Hyposart, 16 g tablets 28 pcs

Cmax in plasma is reached within 3-4 hours. Plasma concentrations increase linearly with increasing dose in the therapeutic range (up to 32 mg). Vd – 0.13 l/kg. Binding to plasma proteins – 99.8%. Slightly metabolized in the liver (20-30%) with the participation of CYP2C to form inactive metabolite.

The final T1/2 is 9 h. It does not cumulate. Total clearance is 0.37 ml/min/kg with renal clearance of approximately 0.19 ml/min/kg. Candesartan is excreted by the kidneys (by glomerular filtration and active tubular secretion): 26% as candesartan and 7% as an inactive metabolite; with bile, 56% and 10%, respectively. After a single dose within 72 hours more than 90% of the dose is excreted.

In elderly patients (over 65 years) Cmax and AUC are increased by 50% and 80%, respectively, compared to younger patients.

In patients with mild to moderate renal impairment, 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 is doubled.

In patients with mild to moderate hepatic dysfunction, a 23% increase in AUC was observed.

Indications

Active ingredient

Composition

1 tablet

Candesartan cylexetil 16 mg.

Auxiliary substances:

Lactose monohydrate – 87 mg,

Corn starch – 20 mg,

Hyprolose (viscosity, water, 25°C (5%) 75-150 cps) – 2 mg,

hyprolose (viscosity, water, 25°C (5%) 1500-3000 cps) – 2 mg,

macrogol 6000 – 2.6 mg,

magnesium stearate – 0.4 mg.

How to take, the dosage

The drug is taken orally, once daily, regardless of meals.

Arterial hypertension

The recommended starting and maintenance dose of Hyposart is 8 mg once daily. If necessary, the dose may be increased to 16 mg once daily. The maximum antihypertensive effect is reached within 4 weeks of therapy. The maximum daily dose is 32 mg once daily.

If adequate BP control is not achieved at the maximum daily dose, it is recommended to add a thiazide diuretic (e.g., hydrochlorothiazide) to therapy. This may increase the antihypertensive effect of Hyposart.

In patients at risk of arterial hypotension (including patients with decreased blood pressure), it is recommended to start therapy with a dose of 4 mg.

In patients with mild to moderate renal dysfunction (CKD 30-80 ml/min/1.73 m2), including patients on hemodialysis, the initial dose of the drug is 4 mg. The dose should be titrated depending on the therapeutic effect. Clinical experience of using the drug in patients with severe renal dysfunction or terminal renal failure (CKR less than 15 ml/min) is limited.

The initial daily dose of the drug in patients with mild to moderate liver disease is 4 mg. It is possible to increase the dose if necessary. There is no clinical experience of using the drug in patients with severe liver dysfunction and/or cholestasis.

Chronic heart failure

The recommended starting dose of Hyposart is 4 mg once daily. Increase to a maximum daily dose of 32 mg once daily or to a maximum tolerated dose by doubling the dose at intervals of at least 2 weeks.

In elderly patients and patients with impaired renal or hepatic function, no adjustment of the initial dose of the drug is required.

The safety and effectiveness of Hyposart in children and adolescents under 18 years of age have not been established.

Companion therapy

Hyposart may be used concomitantly with other drugs for the treatment of CHF, including ACE inhibitors, beta-adrenoblockers, diuretics, cardiac glycosides, or combinations of these drugs.

Interaction

The use of candesartan concomitantly with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (FFR2).

Candesartan has been studied concomitantly with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril; no clinically significant pharmacokinetic interaction was noted.

Candesartan is slightly metabolized in the liver (via CYP2C9 isoenzyme). No effect on CYP2C9 and CYP3A4 isoenzymes has been found; the effect on other cytochrome P450 isoenzymes is currently unknown.

Hypotensive agents potentiate the antihypertensive effect of candesartan. Experience with other drugs acting on the RAAS shows that concomitant use of the drug and potassium-saving diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations, salt substitutes containing potassium, or other agents capable of increasing serum potassium concentration (e.g., heparin) may lead to hyperkalemia.

In concomitant use of lithium and ACE inhibitors, there have been cases of transient increase in serum lithium concentration and development of toxic effects. A similar effect is possible with concomitant use of lithium and angiotensin II receptor antagonists, which requires periodic monitoring of serum lithium concentration when combining these drugs.

The simultaneous use of APA II and NSAIDs, including selective COX-2 inhibitors and non-selective NSAIDs (e.g., acetylsalicylic acid over 3 g/day) may decrease the antihypertensive effect of candesartan.

Double RAAS blockade

As with ACE inhibitors, concomitant use of APA II and NSAIDs increases the risk of reduced renal function, up to and including 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 get enough fluids; renal function should be monitored at the beginning of therapy and thereafter.

Special Instructions

Application in liver function disorders

In the treatment of arterial hypertension, the initial daily dose of the drug in patients with mild to moderate liver disease is 4 mg. It is possible to increase the dose if necessary. Clinical experience of using the drug in patients with severe liver dysfunction and/or cholestasis is lacking.

In treatment of chronic heart failure in patients with hepatic impairment there is no need to adjust the initial dose of the drug. The drug is contraindicated in patients with severe hepatic dysfunction and/or cholestasis.

Application in renal dysfunction

In the treatment of arterial hypertension in patients with mild to moderate renal dysfunction (CKD 30-80 ml/min/1.73 m2), including patients on hemodialysis, the initial dose of the drug is 4 mg. The dose should be titrated depending on the therapeutic effect. Clinical experience of using the drug in patients with severe renal dysfunction or terminal renal failure (CKR less than 15 ml/min) is limited.

In the treatment of chronic heart failure in patients with impaired renal function, no adjustment of the initial dose of the drug is required.

With caution the drug should be prescribed in patients with severe renal impairment (CKD

Application in children

The drug is contraindicated in children and adolescents under 18 years of age (efficacy and safety not established).

Application in elderly patients

The initial dose of the drug does not need to be adjusted in elderly patients.

Ethnicity

The antihypertensive effect of candesartan is less pronounced in patients of the Negro race compared to patients of other races, therefore, increasing the dose of Hyposart and combining with other hypotensive agents is more often required.

Kidney function impairment

Patients with severe or end-stage renal impairment (CKD

In patients with CHF, especially those over 75 years of age, and in patients with impaired renal function, renal function should be monitored periodically. Serum creatinine and potassium concentrations should be monitored during dosing of Hyposart.

Combined therapy with ACE inhibitor in CHF

Hyposart in combination with an ACE inhibitor may increase the risk of side effects: impaired renal function and hyperkalemia. In these cases close monitoring and control of relevant laboratory parameters is necessary.

Hemodialysis

During hemodialysis, BP may be particularly sensitive to AT1-receptor blockade as a result of decreased RBC and activation of the RAAS. Therefore, patients on hemodialysis require BP monitoring and individual dosing of Hyposart.

Renal artery stenosis

Drugs that affect the RAAS, such as ACE inhibitors, may cause hyperuricemia and hypercreatininemia in patients with bilateral renal artery stenosis or artery stenosis of the single kidney. A similar effect may develop with the use of ARA II.

Kidney transplantation

There is no experience with the drug in patients who have recently undergone a kidney transplant.

Arterial hypotension

Hyposart patients receiving Hyposart may develop arterial hypotension. Hypotension is also possible in patients with decreased blood pressure, e.g., those receiving high-dose diuretics. At the beginning of therapy, caution should be exercised and the blood pressure should be compensated if necessary.

Common anesthesia/surgery

In general anesthesia surgical procedures patients taking APA II may experience arterial hypotension due to RAAS blockade. Very rarely, arterial hypotension may be severe and require intravenous administration of fluids and/or vasopressors.

Aortic and/or mitral valve stenosis, GOCMP

Hyposart should be used with caution in patients with hemodynamically significant aortic and/or mitral valve stenosis or GOCMP.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are resistant to antihypertensive drugs that affect the RAAS, so Hyposart is not recommended in these patients.

Hyperkalemia

. Concomitant use of Hyposart and potassium-saving diuretics, potassium preparations, salt substitutes containing potassium, or other agents capable of increasing serum potassium concentration (e.g., heparin) may lead to hyperkalemia in patients with arterial hypertension. Hyperkalemia may also develop in patients with CHF taking Hyposart. During therapy with Hyposart in patients with CHF a periodic monitoring of serum potassium concentration is recommended, especially during simultaneous use of ACE inhibitors and potassium-saving diuretics (spironolactone, eplerenone, triamterene, amiloride).

General

Patients in whom vascular tone and renal function are predominantly dependent on RAAS activity (e.g., patients with severely decompensated CHF or concomitant renal disease, includingincluding unilateral renal artery stenosis), therapy with other drugs affecting the RAAS can be accompanied by the development of arterial hypotension, azotemia, oliguria and, rarely, acute renal failure. It also cannot be excluded for angiotensin II receptor antagonists. Excessive BP reduction in patients with CHD or cerebrovascular disease of ischemic genesis may lead to myocardial infarction or stroke.

Double RAAS blockade with drugs containing aliskiren

Double RAAS blockade by concomitant use of candesartan and aliskiren is not recommended because of increased risk of arterial hypotension, hyperkalemia, and renal function impairment.

Influence on driving and operating machinery

The effect of Hyposart on driving and operating complex machinery has not been studied, but pharmacodynamic properties of the drug indicate that this effect is absent. Caution should be exercised while driving motor transport and engaging in potentially hazardous activities requiring high concentration and quick psychomotor reactions due to risk of dizziness.

Contraindications

With caution the drug should be administered in severe renal dysfunction (CKD

Side effects

Prevalence of side effects: very common (≥1/10); common (≥1/100). Side effects of candesartan are mild and transient. The frequency of side effects is independent of the drug dose and patient age.

Nervous system disorders:often – dizziness, headache, weakness.

From the cardiovascular system: frequently – excessive decrease in BP.

Respiratory system disorders:often – respiratory infections, pharyngitis, rhinitis, cough.

From the digestive system: very rarely – nausea, increased activity of liver transaminases, impaired liver function or hepatitis.

Relations of the urinary system:often – renal dysfunction, including renal failure in predisposed patients.

Muscular system disorders: very rarely – back pain, arthralgia, myalgia.

Hematopoietic system: very rarely – leukopenia, neutropenia, thrombocytopenia and agranulocytosis.

Laboratory parameters:very rarely – hyperkalemia, hyponatremia, increased blood creatinine concentration, hyperuricemia, slight decrease in hemoglobin.

Allergic reactions:very rarely – angioedema, skin rash, pruritus, urticaria.

Others: aggravation of the course of gout, “rushes” of blood to the skin of the face.

Overdose

Symptoms:excessive BP decrease, dizziness, tachycardia. Individual cases of overdose of the drug (up to 672 mg of candesartan cilexetil) have been described, which ended with recovery of patients without severe consequences.

Treatment:In case of excessive BP decrease, the patient should be transferred to a horizontal position with a low headrest; then, measures aimed at increasing the blood circulation (administration of 0.9% sodium chloride solution intravenously) should be taken. If necessary, sympathomimetic drugs may be prescribed. Symptomatic therapy under control of vital body functions is recommended. Hemodialysis is ineffective.

Similarities