Candesartan/ Hydrochlorothiazide

Registered South African indications:

• Essential hypertension
  - In patients stabilised on the individual components given at the same dosages

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Hypersensitivity to sulphonamide-derived medicines
• Pregnancy
• Breastfeeding
• Severe renal impairment (creatinine clearance <30ml/min)
• Moderate to severe hepatic impairment and/or cholestasis
• Gout
• Hereditary or idiopathic angioedema: History of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs); such patients must never again be given these medicines
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Aortic stenosis
• Concomitant therapy with potassium-sparing diuretics such as spironolactone, triamterene or amiloride
• Porphyria
• Addison’s disease
• Anuria
• Lithium therapy: Coadministration may lead to toxic blood concentrations of lithium
• Coadministration with aliskiren-containing products
• Coadministration of fluoroquinolones with ACE inhibitors/renin-angiotensin blockers is contraindicated in patients with moderate to severe renal impairment
• History of previous and/or current basal cell carcinoma and/or squamous cell carcinoma of the skin or lip

South African recommendations

Caution in the following patient groups

• Mild to moderate renal impairment

Pregnancy

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

Renal impairment

• When used in hypertensive patients with renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered
• Prolongation of INR and bleeding complications with concomitant warfarin therapy may occur
• Renal function should be assessed before initiating treatment, and monitored during treatment, with fluoroquinolones or ACE inhibitors/renin-angiotensin receptor blockers

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

• Combining candesartan cilexetil/hydrochlorothiazide with ACE-inhibitors or aliskiren increases risks of severe hypotension, hyperkalaemia, and decreased renal function, including acute renal failure

Renal artery stenosis

• Patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney may experience increased blood urea and serum creatinine

Intravascular volume depletion

• Symptomatic hypotension may occur in patients with sodium or volume depletion, use is contraindicated in these conditions must be corrected before initiating therapy

Kidney transplantation

• There is no experience regarding the administration of candesartan/hydrochlorothiazide in patients with recent kidney transplantation

Electrolyte imbalance

• Periodic determination of serum electrolytes should be performed at appropriate intervals
• Hydrochlorothiazides can cause fluid or electrolyte imbalance
• Caution should be observed when initiating therapy and correction of hypovolaemia should be attempted

Hyperkaelemia

• Concomitant use of potassium-sparing diuretics, supplements, or salt substitutes may lead to increased serum potassium, particularly in patients with heart failure

Anaesthesia and surgery

• Hypotension due to blockade of the renin-angiotensin system may occur during surgery and may require treatment with intravenous fluids or vasopressors

Primary hyperaldosteronism

• Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicines acting through inhibition of the renin-angiotensin-aldosterone system
• Therefore, use in these patients is not recommended

Non-melanoma skin cancer

• Increased cumulative doses of hydrochlorothiazide are associated with a higher risk of basal cell and squamous cell carcinoma; patients should limit UV exposure and regularly check for skin lesions

Metabolic disturbance

• Therapy may impair glucose tolerance, increase serum uric acid (precipitating gout), or cause intermittent elevations in serum calcium

Hypersensitivity reactions

• Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma

Systemic lupus erythematosus

• Hydrochlorothiazide may activate or exacerbate systemic lupus erythematosus in treated patients

Ophthalmologic precautions

• Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion, acute transient myopia and/or acute angle-closure glaucoma
• Symptoms include acute onset of decreased visual acuity, blurred vision or ocular pain and typically occur within hours to weeks of medicine initiation
• Untreated acute angle-closure glaucoma can lead to permanent vision loss
• Discontinue candesartan/hydrochlorothiazide as rapidly as possible

Peri-operative considerations

• Thiazides as contained in candesartan/hydrochlorothiazide, may increase the responsiveness to tubocurarine

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 medicines that affect this system has been associated with acute hypotension, uraemia, azotemia, 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

Lactose warning

• Contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take

Effects on ability to drive and use machines

• Candesartan/hydrochlorothiazide may cause dizziness or weariness and have no or negligible effect on mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision

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

South African registered indications and dosages

Essential hypertension
- In patients stabilised on the individual components given at the same dosages

Candesartan/ Hydrochlorothiazide
16/12.5 (mg)
32/12.5 (mg)
32/25 (mg)

• Oral (tab): 1 tab, once daily

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Candesartan/ hydrochlorothiazide should be taken once daily with or without food

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

Not established for use in children

Pregnancy

South African recommendations

• Contraindicated
• Safety in pregnancy has not been established. When pregnancy is planned or confirmed candesartan/hydrochlorothiazide should be discontinued
• Medicines affecting the renin-angiotensin system, such as candesartan/hydrochlorothiazide, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women
• Hydrochlorothiazide can reduce the plasma volume as well as the uteroplacental blood flow. It may also cause neonatal thrombocytopenia
• Women of childbearing age should ensure effective contraception

Breastfeeding

South African recommendations

• Contraindicated
• Safety in lactation has not been established
• Candesartan as contained in candesartan/ hydrochlorothiazide, is excreted in breast milk
• Hydrochlorothiazide passes into mother’s milk. The safety during lactation has not been established

Fertility

South African recommendations

• No information available

South African recommendations

• Mild to moderate (CrCl≥30ml/min/1.73m² BSA): Caution; no dose adjustment recommended
• Coadministration with fluoroquinolones in moderate to severe renal impairment: Contraindicated
• Severe (CrCl<30ml/min/1.73m² BSA): Contraindicated

South African recommendations

• Mild: No dose adjustment recommended
• Moderate to severe: Contraindicated
• Cholestasis: Contraindicated

South African recommendations

• No dose adjustment recommended

Candesartan cilexetil/ Hydrochlorothiazide

Infections and Infestations

Less frequent

• Nasopharyngitis
• Bronchitis

Metabolism and Nutrition Disorders

Less frequent

• Dyslipidaemia

Nervous System Disorders

Less frequent

• Dizziness
• Headache

Cardiac Disorders

Less frequent

• Tachycardia

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Respiratory infection
• Bronchitis
• Pharyngitis
• Sinusitis
• Cough

Gastrointestinal Disorders

Less frequent

• Abdominal pain
• Nausea

Musculoskeletal, Connective Tissue and Bone Disorders

Less frequent

• Back pain

General Disorders and Administrative Site Conditions

Less frequent

• Influenza-like symptoms
• Urinary tract infection
• Inflicted injury
• Fatigue

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Candesartan cilexetil

Infections and Infestations

Frequent

• Respiratory infection

Blood and the Lymphatic System Disorders

Less frequent (including post-marketing)

• Leukopenia
• Neutropenia
• Agranulocytosis

Immune System Disorders

Less frequent (including post-marketing)

• Angioedema (swelling of the face, lips and/or tongue)

Metabolism and Nutrition Disorders

Frequent

• Hyperkalaemia

Less frequent

• Hyponatraemia

Nervous System Disorders

Frequent

• Dizziness/vertigo
• Headache

Vascular Disorders

Frequent

• Hypotension

Gastrointestinal Disorders

Less frequent

• Nausea

Hepato-biliary Disorders

Less frequent

• Increased liver enzymes
• Abnormal hepatic function (including post-marketing)
• Hepatitis  (including post-marketing)

Skin and Subcutaneous Tissue Disorders

Less frequent

• Rash
• Urticaria
• Pruritus

Musculoskeletal, Connective Tissue and Bone Disorders

Less frequent

• Back pain
• Arthralgia
• Myalgia

Post-marketing

• Muscle pain
• Muscle weakness
• Myositis
• Rhabdomyolysis

Renal and Urinary Disorders

Less frequent (including post-marketing)

• Renal impairment including renal failure in susceptible patients
  Laboratory findings: In patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended

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Hydrochlorothiazide

Blood and the Lymphatic System Disorders

Less frequent (including post-marketing)

• Leukopenia
• Neutropenia
• Agranulocytosis
• Thrombocytopenia
• Aplastic anaemia
• Bone marrow depression
• Haemolytic anaemia

Immune System Disorders

Less frequent

• Anaphylactic reactions (including post-marketing)
• Photosensitivity reactions (post-marketing)

Metabolism and Nutrition Disorders

Frequent

• Hyperglycaemia
• Hyperuricaemia
• Electrolyte imbalance
  - Hyponatraemia
  - Hypokalaemia (including post-marketing)
• Gout
• Hypochloraemic alkalosis

Psychiatric Disorders

Less frequent

• Sleep disturbances
• Depression
• Restlessness

Nervous System Disorders

Frequent

• Light-headedness
• Vertigo
• Headache

Less frequent

• Paraesthesia

Eye Disorders

Less frequent

• Transient blurred vision
• Yellow vision

Post marketing

• Acute angle-closure glaucoma
• Acute myopia
• Choroidal effusion

Cardiac Disorders

Frequency unknown

• Cardiac dysrhythmias

Vascular Disorders

Less frequent

• Postural hypotension
• Necrotising angitis (vasculitis, cutaneous vasculitis) (including post-marketing)

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Respiratory distress (including pneumonitis and pulmonary oedema) (including post-marketing)

Gastrointestinal Disorders

Less frequent

• Anorexia
• Loss of appetite
• Gastric irritation
• Diarrhoea
• Constipation
• Pancreatitis (including post-marketing)

Hepato-biliary Disorders

Less frequent (including post-marketing)

• Jaundice (intrahepatic cholestatic jaundice)

Skin and Subcutaneous Tissue Disorders

Less frequent

• Rash
• Urticaria
• Photosensitivity reactions
• Toxic epidermal necrolysis (including post-marketing)
• Cutaneous lupus erythematosus-like reactions
• Reactivation of cutaneous lupus erythematosus

Frequency not known

• Non-melanoma skin cancer

Musculoskeletal, Connective Tissue and Bone Disorders

Less frequent

• Muscle spasm

Post-marketing

• Cutaneous lupus erythematosus
• Systemic lupus erythematosus

Renal and Urinary Disorders

Frequent

• Glycosuria

Less frequent (including post-marketing)

• Renal dysfunction
• Interstitial nephritis

General Disorders and Administrative Site Conditions

Frequent

• Weakness

Less frequent

• Fever

Investigations

Frequent

• Increases in cholesterol and triglycerides

Less frequent

• Increases in urea and serum creatinine

Candesartan cilexetil/ Hydrochlorothiazide

• Aliskiren-containing products
• Potassium-sparing diuretics
• Spironolactone
• Triamterene
• Amiloride
• Lithium
• Fluoroquinolones
• Angiotensin II receptor blockers
• Warfarin (see Additional Prescribing Points)
• Gout medications
• Allopurinol
• Uricosurics
• Xanthine oxidase inhibitors

Hydrochlorothiazide

• Other medicines associated with potassium loss and hypokalaemia
• Other kaliuretic diuretics
• Laxatives
• Amphotericin
• Carbenoxolone
• Penicillin G sodium
• Salicylic acid derivatives
• Digoxin
• Anti-dysrhythmics
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Colestipol
• Cholestyramine
• Non-depolarising skeletal muscle relaxants
• Tubocurarine
• Calcium supplements
• Vitamin D
• Beta-blockers
• Diazoxide
• Anticholinergic agents
• Atropine
• Biperiden
• Amantadine
• Cytotoxic agents
• Cyclophosphamide
• Methotrexate
• Steroids
• Adrenocorticotropic hormone (ACTH)
• Barbiturates
• Anaesthetics
• Antidiabetic agents
• Insulin
• Pressor amines
• Adrenaline

Other interactions

• Alcohol
• Iodinated contrast media

• Serum potassium
• Creatinine levels
• Renal function

Specific cases may require

• Blood glucose

Additional observations

• Signs of hypersensitivity
• Dermatological examination

Coadministration with warfarin

• Post-marketing reports suggest a rare but significant interaction with prolongation of INR and bleeding, with concomitant warfarin therapy

Candesartan cilexetil

It is a prodrug. Candesartan cilexetil 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. After oral administration it is converted to the active, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. 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 I (AT₁) receptor. The antagonism of the angiotensin AT₁ receptors results in dose-related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Hydrochlorothiazide

Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the distal kidney tubules and promotes the excretion of sodium, chloride and water. The renal excretion of potassium and magnesium increases dose-dependently, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide decreases plasma volume and extracellular fluid and reduces cardiac output and blood pressure. During long-term therapy, reduced peripheral resistance contributes to the blood pressure reduction

Candesartan cilexetil and hydrochlorothiazide

Candesartan cilexetil and hydrochlorothiazide have additive blood pressure lowering properties.

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 - Discontinued (8/11/19)

Tablet 32mg/25mg

• Atacand Plus (AstraZeneca) originator