Bendroflumethiazide Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bendroflumethiazide tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Bendroflumethiazide 5mg BP
Also contains lactose. For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Uncoated tablet
White circular tablets, (PV) on one face and ‘BF’ break line ‘5’ on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Bendroflumethiazide is a thiazide diuretic which reduces the re absorption of electrolytes. Bendroflumethiazide is indicated for the treatment of oedema and hypertension.
4.2 Posology and method of administration
Dosage in Adults:
Oedema:
Adults: Initially, 5-10mg in the morning, daily or on alternative days Maintenance: 5-10 mg one to three times weekly
Hypertension:
Adults: 2.5mg once daily. When bendroflumethiazide is used concurrently with other antihypertensive agents the dose of bendroflumethiazide should be halved. Higher doses are rarely necessary.
Dosage in children:
Initially up to 400pg/kg bodyweight daily. Maintenance: 50 - 100pg/kg bodyweight daily.
Dosage in the elderly:
The dosage of bendroflumethiazide may need to be reduced in the elderly, particularly when renal function is impaired because of the possibility of electrolyte imbalance. Lower initial doses should be used and electrolyte balance and renal function should be carefully monitored.
Method of Administration
For oral administration.
4.3 Contraindications
Bendroflumethiazide is contra-indicated in patients with known hypersensitivity to bendroflumethiazide or other sulphonamide-derived drugs; refractory hypokalaemia, hyponatraemia, hypercalcaemia, severe renal insuffiency or anuria, severe hepatic impairment (risk of precipitation of encephalopathy); symptomatic hyperuricaemia and Addison’s disease. Bendroflumethiazide tablets should not be administered with lithium carbonate.
4.4 Special warnings and precautions for use
Bendroflumethiazide should be used with caution in patients with renal or hepatic encephalopathy (see section 4.3), Addison’s disease and diabetes. The risk of hypokalaemia is increased in patients with hepatic cirrhosis. Renal function and plasma electrolytes should be monitored during thiazide therapy.
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.
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.
The risk of hypomagnesaemia is increased in alcoholic cirrhosis.
Systemic lupus erythematosus (SLE) may be exacerbated by bendroflumethiazide.
All thiazide diuretics can produce a degree of electrolyte imbalance, especially in patients with renal or hepatic impairment or when dosage is high or prolonged. Serum electrolytes should be checked for abnormalities, particularly hypokalaemia, and the latter corrected by the addition of a potassium supplement to the regimen.
Use of thiazide may aggravate diabetes mellitus and gout. Thiazide diuretics sometimes lower carbohydrate tolerance and the insulin dosage of the diabetic patient may require adjustment. Care is necessary when bendroflumethiazide is administered to those with a known predisposition to diabetes. (see section 4.8).
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). 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 ongoing monitoring and blood tests are to be performed in elderly patients and patients who are on long term treatment with bendroflumethiazide.
Caution is required in patients with severe asthma, as hypokalaemia associated with beta2-agonist therapy can be potentiated by concurrent use of diuretics.
This product contains lactose. Patient with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose mal-absorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Bendroflumethiazide may enhance the toxicity of digitalis glycosides by depleting serum-potassium concentrations. Patients should be observed for signs of digitalis intoxication, in particular arrhythmias, when the dosage of digitalis glycosides should be temporarily reduced and a potassium supplement given to restore stability.
Xanthine, ACTH, acetazolamide and carbenoxolone may exacerbate the hypokalaemia associated with thiazide use.
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.
Enhanced hypotensive effect may occur when aldesleukin and thiazide diuretics are used concomitantly.
Enhanced hypotensive effect may occur when general anaesthetics and thiazide diuretics are used concomitantly.
Enhanced hypotensive effect may occur with tizanidine. Bendroflumethiazide may enhance the neuromuscular blocking effects of non-depolarising muscle relaxants such as tubocurarine.
Non-steroidal anti-inflammatory agents may block the diuretic, natriuretic and antihypertensive effects of bendroflumethiazide. Diuretics may increase the risk of nephrotoxicity of NSAIDs.
Serum Lithium concentrations may be increased as a result of reduced renal clearance by the concurrent use of bendroflumethiazide (see section 4.3).
Enhance hypotensive effects may follow the concomitant use of thiazides and barbiturates, alcohol, other anti-hypertensive’s, MAOI’s or narcotics.
Bendroflumethiazide may interfere with a number of laboratory tests including estimation of serum protein-bound iodine and tests of parathyroid function.
Concomitant use of carbamazepine may increase the risk of hyponatraemia. There is an increased risk of hyponatraemia if thiazides are given with ampotericin. The risk of hypercalcaemia is increased by the concomitant intake of calcium salts or vitamin-D preparations. There is an increased risk of developing milk-alkali syndrome in patients given large amounts of calcium or vitamin D in combination with thiazides.
Concomitant use with cisplatin can lead to an increased risk of nephrotoxicity and ototoxicity.
The cardiac toxicity of disopyramide, amiodarone, flecainide and quinidine is increased if hypokalaemia occurs. The action of lidocaine and mexiletine is antagonised by hypokalaemia.
Severe hyponatraemia may occur with concomitant administration of bendroflumethiazide and trimethoprim.
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.
Potential for increased toxicity and hypersensitivity/allergic reactions with concomitant use of allopurinol and thiazide diuretics.
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.
Increased risk of nephrotoxicity and/or hypermagnesaemia with concomitant use of ciclosporin and thiazide diuretics, such as bendroflumethiazide.
Enhanced hypotensive effect may occur when levodopa and thiazide diuretics are used concomitantly.
There is an increased risk of hyponatraemia when thiazides are used concomitantly with aminoglutethimide.
Thiazides can cause an increased risk of hypercalcaemia with toremifene.
Colestipol and colestyramine may reduce the absorption of thiazide diuretics and should therefore be given 2 hours prior to, or after the ingestion of bendroflumethiazide.
Calcium-channel blockers and moxisylyte can cause an enhanced hypotensive effect.
Oestrogens and combined oral contraceptives may antagonise the diuretic effect of thiazides.
There is an increased risk of postural hypotension with tricyclic antidepressants.
There may also be an increased risk of hypokalaemia if thiazides are given with reboxitine.
Concomitant use with monoamine oxidase inhibitors (MOIs), baclofen or tizanidine may also give an increased hypotensive effect. There is an increased risk of first dose hypotensive effect of post-synaptic alpha-blockers such as prazocin.
Hypokalaemia increases the risk of ventricular arrhythmias with primozide or thioridazine or sertindole, therefore, concomitant use should be avoided. Enhanced hypotensive effect may occur when phenothiazines and thiazide diuretics are used concomitantly.
Hypokalaemia or other electrolyte imbalance also increases the risk of ventricular arrhythmias with drugs that prolongs QT interval, such as halofantrine (antimalarials), astemizole and Terfenadine (antihistamines).
Enhanced hypotensive effect may occur when nitrates and thiazide diuretics are used concomitantly.
Hypotensive effect may be potentiated by alprostadil (Prostaglandins).
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.
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 Fertility, pregnancy and lactation
Bendroflumethiazide is best avoided for the management of oedema of pregnancy or hypertension in pregnancy as their use may be associated with increased risk of acute haemorrhagic pancreatitis, hypokalaemia, increased blood viscosity and reductions in maternal blood volume may reduce placental perfusion. There is inadequate evidence of safety in human pregnancy and cases of foetal bone marrow depression, thrombocytopenia and severe electrolyte imbalances, including hypokalaemia and hyponatraemia have been reported in newborn infants. Foetal and neonatal jaundice have also been reported. Cases are rare and should not prevent the use of bendroflumethiazide when indicated in pregnancy.
Bendroflumethiazide is excreted in breast milk and should be avoided in mothers who wish to breast feed. The amount detected in breast milk is too small to be harmful. 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 section 4.4 & 4.5).
Metabolism and nutrition disorders: Blood uric acid levels may be increased with or without gout. It may also precipitate acute attacks of gout.
Electrolyte imbalance including hypochloraemic alkalosis, hypomagnesaemia, hypokalaemia, hyponatraemia and altered plasma lipid concentration. Urinary excretion of calcium may be reduced and the potential for hypercalcaemia may be increased (use in pre-existing 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 section 4.4).
Psychiatric disorders: Reduced libido
Nervous system disorders: Headache, dizziness, paraesthesia. Drowsiness may occur and may be associated with electrolyte imbalance
Cardiac disorders: Postural hypotension
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 are reported less commonly. 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 of over dosage are those caused by excessive diuresis. Treatment must be symptomatic and directed by fluid electrolyte replacement.
Symptoms of over dosage include anorexia, nausea, vomiting, diarrhoea, dehydration, hypotension, dizziness, weakness, muscle cramps, paraesthesia, tetany, gastrointestinal bleeding, hyponatraemia, hypo or hyperglycaemia, hypokalaemia and metabolic alkalosis. Initial treatment consists of either emesis or gastric lavage, if appropriate. Blood pressure should also be monitored. Patients who present within one hour of an overdose may be administered activated charcoal. There is no specific antidote.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: C07BA06
Pharmacotherapeutic group: Thiazide diuretic.
Bendroflumethiazide inhibits the renal tubular absorption of salt and water. Sodium and chloride ions are excreted in equivalent proportions, and there is little or no disturbance of the acid/base equilibrium. There is no important
effect on carbonic anhydrase. The mechanism whereby the thiazides exert their antihypertensive effects has not been clearly established.
The excretion of other electrolytes, notably potassium and magnesium, is also increased. The excretion of calcium is reduced. Thiazides also reduce carbonic anhydrase activity so that bicarbonate excretion is increased, but this effect is generally small and does not appreciably alter the acid base balance or the pH of the urine. Thiazides also have a hypotensive effect, due to a reduction in peripheral resistance and enhance the effects of other antihypertensive agents.
5.2 Pharmacokinetic properties
Bendroflumethiazide has been reported to be completely absorbed from the Gastro-intestinal tract, and there are indications that it fairly extensively metabolised; about 30% is excreted unchanged in the urine.
The onset of diuretic action of the thiazides following oral administration occurs within two hours and the peak effect between three and six hours after administration. The duration of the diuretic action of bendroflumethiazide is between 18 and 24 hours. The onset of the hypotensive action is generally three or four days.
5.3 Preclinical safety data
None stated
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose Maize Starch Povidone
Magnesium Stearate
6.2 Incompatibilities
No major incompatibilities known.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Should be stored in a cool and dry place, protected from bright light.
6.5 Nature and contents of container
Securitainer with polypropylene lids containing bendroflumethiazide tablets (material of container complies with EEC directives for plastic in contact with drugs and food stuff). In packs of 500 and 1000’s tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
Pharmvit Limited
Unit 13, Metropolitan Centre
Derby Road
Greenford
Middlesex
UB6 8UJ.
8 MARKETING AUTHORISATION NUMBER
PL 04556/0012
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/05/1985 / 28/04/2004
10 DATE OF REVISION OF THE TEXT
12/06/2014