Angiacand, tablets 8 mg 28 pcs

Pharmacodynamics

Candesartan is a selective angiotensin II type 1 receptor antagonist (AT1-receptors), it forms a strong bond with them with subsequent slow dissociation. It has vasodilatory, hypotensive and diuretic effects. It does not exhibit agonist properties (does not inhibit angiotensin-converting enzyme (ACE) and does not lead to accumulation of bradykinin or substance P, does not bind with receptors for other hormones, does not block ion channels involved in regulation of cardiovascular system functions). As a result of blocking of AT1-receptors of angiotensin II there is a compensatory dose-dependent increase of renin activity, angiotensin I, angiotensin II concentration and decrease of plasma concentration of aldosterone.

Arterial hypertension
Antihypertensive effect is due to reduction of total peripheral vascular resistance (TPR), with no effect on heart rate (HR). There have been no cases of marked arterial hypotension after the first dose of the drug, and no “withdrawal” syndrome after discontinuation of therapy. The onset of antihypertensive effect after the first dose usually develops within 2 hours. Against the background of continuing therapy with the drug in a fixed dose, the maximum reduction in blood pressure (BP) is usually achieved within 4 weeks and is maintained throughout treatment.

Candesartan increases renal blood flow and does not change or increase glomerular filtration rate, whereas renal vascular resistance and filtration fraction decrease.

It does not affect glucose concentration and lipid profile in patients with arterial hypertension and type 2 diabetes. Provides dose-dependent gradual reduction of blood pressure.

Age and gender do not affect the effectiveness of the drug.

Chronic heart failure

In patients with chronic heart failure and a left ventricular ejection fraction lower than 40%, administration of candesartan was associated with decreased PFS and capillary pressure in the lungs, increased renin activity and plasma angiotensin II concentration, and decreased aldosterone concentration.

Pharmacokinetics

Candesartan is an oral prodrug. It is rapidly (via ester hydrolysis) converted to the pharmacologically active candesartan. Absolute bioavailability of candesartan after oral administration of candesartan cilexetil solution is about 40%. The relative bioavailability of tablet versus oral solution is approximately 34%. Thus, the estimated absolute bioavailability of the tablet form is about 14% and does not depend on the time of food intake. Maximum concentration (Cmax) in blood serum is reached after 3-4 hours. Plasma concentration increases linearly with increasing dose in the therapeutic range (up to 32 mg). The volume of distribution is 0.13 l/kg. Blood plasma protein binding is 99.8%.

It is slightly metabolized in the liver (20-30%) with the participation of cytochrome P450 isoenzyme CYP2C9 with the formation of an inactive derivative. Terminal elimination half-life (T1/2) is 9 h. It does not cumulate. Total clearance is 0.37 ml/min/kg, with renal clearance of about 0.19 ml/min/kg. It is eliminated by kidneys and in bile mainly unchanged, to a small extent – as metabolite: by kidneys (by glomerular filtration and active tubular secretion) – 26% as candesartan and 7% – as inactive metabolite, in bile – 56% and 10%, respectively. After a single oral administration within 72 hours more than 90% of the dose is excreted.

In elderly patients (over 65 years) Cmax and area under the curve “concentration-time” (AUC) are increased by 50% and 80%, respectively, compared to younger patients. However, the antihypertensive effect and the incidence of side effects when using the drug do not depend on the age of patients.

In patients with mild to moderate renal dysfunction, Cmax and AUC are increased by 50% and 70%, respectively, whereas the T1/2 of the drug is unchanged compared to patients with normal renal function.

In patients with severe renal impairment, Cmax and AUC are increased by 50% and 110%, respectively, and the T1/2 of the drug is doubled.

In patients with mild to moderate hepatic impairment an increase in AUC of 23% was observed.

Indications

– Arterial hypertension.
– Chronic heart failure and impaired left ventricular systolic function (reduced left ventricular ejection fraction less than 40%) as additional therapy to angiotensin-converting enzyme (ACE) inhibitors or when ACE inhibitors are intolerant.

Active ingredient

Composition

1 tablet contains:

the active substance:

candesartan cilexetil 8 mg;

excipients:

corn starch pregelatinized,

croscarmellose sodium (primellose),

lactose monohydrate (milk sugar),

magnesium stearate,

povidone-K30.

How to take, the dosage

Overly, regardless of meals, once a day.
Arterial hypertension. The recommended initial and maintenance dose is 8 mg once daily. It is recommended to increase the dose to 16 mg once a day for patients who need further BP reduction. The maximum daily dose of the drug is 32 mg once daily.

The maximal antihypertensive effect comes 4 weeks after the beginning of treatment.
If therapy with Angiacand does not lower BP to optimal target levels, it is recommended to add thiazide diuretic to therapy.

In elderly patients no adjustment of the starting dose is required.
In patients with mild to moderate renal dysfunction (creatinine Cl;30 ml/min) no adjustment of the starting dose is required.
Patients with severe renal dysfunction (creatinine Cl. Chronic heart failure. The recommended starting dose is 4 mg once daily (other formulation of candesartan is possible).

Enlarge the dose to 32 mg once daily or to the maximum tolerated dose by doubling it at intervals of at least 2 weeks.
Patients of advanced age and patients with impaired renal and/or hepatic function need not change the initial dose of the drug.

Interaction

No clinically significant interactions have been found when concomitant use of candesartan with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril.
Concomitant use of lithium with ACE inhibitors reported a reversible increase in serum lithium concentration and development of toxic reactions. Adverse reactions may also occur when using angiotensin II receptor antagonists, and in this regard, it is recommended to monitor serum lithium levels when combining use of these drugs.

The simultaneous use of angiotensin II receptor antagonists and NSAIDs, including selective COX-2 inhibitors and non-selective NSAIDs (e.g., acetylsalicylic acid over 3 g/day) may decrease the hypotensive effect of candesartan. As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists and NSAIDs increases the risk of reduced renal function up to renal failure, which leads to hyperkalemia in patients with impaired renal function. This combination should be used with caution, especially in elderly patients. All patients should receive sufficient fluids. Renal function should be monitored at the beginning of therapy and thereafter.

The drugs affecting the RAAS can increase urea and creatinine concentrations in blood in patients with bilateral renal artery stenosis or artery stenosis of the uniciliary artery.

Diuretics and other hypotensive agents increase the risk of arterial hypotension.

Potassium-saving diuretics, potassium preparations, salt substitutes containing potassium, and other drugs that can increase serum potassium (e.g., heparin) increase the risk of hyperkalemia.

Candesartan is slightly metabolized in the liver (CYP2C9 isoenzyme). Interaction studies have shown no effect of candesartan on CYP2C9 and CYP3A4 isoenzymes. The effect on other isoenzymes of the cytochrome P450 system has not been studied.

Special Instructions

Before and during treatment it is necessary to control BP, renal function (creatinine in plasma), serum potassium, lithium (with combined use of drugs).

Arterial hypotension. Patients with chronic heart failure during therapy with Angiacand may develop hypotension. As with other drugs acting on the RAAS, the cause of hypotension in patients with arterial hypertension can be decreased BOD, as it is observed in patients receiving high doses of diuretics. Therefore, caution should be exercised at the beginning of therapy and, if necessary, correction of hypovolemia should be performed.

Renal artery stenosis. In patients with bilateral renal artery stenosis or renal artery stenosis of the uniciliary artery, preparations affecting the RAAS, in particular ACE inhibitors, may cause increase of serum urea and creatinine concentration. Similar effects can be expected when prescribing angiotensin II receptor antagonists.

Kidney transplantation. There are no data on the use of candesartan in patients who have recently undergone a kidney transplant.

Disordered renal function. During Angiacand therapy, as well as during the use of other drugs that inhibit the RAAS, renal function abnormalities may be observed in some patients.

When using Angiacand in patients with arterial hypertension and significant renal insufficiency, it is recommended to monitor serum potassium and creatinine periodically. Clinical experience with candesartan in patients with severe renal impairment or end-stage renal failure (Cl creatinine

In patients with chronic heart failure, periodic monitoring of renal function is necessary, especially in patients aged 75 years and older and in patients with impaired renal function. If the dose of Angiacand is increased, plasma potassium and creatinine should also be monitored.

Combined use with ACE inhibitors in chronic heart failure. When using Angiacand in combination with ACE inhibitors the risk of side effects may increase, especially renal dysfunction and hyperkalemia. In these cases, close monitoring and control of laboratory parameters are necessary.

General anesthesia and surgery. Patients receiving angiotensin II receptor antagonists during general anesthesia and surgical interventions may develop arterial hypotension as a result of RAAS blockade. Very rarely there may be cases of severe arterial hypotension requiring intravenous administration of fluids and/or vasopressor agents.

Aortic and mitral valve stenosis (hypertrophic obstructive cardiomyopathy). Caution should be exercised when using Angiacand, as well as other vasodilators, in patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant aortic and/or mitral valve stenosis.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism are usually resistant to therapy with hypotensive drugs that affect RAAS activity. Therefore, Angiacand is not recommended for use in these patients.

Hyperkalemia. Clinical experience with other drugs that affect the RAAS shows that concomitant use of candesartan with potassium-saving diuretics, potassium supplements or salt substitutes containing potassium, or other drugs that can increase potassium in the blood (e.g. heparin) can lead to hyperkalemia in patients with arterial hypertension.

General. Patients in whom vascular tone and renal function are predominantly dependent on RAAS activity (e.g., patients with severe chronic heart failure or renal disease, including renal artery stenosis) are particularly sensitive to drugs acting on RAAS. In these patients, the use of such drugs is accompanied by severe arterial hypotension, azotemia, oliguria and, rarely, acute renal failure. The possibility of these effects cannot be excluded even with the use of angiotensin II receptor antagonists. A sharp decrease in BP in patients with CHD or cerebrovascular diseases of ischemic genesis when using any hypotensive agents may lead to myocardial infarction or stroke.

Impact on the ability to drive vehicles, machinery. During treatment dizziness and weakness may occur, therefore caution should be exercised while driving vehicles and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions.

Contraindications

With caution: Severe renal failure (creatinine Cl less than 30 ml/min); bilateral renal artery stenosis; renal artery stenosis of a single kidney; post renal transplant history; hemodynamically significant aortic and mitral valve stenosis; cerebrovascular disease; ischemic heart disease; hypertrophic obstructive cardiomyopathy; reduced RBC; hyperkalemia.

Side effects

Arterial hypertension, the most common side effects (≥1/100,

CNS disorders: dizziness, weakness, headache.

Musculoskeletal system, connective tissue: back pain.

Others: respiratory infections.

Laboratory measures: decreased hemoglobin, hypercreatininemia, increased concentration of urea in blood, hyperkalemia, hyponatremia, increased ALT activity.

Chronic heart failure, the most common side effects (≥1/100,

Particularly cardiac disorders: marked decrease in BP.

Urinary system: impaired renal function.

Laboratory changes: hypercreatininemia, increased concentration of urea in blood, hyperkalemia.

The following adverse effects (incidence less than 1/10000) have been reported during postmarketing use of candesartan

Hematopoietic disorders: leukopenia, neutropenia, and agranulocytosis.

Laboratory findings: hyperkalemia, hyponatremia.

CNS disorders: dizziness, weakness, headache.

Digestive system disorders: nausea.

Hepatic and biliary tract disorders: increased liver transaminase activity, liver dysfunction or hepatitis.

Allergic reactions: angioedema, skin rash, itching, urticaria.

Muscular system, connective tissue: back pain, arthralgia, myalgia.

Transureting system disorders: renal dysfunction, including acute renal failure in predisposed patients.

Respiratory system disorders: cough.

Overdose

Symptoms: marked BP decrease, dizziness, tachycardia.

Treatment: symptomatic. Place the patient on his back, elevate the lower extremities above head level, if necessary increase the blood circulation by infusion of 0.9% sodium chloride solution, administer sympathomimetics. Hemodialysis is ineffective.

Pregnancy use

Animal studies have revealed renal damage in the fetal and neonatal periods when using candesartan. It is assumed that the mechanism of damage is due to the pharmacological effect of the drug on the RAAS.

In the human embryo, the renal blood supply system, which depends on the development of the RAAS, begins to form in the second trimester of pregnancy. Thus, the risk to the fetus increases when candesartan is used in the second and third trimesters of pregnancy. Drugs that have a direct effect on the RAAS may cause fetal abnormalities or have adverse effects on the newborn, up to and including death, when used in the second and third trimesters of pregnancy.

Angiacand should not be used during pregnancy. If pregnancy is detected during treatment with the drug, therapy should be discontinued as soon as possible.

It is not known whether candesartan is excreted into the breast milk. Due to possible adverse effects on infants, Angiacand should not be used while breastfeeding.

Similarities