Description:
Candesartan cilexetil, a prodrug, is hydrolysed to candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT1 subtype angiotensin II receptor antagonist. Candesartan is a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexylcarbonate (ester). Its empirical formula is C33H34N6O6.Its molecular weight is 610.67.

Pharmacological Action:
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, Kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore, independent of the pathways for angiotensin II synthesis.

Pharmacokinetics:
Absorption
Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT1 subtype angiotensin II receptor antagonist. Food with a high fat content does not affect the bioavailability of candesartan cilexetil.
Distribution
The volume of distribution of candesartan is 0.13 L/Kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses.
Metabolism
Candesartan undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. The elimination half-life of candesatan is approximately 9 hours. Absolute bioavailability was estimated to be 15%.
Elimination
Candesartan is mainly excreted unchanged in urine and feces (via bile).

Indications & Usage:
Candesartan is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
Heart Failure: candesartan is indicated for the treatment of heart failure (NYHA class II-IV) in patients with left ventricular systolic dysfunction (ejection fraction ­40%) to reduce cardiovascular death and to reduce heart failure hospitalizations. Candesartan also has an added effect on these outcomes when used with an ACE inhibitor.

Dosage and Administration:
Dosage must be individualized. Blood pressure response is dose related over the range of 2 to 32 mg. The usual recommended starting dose of Candesartan is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. Candesartan can be administered once or twice daily with total daily doses ranging from 8 mg to 32 mg.

Contraindications:
Candesartan is contraindicated in patients who are hypersensitive to any component of this product.

Adverse Effects:
In general, treatment with candesartan was well tolerated. It cannot be determined whether the following events were causally related to candesartan.
Body as a whole: asthenia, fever.
Central and Peripheral Nervous System: paresthesia, vertigo.
Gastrointestinal System Disorder: dyspepsia, gastroenteritis.
Heart Rate and Rhythm Disorders: tachycardia, palpitation.
Metabolic and Nutritional Disorders: increase in creatine phosphokinase, hyperglycemia, hypertriglyceridemia, hyperuricemia.
Musculoskeletal System Disorders: myalgia.
Platelet/Bleeding-Clotting Disorders: epistaxis.
Psychiatric Disorders: anxiety, depression, somnolence.
Respiratory System Disorder: dyspnea.
Skin & Appendages Disorders: rash, increased sweating .
Urinary System Disorders: hematuria.
Other reported events seen less frequently like angina pectoris, myocardial infarction and angioedema.

Warnings & Precautions:
Pregnancy
Pregnancy Category C (First trimester) and D (Second and third trimesters)
There are no adequate and well-controlled studies in pregnant women. Candesartan should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
Nursing Mothers
It is not known whether candesartan is excreted in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Hepatic Impairment
Based on pharmacokinetic data which demonstrate significant increases in candesartan AUC and Cmax in patients with moderate hepatic impairment, a lower initiating dose should be considered for patients with moderate hepatic impairment.
Renal Impairment
In hypertensive patients with renal impairment, serum concentrations of candesartan were elevated. After repeated dosing, the AUC and Cmax were approximately doubled in patients with severe renal impairment (creatinine clearance <30mL/min/1.73m2) compared to patients with normal kidney function. Candesartan cannot be removed by hemodialysis.

Interactions:
No significant drug interactions have been reported in studies of candesartan cilexetil given with other drugs such as glylburide, nifedipine, digoxin, warfarin, hydrochlorothiazide, and oral contraceptives in healthy volunteers, or given with enalapril to patients with heart failure (NYHA class II and III). Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.

Overdosage:
The most likely manifestation of overdosage with candesartan would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension would occur, supportive treatment should be instituted.

Storage:
Store below 30oC. Protect from heat, light and moisture. Keep the medicines out of reach of children.