Each uncoated tablet contains: Candesartan Cilexetil Equivalent to Candesartan 8 mg or 16 mg.
Angiotensin II Antagonist.
Pharmacology: Pharmacodynamics: Mechanism of Action: Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. It also has a role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT1) receptor.
Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an AIIRA, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan cilexetil with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The antagonism of the angiotensin II (AT1) receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
Pharmacokinetics: Absorption and Distribution: Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%. The mean peak serum concentration (Cmax) is reached 3-4 hours following tablet intake. The candesartan serum concentrations increase linearly with increasing doses in the therapeutic dose range. No gender related differences in the pharmacokinetics of candesartan have been observed. The area under the serum concentration versus time curve (AUC) of candesartan is not significantly affected by food. Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of candesartan is 0.1 L/kg. The bioavailability of candesartan is not affected by food.
Biotransformation and Elimination: Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with medicinal products whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.
Total plasma clearance of candesartan is about 0.37 mL/min/kg, with a renal clearance of about 0.19 mL/min/kg. The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the feces as candesartan and 10% as the inactive metabolite.
Candesartan is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
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 has also an added effect on these outcomes when used with an ACE inhibitor.
Hypertension: 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 Cilexetil is 16 mg once daily when used as monotherapy in patients who are not volume depleted. Candesartan Cilexetil can be administered once or twice daily with total daily doses ranging from 8 to 32 mg. Larger doses do not appear to have a greater effect, and there is relatively little experience with such doses. Most of the antihypertensive effect is present within 2 weeks, and maximal blood pressure reduction is generally obtained within 4 to 6 weeks of treatments with Candesartan Cilexetil. If blood pressure is not controlled by Candesartan Cilexetil alone, a diuretic may be added. Candesartan Cilexetil may be administered with other antihypertensive agents.
Heart Failure: The recommended initial dose for treating heart failure is 4 mg once daily. The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient. Or as prescribed by the physician.
No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of Candesartan Cilexetil. In mice, given single oral doses of the primary metabolite, Candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg.
The most likely manifestation of overdosage with Candesartan Cilexetil would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Candesartan cannot be removed by hemodialysis.
Treatment: To obtain up-to-date information about the treatment of overdose, consult the Regional Poison Control Center. In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in patients.
Candesartan is contraindicated in patients who are hypersensitive to any component of this product.
Concomitant therapy with an ACE inhibitor in heart failure: The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when Candesartan Cilexetil is used in combination with an ACE inhibitor. Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and candesartan are also not recommended. Use of these combinations should be under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Haemodialysis: During dialysis the blood pressure may be particularly sensitive to AT1-receptor blockade as a result of reduced plasma volume and activation of the renin-angiotensin-aldosterone system. Therefore, Candesartan Cilexetil should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.
Renal artery stenosis: Medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIRAs), may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.
Kidney transplantation: There is limited clinical evidence regarding Candesartan Cilexetil use in patients who have undergone renal transplant.
Hypotension: Hypotension may occur during treatment with Candesartan Cilexetil in heart failure patients. It may also occur in hypertensive patients with intravascular volume depletion such as those receiving high dose diuretics.
Caution should be observed when initiating therapy and correction of hypovolemia should be attempted.
Anaesthesia and surgery: Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.
Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy): As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism: Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of Candesartan Cilexetil is not recommended in this population.
Hyperkalaemia: Concomitant use of Candesartan Cilexetil with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole) may lead to increases in serum potassium in hypertensive patients. Monitoring of potassium should be undertaken as appropriate.
In heart failure, patients treated with Candesartan Cilexetil, hyperkalaemia may occur. Periodic monitoring of serum potassium is recommended. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and Candesartan Cilexetil is not recommended and should be considered only after careful evaluation of the potential benefits and risks.
General: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with AIIRAs. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.
The antihypertensive effect of candesartan may be enhanced by other medicinal products with blood pressure lowering properties, whether prescribed as an antihypertensive or prescribed for other indications.
Renal impairment: As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with Candesartan Cilexetil.
When Candesartan Cilexetil is used in hypertensive patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. There is limited experience in patients with very severe or end-stage renal impairment (creatinine Cl <15 mL/min). In these patients, Candesartan Cilexetil should be carefully titrated with thorough monitoring of blood pressure.
Evaluation of patients with heart failure should include periodic assessments of renal function, especially in elderly patients 75 years or older, and patients with impaired renal function. During dose titration of Candesartan Cilexetil, monitoring of serum creatinine and potassium is recommended. Clinical trials in heart failure did not include patients with serum creatinine >265 μmol/L (>3 mg/dL).
Use in Pregnancy: Angiotensin II antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
In post-menarche patients the possibility of pregnancy should be evaluated on a regular basis. Appropriate information should be given and/or action taken to prevent the risk of exposure during pregnancy.
Use in Children: Safety and effectiveness in pediatric patient have not been established.
Use in paediatric patients, including patients with renal impairment: Candesartan has not been studied in children with a glomerular filtration rate less than 30 mL/min/1.73m2.
For children with possible intravascular volume depletion (e.g. patients treated with diuretics, particularly those with impaired renal function), Candesartan Cilexetil treatment should be initiated under close medical supervision and a lower starting dose should be considered.
Pregnancy: Pregnancy Categories C (first trimester) and D (second and third trimester).
Nursing Mothers: It is not known whether Candesartan is excreted in human milk, but Candesartan has been shown to be present in rat 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.
Hypertension: Candesartan has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied at least 6 months and about 200 for at least 1 year. In general, treatment with Candesartan was well-tolerated. The overall incidence of adverse events reported with Candesartan was similar to placebo. The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (i.e., 108 of 3260) of patients treated with Candesartan Cilexetil as monotherapy and 3.5% (i.e., 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (i.e., 57 of 2350) of patients treated with Candesartan and 3.4% (i.e., 35 of 1027) of patients treated with placebo. The most common reason for discontinuation of therapy with Candesartan were headache (0.6%) and dizziness (0.3%).
The adverse events that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Candesartan and at higher incidence in Candesartan Cilexetil (n=2350) than placebo (n=1027) patients included back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract infection (6% vs. 4%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%).
The following adverse events occurred in placebo-controlled clinical trials at a more than 1% rate but about the same or greater incidence in patients receiving placebo compared to Candesartan Cilexetil: fatigue, peripheral edema, chest pain, headache, bronchitis, coughing, sinusitis, nausea, abdominal pain, diarrhea, vomiting, arthralgia and albuminuria.
Other potentially important adverse events that have been reported, whether or not attributed to treatment, with an incidence of 0.5% or greater from 3260 patients worldwide treated in clinical trials with Candesartan Cilexetil are listed as follows. It cannot be determined whether these events were causally related to Candesartan Cilexetil. Body as whole: Asthenia, fever; Central and Peripheral Nervous System: Paresthesia, vertigo; Gastrointestinal System Disorders: Dyspepsia, gastroenteritis; Heart Rate and Rhythm Disorders: Tachycardia, Palpitation; Metabolic and Nutritional Disorders: Increased creatinine phosphokinase, hyperglycemia, hypertriglyceridemia, hyperuricemia; Musculoskeletal System Disorder: Myalgia; Platelet/Bleeding-Clotting Disorder: Epistaxis; Psychiatric Disorders: Anxiety, depression, somnolence; Respiratory System Disorder: Dyspnea; Skin and Appendages Disorders: Rash, increased sweating; Urinary System Disorder: Hematuria. Other reported events seen less frequently included angina pectoris, myocardial infarction and angioedema.
Adverse events occurred at about the same rate in men and women, older and younger patients, and black and non-patients.
Heart Failure: The adverse events profile of Candesartan in heart failure patients was consistent with the pharmacology of the drug and health status of the patients. In the CHARM program, comparing in total daily doses up to 32 mg once daily (n=3803) with placebo-(n=3796), 21.0% of patients discontinued for adverse events vs. 16.1% of placebo patients.
Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products have been identified.
Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products (e.g. heparin) may increase potassium levels. Monitoring of potassium should be undertaken as appropriate.
Dual blockade of the RAAS with AIIRAs, ACE inhibitors, or aliskiren: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with AIIRAs. Use of candesartan with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
When AIIRAs are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Pediatric population: Interaction studies have only been performed in adults.
Store at temperatures not exceeding 30°C.
C09CA06 - candesartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Candego-16 tab 16 mg
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