn’s disease)

The use of fixed combinations of ramipril and hydrochlorothiazide is contraindicated because patients with primary aldosteronism are not sensitive to antihypertensive agents whose action is based on inhibition of the renin-angiotensin system.

Renal dysfunction

In patients with heart failure at the beginning of treatment with ACE inhibitors, worsening of renal function may be observed. Cases of acute renal failure, usually transient, have been described in such situations.

In some patients with narrowing of both renal arteries or with arterial stenosis of the sole kidney, ACE inhibitors increase blood urea and serum creatinine levels; these changes usually resolve after discontinuation of the drugs. The likelihood of this is particularly high in renal insufficiency. In the presence of renovascular hypertension, the risk of severe arterial hypotension and renal failure is high. In such patients, treatment should be started under close medical supervision with low doses that should be precisely adjusted. Because diuretics may contribute to the clinical dynamics described above, they should be discontinued during the first weeks of treatment with ramipril and renal function should be monitored closely.

In some patients with arterial hypertension without obvious renal vascular disease, administration of ramipril, especially with diuretics, causes increase in blood urea and serum creatinine levels; these changes are usually minor and transient. The probability of their occurrence is higher in patients already suffering from renal dysfunction. In such cases it may be necessary to reduce the dose and/or discontinue diuretic and/or ramipril.

The condition after kidney transplantation
Due to the lack of experience in using ramipril in patients who have recently undergone a kidney transplantation, ramipril is not recommended for these patients.

Hypersensitivity/angioneurotic edema

Angioneurotic edema of the face, extremities, lips, tongue, vocal cords and/or larynx rarely develops in patients receiving ACE inhibitors, including ramipril. Angioneurotic edema may develop at any time during treatment. In this case, ramipril should be stopped immediately, appropriate treatment should be given and the patient should be observed and it should be ensured that all symptoms of edema are resolved before the patient is released. Even when oedema is limited to the tongue and no signs of respiratory distress are present, patients may require prolonged observation, as treatment with anhistamines and corticosteriods may not be sufficient. Rarely, death has been reported in patients due to angioedema of the larynx or tongue.

If swelling extends to the tongue, vocal cords, or larynx, airway obstruction is very likely, particularly in patients with previous respiratory surgery. In such cases, it is necessary to take emergency therapy (see section Overdose). This may include administration of epinephrine (adrenaline) and/or maintenance of airway patency. The patient should be under close medical supervision until the symptoms have completely and permanently disappeared.

Patients with a history of angioedema not associated with ACE inhibitor administration may be at increased risk of developing angioedema in response to ACE inhibitor administration.

Anaphylactoid reactions in patients treated with hemodialysis

There have been reports of anaphylactoid reactions in hemodialysis patients using high hydraulic permeability membranes (such as AN 69) when ACE inhibitors are used simultaneously. In such cases, another type of membrane or antihypertensive agents of another class should be considered.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

. In rare cases, patients taking an ACE inhibitor against low-density lipoprotein (LDL) apheresis with dextran sulfate develop life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily refraining from taking an ACE inhibitor before each apheresis procedure.

Desensitization

Patients taking ACE inhibitors against a background of desensitization therapy (e.g., by hymenopteran venom) develop long-term anaphylactoid reactions. If such patients refrained from taking ACE inhibitors during desensitization, no reactions were observed, but accidental ACE administration provoked an anaphylactoid reaction.

Hepatic failure

A rare syndrome has been associated with ACE inhibitor administration that begins with cholestatic jaundice or hepatitis and progresses to transient liver necrosis, sometimes fatal. The mechanism of this syndrome is not clear. If patients taking ramipril develop jaundice or significantly increased “hepatic” enzyme activity, the drug should be discontinued, leaving the patient under medical supervision until the symptoms disappear.

Neutropenia/agranulocytosis

It has been reported that neutropenia/agranulocytosis, thrombocytopenia and anemia may develop in patients taking ACE inhibitors. Neutropenia is rare in normal renal function and in the absence of complications. Neutropenia and agranulocytosis are reversible and disappear after discontinuation of ACE inhibitor. Extreme caution should be exercised when prescribing ramipril to patients suffering from connective tissue diseases with vascular manifestations, undergoing treatment with antidepressants, taking allopurinol or procainamide, as well as in combination of these factors, especially in the background of renal dysfunction. Some of these patients develop severe infections that do not always respond to intensive antibiotic therapy. If ramipril is used in the treatment of such patients, it is recommended that the white blood cell count be checked periodically, and patients should be warned to report any signs of infection.

Raciality

The ACE inhibitors are more likely to cause angioedema in patients of the Negro race compared to patients of other racial backgrounds.

Like other ACE inhibitors, ramipril may be less effective in lowering BP in black patients compared with those of other races, possibly due to the higher incidence of individuals with low renin levels in the black patient population with arterial hypertension.

Cough

It has been reported that the administration of ACE inhibitors may be accompanied by coughing. Characteristically, the cough is dry and persistent; it goes away after discontinuation of the drug. The fact that the cough is caused by taking an ACE inhibitor should be considered a differential diagnostic feature.

Surgery/general anesthesia

In patients undergoing surgery or general anesthesia with BP-lowering drugs, ramipril may block increased angiotensin II formation under the influence of compensatory renin release. If it is assumed that arterial hypotension develops by this mechanism, it may be corrected by increasing circulating blood volume.

Hyperkalemia

Some patients taking ACE inhibitors, including ramipril, have elevated serum potassium levels. The risk of hyperkalemia includes patients with renal insufficiency or diabetes who take potassium-saving diuretics or potassium-containing salt substitutes, as well as patients who take other drugs that increase serum potassium levels (e.g., heparin). If taking the above mentioned drugs during ACE inhibitor treatment is considered necessary, regular monitoring of serum potassium levels is recommended (see section Interactions).

Diabetic patients

In diabetic patients taking oral hypoglycemic agents or insulin, blood sugar levels should be monitored carefully during the first month of treatment with the ACE inhibitor (see section Interactions).

Lithium
It is generally not recommended to combine lithium and ramipril (see section Interaction).
Potassium-containing food supplements, potassium-saving diuretics or potassium-containing salt substitutes

While serum potassium levels in clinical trials of ACE inhibitors have generally remained within normal limits, some patients have still developed hyperkalemia. A number of factors have been associated with the risk of hyperkalemia, including renal insufficiency, diabetes mellitus, and concomitant use of potassium-saving diuretics (such as spironolactone, triamterene, or amiloride) and potassium-containing supplements or saline substitutes. Use of potassium-containing food supplements, potassium-saving diuretics or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels, especially in patients with impaired renal function.
When ramipril is taken against a background of potassium-containing diuretics, the hypokalemia caused by their administration may be attenuated.

Hydrochlorothiazide

Kidney function impairment
Thiazides may cause azotemia in patients with kidney disease. Taking the medication against a background of impaired renal function may lead to cumulative effects. If renal failure progresses, characterized by an increase in non-protein nitrogen, the need for therapy should be carefully evaluated and discontinuation of diuretics should be considered.

Hepatic impairment
Tiazides should be administered with caution in patients with impaired or progressive hepatic impairment because even minor fluctuations in water-electrolyte balance may cause hepatic coma.

Metabolic and endocrine effects
Tiazide therapy may decrease glucose tolerance. In diabetes mellitus, it may be necessary to adjust the dose of insulin or oral hypoglycemic agents.

Thiazide therapy may cause a manifestation of latent diabetes mellitus.
An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy. Some patients receiving thiazide diuretics may have increased uric acid levels or manifestations of gout.

Gout
In some patients, thiazide therapy may increase uric acid levels and/or cause gout. However, ramipril may increase uric acid excretion, thus attenuating the degree to which hydrochlorothiazide increases uric acid levels.

Water-electrolyte disturbances
Any patient treated with diuretics should have serum electrolyte levels determined periodically.

The thiazides, including hydrochlorothiazide, may cause abnormal water-electrolyte balance (hypokalemia, hyponatremia and hypochloremic alkalosis). Precursors of water or electrolyte imbalance include dry mouth, thirst, weakness, lethargy, sleepiness, restlessness, myalgia or muscle cramps, muscle fatigue, arterial hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.

While the use of thiazide diuretics may lead to hypokalemia, simultaneous administration of ramipril may reduce the severity of hypokalemia caused by diuretics. The probability of hypokalemia is highest in liver cirrhosis, in patients with increased diuresis, with inadequate oral administration of electrolytes, as well as during treatment with corticosteroids and ACTH. In hot weather, hyponatremia may develop in patients with peripheral edemas. Chloride deficiency is usually insignificant and does not require treatment. Thiazides may decrease urinary excretion of calcium ions, resulting in a slight intermittent increase in blood calcium levels even in the absence of overt calcium metabolism abnormalities. Apparent hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued until the results of a parathyroid function study are available. Thiazides have been shown to increase renal excretion of magnesium, which may result in lower blood magnesium levels.

Neutropenia/agranulocytosis
The fixed-dose combination of ramipril and hydrochlorothiazide should be discontinued if neutropenia (neutrophil count less than 1000/mm3) occurs or is suspected.

Antidoping tests
The hydrochlorothiazide in this medication may give a positive reaction in anti-doping controls.

Other
Regardless of a history of allergies or bronchial asthma, patients may develop hypersensitivity reactions. The possibility of exacerbation of the course of systemic lupus erythematosus has been reported.

Lactose intolerance
This drug contains lactose monohydrate.
It should not be prescribed to patients with rare hereditary galactose tolerance disorder, hereditary lactose deficiency or glucose-galactose malabsorption syndrome.

Impact on driving and operating machinery

Hartil-D has mild to moderate effect on the ability to drive and operate machinery. Due to differences in individual reactions, some patients may have impaired ability to drive, operate machinery, and perform other types of work requiring increased attention. This is especially pronounced at the beginning of treatment and/or after increasing the dosage.

Contraindications

With caution: Severe coronary and cerebral artery lesions (risk of reduced blood flow with excessive BP reduction), unstable angina pectoris, severe ventricular arrhythmias, chronic heart failure stage IV, decompensated “pulmonary heart”, conditions accompanied by decreased circulating blood volume (including diarrhea, vomiting), systemic connective tissue diseases, diabetes, suppression of bone marrow hematopoiesis, advanced age, aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis or artery stenosis of the single kidney, gout, hyperkalemia, hyponatremia (including against the background of diuretics and salt restricted diet), hypokalemia, hypercalcemia, coronary heart disease, renal and/or hepatic insufficiency, liver cirrhosis.

Side effects

A number of adverse reactions have been reported while taking ACE inhibitors, ramipril or hydrochlorothiazide.

A pronounced arterial hypotension was observed at the beginning of treatment and after increasing the dose. This effect is especially characteristic of some risk groups. Symptoms such as dizziness, general weakness, blurred vision, sometimes combined with loss of consciousness (fainting) may be observed. Individual cases of tachycardia, palpitations, arrhythmias, angina, myocardial infarction, severe arterial hypertension and shock, dynamic cerebral circulation disorders, cerebral hemorrhage and ischemic stroke have been observed while taking ACE inhibitors against the background of arterial hypotension. Frequency is defined as follows: frequently (>1/100, 1/1000, 1/10000, Blood and lymphatic system disorders: rare: decrease in hemoglobin concentration and hematocrit, leukopenia, thrombocytopenia, very rare: agranulocytosis, pancytopenia, eosinophilia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency

Metabolic and nutritional disorders: often: hypokalemia, elevated blood levels of uric acid, urea and creatinine, hyperglycemia, gout, infrequent: hyperkalemia, hyponatremia, hypomagnesemia, hyperchloremia, hypercalcemia, rarely: disorders of water-electrolyte balance (especially in patients with renal disease), hypochloremia, metabolic alkalosis, very rare: increased serum triglyceride levels, hypercholesterolemia, increased serum amylase, decompensation of diabetes.

Psychiatric disorders: infrequent: apathy, nervousness, rarely: anxiety, confusion, sleep disorders.

Nervous system disorders: frequently: dizziness, fatigue, headache, weakness, infrequent: drowsiness, rarely: anxiety, disorders of smell, balance disorders, paresthesias.

Visual disorders: infrequent: conjunctivitis, blepharitis, rarely: transient myopia, blurred vision.

Hearing organ disorders: rare: tinnitus.

Cardiovascular system disorders: pronounced BP decrease, infrequent: ankle edema, rare: syncope, thromboembolic complications, very rare: angina pectoris, myocardial infarction, arrhythmias, palpitations, tachycardia, dynamic impairment of cerebral circulation, cerebral hemorrhage, exacerbation of the course of Raynaud’s disease, vasculitis, vein disease, thrombosis, embolism.

Respiratory system disorders: dry cough, bronchitis, rarely: shortness of breath, sinusitis, rhinitis, pharyngitis, glossitis, bronchospasm, allergic interstitial pneumonia, very rare: Angioneurotic edema with fatal airway obstruction1), pulmonary edema due to hypersensitivity to hydrochlorothiazide

Digestive disorders: nausea, abdominal pain, vomiting, dyspepsia, infrequent: epigastric cramps, thirst, constipation, diarrhea, loss of appetite, rare: dry mouth, vomiting, taste disorders, inflammation of the mucous membranes of the mouth and tongue, sialadenitis, glossitis, very rare: bowel obstruction, (hemorrhagic) pancreatitis

Hepatic disorders: rare: increased activity of “liver” enzymes and/or bilirubin2), very rare: cholestatic jaundice2), hepatitis, cholecystitis (in the background of cholelithiasis), liver necrosis

Skin and subcutaneous fat disorders3): infrequent: photosensitization, skin itching, urticaria, rare: “flushes” of blood to the skin of the face, increased sweating, peripheral edema, very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriatic or pemphigoid type skin reactions, systemic lupus erythematosus, alopecia, psoriasis exacerbation, onycholysis.

Muscular and connective tissue disorders: rare: muscle spasm, myalgia, arthralgia, muscle weakness, arthritis, very rare: paralysis.

Urinary system disorders: infrequent: proteinuria, rare: worsening of renal function, increased residual nitrogen and serum creatinine, dehydration, very rare: (acute) renal failure, nephrotic syndrome, interstitial nephritis, oliguria

Reproductive organ and mammary gland disorders: infrequent: decreased libido, rare: impotence

General disorders: very rare: anaphylactic reactions, angioedema1).
1) Angioneurotic edema develops more often in persons with dark skin. In a small group of patients, the occurrence of angioedema of the face and oropharyngeal area is associated with the administration of ACE inhibitors.
2) In case of jaundice or increased liver enzyme activity, the patient should be taken under medical supervision.
3) If skin reactions are pronounced, immediate medical consultation is necessary.

It has been reported that taking this drug may result in a symptom complex represented by at least one of the following Fever, vasculitis, myalgia, arthralgia/arthritis, anti-nuclear antibody positivity, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitization (other skin manifestations are also possible).

Overdose

Symptoms

Depending on the degree of overdose the following symptoms may occur: urinary retention, electrolyte disturbances, marked BP decrease, impaired consciousness (including coma), seizures, paresis, arrhythmia, bradycardia, shock, renal failure and bowel obstruction (paralysis).

Treatment

The treatment of overdose or poisoning depends on the method and duration of the drug administration, as well as the type and severity of symptoms. In addition to general measures (prevention of absorption by gastric lavage and administration of activated charcoal, acceleration of passage through the intestine with sodium sulfate) monitoring and supportive (sometimes intensive) therapy are necessary. Ramipril can be completely eliminated from the body by dialysis (note Anaphylactoid reactions in patients on hemodialysis).

The first measure in severe BP decrease is restoration of fluid volume with saline solution. In the absence of an adequate response, intravenous catecholamines may be administered. Angiotensin II may be considered. In severe bradycardia an artificial pacemaker should be installed. Circulating blood volume, electrolyte levels, acid-base status, blood glucose levels, and diuresis should be monitored. In hypokalemia it is necessary to restore potassium level.

If angioedema is life-threatening and involves the tongue, vocal cleft and/or larynx, the following emergency measures are recommended:

Pregnancy use

Pregnancy

Hartil-D is not recommended during the first trimester of pregnancy. If pregnancy is planned or confirmed, switch to another therapy as soon as possible. There have been no controlled studies of ACE inhibitors in pregnancy.

Hartil-D is contraindicated during the second and third trimesters of pregnancy. Prolonged use during the second and third trimesters may cause signs of intoxication in the fetus (decreased renal function, oligohydramnios, delayed cranial ossification) and the newborn (neonatal renal failure, arterial hypotension, hyperkalemia).

Long-term administration of hydrochlorothiazide during the third trimester of pregnancy may cause fetal and placental ischemia and risk of growth retardation. Moreover, in some cases the intake shortly before delivery may cause hypoglycemia and thrombocytopenia in the newborn. Hydrochlorothiazide may decrease blood plasma volume and decrease uteroplacental blood flow.

Women who have taken Hartil-D during pregnancy (starting in the second trimester) should have an ultrasound scan to check the condition of the kidneys and skull of the fetus.

Lactation period

Hartil-D is contraindicated during breastfeeding. Both ramipril and hydrochlorothiazide are excreted in breast milk. Decreased and discontinued milk excretion has been associated with thiazide intake during breastfeeding.

High sensitivity reactions to drugs of sulfonamide group, hyperkalemia and nuclear jaundice may be observed. Because of the possibility of serious side effects in infants, it is necessary to consider stopping breastfeeding.

Similarities