Treatment of primary hypertension in adult patients who have not achieved optimal control of blood pressure during candesartan or hydrochlorothiazide monotherapy.
Antihypertensive preparation containing two antihypertensive agents with complementary mechanisms of action: angiotensin II receptor antagonist (candesartan) and thiazide diuretic (hydrochlorothiazide). Candesartan cilexetil is a pro-drug which, when absorbed from the gastrointestinal tract, is rapidly converted (by ester hydrolysis) to the active form - candesartan. Candesartan is an angiotensin II receptor antagonist that acts selectively on AT receptors1. It is characterized by strong binding to the receptor and slow unblocking of this connection. There is no agonist activity. It does not reduce ACE (ACE) enzyme activity, thanks to which it does not increase the effects of bradykinin-dependent effects. It does not bind to other receptors or ion channels important for regulation in the circulatory system. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the reabsorption of electrolytes in the renal tubules, directly increasing the excretion of sodium and chloride and water. The elimination of potassium and Magnesium by the kidneys increases in a dose-dependent manner, while increasing Calcium reabsorption. Hydrochlorothiazide reduces plasma volume and extracellular fluid, decreases cardiac output and decreases blood pressure. During long-term treatment, a reduction in peripheral resistance contributes to lowering the blood pressure. Co-administration of candesartan and hydrochlorothiazide does not affect the pharmacokinetics of any of these active substances. Bioavailability of candesartan given in the form of is about 34%. The maximum concentration of candesartan in the blood occurs after 3-4 hours. Candesartan is strongly bound to plasma proteins (over 99%). A small part of the drug is metabolised in the liver with the participation of CYP2C9. It is excreted mainly in unchanged form with urine and bile. T0,5 is about 9 hours. Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of about 70%. It binds to plasma proteins in about 60%. It is not metabolized, it is almost completely excreted unchanged in the urine. T0,5 is about 8 hours.
Contraindications:
Hypersensitivity to candesartan, hydrochlorothiazide, other sulfonamide derivatives or other components of the preparation. Severe renal dysfunction (creatinine clearance <30 ml / min / 1.73 m2 pc.). Severe hepatic impairment and / or cholestasis (cholestasis). Guided hypokalemia and hypercalcemia. Gout. Concomitant use with aliskiren-containing products in patients with diabetes or renal impairment (glomerular filtration rate, GFR <60 ml / min / 1.73 m2). II and III trimester of pregnancy.
Precautions:
In patients with renal impairment, loop diuretics are more favorable than the thiazides. In patients with impaired renal function, periodic monitoring of potassium, creatinine and uric acid in blood is recommended. There are no data on the use of the preparation in patients after a recent kidney transplantation. In patients with bilateral renal artery stenosis or renal artery stenosis that supplies the sole kidney, drugs that affect the renin-angiotensin-aldosterone system may increase urea and creatinine in the blood. In patients with circulating and / or sodium-depleted blood volume, symptomatic hypotension may occur after administration of the preparation - these disorders should be corrected before administration. In patients treated with angiotensin II receptor antagonists, anesthesia and / or surgery may result in hypotension due to inhibition of the renin-angiotensin-aldosterone system; very rarely hypotension can be so severe that it may be necessary to administer intravenous fluids and / or drugs to increase blood pressure. In patients whose vascular tone and renal function depend mainly on the activity of the renin-angiotensin-aldosterone system (e.g.patients with severe congestive heart failure or kidney disease, including renal artery stenosis), the use of drugs such as candesartan affecting the system was associated with severe hypotension, hyperazotemia, oliguria and rarely with severe renal insufficiency. Patients with primary aldosteronism usually do not respond to treatment with antihypertensive drugs acting through the inhibition of the renin-angiotensin system - the use of the preparation in these cases is not recommended. As with other antihypertensive agents, excessive hypotension in patients with ischemic heart disease or with cerebrovascular atherosclerotic lesions may cause a heart attack or stroke. Special care should be taken in patients with haemodynamically significant aortic or mitral valve stenosis or with hypertrophic cardiomyopathy with narrowing of the outflow route. In patients with impaired liver function or progressive liver disease, thiazides should be used with caution, as slight changes in fluid and electrolyte balance may lead to hepatic coma. There is no clinical experience with the use of the preparation in patients with impaired liver function. Caution in patients with diabetes, as thiazide therapy may impair Glucose tolerance - you may need to adjust your insulin dose or oral antidiabetic medicines. Thiazides may accelerate the onset of diabetes in patients with latent diabetes; may cause or exacerbate the symptoms of systemic lupus erythematosus; they can cause hyperuricemia and trigger a gout attack; they can cause hypomagnesaemia; may cause slight and transient hypercalcemia - significant hypercalcemia may indicate an unrecognized hyperparathyroidism. Thiazides should be discontinued before performing parathyroid function tests. The risk of hypokalaemia (due to the presence of hydrochlorothiazide) is higher in patients with liver cirrhosis, in patients with rapid diuresis, in patients who take orally inadequate amounts of electrolytes and in patients who are treated with corticosteroids or ACTH simultaneously. Risk factors associated with the occurrence of hyperkalemia (due to the presence of candesartan) include renal failure, heart failure and the use of preparations that increase the concentration of potassium in the blood. Blood electrolytes should be monitored regularly. Hypersensitivity reactions to hydrochlorothiazide may occur in or with allergy or bronchial asthma, but are more likely in patients with history. Hydrochlorothiazide may cause photosensitivity reaction (in the case of photosensitivity reactions, it is recommended to stop the treatment, if it is necessary to resume therapy with a diuretic, it is recommended to protect the body against sunlight or artificial UV radiation). The concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalaemia and renal dysfunction (including acute renal failure) - therefore, dual blocking of the RAA system is not recommended by concomitant use of ACE inhibitors, angiotensin II receptor antagonists 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, and the vital parameters of the patient, such as kidney function, electrolyte concentration and blood pressure should be closely monitored. In patients with diabetic nephropathy, ACE inhibitors and angiotensin II receptor antagonists should not be used concurrently. The safety and efficacy of the preparation in children and adolescents <18 years have not been established. Due to the lactose content, the preparation should not be used in patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Pregnancy and lactation:
The use of candesartan in the first trimester of pregnancy is not recommended (there is a risk of teratogenicity). The use of candesartan in the second and third trimester of pregnancy is contraindicated. Candidartrate 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. Hydrochlorothiazide crosses the placental barrier. Used in the second and third trimester of pregnancy may reduce the blood flow through the placenta and may cause such effects in the fetus and newborn, such as electrolyte abnormalities, jaundice, and thrombocytopenia.The drug should not be used to treat oedemas in pregnant women, gestational hypertension and preeclampsia. Hydrochlorothiazide should not be used in pregnant women with severe primary hypertension, except in rare cases when alternative treatment is not possible. The preparation is not recommended during breastfeeding; in case of administration, the lowest possible dose should be used. There are no data on the use of candesartan during lactation; it is advisable to change the treatment to an alternative with a better established safety profile, especially when feeding newborns and premature babies. Thiazides are excreted in breast milk; they can also inhibit lactation.
Side effects:
Undesirable effects on individual components may be potential adverse events when using a combined preparation.candesartan. Common: respiratory tract infections, dizziness, headache. Very rare: leukopenia, neutropenia, agranulocytosis, hyperkalemia, hyponatremia, cough, nausea, increased liver enzymes, liver dysfunction or inflammation of the liver, angioneurotic edema, rash, urticaria, pruritus, back pain, joint pain, muscle pain, kidney dysfunction (including renal failure in hypersensitive patients).hydrochlorothiazide. Thiazides, including hydrochlorothiazide, can cause fluid and electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatremia, hypomagnesaemia and hypochloraemia alkalosis). Common: hyperglycemia, hyperuricaemia, electrolyte imbalance, feeling of "emptiness in the head", dizziness, glycosuria, weakness, increased cholesterol and triglycerides in the blood. Uncommon: orthostatic hypotension, anorexia, decreased appetite, stomach irritation, diarrhea, constipation, rash, urticaria, hypersensitivity reactions to light. Rare: leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, bone marrow suppression, haemolytic anemia, anaphylactic reactions, sleep disturbances, depression, anxiety, paresthesias, transient blurred vision, arrhythmias, necrotizing arteritis (vasculitis, vasculitis dermatitis), respiratory failure (including alveolitis and pulmonary edema), pancreatitis, jaundice (intrahepatic cholestatic jaundice), toxic epidermal necrolysis, skin-like reactions of lupus erythematosus, activation of cutaneous lupus erythematosus, muscle spasms, renal dysfunction and interstitial nephritis, fever, increases in urea nitrogen (BUN) and creatinine in the blood.
Dosage:
Oral: 1 tablet once a day. A dose adjustment of each component of the preparation is recommended before using a fixed dose of the combined preparation. It is recommended to gradually increase the dose of individual components (candesartan and hydrochlorothiazide). If this is considered clinically appropriate, a direct change from monotherapy to combination therapy may be considered. Full antihypertensive effect is usually achieved within 4 weeks of starting treatment.Special groups of patients. There is no need to change the dose in elderly patients. In patients at risk of hypotension (eg in patients with circulating blood volume reduction), a titre of candesartan is recommended (an initial dose of 4 mg candesartan should be considered in this patient group). In patients with mild to moderate renal impairment (creatinine clearance ≥30 ml / min / 1.73 m2 p.) or mild to moderate hepatic impairment, it is recommended to gradually increase the dose of candesartan before starting treatment with the combined preparation (in these patients the recommended initial dose of candesartan is 4 mg). The drug can be taken with or without food.
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