Hartil-D, tablets 2.5mg+12, 5 mg 28 pcs.

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

Indications

Active ingredient

How to take, the dosage

Tablets 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 portions.

Hartil®-D is recommended for adults only after individual selection of doses of each component. 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.

In elderly patients and patients with a CK of 30 to 60 mL/min, the 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 function impairment (CK<30 ml/min/1.73 m2).

Before switching to Hartil®-D, patients with mild to moderate impairment of liver function should have the dose of ramipril adjusted.

Hartil®-D should not be used in patients with severe hepatic impairment and/or cholestasis.

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 and drugs containing hydrochlorothiazide.

Ramipril

When used concomitantly with diuretics, a summation of the antihypertensive effect is noted. In patients who are already taking diuretics, especially those who have recently been prescribed diuretics, the addition of ramipril may sometimes cause an excessive decrease in BP. The likelihood of arterial hypotension symptoms under the influence of ramipril is reduced if the diuretic is discontinued before starting ramipril treatment.

The administration of some anesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors may increase arterial hypotension.

Sympathomimetics may decrease the hypotensive effect of ACE inhibitors, so patients require close monitoring.

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. This likelihood is especially high during the first weeks of combined treatment of patients, as well as in case of impaired renal function.

Ramipril can be used while taking thrombolytics and beta-adrenoblockers.

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

Ramipril can be taken concomitantly with acetylsalicylic acid (at a dose of 3 g/day under medical supervision).

Long-term use of NSAIDs may weaken the hypotensive effect of ACE inhibitors. The effects of NSAIDs and ACE inhibitors on elevated 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.

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

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

The concomitant use of ACE inhibitors and lovastatin increases the risk of hyperkalemia.

Concomitant use of procainamide, cytostatics and immunosuppressants 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-intensity current membranes is often accompanied by anaphylactoid reactions. This combination is unacceptable.

Hydrochlorothiazide

In concomitant use with amphotericin B (parenteral), carbenoxolone, GCS, corticotropin (ACTH) or stimulant laxatives, hydrochlorothiazide may cause electrolyte imbalances, especially hypokalemia.

Concomitant use of calcium salts with thiazide diuretics may cause hypercalcemia (with reduced excretion of calcium ions).

The concomitant use of cardiac glycosides increases the risk of digitalis intoxication and hypokalemia.

Colestyramine resins and colestipol may reduce or delay absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be taken at least 1 h before or 4-6 h after taking these drugs.

Hydrochlorothiazide may increase the effect of nondepolarizing myorelaxants (tubocurarine chloride).

The simultaneous use of hydrochlorothiazide and drugs that cause pirouette-type tachycardia, such as some antipsychotics, increases the risk of hypokalemia.

Concomitant use with sotalol increases the risk of arrhythmia.

Ramipril/hydrochlorothiazide

While serum potassium levels in clinical studies 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, including renal insufficiency, diabetes mellitus, and concomitant use of potassium-saving diuretics (such as spironolactone, triamterene, or amiloride) as well as 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. While taking ramipril against the background of potassium-containing diuretics, hypokalemia caused by their intake may be attenuated.

Concomitant 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 when such a combination is necessary.

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

Hydrochlorothiazide may attenuate the hypoglycemic effect of oral hypoglycemic agents (e.g., sulfourea derivatives and biguanidines such as metformin) and insulin, whereas ramipril potentiates it.

When used concomitantly with sodium chloride, a weakening of the antihypertensive effect of the fixed combination of ramipril and hydrochlorothiazide has been noted.

Hydrochlorothiazide may increase the CNS toxic effects of salicylates used in high doses (>3 g/day).

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 BOD (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 with an increased risk of arterial hypotension need close monitoring during the initial treatment period and during dose selection. This also applies to patients with CHD or cerebrovascular disease in whom a significant drop in BP could 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 IV 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

Like other ACE inhibitors, ramipril should be prescribed with caution in 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 hydrochlorothiazide 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 that are 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. 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 elevations in blood urea and serum creatinine; these changes are usually subtle and transient. The likelihood of their occurrence is higher in patients already suffering from renal dysfunction. In such cases, it may be necessary to decrease the dose and/or discontinue the diuretic and/or ramipril.

The condition after kidney transplantation

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

Ensensitivity/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; before releasing the patient, it should be ensured that all symptoms of edema are eliminated. Even when oedema is limited to the tongue and no signs of respiratory distress are present, patients may require prolonged observation, as treatment with antihistamines and GCS may not be sufficient. Rarely, death has been reported in patients with angioedema of the larynx or tongue.

If swelling extends to the tongue, vocal cords, or larynx, airway obstruction is very likely, particularly in patients who have had previous respiratory surgery. In such cases, emergency treatment (epinephrine and/or airway management) should be initiated. The patient should be under close medical supervision until symptoms have completely and permanently disappeared.

In patients with a history of angioedema not associated with ACE inhibitor administration, there may be an increased risk of developing angioedema in response to ACE inhibitor administration.

Anaphylactoid reactions in patients on hemodialysis

There have been reports of anaphylactoid reactions in patients on hemodialysis using high hydraulic permeability membranes (e.g., AN69) when concomitant use of ACE inhibitors. In such cases, another type of membrane or another class of antihypertensive agents should be considered.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions develop in patients taking an ACE inhibitor during LDL apheresis with dextran sulfate. Such reactions can be avoided by temporarily refraining from taking an ACE inhibitor before each apheresis procedure.

Desensitization

Patients taking ACE inhibitors with desensitizing therapy (e.g., 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 hepatic necrosis, sometimes fatal. The mechanism of this syndrome is not clear. If patients taking ramipril develop jaundice or have significantly increased hepatic enzyme activity, the drug should be withdrawn, leaving the patient under medical supervision until the symptoms disappear.

Neutropenia/agranulocytosis

It has been reported that neutropenia/agranulocytosis, thrombocytopenia and anemia may occur 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 these patients, it is recommended that the white blood cell count be checked periodically, and patients should be warned to report any signs of infection.

Racial identity

Area 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 to 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, passing after discontinuation of the drug. The fact that 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 the increase in angiotensin II formation under the influence of compensatory renin release. If arterial hypotension is assumed to develop by this mechanism, it may be corrected by increasing the BOD.

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 which increase serum potassium level (e.g., heparin). If taking the above mentioned drugs with ACE inhibitor treatment is considered necessary, regular monitoring of serum potassium level is recommended.

Diabetic patients

In diabetic patients taking oral hypoglycemic agents or insulin, blood glucose levels should be monitored closely during the first month of ACE inhibitor treatment.

Lithium

Combining lithium and ramipril is generally not recommended.

Hydrochlorothiazide

In patients with renal impairment, thiazides may cause azotemia. Taking the medication against a background of impaired renal function may lead to cumulative effects. If renal impairment 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

Patients with impaired or progressive liver function should be prescribed thiazides with caution because even minor fluctuations in water-electrolyte balance can cause hepatic coma.

Metabolic and endocrine effects

Tiazide therapy may decrease glucose tolerance. Diabetes mellitus may require adjusting the dose of insulin or oral hypoglycemic agents. Thiazide therapy may cause manifestation of latent diabetes mellitus. Thiazide diuretics therapy is associated with increased levels of cholesterol and triglycerides. Some patients on thiazide diuretics may have increased uric acid levels or manifestations of 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.

Perhaps water-electrolyte disturbances

Any patient treated with diuretics should have their serum electrolytes determined periodically.

The thiazides, including hydrochlorothiazide, can cause electrolyte and water imbalances (hypokalemia, hyponatremic alkalosis). Symptoms of water-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 likelihood of hypokalemia is highest in cirrhosis, in patients with increased diuresis, with inadequate oral administration of electrolytes, as well as during treatment with corticosteroids and ACTH.

In hot weather it is possible hyponatremia in patients with peripheral edemas. Chloride deficiency is usually mild and does not require treatment.

The 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/μL) occurs or is suspected.

Antidoping tests

The hydrochlorothiazide in this medication may react positively in anti-doping controls.

Other

Whether or not there is a history of allergies or bronchial asthma, patients may develop hypersensitivity reactions. It has been reported about the possibility of worsening the course of systemic lupus erythematosus.

The drug contains lactose monohydrate. It should not be prescribed to patients with rare hereditary galactose tolerance disorder, hereditary lactase 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

Side effects

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

A pronounced arterial hypotension has been 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 pectoris, myocardial infarction, severe arterial hypertension and shock, cerebral hemorrhage and ischemic stroke have been observed while taking ACE inhibitors with a background of arterial hypotension.

The incidence of side effects is defined as follows: frequently (>1/100, < 1/10), infrequently (>1/1000, < 1 /100), rarely (>1/10 000, < 1/1000), very rarely (< 1/10 000, including isolated cases).

Hematopoietic system: rarely – decreased concentration of hemoglobin and hematocrit, leukopenia, thrombocytopenia; very rarely – agranulocytosis, pancytopenia, eosinophilia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Laboratory findings: frequent – 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 kidney disease), hypochloremia, metabolic alkalosis; very rarely – increased serum triglyceride levels, hypercholesterolemia, increased serum amylase, decompensation of diabetes.

CNS disorders: frequently – dizziness, fatigue, headache, weakness; infrequently – apathy, nervousness, somnolence; rarely – anxiety, confusion, sleep disorders, restlessness, olfactory disorders, balance disorders, paresthesias.

An organ of vision: infrequent – conjunctivitis, blepharitis; rare – transient myopia, blurred vision.

Hearing organ: rare – tinnitus.

Cardiovascular system disorders: pronounced BP decrease; infrequent – ankle edema; rare – syncope, thromboembolic complications; very rare – angina, myocardial infarction, arrhythmias, palpitations, tachycardia, dynamic cerebral circulatory disorders, brain hemorrhage, worsening of Raynaud’s disease course, vasculitis, vein disease, thrombosis, embolism.

Respiratory system: dry cough, bronchitis; rarely – shortness of breath, sinusitis, rhinitis, pharyngitis, glossitis, bronchospasm, allergic interstitial pneumonia; very rarely – angioedema with fatal airway obstruction*, pulmonary edema due to hypersensitivity to hydrochlorothiazide.

Digestive system disorders: Nausea, abdominal pain, vomiting, dyspepsia; infrequent – epigastric spasms, thirst, constipation, diarrhea, loss of appetite; rare – dry mouth, vomiting, taste disorders, inflammation of mucous membranes of the mouth and tongue, sialadenitis, glossitis; very rare – bowel obstruction, hemorrhagic pancreatitis.

Hepatic disorders: rare – increased liver enzymes and/or bilirubin**; very rare – cholestatic jaundice**, hepatitis, cholecystitis (with gallstone disease), liver necrosis.

Dermatological reactions: infrequent – photosensitization, skin itching, urticaria; rare – flushes 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.

If skin reactions are severe, immediate medical consultation is necessary. It has been reported that this drug can produce a symptom complex of at least one of the following: fever, vasculitis, myalgia, arthralgia/arthritis, antinuclear antibody positive, elevated sedimentation rate, eosinophilia and leukocytosis, rash, photosensitization (other skin manifestations may also occur).

Muscular system disorders: rare – muscle spasm, myalgia, arthralgia, muscle weakness, arthritis; very rare – paralysis.

As to the urinary system: infrequent – proteinuria; rare – deterioration of renal function, increased residual nitrogen and serum creatinine, dehydration; very rare – acute renal failure, nephrotic syndrome, interstitial nephritis, oliguria.

With the sexual system: infrequent – decreased libido; rarely – impotence.

Allergic reactions: very rare – anaphylactic reactions, angioedema*.

* Angioneurotic edema develops more often in people of non-human race. In a small group of patients, the occurrence of angioedema of the face and oropharyngeal area is associated with the use of ACE inhibitors.

** If jaundice or increased liver enzyme activity occurs, the patient should be monitored.

Overdose

Symptoms: urinary retention, electrolyte level disorders, marked BP decrease, impaired consciousness (including coma), seizures, paresis, arrhythmia, bradycardia, shock, renal failure, bowel obstruction (paralysis).

Treatment: treatment in case of overdose or poisoning depends on the method and duration of taking the drug, 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.

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

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

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