Bendroflumethiazide 5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bendroflumethiazide 5mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Bendroflumethiazide BP 5mg For excipients, see 6.1.
3 PHARMACEUTICAL FORM
White, circular flat faced tablets with bevelled edges having a CP logo on one face and B 5 separated by a breakline on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Bendrofluazide is a diuretic. The tablets are indicated in the treatment of essential hypertension and oedema associated with such conditions as nephrotic syndrome, cirrhosis of the liver, congestive heart failure and pre-menstrual syndrome.
4.2 Posology and method of administration
Adults
Oedema: 5-10mg daily in the morning initially. Maintenance:
usually 2.5mg-5mg on only two or three days in the week. A single dose may be sufficient.
Essential Hypertension: 2.5mg in the morning. Doses above 2.5mg are rarely
necessary.
Pre-menstrual syndrome:
2.5mg each morning for seven days before the period is due.
Elderly
Particular caution is needed in the elderly because of their susceptibility to electrolyte imbalance. Lower initial doses should be used and electrolyte balance and renal function should be carefully monitored.
Children
Oedema: Up to 400pg per kg body weight daily initially,
reducing to 50-100pg per kg for maintenance.
4.3 Contraindications
Sensitivity to bendroflumethiazide or other sulphonamide-derived drugs. Hypercalcaemia. Severe renal insufficiency or anuria, severe hepatic impairment (risk of precipitation of encephalopathy), Addison’s disease. Bendroflumethiazide tablets should not be administered with lithium carbonate.
4.4 Special warnings and precautions for use
Continued or intensive use of bendroflumethiazide may produce potassium depletion. A potassium chloride supplement is recommended in these circumstances. Potassium replacement or conservation is also likely to be necessary in patients at risk from the cardiac effects of hypokalaemia, such as those with severe heart disease, those taking digitalis preparations or high doses of diuretics and in patients with severe liver disease. Potassium supplements should not be given in renal insufficiency complicated by hyperkalaemia.
Potassium supplementation alone may not be sufficient to correct hypokalaemia in patients who are also deficient in magnesium. Magnesium depletion has also been implicated as a risk factor for arrhythmias.
Use with caution in renal impairment (severe renal insufficiency is a contraindication to use, see 4.3). Use with caution in hepatic impairment (severe hepatic impairment is a contraindication to use, see 4.3). The risk of hypokalaemia is increased in patients with hepatic cirrhosis.
In seriously ill patients, reversible increases in blood urea have been reported accompanying vigorous diuresis, hepatic cirrhosis, ascites and metabolic alkalosis or those with resistant oedema. Serum electrolyte and blood urea levels should be carefully monitored in these patients.
Hyponatraemia: Some patients may be particularly susceptible to hyponatraemia, including the elderly and those with severe heart failure who are very oedematous, particularly with large doses of thiazides in conjunction with restricted salt in the diet. The onset of hyponatraemia can be sudden and life-threatening(see also 4.8 Undesirable Effects, Electrolyte Balance) All patients, including the elderly who may be particularly susceptible, should be carefully observed for signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid therapy. Regular serum electrolyte determinations should be performed in the elderly and in patients receiving long-term therapy.
Use of thiazides may aggravate diabetes mellitus and gout (see 4.8 Undesirable Effects, Endocrine & Metabolic subsections).
Exacerbation or activation of systemic lupus erythematosus by thiazides has been reported.
Caution is required in patients with severe asthma, as hypokalaemia associated with beta2-agonist therapy can be potentiated by concurrent use of diuretics.
4.5 Interaction with other medicinal products and other forms of interaction
Alcohol: Co-administration of alcohol may potentiate orthostatic hypotension.
Aldesleukin: Enhanced hypotensive effect may occur when aldesleukin and thiazide diuretics are used concomitantly.
Anaesthetics, general: Enhanced hypotensive effect may occur when general anaesthetics and thiazide diuretics are used concomitantly.
Analgesics: Some Non-steroidal anti-inflammatory drugs (NSAIDs), notably indometacin, may attenuate the diuretic, natriuretic and antihypertensive effects of diuretics. Diuretics may increase the risk of nephrotoxicity of NSAIDs.
Anion-exchange resins: Cholestyramine and colestipol reduce absorption of thiazides and should be given at least two hours apart.
Anti-arrhythmics: Cardiac toxicity of amiodarone, disopyramide, flecainide and quinidine is increased if hypokalaemia occurs. Action of lidocaine and mexiletine is antagonised by hypokalaemia. Hypokalaemia increases risk of ventricular arrhythmias with sotalol, a beta-blocker.
Antibacterials: Severe hyponatraemia may occur with concomitant administration of bendroflumethiazide and trimethoprim.
Antidepressants: Co-administration of tricyclic antidepressants may increase the risk of postural hypotension. Enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs). Possibly increased risk of hypokalaemia if thiazides given with reboxetine.
Antidiabetics: Bendroflumethiazide may antagonise the hypoglycaemic effects of antidiabetic drugs including insulin possibly necessitating adjustment of the dose of the antidiabetic agent. Bendroflumethiazide can act synergistically with chlorpropamide to increase the risk of hyponatraemia.
Antiepileptics: There is a risk of hyponatraemia occurring when thiazide diuretics, such as bendroflumethiazide, are used concomitantly with carbamazepine.
Antifungals: Increased risk of hypokalaemia with concurrent use of thiazide diuretics and amphotericin.
Antigout agents: Potential for increased toxicity and hypersensitivity/allergic reactions with concomitant use of allopurinol and thiazide diuretics.
Antihistamines: Bendroflumethiazide-induced hypokalaemia may increase the risk of arrhythemias with drugs that prolong the QT interval, such as astemizole and terfenadine.
Antihypertensives: Thiazide diuretics may enhance the effect of other hypotension producing medications, including angiotensin-converting enzyme (ACE) inhibitors (potential for enhanced first-dose hypotension), angiotensin-II antagonists, calcium channel blockers, beta-blockers (increased risk of first dose hypotension with alpha-blockers (increased risk of first-dose hypotension with alpha-blockers such as prazosin), hydralazine and diazoxide. The dosage of concomitantly administered antihypertensive drugs may need to be reduced when bendroflumethiazide is added to the regimen.
Concurrent administration of thiazides with beta-blockers or diazoxide has the potential to produce hyperglycaemia which may necessitate adjustment of the dose of antidiabetic medication including insulin.
Intravascular immune haemolysis may occur in patients taking bendroflumethiazide and methyldopa.
Antimalarials: Bendroflumethiazide -induced hypokalaemia may increase the risk of arrhythmias with drugs that prolong the QT interval, such as halofantrine.
Antipsychotics: Diuretic-induced hypokalaemia increases the risk of ventricular arrhythmias with primozide and sertindole, concurrent use should be avoided. Enhanced hypotensive effect may occur when phenothiazines and thiazide diuretics are used concomitantly.
Calcium salts & Vitamins: There is a risk of hypercalcaemia with calcium salts and vitamin D. There is an increased risk of developing milk-alkali syndrome in patients given large amounts of calcium or vitamin D in combination with thiazides.
Cardiac Glycosides: Potential for diuretic-induced hypokalaemia to increase the risk of cardiac glycoside toxicity. Diuretic-induced hypokalaemia intensifies the effect of cardiac glycosides on cardiac muscle and treatment with cardiac glycosides may have to be temporarily suspended.
Ciclosporin: Increased risk of nephrotoxicity and/or hypermagnesaemia with concomitant use of ciclosporin and thiazide diuretics, such as bendroflumethiazide.
Corticosteroids: Increased risk of thiazide-induced hypokalaemia, mainly with the naturally occurring corticosteroids such as cortisone and hydrocortisone. The synthetic corticosteroids have a much less marked potassium-losing effect. Fluid retention associated with corticosteroid use may antagonise the diuretic/antihypertensive effect.
Diuretics: Increased risk of hypokalaemia with concurrent administration of other thiazides and other diuretics including acetazolamide and loop diuretics.
Dopaminergics: Enhanced hypotensive effect may occur when levodopa and thiazide diuretics are used concomitantly.
Hormone antagonists: Thiazide diuretics may increase the risk of hypercalcaemia with toremifene.
Lithium: Lithium may accumulate as a result of reduced renal clearance (see 4.3 Contraindications).
Muscle relaxants: Enhanced hypotensive effect may occur with tizanidine. Diuretic-induced hypokalaemia may potentiate the blockade of non-depolarising neuromuscular blocking agents.
Nitrates: Enhanced hypotensive effect may occur when nitrates and thiazide diuretics are used concomitantly.
Prostaglandins: Hypotensive effect may be potentiated by alprostadil.
Sympathomimetics: Increased risk of hypokalaemia with thiazide diuretics and high doses of beta2 sympathomimetics. (See 4.4 Special warnings and precautions for use, use of beta2-agonists in severe asthma).
Ulcer-healing drugs: Potential for severe hypokalaemia with carbenoxolone.
Fluid retention associated with carbenoxolone may cause antagonism of diuretic/antihypertensive effect.
Vitamins: See under Calcium salts & Vitamins.
Drug/laboratory tests: Because thiazides may affect calcium metabolism, bendroflumethiazide may interfere with tests for parathyroid function. Bendroflumethiazide should be stopped before parathyroid function is tested.
4.6 Pregnancy and lactation
Expectant mothers using bendroflumethiazide may be at increased risk of acute haemorrhagic pancreatitis, reductions in maternal blood volume may decrease placental perfusion. Neonatal jaundice, thrombocytopenia, and severe electrolyte imbalances, including hypokalaemia and hyponatraemia have been reported in newborn infants. Cases are rare and should not prevent the use of bendroflumethiazide when indicated in pregnancy. Bendroflumethiazide is secreted in mother's milk, therefore breast feeding should be avoided. Treatment with large doses of thiazides may suppress lactation.
4.7 Effects on ability to drive and use machines
Dizziness, drowsiness, postural hypotension and mental confusion may occur. This may impair ability to drive or operate machinery
4.8 Undesirable effects
Blood and lymphatic system disorders: Blood dyscrasias may occur, including thrombocytopenia and rarely neutropenia, leucopenia, agranulocytosis or aplastic anaemia. A few cases of serious thrombocytopenia, agranulocytosis or aplastic anaemia have been reported.
Immune system disorders: Hypersensitivity reactions may occur and may involve pruritus, skin rashes, pulmonary oedema, pneumonitis, toxic epidermal necrolysis and anaphylaxis (see also Skin and subcutaneous tissue disorders below).
Endocrine disorders: Thiazides may cause hyperglycaemia and aggravate or unmask diabetes mellitus. Blood glucose concentrations should be monitored in patients taking antidiabetics since requirements may change (see 4.5 Interactions, Antidiabetics).
Metabolism and nutrition disorders: Blood uric acid levels may be increased with or without gout.
Electrolyte imbalance including hypochloraemic alkalosis, hypomagnesaemia, hypokalaemia and hyponatraemia. Urinary excretion of calcium may be reduced and the potential for hypercalcaemia may be increased (use in preexisting hypercalcaemia is contraindicated). Hyponatraemia as a complication is rare, but constitutes a medical emergency, as onset may be rapid. The symptoms of hyponatraemia may be non-specific and include nausea, lethargy, weakness, mental confusion, irritability, muscle cramps and anorexia, but it may be an important cause of morbidity. Severe sequelae of hyponatraemia include tonic-clonic seizures and clinical features resembling subarachnoid haemorrhage (see also 4.4 Special warnings & precautions for use).
Psychiatric disorders: Reduced libido
Nervous system disorders: Headache, dizziness, paraesthesia. Drowsiness may occur and may be associated with electrolyte imbalance
Cardiac disorders: Postural hypotension
Vascular disorders: Vasculitis
Gastrointestinal disorders: Diarrhoea, constipation. Other mild gastrointestinal effects, including nausea, vomiting, dry mouth and thirst may be associated with hypokalaemia. Pancreatitis.
Hepatobiliary disorders: Cholecystitis; cholestasis
Skin and subcutaneous tissue disorders: Rash, photosensitivity, which may persist after thiazide withdrawal. Eruptions resembling lichen planus and subacute cutaneous lupus erythematosus may be due to photosensitivity reactions. Erythema multiforme, pseudoporphyria
Renal and urinary disorders: Acute interstitial nephritis, non-opaque urate calculi. Oliguria may occur and may be associated with electrolyte imbalance
Reproductive and breast disorders: Impotence.
Investigations: Increased triglyceride, total cholesterol, low-density and very-low-density lipoprotein cholesterol concentrations.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms
The most likely signs and symptoms are those attributable to fluid depletion (dehydration and hypotension) and electrolyte imbalance.
Treatment
Patients who present within one hour of an overdose may be administered activated charcoal. Symptomatic treatment involves fluid and electrolyte replacement.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Bendroflumethiazide is a thiazide diuretic and reduces the reabsorption of electrolytes from renal tubules thereby increasing the excretion of sodium and chloride and subsequently of water.
5.2 Pharmacokinetic properties
Bendroflumethiazide may be completely absorbed from the gastrointestinal tract. It is fairly extensively metabolised, about 30% is excreted unchanged in the urine. It is estimated to have a plasma half-life of about 3 to 4 hours. Its biological half-life is much longer.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to those included in other sections.
6.1 List of excipients
Lactose powder Pregelatinised maize starch Maize starch Purified talc Magnesium stearate Water
6.2 Incompatibilities
None known.
6.3 Shelf life
36 months in polyethylene/polypropylene containers. 24 months in PVC/aluminium foil blister packs.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package.
6.5 Nature and contents of container
Amber glass bottles with plastic cap containing 50 tablets.
Polypropylene or polyethylene containers containing 100, 250, 500, 1000 and bulk amount of tablets.
Blister packs of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or 14, 28, 56, 84, 112 tablets.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd,
Ash Road North,
Wrexham,
LL13 9UF,
United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0023
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30th June 1982
10 DATE OF REVISION OF THE TEXT
01/05/2015