Atacand Plus
Active material: Candesartan cïleksetïl, Gidroxlorotiazid
When ATH: C09DA06
CCF: Antihypertensive drugs
ICD-10 codes (testimony): I10
When CSF: 01.09.16.05
Manufacturer: ASTRAZENECA AB {Sweden}
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Pills Pink colour, Oval, lenticular, with a notch on both sides and engraved “A/CS” on one side.
| 1 tab. | |
| Candessartan Tsiglexil | 16 mg |
| gidroxlorotiazid | 12.5 mg |
Excipients: carmellose calcium, giproloza, lactose monohydrate, magnesium stearate, corn starch, macrogol, dye iron oxide yellow, iron oxide red dye.
14 PC. – blisters (2) – packs cardboard.
Pharmacological action
Combined antihypertensive drug.
Angiotensin II – The main hormone of the Renin-angiotensin-aldosterone system, which plays an important role in the pathogenesis of arterial hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II are vasoconstriction, Stimulation of aldosterone products, regulation of a water-electrolyte state and stimulation of cellular growth. The effects are mediated by the interaction of angiotensin II with angiotensin receptors of the type 1 (AT1-receptors).
Kandhedanskant – Selective antagonist AT1-Angiotensin II receptor, It does not inhibit ACE (transforming angiotensin I into angiotensin II, destroys bradykinin), does not lead to the accumulation of bradykinin or substance p. As a result of blocking AT1-Angiotensin II receptors are in a dose -dependent increase in renin levels, Angiotensina and, Angiotensin II and a decrease in the concentration of aldosterone in blood plasma.
When comparing a pleus with ACE inhibitors, coughing was less common in patients, The cigarette tanks receiving Candesartan. Candesartan is not associated with receptors of other hormones and does not block ion channels, involved in the regulation of cardiovascular functions.
The clinical effect of the ziglesectal of the cigarette case on the level of incidence and mortality when used in the dose 8-16 mg (the average dose 12 mg) 1 once/day was studied during a randomized clinical study with the participation 4937 patients aged 70 to 89 years (21% patients aged 80 and older) with arterial hypertension of mild and moderate severity, receiving therapy with Candesartan Cleiglestyl, average, during 3.7 years (SCOPE research – study of cognitive functions and forecasting in elderly patients). Patients received candesartan or placebo, if necessary, in combination with other antihypertensives.
In the group of patients, receiving a candesartan, a decrease in blood pressure was noted 166/90 to 145/80 mmHg. and in the control group with 167/90 to 149/82 mmHg. Statistically significant differences in the frequency of cardiovascular complications (mortality as a result of cardiovascular diseases, myocardial and stroke heart attack frequency, not leading to death) There were no patients noted between the two groups of patients.
Gidroxlorotiazid – tiazidopodobnый diuretic, depresses active reabsorption of sodium, primarily, in the distal sections of the renal tubules and enhances the allocation of sodium ions, chlorine and water. The release of potassium and magnesium by the kidneys is enhanced depending on the dose, While calcium begins to reabsorpilize in large quantities, than before.
Hydrochlorotiazide reduces the volume of blood plasma and extracellular fluid, reduces the intensity of blood vehicles with a heart, lowers blood pressure. During long -term treatment, The hypotensive effect develops due to the expansion of arterioles. With prolonged use of hydrochlorotiazide, the risk of cardiovascular diseases and mortality decreases.
Pandesartan and hydrochlorotiazide have a summarized hypotensive effect. In patients with arterial hypertension of attack® Plus causes an effective and prolonged decrease in blood pressure without an increase in heart rate. Orthostatic arterial hypotension at the first administration of the drug is not observed, after the end of treatment, arterial hypertension does not increase.
After a one -time administration of the drug Atacand® Plus the main antihypertensive effect develops during 2 no. Use of the drug 1 once/day effectively and gently reduces blood pressure during 24 H with a slight difference between the maximum and average action effect. With prolonged treatment, a stable decrease in blood pressure occurs during 4 weeks after taking the drug and can be maintained with a long course of treatment.
In clinical studies, the frequency of development of side effects, Especially coughing, was less common when using attack® Plus, than when taking a combination of ACE inhibitors with hypotiazide.
Currently, there are no data on the use of a combination of candesartan/hydrochlorotiazide in patients with renal failure, nephropathy, reduced function of the left ventricle, acute heart failure and suffered myocardial infarction.
The effectiveness of the combination of candesartan and hydrochlorotiazide does not depend on the gender and age of the patient.
Pharmacokinetics
Absorption and distribution
Candessartan Tsiglexil
Candesartan Cleaves is a prodber for oral administration. When sucking from the gastrointestinal tract, the ziglexile by means of etheric hydrolysis quickly turns into an active substance – Kandhedanskant, firmly associated with AT1-receptors and slowly dissociates, does not have the properties of an agonist. The absolute bioavailability of Candesartan after taking a ziglesectal of the piclexyle of the plywood is about 40%. The relative bioavailability of the tablet drug compared to the solution for oral administration is approximately 34%. Thus, The calculated absolute bioavailability of the tablet form is 14%. Eating does not have a significant effect on the area under the curve “concentration-time” (AUC), ie. food does not significantly affect the bioavailability of the drug.
Cmax of serum is reached after 3-4 h after taking the tablet form of the drug. With an increase in the dose of the drug to the recommended limits, the concentration of Canmartan increases linearly. Binding of candesartan with blood plasma proteins – more 99%. Plasma vd Candessartan is 0.1 l / kg.
Pharmacokinetic parameters of Kandesartan are not dependent on the patient's gender.
Gidroxlorotiazid
Hydrochlorotiazide is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 70%. The accompanying meal increases the absorption by approximately 15%. Bioavailability can be reduced in patients with heart failure and severe edema.
Binding to blood plasma proteins is approximately 60%. Visible vd is approximately 0.8 l / kg.
Metabolism and excretion
Candessartan Tsiglexil
Kandhedanskant, primarily, It is excreted from the body with urine and bile in unchanged form and only in a slight degree is metabolized in the liver.
T1/2 Kandesartan is approximately 9 no. Cumulation of the drug in the body is not observed.
The general clearance of Pandesartan is about 0.37 ml / min / kg, At the same time, renal clearance – about 0.19 ml / min / kg. The renal excretion of Kandesartan is carried out by glomerular filtration and active tubular secretion.
When taking the radioactive-lame capesartan of the ziglexile near 26% From the introduced amount is removed with urine in the form 7% Vide in neaktivnogo metabolite, Whereas in Kala is detected 56% from the entered number in the form 10 % Vide in neaktivnogo metabolite.
Gidroxlorotiazid
Hydrochlorotiazide is not metabolized and is released almost completely in the form of an active form of the drug by glomerular filtration and active tubular secretion in the proximal nephron department. T1/2 is about 8 C and does not change when jointly reception with Candesartan. About 70% dose, taken inside, displayed in the urine during 48 no. When using a combination of drugs, no additional accumulation of hydrochlorotiazide is detected in comparison with monotherapy.
Pharmacokinetics in special clinical situations
Candessartan Tsiglexil
Pharmacokinetic parameters of Kandesartan are not dependent on the patient's gender
Patients older 65 years pmax and the AUC of Candessartan increases by 50% and 80%, respectively, compared to younger patients. But, The hypotensive effect and frequency of development of side effects when using Atacand® Plus do not depend on the age of patients.
In patients with a mild and moderate impaired renal function Cmax and the AUC of Pandesartan increased on 50% and 70% respectively, Whereas t1/2 the drug does not change compared to patients with normal renal function.
In patients with severe impaired renal function and/or in hemodialysis Cmax and the AUC of Pandesartan increased on 50% and 110% respectively, a T1/2 the drug increased in 2 times.
In patients with a mild and moderate impaired liver function, an increase in Pandesartan AUC was observed by 23%.
Gidroxlorotiazid
T1/2 longer in patients with renal failure.
Testimony
- treatment of arterial hypertension in patients, which shows the combination therapy.
Dosage regimen
Atakand® Plus should be taken 1 times / day, regardless of the meal.
The recommended dose – 1 tab. 1 time / day.
It is recommended to title of the dose of Canmartan before the patient transfer to Atacand therapy® Plus. If necessary, patients are translated from atakacd monotherapy® for therapy with the drug Atacand® Plus. The main antihypertensive effect is achieved, usually, first 4 weeks after initiation of treatment.
Patients with impaired renal function The use of loop diuretics compared to thiazide. Before starting therapy with the drug Atacand® Plus in patients with light or moderate impaired kidney (CC > 30 ml / min / 1.73 m2), including patients, located on the gemodialize, Dosage title is recommended (by means of monotherapy with an attack®), beginning with 4 mg.
Atacand® Plus is contraindicated in patients with renal failure severe (CC < 30 ml / min / 1.73 m2).
For patients with the risk of arterial hypotension (eg, with reduced BCC), Dosage title is recommended (by means of monotherapy with an attack®), beginning with 4 mg.
Patients Seniors dose adjustment is required.
Side effect
Side effects, identified during clinical studies, were moderate and transient and were comparable in frequency with the placebo group. The frequency of cessation of therapy due to side effects was similar to the use of a combination of candesartan/hydrochlorotiazide (3.3%) placebo (2.7%).
In the combined analysis of the results of clinical research, the following side effects were noted, caused by the purpose of the combination of Kandesartan and hydrochlorotiazide.
The described side effects were observed with a frequency at least 1% better, than placebo.
CNS: dizziness, weakness.
Candessartan Tsiglexil
The following side effects during the post -marketing use of the drug were reported very rarely (<1/10.000).
From the hematopoietic system: leukopenia, neutropenia and agranulocytosis.
CNS: dizziness, headache.
From the digestive system: nausea, increase in liver enzymes, abnormal liver function, hepatitis.
On the part of the musculoskeletal system: backache, arthralgia, myalgia.
From the urinary system: impairment of renal function (incl. renal failure in predisposed patients).
Metabolism: hyperkalemia, giponatriemiya.
Allergic reactions: angioedema, rash, hives, itching.
Gidroxlorotiazid
With monotherapy with hydrochlorotiazide in the dose 25 mg or more the following side effects with the frequency were noted: often (>1/100), sometimes (>1/1000 and <1/100), rarely (<1/1000).
From the hematopoietic system: rarely – leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplasticheskaya anemia, bone marrow depression, anemia.
From the central and peripheral nervous system: often – dizzy, headache; rarely – sleep disturbance, depression, anxiety, paresthesia.
From the senses: rarely – The transient fuzziness of the image.
Cardio-vascular system: sometimes – orthostatic hypotension; rarely – arrhythmia, Necrotizing Vasculitis, kozhnыy vasculitis.
The respiratory system: rarely – labored breathing (pneumonia and pulmonary edema).
From the digestive system: sometimes – loss of appetite, diarrhea, constipation; rarely – pancreatitis, Cholestatic jaundice vnutripečenočnaâ.
On the part of the musculoskeletal system: rarely – myalgia.
From the urinary system: often – glycosuria; rarely – impairment of renal function, interstitial nephritis.
Metabolism: often – giperglikemiâ, hyperuricemia, giponatriemiya, kaliopenia, hypercholesterolemia, hypertriglyceridemia; rarely – increased creatinine.
Allergic reactions: sometimes – skin rash, hives, photosensitivity; rarely – anaphylactic reactions, Necrosis of the epidermis, relapse of skin erythematosis, reaction, Similar with skin erythematosis.
Other: often – weakness; rarely – feeling the heat.
Increasing the content of uric acid and ALT in blood plasma and blood glucose levels, were noted as side effects, Cleaders encountered when using the candy (Approximate frequency of complaints 1.1 %, 0.9% and 1% respectively) Slightly more often, than when using a placebo (0.4%, 0% and 0.2% respectively).
For some patients, Accepting candesartan/hydrochlorotiazide, There was a slight decrease in hemoglobin concentration and an increase in ACT in blood plasma. There was also an increase in creatinine content, urea, hyperkalemia and hyponatriemia.
Contraindications
- impaired liver function and/or cholestasis;
- Renal dysfunction (CC < 30 ml / min / 1.73 m2);
- Anurija;
- refractory hypokalemia and hypercalcemia;
- Gout;
- Pregnancy;
- Lactation (breast-feeding);
- Childhood and adolescence up 18 years (efficacy and safety have not been established);
- increased sensitivity to active or auxiliary components of the drug;
- Hypersensitivity to sulfonamide derivative.
FROM caution The drug is used in severe chronic heart failure, bilateral renal artery stenosis, stenosis of the artery to a solitary kidney, hemodynamically significant stenosis of the aortic and mitral valve, In patients with cerebrovascular diseases, CHD, hypertrophic obstructive cardiomyopathy, with reduced BCC, cirrhosis of the liver, With lactose intolerance, violation of the absorption of lactose and galactose, hyponatremia, primary giperal′dosteronizmom, surgical intervention, after kidney transplantation, renal failure and diabetes mellitus.
Pregnancy and lactation
Experience in the use of the drug Atacand® Plus in pregnant women limited. This data is not enough to judge a possible danger to the fetus in the first trimester of pregnancy.
The human embryo has a blood supply system, which depends on the development of the renin-angiotensin-aldosterone system, begins to form in the II trimester of pregnancy: The risk for the fetus increases with the appointment of Atacand® Plus in the last 6 months of pregnancy.
Funds, have a direct effect on renin-angiotensin-aldosterone system, can cause fetal development or a negative effect on the newborn (hypotension, impairment of renal function, oliguria and/or anuria, oligogidramnion, hypoplasia of the skull bones, intrauterine growth retardation), until death, When using the drug in the last six months of pregnancy. Cases of lung hypoplasia were also described, facial anomalies and limb contractures.
In animal studies, kidney damage in the embryonic and neonatal periods was revealed with the use of Pandesartan. Expected, that the damage mechanism is due to the pharmacological effect of the drug on the renin-angiotensin-aldosterone system.
Hydrochlorotiazide can reduce blood plasma volume, uterine-placental blood flow and cause thrombocytopenia in a newborn.
Based on the information received, Atacand should not be used® Plus during pregnancy. If pregnancy has occurred during the treatment for Atacande® Plus, Therapy must be discontinued.
It is currently unknown, whether candesartan penetrates into breast milk. However, the candesartan is released from the milk of vapulating rats. Hydrochlorotiazide penetrates the milk of the mother. Due to the possible undesirable effect on infants, attack® Plus should not be used during breastfeeding.
Cautions
Impaired renal function
In this situation, application “loop” Diuretics are preferable to thiazid -like. For patients with renal failure in Atacand therapy® Plus it is recommended to constantly monitor potassium level, creatinine and uric acid.
Kidney transplant
Data on the use of Atacand® Plus in patients, recently transferred kidney transplantation, no.
Renal artery stenosis
Other drugs, vliyayushtie renin-angiotensin-alydosteronovuyu sistemu (eg, ACE inhibitors), They can lead to an increase in urea in the blood and the level of creatinine in the serum of patients with double -sided stenosis of the renal artery or artery stenosis of the only kidney. A similar effect should be expected from antagonists of angiotensin II receptors.
Ock Discount
In patients with a deficiency of intravascular volume and/or sodium, symptomatic arterial hypotension is possible: It is not recommended to use attack® Plus until these symptoms disappear.
General anesthesia and surgery
Patients, receiving angiotensin II antagonists, During anesthesia and surgical interventions, arterial hypotension may develop as a result of the blockade of the renin-angiotensin system. Cases of severe arterial hypotension can be very rarely noted, requiring in/in the introduction of fluid and/or vasoconstrictors.
Hepatic failure
Patients with impaired liver function or progressive liver disease should use thiazid -like diuretics with caution: Minor fluctuations in the volume of fluid and electrolyte composition can cause liver to whom. Data on the use of attack® Plus patients with liver failure are absent.
Aortic and mitral valve stenosis (gipertroficheskaya obstruktivnaya cardiomyopathy)
When appointing Atacand® Plus, patients with obstructive hypertrophic cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve should be careful.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism are usually resistant to antihypertensional therapy, influencing renin-angiotensin-aldosterone system. In this regard, it is not recommended to prescribe attacks to such patients® Plus.
Violation of the water-salt balance
As in all cases of taking drugs, with diuretic action, Electrolytes in blood plasma should be controlled.
Tiazid -based preparations, with diuretic action, able to reduce the release of calcium ions in urine and can cause spasmodic changes and a slight increase in the concentration of calcium ions in blood plasma.
Tiazidы, incl. and hydrochlorotiazide, can cause violations of water-salt balance (hypercalcemia, kaliopenia, giponatriemiya, Hypomagnium and hypochlorine alkalosis).
Ideated hypercalcemia can be a sign of hidden hyperthyroidism. The use of thiazid -like diuretics should be stopped before obtaining the results of tests of parathyroid studies.
Hydrochlorotiazide dose -dependibly increases potassium secretion, What can cause hypokalemia. Such an action of hydrochlorotiazide is manifested less, If you use it in combination with kandesartan by a cigarette. The risk of hypokalemia is increased in patients with cirrhosis, increased diuresis, taking fluid with low salts, the course of the treatment of GKS or ACTH..
Based on the experience of the use of drugs, vliyayushtih renin-angiotensin-alydosteronovuyu sistemu, Parallel use of Atacand® Plus and increasing potassium release of diuretics can be compensated by the use of food additives, containing potassium or other drugs, capable of increasing potassium in blood plasma.
The use of attacks® Plus can cause hypokalemia, especially in patients with heart or renal failure (Such cases are not documented).
Tiazid -like diuretics increase magnesium secretion, What can cause hypomagnesia.
Influence on metabolism and endocrine system
The use of thiazid -like diuretics can change the level of glucose in the blood up to the manifestation of latent diabetes. A dose of hypoglycemic agents may be required, in t. no. insulin.
With the use of thiazid -like diuretics, an increase in the level of cholesterol and triglyceride in blood plasma is binded. However, when using attack® Plus in the dose 12.5 MG observed a minimum number or lack of similar effects.
Tiazid -like diuretics increase the concentration of uric acid in blood plasma and can contribute to gout in predisposed patients.
General
Patients, In which vascular tone and kidney function mainly depend on the activity of the renin-angiotensin-aldosterone system (eg, Patients with severe chronic heart failure, kidney diseases, including renal artery stenosis), Particularly sensitive to drugs, operating on renin-angiotensin-aldosterone system. The appointment of such drugs is accompanied in these patients with sharp arterial hypotension, azotemia, oliguria and less often - acute renal failure. The possibility of developing the listed effects is not excluded when using antagonists of angiotensin II receptors. A sharp decrease in blood pressure in patients with ischemic cardiopathy, cerebrovascular diseases of ischemic genesis when using any antihypertensive agents, can lead to the development of myocardial infarction or stroke.
The manifestation of reactions of increased sensitivity to hydrochlorotiazide is most likely in patients with bronchial asthma, history of allergic reactions; which does not exclude the appearance of allergic symptoms in other patients.
When using thiazid -like diuretics, cases of exacerbation or the appearance of symptoms of stagnant seborrhea are noted.
The drug contains lactose, Therefore, it should not be taken by patients with rare hereditary diseases, manifested in the absence of tolerance to lactose, deficiency of lactose or violation of glucose and lactose absorption.
Use in Pediatrics
Safety and efficiency of Atacand's use® Plus children and adolescents to the age of 18 years not set.
Effects on ability to drive vehicles and management mechanisms
Influence on the ability to drive a car or work with equipment was not studied, but the pharmacodynamic properties of the drug indicate, that such an influence is absent. Patients should be acute when driving vehicles or work with equipment, since dizziness may occur during treatment and increased fatigue can be observed.
Overdose
Symptoms
Analysis of the pharmacological properties of the drug allows us to assume, which is the main manifestation of an overdose can be a clinically expressed decrease in blood pressure, dizziness. Certain cases of an overdose of the drug were described (to 672 MG Pandesartan), ending with recovery of patients without severe consequences. The main manifestation of an overdose of hydrochlorotiazide is acute loss of fluid and electrolytes. Such symptoms were also observed, as dizzy, decrease in blood pressure, dry mouth, tachycardia, ventricular arrhythmia, loss of consciousness and muscle cramps.
Treatment
With the development of a clinically pronounced decrease in blood pressure, it is necessary to carry out symptomatic treatment and control the patient's condition. Put the patient on the back and raise his legs. If necessary, it should be increased by the BCC, eg, by iv administration of an isotonic solution of sodium chloride. If necessary, sympathomy can be prescribed if necessary. The excretion of candesartan and hydrochlorotiazide using hemodialysis is unlikely.
Drug Interactions
In pharmacokinetic studies, the combined use of Atacand was studied® Plus with hydrochlorotiazide, varfarinom, digoksinom, oral contraceptives (ethinyl estradiol / levonorgestrel), glibenclamide, Nifedipin and enalapril. Clinically significant drug interactions were not revealed.
Candesartan is metabolized in the liver to a slight degree (CYP2C9). Interaction studies did not reveal the effect of the drug on CYP2C9 and CYP3A4, action on other isoenzyme systems of the cytochrome P450 has not been studied.
Joint application of Atacakd® Plus with other antihypertensive agents potentiates the hypotensive effect. The action of hydrochlorotiazide, casis, can intensify by other means, leading to the loss of potassium and hypokalemia (eg, Diuretic, laxatives, Amphotericin, karʙenoksolon, Penicillin G Sodium, derivatives of salicylic acid).
Experience in the use of other drugs, acting on renin-angiotensin-aldosterone system, shows, what is the accompanying therapy with potassium -saving diuretics, potassium supplements, salt substitutes, containing potassium, and other means, improving the level of potassium in blood serum (eg, Heparin) can lead to the development of hyperkalemia.
Hypokalemia and hypomagnesia induced by diuretic agents predispose to the possible cardiotoxic effects of glycoside of the glycoside and antiarrhythmic agents. In adopting Atacand® Plus, in parallel with such drugs, control of potassium in the blood is required.
With the combined prescription of lithium preparations with ACE inhibitors, there is a reversible increase in the concentration of lithium in the blood serum and the development of toxic reactions. Similar reactions can be found when using antagonists of angiotensin II receptors, в связи с чем рекомендуется контролировать уровень лития в сыворотке крови при комбинированном применении этих препаратов.
Мочегонное, натрийуретическое и гипотензивное действия гидрохлоротиазида ослабляются НПВС.
Всасывание гидрохлоротиазида ослабляется при применении колестипола, колестирамина.
Действие недеполяризующих миорелаксантов (eg, tuʙokurarina) может быть усилено гидрохлоротиазидом.
Тиазидоподобные диуретики могут вызывать повышение уровня кальция в крови в связи с уменьшением его экскреции. При необходимости применения кальцийсодержащих пищевых добавок или витамина D, следует контролировать уровень кальция в плазме крови и при необходимости корректировать дозу.
Тиазидоподобные диуретики усиливают гипергликемическое действие бета-адреноблокаторов и диазоксида.
Антихолинэргические средства (eg, atropyn, biperidin) могут увеличивать биодоступность тиазидоподобных мочегонных средств вследствие снижения моторики ЖКТ.
Тиазидоподобные диуретики могут увеличить риск неблагоприятного действия амантадина.
Тиазидоподобные диуретики способны замедлить выведение цитостатических средств (таких как циклофосфамид, methotrexate) из организма и усилить их миелоподавляющее действие.
Риск гипокалиемии может увеличиться при сопутствующем приеме ГКС или АКТГ.
На фоне применения препарата Атаканд® Плюс может увеличиваться частота развития ортостатической артериальной гипотензии при приеме алкоголя, барбитуратов или общих анестетиков.
При лечении тиазидоподобными диуретиками возможно снижение толерантность к глюкозе, в связи с чем может потребоваться подбор дозы гипогликемических препаратов (in t. no. insulin).
Гидрохлоротиазид может уменьшить влияние сосудосуживающих аминов (eg, epinephrine).
Гидрохлоротиазид может увеличить риск развития острой почечной недостаточности, особенно в совокупности с большими дозами йодированного наполнителя.
Значительного взаимодействия гидрохлоротиазида с пищей не обнаружено.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
List B. The drug should be stored out of reach of children at or above 30 ° C. Shelf life – 3 year.
