BENDROFLUMETHIAZIDE TABLETS - summary of medicine 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 400^g/kg bodyweight daily.

Maintenance: 50 – 100^g/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.

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 may raise serum uric acid levels with consequent exacerbation of gout insusceptible patients.

Bendroflumethiazide should be used with caution in patients with mild to moderate hepatic or renal impairment (avoid if severe). Renal function should be continuously monitored during thiazide therapy. Thiazide diuretics may exacerbate or activate systemic lupus erythematosus in susceptible patients.

All thiazide diuretics can produce a degree of electrolyte imbalance, which is more severe 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. Aggravates diabetes mellitus and gout; increased risk of hypomagnesaemia in alcoholic cirrhosis.

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 when treating patients with porphyria.

Patients taking pimozide or thioridazine. (see section 4.5)

This product contains the excipients lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Regular ongoing monitoring and blood tests are to be performed in elderly patients and patients who are on long term treatment with Bendroflumethi­azide.

4.5 Interaction with other medicinal products and other forms of interaction

Digoxin: Sensitivity to digitalis glycosides may be increased by the hypokalaemic effect of concurrent bendroflumethi­azide. Patients should be observed for signs of digitalis intoxication, in particular arrhythmias, and if these appear, the dosage of the

digitalis glycoside should be temporarily reduced and a potassium supplement given to restore stability.

Lithium: Bendroflumethiazide inhibits the tubular elimination of lithium, resulting in an elevated plasma lithium concentrations and risk of toxicity. Plasma lithium concentrations must be monitored when these drugs are given concurrently.

NSAIDs: Non-steroidal anti-inflammatory agents may blunt the diuretic and antihypertensive effects of thiazide diuretics. Diuretics may increase the risk of nephrotoxicity of NSAIDs. Indometacin and ketorolac antagonise the diuretic effect of Bendroflumethi­azide, this occurs to a lesser extent with ibuprofen, piroxicam and naproxen. The effects of concurrent use should be monitored and the dose of bendroflumethiazide modified if necessary.

Others: Xanthines, beta-agonists, ACTH, and acetazolamide may exacerbate the

hypokalaemia associated with thiazide use.

Muscle relaxants: The hypotensive effect of Bendroflumethiazide may be increased by baclofen and tizanidine. Thiazide diuretics may enhance the neuromuscular blocking effects of the non-depolarising muscle relaxants, e.g. tubocurarine, gallamine, alcuronium and pancuronium.

Corticosteroids: Corticosteroids may exacerbate hypokalaemia associated with Bendroflumethiazide and its diuretic activity may be antagonized.

Alcohol, barbiturates and opioids: Postural hypotension associated with therapy may be enhanced by concomitant ingestion of alcohol, barbiturates or opioids.

Anti-epileptic: Concomitant use of carbamazepine may increase the risk of hyponatraemia.

Anti-fungal: There is an increased risk of hyponatraemia if thiazides are given with amphotericin.

Vitamins: The risk of hypercalcaemia is increased by the concomitant intake of calcium salts or vitamin D preparations.

Cytotoxics: Concomitant use with cisplatin can lead to an increased risk of nephrotoxicity and ototoxicity.

Anti-arrhythmics: The cardiac toxicity of disopyramide, amiodarone, flecainide and quinidine is increased if hypokalaemia occurs. The action of lidocaine and mexiletine is antagonised by hypokalaemia.

Hormone antagonists: There is an increased risk of hyponatraemia when thiazides are

used concomitantly with aminoglutethimide. Thiazides can cause an increased risk of

hypercalcaemia with toremifene.

Anion exchange resins: 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 peripheral vasodilators: The hypotensive effect of

calcium-channel blockers and moxisylyte may be enhanced when coadministered

with Bendroflumethi­azide.

Anti-depressants: 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 reboxetine. Concomitant use with monoamine oxidase inhibitors (MAOIs)

may also give an increased hypotensive effect.

Oestrogens and progesterons: Oestrogens and combined oral contraceptives may antagonise the diuretic effect of thiazides.

Antipsychotics: Hypokalaemia increases the risk of ventricular arrhythmias with

pimozide or thioridazine; therefore, concomitant use should be avoided.

Terfenadine: Hypokalaemia or other electrolyte imbalance also increases the risk of

ventricular arrhythmias with terfenadine.

Laboratory tests: Bendroflumethiazide may interfere with a number of laboratory tests, including estimation of serum protein-bound iodine and tests of parathyroid function.

Allopurinol: Bendroflumethiazide may antagonise the action of allopurinol by causing retention of urate in the kidney. Caution is advised when using this combination.

Antidiabetics: Bendroflumethiazide antagonises the hypoglycaemic effect of sulfonylureas, with a potential loss of diabetic control.

Antihypertensive: Bendroflumethiazide may enhance the antihypertensive effect of ACE inhibitors and angiotensin-II antagonists. There is an increased risk of first dose hypotensive effect of post-synaptic alpha-blockers such as prazosin.

Calcium salts: Bendroflumethiazide reduces urinary excretion of calcium so there is an increase risk of hypercalcaemia when calcium salts are taken concurrently. Serum calcium levels should be monitored to ensure that they do not become excessive.

Sympathomimetics: Sympathomimetics can cause hypokalaemia. The risk of serious

heart arrhythmias in asthamatic patients may be increased if Bendroflumethi­azide is

added to their medicaction.

Theophylline: Concomitant administration of theophylline and Bendroflumethiazide increases the risk of hypokalaemia.

Ulcer healing drugs: There is an increased risk of hypokalaemia and a decrease in diuretic activity when carbenoxolone and Bendroflumethiazide are taken together. Patients should be monitored and given potassium supplements when required.

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

The following undesirable effects, which are listed in system order class, have previously been associated with Bendroflumethi­azide. Specific frequencies for the occurrence of these effects are not available.

All thiazide diuretics can produce a degree of electrolyte imbalance, e.g. hypokalaemia.

Immune system disorders:

Hypersensitivity reactions

Metabolism and nutrition disorders:

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 (hyperglycaemia reported).

Bendroflumethiazide may raise the serum uric acid levels with subsequent exacerbation of gout in susceptible subjects (hyperuricaemia). Plasma lipids may be altered in patients taking Bendroflumethi­azide.

Cardiac and vascular disorders:

Postural hypotension

Gastrointestinal disorders:

Mild gastro-intestinal effects, nausea, vomiting, diarrhoea, constipation and gastric irritation have all been reported.

Investigations:

Hypokalaemia, hypomagnesaemia, hyponatraemia, hypercalcaemia, hypochloraemic alkalosis, hyperuricaemia,. Hypokalaemia may result in polyurea, malaise, muscle weakness or cramp, dizziness, nausea, anorexia or vomiting.

Hepatobiliary disorders:

Pancreatitis, intrahepatic cholestasis

Respiratory, thoracic and mediastinal disorders:

Hypersensitivity reactions (including pneumonitis, pulmonary oedema,) also reported.

Blood and lymphatic system disorders:

Blood dyscrasias including agranulocytosis, aplastic anaemia, neutropenia, thrombocytopenia (neonatal thrombocytosis is reported when given in late pregnancy) and leucopenia, and pancreatitis have been reported with long term therapy may occur rarely.

Reproductive system and breast disorders:

Impotence (reversible on withdrawal of treatment)

Skin and subcutaneous tissue disorders:

Rash (including exfoliative dermatitis), photosensitivity, severe skin reactions may occur.

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.