primobolan for sale

One primobolan for sale contains active substance candesartan cilexetil 8 mg or 16 mg.

Excipients
carmellose calcium salt, hydroxypropyl cellulose, iron krasnokorichnevy dioxide E 172, lactose monohydrate, magnesium stearate, corn starch, polyethylene glycol 8000, purified water.

Description

Atacand 8 mg: light pink round biconvex primobolan for sale scored

and engraved on one side A


CG

and 008 on the other side.

Fracture primobolan for sale uniform, light pink.

Atacand 16 mg: pink round biconvex primobolan for sale scored

and engraving A


CH

on one side and 016 on the other.

Fracture primobolan for sale uniform, pink color.

 

Pharmacotherapeutic group:

angiotensin II receptor antagonist.

ATC code: CO9CA06

pharmacological properties

pharmacodynamics

Angiotensin  II- principal hormone of the renin-angiotensin-aldosterone system, which plays an important role in the pathogenesis of hypertension, heart failure and other cardiovascular diseases. The major physiological effects of angiotensin II include vasoconstriction, stimulation of aldosterone production, regulation of water and electrolyte homeostasis and stimulation of cell growth. All these effects are mediated by the interaction with the angiotensin II type 1 angiotensin receptor (AT 1 receptors).

Candesartan – selective antagonist of angiotensin II receptor type 1 (AT 1 receptors). Candesartan does not inhibit the angiotensin converting enzyme (ACE), which performs the conversion angiotenzinp I to angiotensin II and bradykinin destroys; no effect on ACE and does not lead to accumulation of bradykinin or substance P. In comparing candesartan with ACE inhibitors develop a cough is less common in patients receiving candesartan cilexetil. Candesartan does not bind to receptors of other hormones and does not block the ionic channels involved in the regulation of cardiovascular functions. As a result, block AT 1, angiotensin II receptor occurs dose-dependent increase in renin, angiotensin I, angiotensin II and aldosterone decline in plasma concentration.

Arterial hypertension

In hypertension, candesartan causes a dose-dependent long-term reduction in blood pressure (BP). The antihypertensive effect of the drug due to a decrease in total peripheral vascular resistance, with no changes in heart rate (HR). There were no cases of severe arterial hypotension after the first dose of the drug, as well as the effect of the cancellation ( “ricochet” syndrome) after cessation of therapy. Home antihypertensive action after the first dose of candesartan cilexetil usually develops within 2 hours. Against the background of continuing therapy with a fixed dose of the maximum reduction in blood pressure is usually reached in 4 weeks and maintained throughout the treatment. Candesartan tsileksetnl appointed once daily provides effective and smooth reduction in blood pressure for 24 hours, with minor fluctuations in blood pressure in the intervals between doses of the next dose. Use of candesartan cilexetil and hydrochlorothiazide together leads to increased hypotensive effect. The combined use of candesartan cilexetil and hydrochlorothiazide (or amlodipine) is well tolerated.

Efficacy does not depend on the age and sex of the patient. Candesartan cilexetil increases renal blood flow and does not change or increases glomerular filtration rate while renal vascular resistance and filtration fraction are reduced. Receiving a dose of candesartan cilexetil 8-16 mg for 12 weeks did not adversely affect the level of glucose and lipid profile in patients with hypertension and type II diabetes.

Clinical effect of candesartan cilexetil on morbidity and mortality when receiving a dose of 8-16 mg (mean dose 12 mg) once daily, was studied in a randomized clinical trial involving 4937 elderly patients (age 70 – up to 89 years, 21 % of patients aged 80 years and older) with arterial gipertenzney mild to moderate severity, receiving therapy with candesartan tsileksetilom on average (research SORE- study of cognitive function and prognosis in elderly patients over 3.7 years). Kapdesartan patients received placebo or, where appropriate, in combination with other drugs antgipertenzivnymi. In the group of patients treated with candesartan, marked reduction in blood pressure from 166/90 to 145/80 mmHg in the control group with the 167/90 to 149/82 mm Hg Statistically significant differences in cardiovascular events (mortality due to cardiovascular disease, the incidence of myocardial infarction and stroke, not leading to death) were observed between the two groups of patients.

In the group of patients treated with candesartan, it was observed 26.7 cases of occurrence of cardiovascular events per 1000 patient-years, compared with 30.0 cases per 1000 patient-years in the control group (hazard ratio = 0.89, 95% CI 0.75 – 1.06, p = 0.19).

Heart failure

According to the study CHARM (Kadensatran in Heart Failure – Assessment of Reduction of mortality and morbidity) use of candesartan cilexetil resulted in a decrease in the frequency of deaths and the need for hospitalization for congestive heart failure and to improve left ventricular systolic function. Patients with chronic heart failure in addition to basic therapy received candesartan cilexetil in a dose of 4-8 mg per day, with increasing doses up to 32 mg per day, or up to the maximum tolerated dose therapy (mean dose of 24 mg of candesartan). The median duration of follow-up was 37.7 months. After 6 months of treatment 63% of patients who continued taking candesartan cilexetil (89%) received a therapeutic dose of 32 mg. In another study CHARM- alternative study (n = 2028) included patients with reduced left ventricular ejection fraction (LVEF) ‚ȧ 40% not treated with an ACE inhibitor because of intolerance (mainly due kashli- 72%); performance frequency deaths from cardiovascular disease and the first hospitalization for congestive heart failure was significantly lower in patients treated with candesartan compared with placebo (hazard ratio = 0.77, 95% CI 0.67- 0.89, p <0.001 ) The relative risk reduction was 23%. Statistically, in this study to prevent one case of death or cardiovascular complications or hospitalization for congestive heart failure was needed to treat 14 patients throughout the study period.Combined criterion, included the frequency of deaths, regardless of their causes, and the index of the first hospitalization for congestive heart failure was also significantly lower in patients receiving candesartan (hazard ratio – 0.80, 95% confidence interval 0,70-0.92, p = 0.001). It was noted a positive effect of candesartan on each of the components of this combined test frequency of deaths and morbidity (incidence rate of hospitalization for heart failure). The use of candesartan cilexetil resulted in improved functional class chronic heart failure of NYHA classification (p = 0.008).

In CHARM-PLUS study (n = 2548) in patients with reduced LVEF = <40% treated with ACE inhibitors. Combined criteria included the mortality rate from cardiovascular disease and the first hospitalization for congestive heart failure was significantly lower in patients receiving candesartan compared with placebo (hazard ratio = 0.85, 95% confidence interval 0.75 0.96, p 0.011), which corresponds to a relative risk reduction of 15%. In this study, in order to prevent one case of death from cardiovascular complications or hospitalization for chronic heart failure have been necessary to treat 23 patients throughout the study period. The value of the combined performance criteria include an assessment of the frequency of deaths, regardless of cause or frequency of first hospitalization for congestive heart failure was significantly lower in the group of patients treated with candesartan (hazard ratio = 0.87, 95% CI 0.78- 0.98, p = 0.021), which also indicated the positive effect of the application of candesartan. The use of candesartan cilexetil resulted in improved functional class chronic heart failure of NYHA classification (p = 0.020).

The study CHARM – prevention (n = 3023) in patients with preserved systolic function (LVEF > 40%), there was no statistically significant difference between the value of the combined performance criteria, which included the frequency of deaths and frequency of first hospitalization for congestive heart failure in the candesartan group and the placebo group (hazard ratio = 0.89, 95% confidence interval 0.77-1,03, p = 0.118). A small numerical reduction of this criterion was due to a decrease in the frequency of hospitalizations for congestive heart failure. In this study it was shown not to influence the frequency of candesartan deaths.

In separate analyzes of the results of 3 studies CHARM program was not obtained significant differences in the frequency of deaths in the candesartan and placebo groups. However, the death rate was estimated at a combined population of CHARM-Alternative and CHARM-Research plus in all 3 studies (hazard ratio = 0.91, 95% confidence interval 0.83 1.00, p = 0.055) reduction in mortality rate outcomes and the frequency of hospitalizations for congestive heart failure during therapy with candesartan did not depend on age, gender and concomitant therapy. Candesartan was also effective in patients taking beta-blockers in combination with ACE ngibitorami while candesartan efficiency does not depend on whether the patient receives optimum dose of the ACE inhibitor or not. In patients with chronic heart failure and reduced left ventricular systolic function (LVEF <40%), receiving candesartan helped reduce the total peripheral vascular resistance and pulmonary capillary pressure, increased renin activity and concentrations of angiotensin II in the plasma, as well as lower levels of aldosterone.

Pharmacokinetics

Absorption and distribution

Candesartan cilexetil is a prodrug for oral use. Is rapidly converted to the active ingredient – candesartan by ester hydrolysis during absorption from the digestive tract, it binds strongly to the AT 1 -receptor and dissociates slowly, no agonist properties. The absolute bioavailability after oral administration of candesartan, candesartan cilexetil solution is about 40%, relative biodostupnosg primobolan for sale formulation compared to the oral solution is approximately 34%. Thus, the estimated absolute bioavailability of the primobolan for sale form of the drug is 14%. Maximum serum concentration (Cmax) is achieved within 3-4 hours after administration of the primobolan for sale form of the drug. With increasing doses of the drug within the recommended concentration rises linearly candesartan. The pharmacokinetic parameters of candesartan not depend on the patient’s sex. Food intake has no significant effect on the area under “concentration-time” curve (AUC), ie Food did not significantly affect the bioavailability of the drug. Candesartan is actively bound to plasma proteins (> 99%). The volume of distribution of candesartan is 0.1 l / kg.

Metabolism and excretion

Candesartan is mainly excreted in urine N bile as unchanged, and only to a small extent metabolized in the liver.

The half-life of candesartan is approximately 9 hours. Drug accumulation in the body is observed.

Total clearance of candesartan is about 0.37 ml / min / kg, with renal clearance – about 0.19 ml / min / kg. Renal excretion kandesartapa accomplished by glomerular filtration and active tubular secretion. For oral reception of radioactive-labeled candesartan cilexetil about 26% of the administered amount is excreted in urine in the form of candesartan and 7% as an inactive metabolite while feces detected 56% of the introduced quantity of kandssartana and 10% as an inactive metabolite.

In elderly patients (65 years) Cmax and AUC of candesartan increased by 50% and 80%, respectively, compared to young patients. However, the hypotensive effect and the frequency of side effects with Atacand not depend on patient age,

Patients with mild to moderate renal function violation Cmax and AUC of candesartan increased by 50% and 70%, respectively, whereas the drug poluayvedeniya period does not change compared with patients with normal renal function. In patients with severe renal impairment Cmax and AUC of candesartan increased by 50% and 110%, respectively, and elimination half-life of the drug was increased 2-fold in patients on hemodialysis were identified such as farmakokineticheekie parameters of candesartan in patients with severe renal function.

In patients with mild and moderate hepatic impairment showed an increase of candesartan AUC by 23%.

testimony

Arterial hypertension

Heart failure and disruption of left ventricular systolic function (LVEF decrease <40%) as an adjunctive therapy to angiotenzinprevraschayuschsgo inhibitors of the enzyme (ACE) inhibitors or intolerance to ACE inhibitors (see. “Pharmacodynamic properties” section).

Contraindications

Hypersensitivity to candesartan tsileksetilu or other components of the drug.
Pregnancy and lactation (see section “Pregnancy and lactation”).

Precautions: in patients with renal impairment, in patients with severe hepatic impairment and / or cholestasis in patients with chronic heart failure, bilateral renal artery stenosis, stenosis of the aortic and mitral valve after kidney transplant in history, in patients with reduced the volume of circulating blood, with hyperkalemia, severe renal impairment or end-stage renal failure, clinical experience is limited (creatinine clearance <15 mL / min), the age of 18 years (effectiveness and safety have been established).

Beremennost and lactation

Pregnancy

The human embryonic kidney blood supply system, which depends on the development of the renin-angiotensin-aldosterone system, begins to form in the second trimester of pregnancy. Thus, the risk to the fetus increases if Atacand appointment of the second and third trimesters of pregnancy. Drugs that have a direct effect on the renin-angiotensin-aldosterone system can cause fetal or violations have a negative effect on the newborn, including death, when using the drug in the second and third trimesters of pregnancy.

In animal studies showed kidney damage in the embryonic and neonatal periods in the application of candesartan cilexetil. It is assumed that the damage mechanism is caused by exposure to a pharmacological preparation on the renin-angiotensin system aldosteropovuyu.

Based on the received information, Atacand should not be used during pregnancy. If pregnancy is detected during treatment with Atacand, therapy should be discontinued (see. “Contraindications”).

lactation

Currently, it is not known whether candesartan passes into breast milk. In connection with the possible adverse effects on the infant, Atacand should not be used during breast-feeding.

However, candesartan is extracted from the milk of lactating rats.

Dosing and Administration

Atacand should be taken once daily without regard to food.

Arterial hypertension

The recommended initial and maintenance dose of Atacand is 8 mg once daily. Patients requiring further reduction in blood pressure, it is recommended to increase the dose to 16 mg once daily.Antigipergenzivny maximum effect is reached within 4 weeks of starting treatment.

If Atacand therapy does not lead to lower blood pressure to an optimal level, it is recommended to add a thiazide diuretic therapy.

Elderly patients

Patients older vochrasta no need to adjust the initial dose.

Patients with impaired renal function

In patients with mild or moderate renal impairment (creatinine clearance> 30 mL / min / 1.73m 2 body surface area) is not required to change the initial dose.

Clinical experience with the drug in patients with severe renal impairment (creatinine clearance <30 mL / min / 1.73 m 2 of body surface area) is limited; in this case should be considered the start of treatment with a daily dose of 4 mg.

Patients with hepatic impairment

Changing the initial dose is required in patients with liver disease and mild to moderate severity. Clinical experience with the drug

in patients with severe hepatic impairment and / or holsstazom limited. Therefore, such patients rekomenduegsya begin treatment with a daily dose of 4 mg.

concomitant therapy

Atacand can be administered in conjunction with other drugs used in chronic heart failure, such as ACE inhibitors, beta-blockers, diuretics and cardiac glycosides (see. “Special Instructions”, “Pharmacodynamic properties” section).

Heart failure

Atacand recommended starting dose is 4 mg once daily, Increasing the dose to 32 mg once daily or until maximum tolerated dose is done by doubling it at intervals of not less than 2 weeks, (see. The “special instructions” section).

Special patient groups

Elderly patients and patients with impaired renal or hepatic function is not required to change the initial dose.

Use in children and adolescents

The safety and efficacy of Atacand in children and adolescents (under 18 years) have not been established.

Side effects

Arterial hypertension

Side effects of n clinical trials were mild and transient in nature and were of similar frequency in the placebo group. The overall incidence of adverse reactions in patients receiving Atacand is not dependent on the dose and the patient’s age. in connection with the incidence of side effects was similar cessation therapy using candesartan cilexetil (2.4%) and placebo (2.6%).

In the course of the research data analysis reported the following side effects frequently (> 1/100) occurs against the backdrop of receiving candesartan cilexetil. Described adverse reactions were observed at a frequency of at least 1% higher than in the placebo group.

With the central nerevoy system: dizziness / weakness, headache;

With part of the musculoskeletal system, connective tissue: back pain

Infections and infestations: respiratory infections;

Laboratory tests: in general when using Atacand there were no clinically relevant changes in standard laboratory parameters. As with other inhibitors of the renin-angiotensin-aldosterone system, there may be a slight decrease in hemoglobin. There was an increase in creatinine, urea or calcium and reducing the sodium content. Increased ALT levels was observed more frequently when using Atacand compared with placebo (1.3% instead of 0.5%). In the application of Atacand is not normally required routine monitoring of laboratory parameters, however, in patients with impaired renal function is recommended to periodically monitor the level of potassium and creatinine serum.

Heart failure

Adverse reactions identified during treatment with Atacand in heart failure patients, consistent with the pharmacological properties of the drug and the patient’s condition overstated. In clinical trials comparing Atacand CHARM conducted at doses up to 32 mg (n = 3803) with placebo (n = 379b), 21% of patients in the group of patients treated with Candesartan tsileketil, and 16.1% of patients in the group of patients receiving placebo discontinued treatment due to the occurrence of adverse reactions.

The most common adverse reactions (> 1/100, <1/10):

On the part of the vascular system: arterial hypotension;

Metabolic disorders and diseases caused by metabolic disorders: hyperkalemia;

From the mochevyvodyaschei system: renal dysfunction;

Laboratory changes, increased creatinine, urea, and potassium.

It is recommended to control the level of creatinine and serum potassium;

On the following adverse reactions during post-marketing use of the drug was reported very rarely (<1/10000):

From the circulatory and lymphatic system: leukopenia, neutropenia, and agranulocytosis;

Hapyshenue metabolism and diseases caused by metabolic disorders: hyperkalemia, hyponatremia;

From the nervous system: dizziness, headache;

With hand zheludochpo tract: nausea;

On the part of the liver and biliary tract: raising the level of “liver” enzymes, liver dysfunction or hepatitis;

Skin: angioedema, rash, hives, itchy skin;

On the part of the musculoskeletal system, connective tissue: back pain, arthralgia, myalgia;

From the urinary system: renal impairment, including renal failure in susceptible patients.

Overdose

symptoms

The analysis of pharmacological data of the drug suggests that the main manifestation of an overdose may be symptomatic hypotension and dizziness. isolated cases of overdose have been described (up to 672 mg candesartan cilexetil), ended recovery of patients without severe consequences.

Treatment

With the development of clinically significant hypotension is necessary to carry out symptomatic treatment and monitor the patient’s condition.

Place the patient on his back with his head bowed down. If necessary, to increase circulating plasma, for example by intravenous isotonic sodium rastvorahlorida. sympathomimetic drugs can be administered in case of need. Withdrawal of candesartan by hemodialysis is unlikely.

The interaction with other drugs and other forms of drug interactions

In pharmacokinetic studies of the combined use of Atacand with hydrochlorothiazide was studied, warfarin, digoxin, oral contraceptives (ethinyl estradiol / levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant drug interactions have been identified.

Candesartan is metabolized in the liver to a slight degree (CYP2C9)

Studies on the interaction did not reveal the effect of the drug on CYP2C9 and CYP3A4, effect on other cytochrome P450 isoenzymes is not known.

The combined use of Atacand with other antihypertensive agents potentsiirueg hypotensive effect.

Experience with other drugs acting on the renin-angiotensin-aldosterone system, showing that concomitant therapy kalnysberegayuschimim diuretics, drugs potassium salt substitutes containing potassium and other agents that can increase the level of potassium in the serum (e.g., heparin) can lead to the development of hyperkalemia.

When combined appointment of drugs lithium with ACE inhibitors was reported a reversible increase in serum lithium concentration in the blood and the development of toxic reactions. Similar reactions can occur when using and angiotensin II receptor antagonists and therefore, it is advisable to monitor the blood serum levels of lithium in the combined use of these drugs.

The bioavailability of candesartan is independent of food intake.

special instructions

Impaired Renal Function

The therapy Atacand as the use of other drugs which depress the renin-angiotensin-aldosterone system, some patients may experience impaired renal function.

In the application of Atacand in patients n with hypertension and renal insufficiency it is recommended to periodically monitor the level of potassium and creatinine serum. Clinical experience with the drug in patients with severe renal impairment or end-stage renal failure is limited (creatinine clearance <15 mL / min).

In patients with heart failure should periodically monitor renal function, especially in patients aged 75 years and older, as well as in patients with impaired renal function. With increasing doses of Atacand are also encouraged to monitor levels of potassium and creatinine.

In clinical studies Atacand in patients with chronic heart failure did not include patients with serum creatinine levels> 265 umol / L (> 3 mg / dL).

The combined use of inhibitors of ALF in heart failure.

In the application of candesartan in combination with ACE inhibitors may increase the risk of side effenktov, especially renal dysfunction and hyperkalemia (see. “Side Effects” section). In these cases, careful observation and monitoring of laboratory parameters.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney drugs that affect the renin-angiotensin-aldosterone system, such as ACE inhibitors may cause increased levels of urea and creatinine in the blood serum. Similar effects can be expected in the appointment of the angiotensin II receptor antagonists.

kidney transplant

Data on the use of Atacand in patients who have recently had a kidney transplant, no.

hypotension

In patients with heart failure on therapy Atacand can develop hypotension. As with other drugs that affect the renin-angiotensin system aldesteronovuyu, cause of hypotension in hypertensive patients may be a decrease in circulating blood volume as observed in patients receiving high doses of diuretics. Therefore, at the beginning of therapy, caution should be exercised and, if necessary, to carry out the correction of hypovolemia.

Anesthesia and Surgery

In patients receiving angiotensin II receptor antagonists, but during anesthesia and surgery may develop hypotension as a result of the blockade of the renin-angiotensin system. Very rare cases may experience severe hypotension requiring intravenous fluids and / or vasopressors.

Stenosis of the aortic and mitral valve (obstructive hypertrophic cardiomyopathy)

In the appointment of Atacand, as well as other vasodilators in patients with obstructive hypertrophic cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve should be careful.

Primary aldosteronism

Patients with primary hyperaldosteronism generally resistant to therapy antigipertenzivngmi drugs that affect the renin-angiotensin-aldosterone system. Therefore Atacand is not recommended in such patients

hyperkalemia

Clinical experience with other drugs that affect the renin-angiotensin-aldosterone system, shows that co-administration of Atacand with potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium, or other drugs that may increase the potassium in your blood (eg heparin) may lead to the development gipsrkaliemii in hypertensive patients.

In patients with heart failure against Atacand therapy may develop hyperkalemia. In the appointment of Atacand in patients with heart failure it is recommended to regularly monitor potassium levels in the blood, especially with a joint appointment with; ACE inhibitors and potassium-sparing diuretics such as spironolactone.

Are common

Patients whose vascular tone and renal function is mainly dependent on the activity of the renin-angiotensin-aldosterone system (eg patients with severe congestive heart failure or renal disease, including renal artery stenosis), are particularly sensitive to drugs acting on the renin-angiotensin-aldosterone system. The purpose of such drugs in these patients is accompanied by a sharp arterial hypotension, azotemia, oliguria, and rarely – acute renal failure. The possibility of these effects can not be excluded when using ayagiotenzina II receptor antagonists, sharp reduction of blood pressure in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease, using any antihypertensive drugs, can lead to myocardial infarction or stroke.

Effects on ability to drive or operate machinery

Effects on ability to drive or operate machinery has not been studied, but the pharmacodynamic properties of the drug indicate that such an effect is absent. Patients should be informed that during the treatment may occur dizziness and increased fatigue. Patients should keep this in mind before the road management or working with machinery. oxanabol