Treatment of hypertension. A combined preparation is indicated in patients whose blood pressure is not adequately controlled with either ramipril or hydrochlorothiazide alone.
Composition:
1 tabl contains 2.5 mg ramipril and 12.5 mg hydrochlorothiazide (HL) or 5 mg ramipril and 25 mg hydrochlorothiazide (HD); tablets contain lactose.
Action:
Antihypertensive preparation - combination of an ACE inhibitor (ramipril) with a diuretic (hydrochlorothiazide). Ramipril is converted into the active metabolite, ramipril, a long-acting ACE inhibitor (an enzyme that catalyzes the conversion of angiotensin I to angiotensin II, as well as the breakdown of bradykinin). Reduction of angiotensin II production and inhibition of bradykinin degradation leads to vasodilatation. It also reduces the secretion of aldosterone. In hypertensive patients it causes lowering of blood pressure in supine and standing position without compensatory increase of cardiac function. The onset of antihypertensive effect occurs within 1-2 h after drug administration, maximum effect is observed after 3-6 h, and the effect of one drug dose is usually maintained for 24 h. After oral administration, ramipril is rapidly absorbed (food does not affect absorption) , reaching Cmax within 1 h. The bioavailability of the active metabolite ramiprilat is 45%. Cmax ramiprilat reaches within 2-4 h after ramipril administration. Ramipril is approximately 73% bound to plasma proteins, ramipril is approximately 56% bound. Ramipril is almost completely metabolised to ramiprilat and further to other derivatives. Metabolites are mainly excreted by the kidneys. After repeated doses of ramipril taken once a day, effective T0,5 ramiprilat is 13-17 h for doses of 5-10 mg, it is longer for smaller doses of 1.25-2.5 mg. Hydrochlorothiazide is a thiazide diuretic. The antihypertensive effect is probably based on the change in the sodium economy, the decrease in the volume of intercellular fluid and the volume of plasma, the reduction of blood flow resistance through the renal vessels and the reduction of the receptivity to norepinephrine and angiotensin II. The onset of antihypertensive activity starts after 3-4 hours and may last up to 7 days after the end of treatment. Hydrochlorothiazide in about 70% is absorbed from the gastrointestinal tract, reaching Cmax within 1.5-5 h. It binds to plasma proteins in 40-70%. It is subject to minimal, insignificant hepatic metabolism. It is excreted in> 95% in unchanged form by the kidneys. T0,5 in the elimination phase, it is 5-6 hours.
Contraindications:
Hypersensitivity to ramipril, other ACE inhibitors, hydrochlorothiazide or other thiazide diuretics, sulfonamides or other ingredients of the preparation. History of angioneurotic edema (hereditary, idiopathic, caused by prior use of ACE inhibitors or angiotensin II receptor antagonists). Extracorporeal therapeutic procedures leading to blood contact with surfaces with negative electric charge. Significant bilateral renal artery stenosis or artery stenosis of the only active kidney. Severe renal dysfunction with creatinine clearance (CCr) <30 ml / min in patients not on dialysis. Clinically significant electrolyte disturbances that may worsen after treatment with the preparation. Severe hepatic dysfunction, hepatic encephalopathy. Co-administration with aliskiren in patients with diabetes or renal impairment (GFR <60 ml / min / 1.73 m2). II and III trimester of pregnancy. Breastfeeding period.
Precautions:
Use with caution in patients with increased activation of the renin-angiotensin-aldosterone system (RAA) due to the risk of significant decreases in blood pressure and impaired renal function (medical monitoring is necessary, including monitoring of blood pressure, especially during the initial phase of treatment or after drug dose) - this applies to patients: with severe hypertension; with decompensated congestive heart failure; hemodynamically significant impairment of inflow or outflow from the left ventricle (eg aortic or mitral valve stenosis); with unilateral renal artery stenosis with a second active kidney; with existing or possibly occurring fluid and electrolyte imbalances (including patients taking diuretics); with cirrhosis and / or ascites; undergoing major surgery or anesthetized agents that may cause hypotension (it is recommended to discontinue treatment with an ACE inhibitor one day before surgery).Electrolyte deficiency and / or hypovolaemia should be corrected before initiating therapy, however, in patients with heart failure, consideration should be given to the benefits of fluid delivery in relation to the risk of volume overload. In patients at risk of ischemic heart or brain in the case of acute hypotension, the initial phase of treatment requires special medical supervision. The combination of ramipril with hydrochlorothiazide is not the treatment of choice in primary hyperaldosteronism, but if combined treatment is used, the patient requires careful monitoring of potassium levels in the blood. Before and during treatment, renal function should be evaluated by correcting the dosage based on the results obtained, especially in the first weeks of therapy; Patients with impaired renal function require particularly careful monitoring. The risk of renal dysfunction is particularly high in patients with congestive heart failure, kidney transplantation or renal artery disease, including patients with haemodynamically significant unilateral renal artery stenosis. In the case of progressive renal dysfunction, manifested by an increasing concentration of non-protein nitrogen, a thorough re-evaluation of treatment is necessary, with consideration of discontinuation of diuretics. Due to the risk of hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure), dual RAA blocking is not recommended (eg, through the combined use of an ACE inhibitor with an angiotensin II receptor antagonist or aliskiren); if the use of a dual RAA blockade is absolutely necessary, it should only be carried out under the supervision of a specialist, including monitoring of vital signs of the patient (renal function, electrolyte concentration and blood pressure). At the same time, ACE inhibitors and angiotensin II receptor antagonists should not be used in patients with diabetic nephropathy. The number of leukocytes should be monitored to detect possible leukopenia; more frequent controls are recommended in the initial phase of treatment and in patients with impaired renal function, patients with concomitant collagenosis (eg lupus erythematosus or scleroderma) and patients who are taking other medicines that can change the blood picture. Due to the risk of anaphylactic and anaphylactoid reactions occurring and intensifying on insect venom and other allergens, a temporary discontinuation of the ACE inhibitor against desensitization should be considered. The preparation should be discontinued in case of angioedema and ad hoc treatment should be started in a hospital setting. In differential diagnosis of abdominal pain, angioedema of the intestines should be considered. Angioedema caused by ACE inhibitors is more common in the black patients. ACE inhibitors may be less effective in lowering blood pressure in black patients. In the differential diagnosis of cough, cough induced by ACE inhibitors should be considered. In patients with liver disease, electrolyte disturbances resulting from hydrochlorothiazide may cause hepatic encephalopathy; in case of hepatic encephalopathy, treatment with diuretics should be stopped immediately. Regular monitoring of electrolytes in the blood should be performed during treatment with the product. The first measurement of potassium in the blood should be done within the first week of treatment. Although hypokalemia may occur with thiazide diuretics, concomitant ramipril therapy may reduce the hypokalemia induced by diuretics. Due to hydrochlorothiazide, the preparation should be used with caution in patients at risk of hypokalemia: cirrhosis, rapidly induced diuresis, insufficient supply of electrolytes and patients receiving concomitant corticosteroid therapy or receiving ACTH (hypokalemia detected needs to be corrected). Due to ramipril, caution should be exercised in patients at risk of hyperkalemia: with renal failure,> 70 years of age, with uncontrolled diabetes, taking potassium salts, potassium sparing diuretics and other substances that increase blood potassium, dehydrated, with acute heart failure or exacerbation chronic heart failure, metabolic acidosis. Hyponatraemia from dilution may occur. Initially, the reduction in sodium may be asymptomatic, therefore it is necessary to perform regular tests.Research should be performed more frequently in elderly patients and patients with liver cirrhosis. Caution for patients with diabetes mellitus, as thiazide therapy may impair Glucose tolerance - glucose monitoring should be monitored, or a dose adjustment of insulin or oral antidiabetic agents may be required. Hydrochlorothiazide may accelerate the onset of diabetes mellitus in patients with latent diabetes; may cause increased cholesterol and triglycerides in the blood; may cause hyperuricemia and trigger a gout attack; may cause or exacerbate the symptoms of systemic lupus erythematosus; may cause hypomagnesaemia; may cause hypercalcemia. Hydrochlorothiazide may cause specific reactions (usually resolving within hours or weeks of the start of treatment with the drug) leading to acute transient myopia and acute angle-closure glaucoma; since untreated acute angle-closure glaucoma may lead to permanent loss of vision, treatment is primarily based on the withdrawal of hydrochlorothiazide as soon as possible; if intraocular pressure can not be controlled, immediate surgical or surgical treatment should be considered (risk factors for developing acute angle-closure glare may include a history of sulfonamide or penicillin allergy). Hypersensitivity reactions to hydrochlorothiazide may occur in or with allergy or bronchial asthma, but are more likely in patients with history. Due to the lactose content, do not use the preparation in patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Pregnancy and lactation:
The use of the preparation in the first trimester of pregnancy is not recommended. Use in the second and third trimester of pregnancy is contraindicated. Ramipril used in the second and third trimester of pregnancy is toxic to fetal development (deterioration of renal function, oligohydramnios, delayed ossification of the skull) and newborn (renal failure, hypotension, hyperkalemia) - when exposure to the drug occurred from the second trimester of pregnancy, it is recommended an ultrasound examination of the fetus skull and kidneys; children whose mothers took the drug during pregnancy should be closely monitored for hypotension, oliguria and hyperkalemia. The use of hydrochlorothiazide in the second and third trimester may cause fetal-placental ischaemia and the risk of delayed fetal development; in addition, rare cases of hypoglycaemia and thrombocytopenia in newborns have been reported in the case of exposure around the labor period. Ramipril and hydrochlorothiazide are excreted in breast milk and can potentially cause serious side effects in the infant - the preparation is contraindicated during breast-feeding.
Side effects:
Common: insufficient control of diabetes, reduction of glucose tolerance, increase in blood Glucose, increase in uric acid in the blood, worsening of gout, increase in cholesterol and / or triglycerides, headache, dizziness, unproductive, irritant cough, bronchitis, fatigue, asthenia. Uncommon: decrease in the number of leukocytes, erythrocytes and hemoglobin, haemolytic anemia, thrombocytopenia, anorexia, depressed appetite, hypokalaemia, increased thirst, mood depression, apathy, anxiety, nervousness, sleep disturbances (including somnolence), paresthesia, tremor, imbalance , burning sensation, taste disturbance, lack of taste, blurred vision (including blurred vision), conjunctivitis, tinnitus, myocardial ischemia (including angina pectoris), tachycardia, arrhythmia, palpitations, peripheral edema, hypotension, orthostatic hypotension, fainting, sudden redness of the skin (especially the face), sinusitis, shortness of breath, nasal congestion, gastroenteritis, digestive disorders, stomach discomfort, indigestion, gastritis, nausea, constipation, gingivitis, renal dysfunction (including acute renal failure), increase urinary excretion, increased blood urea, increased blood creatinine, cholestatic or cytolytic hepatitis (very rarely fatal), increased liver enzymes and / or conjugated bilirubin, cholecystitis, angioneurotic edema (very rarely respiratory tract due to angioedema may result in death), psoriatic dermatitis, excessive sweating, rash (in particular maculopapular), pruritus, alopecia, muscle pain, transient impotence, chest pain, fever.Very rare: increase in potassium in the blood due to ramipril, vomiting, aphthous stomatitis, tongue inflammation, diarrhea, upper gastrointestinal pain, dry mouth. Not known: bone marrow failure, neutropenia (including agranulocytosis, pancytopenia, eosinophilia), hypovolaemia, anaphylactic or anaphylactoid blood count, increased antinuclear antibody titres, hyponatraemia, glycosuria, metabolic alkalosis, hypochloraemia, hypomagnesaemia, hypercalcemia, dehydration, confusion , restlessness, attention disorders, cerebral ischemia (including ischemic stroke and transient ischemic attack), psychomotor disorders, olfactory hallucinations, yellow vision, lachrymation reduction, angle-closure glaucoma, impaired hearing, myocardial infarction, thrombosis in case of significant dehydration, vasoconstriction, hypoperfusion, Raynaud's phenomenon, vasculitis, bronchospasm (including asthma exacerbation), allergic alveolitis, non-cardiac pulmonary edema, pancreatitis (extremely rarely fatal cases), increased and pancreatic enzyme activity, angioedema of the small intestine, salivary gland inflammation, worsening of existing proteinuria, interstitial nephritis, acute hepatic failure, cholestatic jaundice, hepatocyte damage, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, exfoliative dermatitis, hypersensitivity reactions to light, separation of the nail plate from the placenta, follicular or lichenoid rash or mucosal rash, urticaria, systemic lupus erythematosus, joint pain, muscle spasms, muscle weakness, musculoskeletal stiffness, tetany, depressed libido, gynecomastia.
Dosage:
Orally. Adults. Administration of a constant combination of ramipril and hydrochlorothiazide is usually recommended after selecting the dose of each component individually. Treatment should be started with the lowest available dose. If necessary, the dose can be gradually increased until the target blood pressure is reached. The maximum daily doses are 10 mg ramipril and 25 mg hydrochlorothiazide.Special groups of patients. Patients treated with diuretics: before discontinuation of the combination product in patients treated simultaneously with diuretics, withdrawal of the diuretic or reduction of its dose should be considered; if diuretics can not be discontinued, treatment should be started with the lowest possible dose of ramipril (1.25 mg per day) administered as a separate medicine; it is further recommended that the change to the initial daily dose of the combination drug should not exceed 2.5 mg ramipril and 12.5 mg hydrochlorothiazide.Patients with impaired renal function: CCr <30 ml / min - do not use; CCr 30-60 ml / min - use only the lowest doses of solid ramipril and hydrochlorothiazide after ramipril monotherapy (the maximum daily dose is 5 mg ramipril and 25 mg hydrochlorothiazide).Patients with impaired liver function: with severe disorders - do not use; with mild or moderate disturbances - the maximum daily doses are 2.5 mg ramipril and 12.5 mg hydrochlorothiazide.Elderly patients: use lower starting doses and a slower rate of increase.Children and youth: the drug is not recommended for use in patients <18 years of age due to insufficient data on safety and efficacy.Way of giving. The tablets can be taken with or without food, once a day at the same time, preferably in the morning. The tablets should not be crushed or chewed. The division line on the HL tablet only makes it easier to crush it, for easier swallowing, and not to divide it into equal doses. The HD tablet can be divided into equal doses.