Instructions for Hartil-H tablets 5 mg + 25 mg blister No. 28
Composition
active ingredients: ramipril, hydrochlorothiazide;
1 tablet contains 5 mg of ramipril and 25 mg of hydrochlorothiazide;
Excipients: lactose monohydrate, hypromellose, crospovidone, microcrystalline cellulose, sodium stearyl fumarate.
Dosage form
Pills.
Main physicochemical properties:
5 mg/25 mg tablets:
White oval tablets with a score on both sides, on one side of the tablet - engraving of the numbers "5" and "25" on both sides of the score.
Pharmacotherapeutic group
Combination drugs of angiotensin-converting enzyme (ACE) inhibitors.
ATX code C09B A05.
Pharmacological properties
Pharmacodynamics
The combination of ramipril/hydrochlorothiazide has antihypertensive and diuretic effects. The antihypertensive effects of both substances are additive, and the hypokalemic effect of hydrochlorothiazide is reduced by ramipril.
Ramipril
Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme, kininase II), which catalyzes the conversion of angiotensin I by tissues to the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. A decrease in the amount of angiotensin II and inhibition of the breakdown of bradykinin causes vasodilation.
Since angiotensin II also stimulates aldosterone release, ramiprilat leads to a decrease in aldosterone release. The increase in bradykinin activity contributes to the cardioprotective effects of ramipril and protects the endothelium.
The use of ramipril causes a marked decrease in peripheral arterial resistance. Usually, no significant changes in renal plasma flow rate and glomerular filtration rate are observed.
Ramipril lowers blood pressure without a compensatory increase in heart rate. The antihypertensive effect is achieved 1-2 hours after a single dose. The degree of severity of the effect reaches a maximum 3-6 hours after administration.
As a rule, the antihypertensive effect after a single administration lasts at least
24 hours. With long-term treatment with ramipril, the maximum antihypertensive effect is usually achieved after 2-4 weeks and can be maintained for 2 years. Abrupt discontinuation of ramipril does not cause a rapid and excessive increase in blood pressure.
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. It inhibits the reabsorption of sodium and chlorine in the distal tubules. Increased renal excretion of these ions is accompanied by increased diuresis (due to osmotic binding of water). Excretion of potassium and magnesium increases, and uric acid decreases. High doses cause increased excretion of bicarbonate, and long-term use also reduces excretion of calcium.
Possible mechanisms of antihypertensive action include: alteration of sodium balance, reduction of extracellular fluid and plasma volume, alteration of renal vascular resistance, or reduction of responses to norepinephrine and angiotensin II.
Excretion of electrolytes and water begins approximately 2 hours after administration, the maximum effect is achieved after 3-6 hours and lasts for 6-12 hours. The antihypertensive effect is achieved after 3-4 days of treatment and lasts for 1 week after the end of the drug.
With prolonged treatment, a decrease in blood pressure is achieved with the use of lower doses than necessary for the diuretic effect. The decrease in blood pressure is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance and plasma renin activity.
Thiazide diuretics may interfere with breast milk production.
Pharmacokinetics
Ramipril is rapidly absorbed from the gastrointestinal tract (at least 56% of the administered dose) and its maximum concentration in the blood plasma is reached within 1 hour. Ramipril is almost completely metabolized (mainly in the liver) with the formation of active and inactive products. Its active metabolite, ramiprilat, is approximately 6 times more active than ramipril. Its maximum concentration in the blood plasma is reached after 2-4 hours. Among the known inactive metabolites are diketopiperazine ester, diketopiperazine acid, as well as glucuronides of ramipril and ramiprilat. The binding of ramipril and ramiprilat to blood proteins is approximately 73% and 56%, respectively. Under conditions of use of usual doses (1 time per day), the equilibrium concentration of the drug in the blood plasma is reached on the 4th day of use of the drug. After administration, 60% of the dose is excreted in the urine (mainly as metabolites) and about 40% in the feces. Approximately 2% of the administered dose is excreted in the urine unchanged.
After oral administration, 70% of hydrochlorothiazide is absorbed in the duodenum and upper jejunum. Peak plasma concentrations are reached after 1.5–4 hours. It is approximately 40% bound to plasma proteins.
95% of hydrochlorothiazide is excreted by the kidneys. Elimination is the result of tubular excretion. The half-life is from 5 to 15 hours. Usually the therapeutic effect of hydrochlorothiazide is achieved 2 hours after administration, and the maximum - after 2-4 hours.
The effect of this combination usually lasts up to 24 hours. Optimal blood pressure reduction is observed after 3-4 weeks of treatment.
Indication
Essential hypertension in patients for whom combination therapy (ramipril and hydrochlorothiazide) is recommended.
Contraindication
Hypersensitivity to the active substance ramipril or to other ACE inhibitors (angiotensin-converting enzyme), hydrochlorothiazide, other thiazide diuretics, sulfonamides or to any of the excipients included in the composition of the drug (see section "Composition").
History of angioedema (hereditary, idiopathic or previously experienced while taking ACE inhibitors or angiotensin II receptor antagonists).
Arterial hypotension or hemodynamically unstable conditions.
Concomitant use of ACE inhibitors and extracorporeal treatments that result in contact of blood with negatively charged surfaces, as such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulphate (see section 4.5).
Significant bilateral renal artery stenosis or unilateral renal artery stenosis in the presence of a single functioning kidney.
Severe renal impairment (creatinine clearance <30 ml/min) in patients not undergoing hemodialysis.
Clinically significant electrolyte imbalances, the course of which may worsen during treatment with the drug (see section "Special instructions").
Treatment-resistant hypokalemia or hypercalcemia.
Refractory hyponatremia.
Symptomatic hyperuricemia (gout).
Anury.
Severe liver dysfunction, hepatic encephalopathy.
Concomitant use with aliskiren-containing products in patients with diabetes or in patients with moderate or severe renal impairment (creatinine clearance <1.0 ml/min)
< 60 ml/min).
Concomitant use with angiotensin-II receptor antagonists in patients with diabetic nephropathy.
Interaction with other medicinal products and other types of interactions
Food: Concomitant food intake has no significant effect on the absorption of ramipril.
Contraindicated combinations
Extracorporeal therapy methods that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis using dextran sulfate - due to the increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Concomitant use with aliskiren-containing products is contraindicated in patients with diabetes or moderate or severe renal impairment (creatinine clearance <60 ml/min) and is not recommended for use in all other patients.
Concomitant use with angiotensin-II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended for use in all other patients.
Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): hyperkalemia may occur, therefore careful monitoring of plasma potassium levels is necessary.
Antihypertensive drugs (e.g. diuretics) and other agents that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): increased risk of arterial hypotension is suspected.
Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril: blood pressure monitoring is recommended.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may alter blood cell counts: increased likelihood of hematological reactions.
Thiazide diuretics may increase the risk of severe hypersensitivity reactions associated with allopurinol therapy, mainly in patients with renal insufficiency.
Lithium salts: ACE inhibitors may reduce the excretion of lithium and therefore may increase its toxicity. Monitoring of lithium levels in the blood is recommended.
Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: a reduction in the antihypertensive effect of ramipril is suspected. Therefore, the combined use of ACE inhibitors and non-steroidal anti-inflammatory drugs may lead to an increased risk of deterioration of renal function and an increase in blood potassium levels.
Oral anticoagulants: hydrochlorothiazide reduces the anticoagulant effect. Corticosteroids, ACTH, amphotericin B, carbenoxolone, large amounts of licorice, laxatives (in case of prolonged use), and other potassium-sparing diuretics or low plasma potassium: increase the risk of hypokalemia. Electrolyte imbalance (e.g. hypokalemia, hypomagnesemia) increases the antiarrhythmic toxicity or reduces the antiarrhythmic effect of digitalis preparations, the active substances of which prolong the QT interval, and antiarrhythmic drugs.
Digitalis preparations, active substances that can increase the duration of the QT interval, antiarrhythmic agents. In the presence of electrolyte imbalance (e.g. hypokalemia, hypomagnesemia), proarrhythmic effects may be enhanced and antiarrhythmic effects may be attenuated.
Methyldopa: possible hemolysis.
Cholestyramine or other ion exchangers: impaired absorption of hydrochlorothiazide.
Sulfonamide diuretics should be taken 1 hour before or 4-6 hours after taking the drug.
Muscle relaxants (curare type): possible enhancement of the effect of muscle relaxants.
Calcium salts and drugs that increase blood calcium levels: an increase in serum calcium levels is to be expected when used concomitantly with hydrochlorothiazide, therefore monitoring is not necessary.
Carbamazepine: possible risk of hyponatremia due to additive effect with hydrochlorothiazide.
Contrast agents containing iodine: In case of dehydration induced by diuretics, including hydrochlorothiazide, there is an increased risk of developing renal failure, this is especially important when dosing contrast agents containing iodine.
Penicillin: hydrochlorothiazide is secreted in the distal tubules and reduces the excretion of penicillin.
Quinine: hydrochlorothiazide reduces the excretion of quinine.
Heparin: Possible increase in serum potassium concentrations.
mTOR inhibitors: An increased incidence of angioedema has been observed in patients receiving concomitant ACE inhibitors and mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus).
Vildagliptin: An increased incidence of angioedema has been observed in patients receiving concomitant ACE inhibitors and vildagliptin.
Periodic monitoring of serum potassium and ECG is recommended when hydrochlorothiazide is administered concomitantly with drugs whose effects are affected by changes in serum potassium (e.g. digitalis glycosides and antiarrhythmics) and the following drugs that induce torsades de pointes (including some antiarrhythmics), as hypokalaemia is a contributing factor to the development of torsades de pointes:
Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide) Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide); some neuroleptics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpiride, tiapride, pimozide, haloperidol, droperidol); other drugs (e.g. bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).
Salicylates
When using high doses of salicylates, hydrochlorothiazide may enhance their toxic effect on the central nervous system.
Cyclosporine
Concomitant use of cyclosporine may exacerbate hyperuricemia and increase the risk of complications such as gout.
Alcohol: Ramipril may lead to increased vasodilation and thus potentiate the effects of alcohol.
Alcohol, barbiturates, narcotics, or antidepressants. May increase orthostatic hypotension.
Salt. The antihypertensive effect of the drug may be weakened with increased salt intake in the diet.
Beta-blockers and diaxozide: Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diaxozide.
Amantadine
Thiazides, including hydrochlorothiazide, may increase the risk of side effects caused by amantadine.
Pressor amines (e.g. adrenaline): The effect of pressor amines may be reduced, but not to the extent that would preclude their use.
Anticholinergics (e.g. atropine, biperiden): Bioavailability of thiazide-type diuretics increases due to decreased gastrointestinal motility and decreased gastric emptying rate.
The effect of drugs on laboratory test results
Due to their effect on calcium metabolism, thiazides may interfere with the results of parathyroid function tests (see section 4.4).
Specific hyposensitization. ACE inhibition increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom. It is believed that this effect may also be observed for other allergens.
Application features
Special patient groups
Pregnancy: Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued ACE inhibitor/angiotensin II receptor antagonist therapy is considered essential, 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/angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Special precautions
Patients at possible risk of hypotension.
Patients with pronounced activity of the renin-angiotensin-aldosterone system.
In patients with a strongly activated renin-angiotensin-aldosterone system, there may be a sharp decrease in blood pressure and deterioration of renal function associated with the use of ACE inhibitors, especially when the ACE inhibitor or concomitant diuretic is prescribed for the first time, or when the dosage is increased.
Medical supervision and blood pressure control are necessary for the following patients with pronounced activity of the renin-angiotensin-aldosterone system:
patients with severe arterial hypertension; patients with decompensated congestive heart failure; with hemodynamically significant obstruction of the inflow and outflow of the left ventricle (for example, aortic or mitral valve stenosis); with unilateral renal artery stenosis of the second functioning kidney; in whom there is or may begin excessive excretion of fluid or sodium chloride (including patients taking diuretics) from the body; with cirrhosis of the liver and/or ascites; who have undergone major surgery, or during anesthesia with drugs that cause arterial hypotension.
It is recommended to correct dehydration, hypovolemia, or excessive sodium chloride excretion before starting treatment (however, in patients with heart failure, the possibility of such corrective measures should be carefully weighed against the risk of volume overload).
Surgery
If possible, treatment with ACE inhibitors such as ramipril should be discontinued 1 day before surgery.
Patients at risk of developing cardiac or cerebral ischemia with acute arterial hypotension.
The initial phase of treatment requires special medical supervision.
Primary hyperaldosteronism
The combination of ramipril and hydrochlorothiazide is not the drug of choice for the treatment of primary aldosteronism. If this combination is used to treat patients with primary aldosteronism, monitoring of plasma potassium levels is not necessary.
Elderly patients: See section "Method of administration and dosage".
Patients with liver disease
Electrolyte disturbances resulting from diuretic therapy, including hydrochlorothiazide, may lead to hepatic encephalopathy in patients with liver disease.
Monitoring kidney function
Renal function should be monitored before and during treatment and the dose adjusted accordingly, especially in the first weeks of treatment. Patients with impaired renal function (see section 4.2) require particularly careful monitoring. There is a risk of worsening renal function, especially in patients with congestive heart failure or after kidney transplantation.
Kidney failure
In patients with renal disease, thiazides may precipitate sudden uremia. In patients with impaired renal function, cumulative effects of the active substances may occur. If progressive renal dysfunction becomes evident, as indicated by an increase in residual nitrogen, the decision to continue treatment should be carefully weighed. Discontinuation of diuretic therapy should be considered (see section 4.3).
Although hypokalemia may develop with thiazide diuretics, concomitant use of ramipril may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with cirrhosis of the liver, in patients with increased diuresis, in patients receiving insufficient electrolytes, and in patients receiving concomitant treatment with corticosteroids and ACTH (see section "Interaction with other medicinal products and other forms of interaction"). Initial plasma potassium levels should be determined during the first week of treatment. If low potassium levels are detected, correction should be made.
Dilutional hyponatremia may occur. Low sodium levels may be asymptomatic at first, so regular testing is important. In elderly patients and patients with cirrhosis, such tests should be performed more frequently.
Thiazides have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia.
Hyperkalemia
Hyperkalemia has been observed in some patients taking ACE inhibitors, including Hartil®-H. Patients who may be at risk of developing hyperkalemia include the following patient groups: patients with renal insufficiency, elderly patients (> 70 years), patients with uncontrolled diabetes mellitus, patients using potassium salts, potassium-sparing diuretics and other agents that lead to an increase in serum potassium, increased levels of active substances or due to conditions such as dehydration, acute heart failure, metabolic acidosis. If concomitant use of the above conditions is appropriate, regular monitoring of serum potassium is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Hyponatremia
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resulting hyponatremia have been observed in patients receiving ramipril.
Hepatic encephalopathy
Electrolyte imbalance due to diuretic therapy, including hydrochlorothiazide, may lead to hepatic encephalopathy in patients with liver disease, symptoms of liver dysfunction, particularly in the first weeks or months. If hepatic encephalopathy occurs, treatment should be discontinued immediately.
Hypercalcemia
Hydrochlorothiazide stimulates renal calcium reabsorption and may lead to hypercalcemia. This may lead to changes in parathyroid function tests.
Angioedema
Angioedema has been reported in patients treated with ACE inhibitors, including ramipril (see section 4.8).
If angioedema occurs, treatment with Hartil®-H should be discontinued. Symptomatic treatment should be initiated as soon as possible. Patients should be observed for 12 to 24 hours.
Cases of intestinal angioedema have been reported in patients treated with ACE inhibitors such as Hartil®-H (see section 4.8). These patients complained of abdominal pain (with or without nausea/vomiting).
Anaphylactic reactions during sensitization
The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased by the use of ACE inhibitors. Treatment with Hartil®-H should be discontinued until desensitization occurs.
Neutropenia/agranulocytosis
Neutropenia/agranulocytosis has been observed rarely, bone marrow suppression has not been reported. It is recommended to monitor the level of white blood cells in the blood, leukopenia may occur. Monitoring is recommended at the beginning of treatment and in patients with impaired renal function, and especially in patients with collagen vascular disease (e.g. lupus erythematosus or scleroderma), as well as in patients taking drugs that cause changes in the blood picture.
Acute myopia and secondary acute angle-closure glaucoma
Hydrochlorothiazide is a sulfonamide drug. Sulfonamides and sulfonamide derivatives may cause idiosyncratic reactions resulting in transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours to weeks of starting the drug.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment for this condition is to discontinue the drug as soon as possible. Urgent medical or surgical attention may be required if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Ethnic differences
ACE inhibitors cause angioedema more often in black patients than in white patients.
As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients, possibly because of the higher prevalence of low-renin hypertension in black patients.
Athletes
Hydrochlorothiazide may give a positive result in a doping control test.
Thiazide diuretics may cause impaired glucose tolerance. Patients with diabetes mellitus may require adjustment of the dose of insulin or oral hypoglycemic agents. Latent diabetes mellitus may become active during treatment with thiazide diuretics.
Thiazide diuretics can also increase cholesterol and triglyceride levels.
Hyperuricemia or acute gout attacks may develop in some patients when using thiazide diuretics.
Cough
Cough may occur with ACE inhibitors. Typically, the cough is nonproductive, persistent, and resolves after discontinuation of therapy. The possibility of ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Others
Drug reactions may occur in patients with/or a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with aliskiren-containing medicinal products
Dual blockade of the renin-angiotensin-aldosterone system through the combined use of Hartil®-H and aliskiren is not recommended, as there is an increased risk of developing arterial hypotension, hyperkalemia and changes in renal function (including acute renal failure).
The combined use of Hartil®-H and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR 60 ml/min) (see section "Contraindications").
If dual blockade therapy is considered necessary, treatment should be carried out under close specialist supervision and renal function, electrolyte levels and blood pressure should be monitored.
ACE inhibitors and angiotensin II receptor blockers should not be used in patients with diabetic nephropathy.
Lactose intolerance
This medicine contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
It is not recommended to drink alcoholic beverages during treatment with the drug.
The drug should be prescribed with caution to patients with gout and diabetes, especially those who use insulin and oral antidiabetic agents.
Extracorporeal treatments that result in contact of the blood with negatively charged surfaces, such as dialysis or hemofiltration with certain membranes with high hydraulic permeability (e.g. polyacrylonitrile), and low-density lipoprotein apheresis with dextrin sulfate, due to an increased risk of severe anaphylactoid reactions. If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Ability to influence reaction speed when driving vehicles or other mechanisms
Some side effects (e.g. symptoms of low blood pressure such as dizziness) may impair the ability to concentrate and react, which may affect the speed of reaction when driving or using other machinery.
These side effects have been observed at the beginning of treatment or when switching from other drugs. After taking the first dose or when increasing the dose, it is not recommended to drive or operate other machinery for several hours.
Use during pregnancy or breastfeeding
Ramipril is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. Epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy have not been conclusive; however, a small increased risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, 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 alternative therapy should be started. ACE inhibitors are known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) when administered during the second trimester of pregnancy. If ACE inhibitors are used from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be carefully observed for hypotension, oliguria, and hyperkalemia.
preeclampsia, the use of the drug may lead to a decrease in plasma volume and placental hypoperfusion. Hydrochlorothiazide is contraindicated in hypertension in pregnant women, except in rare situations where the benefit outweighs the risk. Since there is insufficient information on the use of ramipril during breastfeeding, its use is not recommended and alternative treatments with a better established safety profile are preferable, especially in newborns or premature infants.
Breastfeeding. Hartil®-H is contraindicated during breast-feeding. The amount of ramipril and hydrochlorothiazide that penetrates into breast milk is such that when using therapeutic doses of ramipril and hydrochlorothiazide, the breast-fed infant may be exposed to them. Since there are no adequate data on the use of ramipril during breast-feeding, it is preferable to give preference to other drugs with better established safety profiles during breast-feeding, especially while breastfeeding newborns or premature infants. Hydrochlorothiazide penetrates into breast milk. The use of thiazides in nursing mothers has been accompanied by a decrease or even complete cessation of milk production. Hypersensitivity to sulfonamide derivatives, hypokalemia and kernicterus may occur. Because of the potential for serious adverse reactions in breast-fed infants from both active substances, a decision should be made whether to discontinue breast-feeding or to discontinue therapy, taking into account the importance of the therapy to the mother.
Method of administration and doses
For oral use.
It is recommended to take the drug once a day at the same time, preferably in the morning.
The drug can be taken before, during, and after meals, as food intake does not affect the bioavailability of the drug (see section "Pharmacokinetics"). The tablets should be swallowed whole with water. They should not be chewed or crushed.
Adults: The dose should be adjusted individually, depending on the patient's characteristics (see section "Special instructions") and blood pressure levels. The use of a fixed combination of ramipril and hydrochlorothiazide is generally recommended only after titration of the doses of each of its individual components.
Start treatment with the lowest possible dose. If necessary, the dose can be gradually increased until the target blood pressure is reached. The maximum daily dose is 10 mg ramipril and 25 mg hydrochlorothiazide per day, which corresponds to 2 tablets Hartil®-H 5 mg/12.5 mg.
Special patient groups
Patients receiving diuretics: Caution is advised as hypotension may occur in patients receiving diuretics at the start of treatment. The dose of the diuretic should be reduced or discontinued before treatment with the drug is initiated.
Patients with renal impairment. Due to the presence of the hydrochlorothiazide component, the drug is contraindicated in patients with severe renal insufficiency (creatinine clearance <30 ml/min (see section "Contraindications"). Lower doses of the drug may be indicated in patients with renal impairment. Patients with creatinine clearance 30-60 ml/min should be treated only with the lowest dose of the fixed combination of ramipril/hydrochlorothiazide after ramipril monotherapy. The maximum daily dose* is 5 mg ramipril and 25 mg hydrochlorothiazide.
Patients with hepatic impairment: In patients with mild to moderate hepatic impairment, treatment with the drug should be initiated
