Canuretic 16/12,5 mg, Tablets

CANURETIC is indicated for essential hypertension in patients stabilised on the individual components given at the same dosages.

Posology

CANURETIC should be taken once daily and may be taken with or without food. Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.

Special populations

Elderly patients

No special dosage recommendations.

Patients with impaired renal function

CANURETIC should not be used in patients with moderate to severe renal impairment (creatinine clearance u2264 60 mL / min / 1,73 mu00b2 BSA).

Patients with impaired hepatic function

CANURETIC should not be used in patients with moderate to severe hepatic impairment and / or cholestasis.

Paediatric population

The safety and efficacy of CANURETIC has not been established in children.

Method of administration

CANURETIC should be taken once daily and may be taken with or without food.

• Hypersensitivity to irbesartan, hydrochlorothiazide or to any of the excipients listed in section 6.1.
• Moderate to severe hepatic impairment and/or cholestasis.
• Gout.
• A history of angioedema related to previous therapy with ACE-inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Moderate to severe renal function impairment (creatinine clearance < 30 mL / min).
• 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, amiloride.
• Porphyria.
• CANURETIC contains a thiazide diuretic in (fixed dose) and therefore should not be given to patients with Addison's disease, This therapy is also contraindicated in patients with severe renal impairment or anuria, and in patients who show hypersensitivity to other sulphonamide-derived medicines.
• Lithium therapy: Concomitant administration with CANURETIC may lead to toxic blood concentrations of lithium. (see section 4.5)
• Pregnancy and lactation. (see section 4.6)
• The concomitant use of CANURETIC with aliskiren-containing products is contraindicated. (see section 4.4 and 4.5)
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip (see section 4.4).

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 (see Section 4.5).

ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

When CANURETIC is used in 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 u2264 15 mL / min / 1,73 mu00b2 BSA).

Prolongation of INR and bleeding complications with concomitant warfarin therapy may occur.

Lithium toxicity may occur when CANURETIC is used in combination with lithium therapy (see section 4.5).

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma but are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Laboratory findings

Should a woman become pregnant while receiving CANURETIC, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (See section 4.3 and 4.6).

Increases in serum uric acid, serum creatinine, serum urea, serum potassium, blood glucose and serum alanine transaminase (ALT) may occur. Decreases in haemoglobin and increases in serum aspartate transaminase (AST) have been observed in patients receiving CANURETIC.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC. Patients taking CANURETIC should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in the case of exposure, adequate protection should be advised to the patients to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies.

CANURETIC should not be used by patients who have had previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and/or lip (see section 4.3).

Renal artery stenosis

CANURETIC may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with CANURETIC due to blockade of the renin-angiotensin-aldosterone system. This may be severe such that additional intravenous fluids and/or vasopressors are needed.

Intravascular volume depletion

In patients with intravascular volume and/or sodium depletion, symptomatic hypotension may occur. Therefore, the use of CANURETIC is not recommended until this condition has been corrected.

Renal impairment / kidney transplantation

When CANURETIC is used in patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid levels is recommended. Loop diuretics are preferred to CANURETIC in this population. There is no experience regarding the administration of CANURETIC in patients with recent kidney transplantation.

Hepatic impairment

There is no experience in patients with moderate to severe hepatic impairment and/or cholestasis.

Aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy

Special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy (see section 4.3)

Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. CANURETIC can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatraemia, hypomagnesaemia and hypochloraemic alkalosis). Marked hypercalcaemia may be a sign of hyperparathyroidism. CANURETIC should be discontinued before carrying out tests for parathyroid function.

Hydrochlorothiazide (a component of CANURETIC) dose-dependently increased urinary potassium excretion which may result in hypokalaemia, e.g. in liver cirrhosis, after brisk diuresis, inadequate intake of electrolytes and in patients receiving corticosteroids. Concomitant use of CANURETIC and potassium-sparing diuretics, potassium supplements or salt substitutes or other medicines that may increase potassium levels (e.g. heparin sodium) may lead to increases in serum potassium.

Metabolic and endocrine effects

Treatment with CANURETIC may impair glucose tolerance. Dosage adjustment of antidiabetic medicines, including insulin, may be required. Latent diabetes mellitus may manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with hydrochlorothiazide therapy. At the doses contained in CANURETIC only minimal effects were observed. Hydrochlorothiazide may increase serum uric acid concentration and may precipitate gout in susceptible patients.

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 such as CANURETIC has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure as has been observed in post marketing data. Excessive blood pressure decrease in patients with ischaemic heart disease or atherosclerotic cerebrovascular disease may result in myocardial infarction or stroke.

Excipients: lactose intolerance

CANURETIC contains lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 (see Sections 4.3, 4.4 and 5.1).

No medicine interactions of clinical significance have been identified for candesartan cilexetil.

Compounds which have formally been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol / levonorgestrel), glibenclamide and nifedipine.

Post marketing report suggests a rare but significant interaction with prolongation of INR and bleeding, with concomitant warfarin therapy.

The bioavailability of candesartan is not affected by food.

The antihypertensive effect of CANURETIC may be enhanced by other antihypertensives.

The potassium-depleting effect of hydrochlorothiazide could be expected to be potentiated by other medicines associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives). Diuretic-induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides and anti-arrhythmics. Periodic monitoring of serum potassium is recommended when CANURETIC is administered with such medicines.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with CANURETIC. Careful monitoring of serum lithium levels is recommended during concomitant use.

The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is blunted by NSAIDs. The absorption of hydrochlorothiazide is reduced by colestipol or cholestyramine. The effect on non-depolarizing skeletal muscle relaxants (e.g. tubocurarine) may be potentiated by hydrochlorothiazide. Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or Vitamin D must be prescribed, serum calcium levels should be monitored and dosage adjusted accordingly. The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach-emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects. The risk for hypokalaemia may be increased during concomitant use of steroids or adrenocorticotropic hormone (ACTH). Postural hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or anaesthetics.

Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed CANURETIC should be discontinued.

Pregnancy

Medicines affecting the renin-angiotensin system, such as CANURETIC, 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

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 CANURETIC is considered essential.

Fertility

No data

The effect of CANURETIC 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 occasionally dizziness or weariness may occur during treatment of hypertension.

Candesartan cilexetil

The following adverse reactions have been reported very rarely (u2264 1/10 000) with candesartan cilexetil in post-marketing experience:

Very rare: u2264 1/10 000

Blood and lymphatic system disorders: Leukopenia, neutropenia and agranulocytosis

Metabolism and nutrition disorders: Hyperkalaemia, hyponatraemia

Hepato-biliary disorders: Increased liver enzymes, abnormal hepatic function or hepatitis

Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, pruritis

Musculoskeletal, connective tissue and bone disorders: Back pain

Renal and urinary disorders: Renal impairment, including renal failure in susceptible patients

Hydrochlorothiazide:

The following adverse reactions have been reported with hydrochlorothiazide monotherapy, usually in doses of 25 mg or greater. The frequencies used are: Common (u2265 1/100), Uncommon (u2265 1/1 000 and u2264 1/100) and Rare (u2264 1/1 000).

Common (u2265 1/100)

Metabolism and nutrition disorders: Hyperglycaemia, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia)

Nervous system disorders: Light-headedness, vertigo

Renal and urinary disorders: Glycosuria

General disorders and administration site conditions: Weakness

Investigations: Increases in cholesterol and triglycerides

Uncommon (u2265 1/1 000 and u2264 1/100)

Vascular disorders: Postural hypotension

Gastrointestinal disorders: Anorexia, loss of appetite, gastric irritation, diarrhoea, constipation

Skin and subcutaneous tissue disorders: Rash, urticaria, photosensitivity reactions

Blood and lymphatic system disorders: Leukopenia, neutropenia/ agranulocytosis, thrombocytopenia, aplastic anaemia, bone marrow depression, haemolytic anaemia

Immune system disorders: Anaphylactic reactions

Rare (u2264 1/1 000)

Psychiatric disorders: Sleep disturbances, depression, restlessness

Nervous system disorders: Paraesthesia

Eye disorders: Transient blurred vision

Cardiac disorders: Cardiac arrhythmias

Vascular disorders: Necrotising angiitis (vasculitis, cutaneous vasculitis)

Respiratory, thoracic and mediastinal disorders: Respiratory distress (including pneumonitis and pulmonary oedema

Gastrointestinal disorders: Pancreatitis

Hepato-biliary disorders: Jaundice (intrahepatic cholestatic jaundice)

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, cutaneous disorders: lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus

Musculoskeletal and connective tissue disorders: Muscle spasm

Renal and urinary disorders: Renal dysfunction and interstitial nephritis

General disorders and administration site conditions: Fever

Investigations: Increases in urea and serum creatinine

Description of Selected Adverse Reactions

Non-melanoma skin cancer: (see section 4.3 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms

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

The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes. Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/impairment of consciousness and muscle cramps can also be observed.

Treatment

No specific information is available on the treatment of overdosage with CANURETIC. The following measures are, however, suggested in case of overdosage. When indicated, induction of vomiting should be considered. If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. Candesartan is not removed by haemodialysis. It is not known to what extent hydrochlorothiazide is removed by haemodialysis.