Candesartan

Registered South African indications:

• Mild to moderate hypertension
• Heart failure

Should a women become pregnant while receiving candesartan, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy (second and third trimester)
• Breastfeeding
• Severe renal impairment (creatinine clearance <30ml/min)
• Severe hepatic impairment and/or cholestasis
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Aortic valve stenosis
• History of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs); such patients must never again be given these medicines
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Concomitant therapy with potassium-sparing diuretics such as spironolactone, triamterene or amiloride
• Porphyria
• Lithium therapy: concomitant administration with candesartan may lead to toxic blood concentrations of lithium
• Children aged below 1 year
• Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60ml/min/1.73m²)
• Concomitant use of fluoroquinolones with ACE inhibitors or renin-angiotensin blockers in patients with moderate to severe renal impairment

South African recommendations

Caution in the following patient groups

• Pregnancy (first trimester)
• Mild to moderate renal impairment
• Elderly

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

• Concomitant use with ACE-inhibitors or aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function, and is contraindicated (see Contraindications)
• Combined use of candesartan and ACE-inhibitors should not be used in patients with diabetic nephropathy

Intestinal angioedema

• Patients presenting with abdominal pain, nausea, vomiting, or diarrhoea should be evaluated for intestinal angioedema and the medicine discontinued if diagnosed

Renal impairment

• Use with fluoroquinolones may precipitate acute kidney injury, particularly in the elderly or those with existing moderate to severe renal impairment
• 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 (creatinine clearance <15ml/min/1.73m² BSA). In these patients, candesartan should be carefully titrated with thorough monitoring of blood pressure

Heart failure

• Evaluation should include periodic assessment of renal function, especially in patients aged 75 years or older or those with pre-existing renal impairment
• The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when candesartan is used in combination with an ACE-inhibitor
• Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and candesartan is 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

Haemodialysis

• Blood pressure may be highly sensitive to candesartan during dialysis due to reduced plasma volume, requiring careful titration and thorough monitoring

Kidney transplantation

• There is no clinical experience for use in patients who have recently undergone kidney transplantation

Hypotension

• Symptomatic hypotension may occur in patients with heart failure or those with intravascular volume depletion, caution should be observed when initiating therapy and correction of hypovolaemia should be attempted

Anaesthesia and surgery

• Blockade of the renin-angiotensin system may lead to hypotension during surgical procedures, which may occasionally be severe enough to require intravenous fluids

Primary hyperaldosteronism

• Use is not recommended as these patients generally do not respond to antihypertensive medicines that inhibit the renin-angiotensin-aldosterone system

Hyperkalaemia

• Periodic monitoring of serum potassium is recommended in heart failure patients, particularly when candesartan is taken with potassium-sparing diuretics or ACE inhibitors

Vascular tone and renal disease

• In patients whose vascular tone and renal function depend predominantly on the activity of the reninangiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicines that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure
• Excessive blood pressure decreases 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 medicines with blood pressure lowering properties, whether prescribed as an antihypertensive or prescribed for other indications

Paediatric population

• Candesartan has not been studied in children with a glomerular filtration rate less than 30ml/min/1.73m²
• For children with possible intravascular volume depletion (e.g. patients treated with diuretics, particularly those with impaired renal function), candesartan treatment should be initiated under close medical supervision and a lower starting dose should be considered
• 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

Lactose intolerance

• Candesartan should not be taken by patients with total lactase deficiency, glucose-galactose malabsorption, or rare hereditary galactose intolerance

Effects on ability to drive and use machines

• The effect of candesartan on the ability to drive and use machines has not been studied
• When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Hypertension - mild to moderate
- As monotherapy or in combination with other antihypertensive agents such as thiazide diuretics and dihydropyridine calcium antagonists, for enhanced efficacy

• Oral (tab): Initial: 8mg, once daily; Usual maintenance: 8-16mg, once daily; Some patients may receive an additional benefit by increasing the dose to: 32mg, once daily

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The maximal antihypertensive effect is attained within 4 weeks of initiation of treatment

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Heart failure
- Reduces mortality, reduces hospitalisation due to heart failure, and improves symptoms in patients with left ventricular systolic dysfunction (LVEF ≤40 %)

• Oral (tab): Initial: 4mg, once daily; Titrate by doubling dose at intervals of 2 weeks; Target dose: 32mg, once daily or the highest tolerated dose

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Method of administration: For oral use. Candesartan should be taken once daily with or without food

Not established for use in children

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Contraindicated in children below 1 year (see Contraindications)

Pregnancy

South African recommendations

• Caution; not recommended (first trimester)
• Contraindicated (second and third trimester)

The use of candesartan is not recommended during the first trimester of pregnancy The use of candesartan is contraindicated during the second and third trimesters of pregnancy. When used in pregnancy during the second and third trimesters, medicines that act directly on the renin-angiotensin system can cause foetal and neonatal injury and death These medicines pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms Oligohydramnios as well as hypotension, oliguria and anuria in newborns, have been reported after administration in the second and third trimester Cases of defective skull ossification have been observed. Premature and low birth mass can occur. Should exposure to angiotensin II receptor antagonists (AIIRAs) have occurred from the second trimester of pregnancy, an ultrasound check of renal function and the skull is recommended Should a woman become pregnant while receiving candesartan, the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should institute alternative medication

• Safety in pregnancy has not been established
• When pregnancy is planned or confirmed, candesartan should be discontinued. Medicines affecting the renin-angiotensin system, such as candesartan, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women
• Women of childbearing age should ensure effective contraception. Candesartan is contraindicated in pregnancy
• Infants whose mother have taken AIIRAs should be closely observed for hypotension

Breastfeeding

South African recommendations

• Contraindicated
• Safety in lactation has not been established
• Candesartan is excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, breastfeeding should be discontinued if the use of candesartan is considered essential

Fertility

South African recommendations

• No information available

South African recommendations

• Mild to moderate (CrCl≥30ml/min/1.73m² BSA): Caution; no dose adjustment recommended
  No initial dosage adjustment is necessary in patients with mild to moderate renal impairment
• Severe (CrCl<30ml/min/1.73m² BSA): Contraindicated
• Coadministration with fluoroquinolones in moderate to severe renal impairment: Contraindicated
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing agents: Contraindicated

South African recommendations

• Mild to moderate: No dose adjustment recommended
  No initial dosage adjustment is necessary in patients with mild to moderate hepatic impairment
• Severe: Contraindicated
  There is no experience available in patients with severe hepatic impairment and/or cholestasis

South African recommendations

• Caution; no dose adjustment recommended
  No initial dosage adjustment is necessary for elderly patients with normal renal and hepatic function

Central Nervous System Disorders

• Dizziness
• Vertigo
• Headache

Respiratory Disorders

• Cough

Gastrointestinal Disorders

• Nausea

Hepatobiliary Disorders

• Increased liver enzymes
• Abnormal hepatic function 
• Hepatitis

Genitourinary Disorders

• Renal impairment
• Renal failure 

Endocrine and Metabolic Disorders

• Hyperkalaemia
• Hyponatraemia

Musculoskeletal Disorders

• Back pain
• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Angioedema
• Rash
• Urticaria
• Pruritus

Immune, Blood and Lymphatic System Disorders

• Leucopenia
• Neutropenia
• Agranulocytosis
• Respiratory infection

• Agents that increase serum potassium
• Spironolactone
• Triamterene
• Amiloride
• Fluoroquinolones
• Lithium
• Non-steroidal anti-inflammatory drugs
• Aliskiren
• Angiotensin-converting enzyme inhibitors
• Angiotensin receptor blockers

• Serum potassium
• Renal function  

Specific cases may require

• Hepatic function

Concomitant therapy

In hypertension

• Candesartan can be used as monotherapy or in combination with other antihypertensive medicines, such as thiazide diuretics and dihydropyridine calcium antagonists, e.g. amlodipine, for enhanced efficacy

In heart failure

• Candesartan can be administered with other heart failure treatment, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicines

Use in black patients

• The antihypertensive effect of candesartan is less in black than non-black (Caucasian, Asian and other) patients. Consequently, up-titration of candesartan and concomitant therapy (such as thiazide diuretics) may be more frequently needed for blood pressure control in black than non-black patients

Candesartan selectively blocks the binding of angiotensin II to AT1-receptors found in many tissues, including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure.

Tablet 8mg

• Abecard (Forrester Pharma)
• Atacand (AstraZeneca) originator - Discontinued (8/11/19)
• Aterwin (Zentiva)
• Candagen (Ranbaxy)
• Candesartan Zydus (Zydus)
• Mylacand (Mylan)
• Zidesart (Zydus)

Tablet 16mg 

• Abecard (Forrester Pharma)
• Atacand (AstraZeneca) originator
• Aterwin (Zentiva)
• Candagen (Ranbaxy)
• Candesartan Zydus (Zydus)
• Mylacand (Mylan)
• Zidesart (Zydus)

Tablet 32mg

• Abecard (Forrester Pharma)
• Atacand (AstraZeneca) originator
• Aterwin (Zentiva)

COMBINATION PREPARATIONS

Candesartan Cilexetil/ Hydrochlorothiazide

Tablet 16mg/12.5mg

• Atacand Plus (AstraZeneca) originator
• Candepres Plus (Sandoz)
• Candesartan Plus HTZ Oethmaan (Oethmaan)
• Mylacand Plus (Mylan)

Tablet 32mg/12.5mg

• Atacand Plus (AstraZeneca) originator

Tablet 32mg/25mg

• Atacand Plus (AstraZeneca) originator