Bendroflumethiazide Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bendroflumethiazide Tablets 5 mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of bendroflumethiazide. For excipients, see 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White, biconvex tablets. Engraving: BERK 2G5 on one side with a breakline on the reverse, or 2G5 on one side with a breakline on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Bendroflumethiazide is a diuretic which is indicated for the treatment of oedema, hypertension and the inhibition of lactation.
4.2 Posology and method of administration
For oral administration.
Adults
Oedema
5 - 10 mg daily in the morning or on alternate days. The maintenance dose is 5 - 10 mg one to three times weekly.
Hypertension
2.5 mg daily in the morning. Higher doses are rarely necessary.
Inhibition of lactation
5 mg in the morning and 5 mg at noon for five days is usually adequate.
Children
Up to 400 mcg/kg bodyweight initially, reducing to a maintenance dose of 50 - 100 mcg/kg bodyweight daily.
Elderly
The dosage may need to be reduced, especially in patients with renal or hepatic impairment.
4.3 Contraindications
Bendroflumethiazide is contraindicated in severe renal and hepatic insufficiency, refractory hypokalaemia, hyponatraemia, symptomatic hyperuricaemia, hypercalcaemia and Addison’s disease.
In patients with a known hypersensitivity to thiazides.
4.4 Special warnings and precautions for use
Bendroflumethiazide should be used with caution in patients with mild to moderate renal or hepatic disorders (avoid if severe). Renal function should be monitored frequently during thiazide therapy.
Caution should be observed in the elderly. Lower initial doses should be used as the elderly are more susceptible to the side effects. Adjustment of the dosage should then be according to renal function. Thiazide diuretics may exacerbate or activate SLE in susceptible patients.
As with all thiazide diuretics a certain degree of electrolyte imbalance can occur, especially in elderly patients and patients with hepatic or renal impairment or when dosage is prolonged or high. Serum electrolytes should be checked for abnormalities, particularly hypokalaemia, and the latter corrected by addition of a potassium supplement to the regimen. There is an increased risk of hypomagnesaemia in alcoholic cirrhosis.
As serum uric acid levels may rise when thiazide diuretics are administered this may consequently exacerbate gout in susceptible patients.
Care is advised in those with a known pre-disposition to diabetes as thiazide diuretics sometimes lower carbohydrate tolerance, and the insulin dosage of the diabetic patient may require adjustment.
4.5 Interaction with other medicinal products and other forms of interaction
As sensitivity to digitalis glycosides may be increased by the hypokalaemic effect of bendroflumethiazide, patients should be observed for signs of digitalis intoxication, in particular arrhythmias, if given concurrently with bendroflumethiazide. It may be necessary to temporarily reduce the dosage of digitalis glycosides and to give a potassium supplement to restore stability.
Serum lithium concentrations may be increased by concurrent use of thiazide diuretics.
Non-steroidal anti-inflammatory agents may reduce the diuretic and anti-hypertensive effects of thiazide diuretics. Diuretics may increase the risk of nephrotoxicity of NSAIDS.
ACTH, acetazolamide, corticosteroids, and carbenoxolone may exacerbate the hypokalaemia associated with thiazide use. Thiazide diuretics may enhance the neuromuscular blocking effect of the non-depolarising muscle relaxants e.g. tubocurarine.
Concomitant use of carbamazepine may increase the risk of hyponatraemia.
There is an increased risk of hyponatraemia if thiazides are given with amphotericin.
The risk of hypercalcaemia is increased by the concomitant intake of calcium salts or vitamin D preparations.
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.
There is an increased risk of hyponatraemia when thiazides are used concomitantly with aminoglutethimide. Thiazides can cause an increased risk of hypercalcaemia with toremifene.
Thiazides may intensify the effect of antihypertensive agents, while postural hypotension associated with therapy may be increased by concomitant ingestion of alcohol, opioids or barbiturates
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.
There is an increased risk of postural hypotension with tricyclic anti-depressants. There may also be an increased risk of hypokalaemia if thiazides are given with reboxetine. Concomitant use with monoamine-oxidase inhibitors, baclofen or tizanidine may also give an increased hypotensive effect.
Oestrogens and combined oral contraceptives may antagonise the diuretic effect of thiazides.
There is an increased risk of first-dose hypotensive effect of post-synaptic alpha-blockers such as prazosin.
Hypokalaemia increases the risk of ventricular arrhythmias with pimozide or thioridazine, therefore, concomitant use should be avoided. Hypokalaemia or other electrolyte imbalance also increases the risk of ventricular arrhythmias with terfenadine.
It should be noted that bendroflumethiazide may interfere with some laboratory tests. These include tests of parathyroid function and the estimation of serum protein-bound iodine.
4.6 Pregnancy and lactation
Diuretics are not recommended for the management of oedema in pregnancy or hypertension in pregnancy as their use may be associated with reduced placental perfusion, increased blood viscosity and hypokalaemia.
There is insufficient evidence of safety in human pregnancy. Foetal bone marrow depression and thrombocytopaenia have been reported. Foetal and neonatal jaundice have also been reported.
Breast feeding should be avoided as diuretics pass into the breast milk and Bendroflumethiazide can suppress lactation.
4.7 Effects on ability to drive and use machines
None known.
4.8 Undesirable effects
All thiazide diuretics can produce a degree of electrolyte imbalance, e.g. hypokalaemia.
Thiazide diuretics may raise the serum uric acid levels with subsequent exacerbation of gout in susceptible subjects.
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.
Postural hypotension and mild gastro-intestinal effects; hypokalaemia,
hypomagnesaemia, hyponatraemia, hypercalcaemia, hypochloraemic alkalosis, hyperuricaemia, gout, hyperglycaemia and altered plasma lipid concentration.
Less commonly, rashes, photosensitivity: blood disorders (including neutropenia and thrombocytopenia - when given in late pregnancy neonatal thrombocytopenia has been reported): pancreatitis, intrahepatic cholestasis and hypersensitivity reactions (including pneumonitis, pulmonary oedema, severe skin reactions) have also been reported.
Rarely, blood dyscrasias, including agranulocytosis, aplastic anaemia,
thrombocytopenia and leucopenia, and pancreatitis have been reported with long term therapy. Skin rashes and impotence (reversible on withdrawal of treatment) have occasionally been reported.
4.9 Overdose
Initial treatment consists of either emesis or gastric lavage, if appropriate. Treatment should be symptomatic and supportive including the correction of fluid and electrolyte imbalance. Blood pressure should also be monitored. Symptoms include nausea, vomiting, anorexia, diuresis, diarrhoea, dehydration, dizziness, hypotension, weakness, muscle cramps, tetany, paraesthesia, gastrointestinal bleeding, hyponatraemia, hypo- or hyperglycaemia, hypokalemia and metabolic acidosis.
There is no specific antidote.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: C03 A01 (Low ceiling diuretics, thiazides).
Bendroflumethiazide is a thiazide diuretic which reduces the absorption of electrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. 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 gastrointestinal tract and there are indications that it is 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
Preclinical information has not been included because the safety profile of Bendroflumethiazide has been established after many years of clinical use. Please refer to section 4.
6.1 List of excipients
Lactose monohydrate
Maize starch Povidone
Sodium starch glycollate (Type A) Magnesium stearate Silica, colloidal anhydrous.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months.
Amber glass bottles with plastic screw caps: 24 months
6.4 Special precautions for storage
No special precautions for storage.
6.5 Nature and contents of container
Grey polypropylene containers with white polyethylene lids, in packs of 100,
1000 or
10,000.
HDPE containers with LDPE lids or child resistant caps, in packs of 10 x 25, 100, 1000 or 10,000.
Grey polypropylene snap-secure containers with white polyethylene lids, in packs of 100, 1000 or 10,000.
Amber glass bottles with plastic screw caps, in packs of 10 x 25.
Blister strips in packs of 7, 10, 14, 21, 28, 30, 56, 60, 84, 90, 100, 110, 112, 120, 150, 160 and 168.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited Brampton Road Hampden Park Eastbourne BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 0289/0173
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/09/1991 / 11/04/2002
10 DATE OF REVISION OF THE TEXT
10/10/2011