APO-CANDESARTAN Tablets 4 mg: White to off white coloured, round shaped, biconvex tablets, engraved "APO" on one side and "CA" scored "4" on the other side. APO-CANDESARTAN Tablets 8 mg: Pink to light pink coloured, round shaped, biconvex tablets, engraved "APO" on one side and "CA" bisect "8" on the other side. APO-CANDESARTAN Tablets 16 mg: Pink to light pink coloured, round shaped, biconvex tablets, engraved "APO" on one side and "CA" bisect "16" on the other side. APO-CANDESARTAN Tablets 32 mg: Pink to light pink coloured, round shaped, biconvex tablets, engraved "APO" on one side and "CA" bisect "32" on the other side. Do not halve tablet. Dose equivalence when the tablet is divided has not been established.

Dosage and Administration

Dosage in Hypertension

The recommended initial and maintenance dose of candesartan is 8 mg once daily. The dose may be increased to 16 mg once daily. In patients who require further blood pressure reduction, the dose may be increased to 32 mg once daily. Therapy should be adjusted according to blood pressure response. The maximal antihypertensive effect is attained within 4 weeks after initiation of treatment. In patients with less than optimal blood pressure reduction on candesartan combination with a thiazide diuretic is recommended.

No initial dosage adjustment is necessary in patients with mild to moderate impaired renal function (i.e. creatinine clearance >=30 mL/min/1.73 m2 BSA). In patients with severe impaired renal function (i.e. creatinine clearance <30 mL/ min/1.73 m2 BSA), including patients on haemodialysis a lower initial dose of 4 mg should be considered.

No initial dosage adjustment is necessary in patients with mild to moderate chronic liver disease. There is only limited experience available in patients with severe hepatic impairment and/or cholestasis. A lower initial dose of 4 mg should therefore be considered in these patients.

APO-CANDESARTAN may be administered with other antihypertensive agents (see also "USES").

Dosage in Heart Failure

The usual recommended initial dose for candesartan is 4 mg once daily. Up-titration to the target dose of 32 mg once daily or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks (see WARNINGS AND PRECAUTIONS).

No initial dose adjustment is necessary for elderly patients or in patients with renal or hepatic impairment.

APO-CANDESARTAN can be administered with other heart failure treatment, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicinal products (see PHARMACOKINETICS).

ADMINISTRATION

Do not halve tablet. Dose equivalence when the tablet is divided has not been established.

Contraindications

APO-CANDESARTAN must not be administered during pregnancy or lactation. Known hypersensitivity to the active substance or to any of the excipients of this product.

Warnings and Precautions

Hypotension may occur during treatment with candesartan in heart failure patients. As described for other agents acting on the renin-angiotensin-aldosterone system, it may also occur in hypertensive patients with intravascular volume depletion. Caution should be observed when initiating therapy and correction of hypovolaemia should be attempted.

Other drugs that affect the renin-angiotensin-aldosterone system, i.e. angiotensin converting enzyme (ACE) inhibitors, may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. A similar effect may be anticipated with angiotensin II receptor antagonists.

As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with candesartan. When candesartan is used in hypertensive patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered. There is very limited experience in patients with very severe or end-stage renal impairment (ie. creatinine clearance <15 mL/min/1.73 m2 BSA). Evaluation of patients with heart failure should include periodic assessments of renal function. During dose titration of candesartan, monitoring of serum creatinine and potassium is recommended.

Concomitant Therapy with an Ace Inhibitor (Dual Blockade of the Renin-Angiotensin- Aldosterone System)

The risk of adverse reactions, especially hypotension, renal function impairment and hyperkalaemia, may increase when candesartan is used in combination with an ACE inhibitor, particularly in heart failure patients (see ADVERSE EFFECTS). Patients with such treatment should be monitored regularly and carefully.

There is no experience regarding the administration of candesartan in patients with a recent kidney transplantation.

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 should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis. (See DOSAGE AND ADMINISTRATION).

There is only limited experience in patients with severe hepatic impairment and/or cholestasis.

As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Based on experience with the use of other drugs that affect the renin-angiotensin-aldosterone system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g. heparin) may lead to increases in serum potassium in hypertensive patients. In heart failure patients treated with candesartan, hyperkalaemia may occur. During treatment with candesartan in patients with heart failure, periodic monitoring of serum potassium is recommended, especially when taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as spironolactone.

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockage of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

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 drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or atherosclerotic cerebrovascular disease could result in a myocardial infarction or stroke.

The use of candesartan is contraindicated during pregnancy (see CONTRAINDICATIONS). Patients receiving candesartan should be made aware of that before contemplating a possibility of becoming pregnant so that they can discuss appropriate options with their treating physician. When pregnancy is diagnosed, treatment with candesartan must be stopped immediately and if appropriate, alternative therapy should be started. When used in pregnancy, medicines that act directly on the renin-angiotensin system can cause foetal and neonatal injury and death. Exposure to angiotensin II receptor antagonist therapy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see FURTHER INFORMATION, Pre-clinical Safety Data).

It is not known whether candesartan is excreted in human milk. However, candesartan is excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, breast feeding should be discontinued if the use of candesartan is considered essential (see CONTRAINDICATIONS).

The effect of candesartan on the ability to drive and use machines has not been studied, but based on its pharmacodynamic properties candesartan is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment.

Adverse Effects

Treatment of Hypertension

Candesartan was well tolerated in controlled clinical studies showing an adverse event profile comparable to that of placebo. Generally adverse events were mild and transient. The overall incidence of adverse events showed no association with dose, age or gender. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil (3.1%) and placebo (3.2%).

Laboratory findings

In general, there were no clinically important influences of candesartan on routine laboratory variables. As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. Increases in creatinine, urea or potassium and decreases in sodium have been observed. Increases in SALAT (S-GPT) were reported as adverse events slightly more often with candesartan than with placebo (1.3% vs 0.5%). No routine monitoring of laboratory variables is necessary for patients receiving candesartan. However, in patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered.

TREATMENT OF HEART FAILURE

The adverse experience profile of candesartan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM clinical programme, comparing candesartan in doses up to 32 mg (n=3,803) to placebo (n=3,796), 21.0% of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment because of adverse events. Adverse reactions commonly (>=1/100, <1/10) seen were:

Vascular disorders:

Hypotension.

Metabolism and nutrition disorders:

Hyperkalaemia.

Renal and urinary disorders:

Renal impairment.

Laboratory findings

Increases in creatinine, urea and potassium. Periodic monitoring of serum creatinine and potassium is recommended (see WARNINGS AND PRECAUTIONS).

POST MARKETING

The following adverse reactions have been reported very rarely (<1/10,000) in post marketing experience:

Blood and lymphatic system disorders:

Leukopenia, neutropenia and agranulocytosis

Metabolism and nutrition disorders:

Hyperkalaemia, hyponatraemia

Nervous system disorders:

Dizziness

Respiratory, thoracic and mediastinal disorders:

Cough

Hepato-biliary disorders:

Increased liver enzymes, abnormal hepatic function or hepatitis

Skin and subcutaneous tissue disorders:

Angioedema, rash, urticaria, pruritus

Musculoskeletal, connective tissue and bone disorders:

Back pain

Renal and urinary disorders:

Renal impairment, including renal failure in susceptible patients (see WARNINGS AND PRECAUTIONS). Although causality to candesartan has not been established, palpitation has been very rarely reported as an adverse event during post-marketing surveillance

Interactions

Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol / levonorgestrel), glibenclamide, nifedipine and enalapril. No pharmacokinetic interactions of clinical significance were identified in these studies. 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 angiotensin II receptor antagonists (AIIRAs) and careful monitoring of serum lithium levels is recommended during concomitant use. Attenuation of the antihypertensive effect may occur when simultaneously administering AIIRAs and non-steroidal anti-inflammatory drugs (NSAIDs; i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs). 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 older patients and in volume depleted patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter. The antihypertensive effect of candesartan may be enhanced by other antihypertensives. The bioavailability of candesartan is not affected by food.

Overdosage

Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. In single case reports of overdose (up to 672 mg candesartan cilexetil), patient recovery was uneventful.

If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of, for example, isotonic saline solution. Sympathomimetic drugs may be administered if the above-mentioned measures are not sufficient. Candesartan is not removed by haemodialysis.

Further Information

Actions

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. It also has an important 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 is a prodrug suitable for oral use. It is rapidly converted to the active drug, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist, 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. Since there is no effect on the degradation of bradykinin, angiotensin II receptor antagonists are unlikely to be associated with cough. In controlled clinical studies comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan. 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 activity, angiotensin I and angiotensin II concentrations and a decrease in plasma aldosterone concentration.

In hypertension, candesartan causes a dose-dependent, long-lasting reduction in arterial blood pressure. The antihypertensive action is due to decreased systemic peripheral resistance, while heart rate, stroke volume and cardiac output are not affected. There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment. After administration of a single dose of candesartan onset of antihypertensive effect generally occurs within 2 hours. With continuous treatment, the maximum reduction in blood pressure with any dose is generally attained within four weeks and is sustained during long-term treatment. Candesartan once daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval. In two 8- week randomised, double-blind studies, the blood pressure lowering effects of candesartan and losartan were evaluated in a total of 1,268 patients with mild to moderate hypertension. In both studies, the reduction of systolic and diastolic blood pressure was significantly greater with candesartan (32 mg once daily). In a pooled analysis, the trough blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg with candesartan and 10.0/8.7 mmHg with losartan potassium (100 mg once daily). The mean difference in blood pressure reduction was 3.1/1.8 mmHg (p<0.0001/p<0.0001). Candesartan can be used as monotherapy or in combination with other antihypertensive drugs, such as thiazide diuretics, dihydropyridine calcium antagonists and lisinopril, for enhanced efficacy. Candesartan is similarly effective in patients irrespective of age and gender. Candesartan is effective in reducing blood pressure regardless of race, although the effect is somewhat less in black patients (usually a low-renin population). This is generally true for drugs that block the renin-angiotensin-aldosterone system. Candesartan increases renal blood flow and either has no effect on or increases glomerular filtration rate while renal vascular resistance and filtration fraction are reduced. Candesartan also reduces urinary albumin excretion in patients with type II diabetes mellitus, hypertension and microalbuminuria. In hypertensive patients with type II diabetes mellitus, 12 weeks treatment with candesartan 8 mg to 16 mg had no adverse effects on blood glucose or lipid profile. In the SCOPE (Study on Cognition and Prognosis in the Elderly) trial, the effects of candesartan cilexetil based antihypertensive treatment on cardiovascular morbidity and mortality, cognitive function and quality of life were assessed in 4,937 elderly patients (aged 70-89 years) with hypertension (SBP 160-179 mmHg and/or DBP 90-99 mmHg). The table shows the study results for the primary endpoint (major cardiovascular events) and its components. Both treatment regimens lowered systolic and diastolic blood pressure effectively and were generally well tolerated. Cognitive function and quality of life were well maintained in both treatment arms.

*Any previous antihypertensive treatment was standardized to hydrochlorothiazide 12.5 mg once daily before randomisation. Other antihypertensive treatment was added to the double-blind study medication (candesartan cilexetil 8-16 mg or corresponding placebo once daily) if SBP remained >= 160 mmHg and/or DBP >= 90 mmHg.

In patients with chronic heart failure (CHF) and depressed left ventricular systolic function (left ventricular ejection fraction, LVEF <=40%), candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels. Treatment with candesartan reduces mortality and hospitalisation due to CHF and improves symptoms as shown in the candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity (CHARM) programme. This multinational, placebo controlled, double-blind study programme in CHF patients with NYHA functional class II to IV consisted of three separate studies: CHARM-Alternative (n=2,028) in patients with LVEF <=40% not treated with an ACE inhibitor because of intolerance, CHARM-Added (n=2,548) in patients with LVEF <=40% and treated with an ACE inhibitor, and CHARM-Preserved (n=3,023) in patients with LVEF >40%. Patients on optimal baseline therapy were randomised to placebo or candesartan (titrated from 4 mg or 8 mg once daily to 32 mg once daily or the highest tolerated dose, mean dose 24 mg) and followed for a median of 37.7 months. The composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo in CHARM-Alternative (hazard ratio (HR) 0.77, 95% CI 0.67-0.89, p<0.001) and in CHARM-Added (HR 0.85, 95% CI 0.75-0.96, p=0.011). This corresponds to a relative risk reduction of 23% and 15% respectively. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan in CHARM-Alternative (HR 0.80, 95% CI 0.70-0.92, p=0.001) and CHARM-Added (HR 0.87, 95% CI 0.78-0.98, p=0.021). Both the mortality and morbidity (CHF hospitalisation) components of the composite endpoints contributed to the favourable effects of candesartan in CHARM-Alternative and CHARM-Added. In CHARM-Preserved, no statistically significant reduction was achieved in the composite endpoint of cardiovascular mortality or first CHF hospitalisation. All-cause mortality was also assessed in pooled populations, CHARM-Alternative and CHARM- Added (HR 0.88, 95% CI 0.79-0.98, p=0.018) and all three studies (HR 0.91, 95% CI 0.83-1.00, p=0.055). Treatment with candesartan resulted in improved NYHA functional class in CHARM-Alternative and CHARM-Added (p=0.008 and p=0.020, respectively). The beneficial effects of candesartan on cardiovascular mortality and CHF hospitalisation were consistent irrespective of age, gender and concomitant medication. Candesartan was effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the benefit was obtained whether or not patients were taking ACE inhibitors at the target dose recommended by treatment guidelines.

Pharmacokinetics

Following oral administration, candesartan cilexetil is converted to the active drug 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 mean peak serum concentration (Cmax) is reached 3 to 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.

Candesartan is mainly eliminated unchanged via urine and bile and only eliminated by hepatic metabolism (CYP2C9) to a minor extent. 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 drugs 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 faeces as candesartan and 10% as the inactive metabolite.

In the elderly (over 65 years) both Cmax and AUC of candesartan are increased by approximately 50% and 80% respectively, in comparison to young subjects. However, the blood pressure response and the incidence of adverse events are similar after a given dose of candesartan in young and elderly patients. In patients with mild to moderate renal impairment Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but t1/2 was not altered compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment were approximately 50% and 110% respectively. The terminal t1/2 of candesartan was approximately doubled in patients with severe renal impairment. The AUC of candesartan in patients undergoing haemodialysis was similar to that in patients with severe renal impairment (See DOSAGE AND ADMINISTRATION). In patients with mild to moderate hepatic impairment, there was an increase in the AUC of candesartan of approximately 20%. In patients with moderate to severe hepatic impairment, the increase in the AUC of candesartan was approximately 80%. There is only limited experience in patients with severe hepatic impairment and/or cholestasis (See DOSAGE AND ADMINISTRATION).

Pharmaceutical Precautions

4 mg and 8 mg: 18 months from the date of manufacture 16 mg: 24 months from the date of manufacture 32 mg: 12 months from the date of manufacture

Package Quantities

APO-CANDESARTAN tablets are available in the following presentations: Blister Pack: 7, 28 and 30 tablets Bottles: 28, 30, and 100

Medicine Schedule

Name and Address

Apotex NZ Ltd 32 Hillside Road Glenfield Private Bag 102-995 North Shore Mail Centre Auckland Telephone: (09) 444 2073 Fax: (09) 444 2951

	Candesartan cilexetil * Number of patients with a first event (N=2477)	Control * Number of patients with a first event (N=2460)	Relative risk (95% CI)	P-value
Major CV events	242	268	0.89 (0.75-1.06)	0.19
- CV mortality	145	152	0.95 (0.75-1.19)	0.63
- Non-fatal stroke	68	93	0.72 (0.53-0.99)	0.04
- Non-fatal MI	54	47	1.14 (0.77-1.68)	0.52

Presentation

Indications