This information is intended for use by health professionals

1. Name of the medicinal product

BENDROFLUMETHIAZIDE TABLETS BP 2.5mg

2. Qualitative and quantitative composition

Each tablet contains 2.5mg Bendroflumethiazide PhEur.

Excipient with known effect:

Each 2.5mg tablet contains 50mg Lactose

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

White uncoated tablets.

4. Clinical particulars
4.1 Therapeutic indications

Bendroflumethiazide is indicated for:

1. Cases where the reduction of fluid retention by diuresis is required; oedema of cardiac, renal or hepatic origin and iatrogenic oedema

2. Bendroflumethiazide produces a moderate but usefully prolonged fall of blood pressure in hypertensive patients. It may be used as the sole antihypertensive agent, or, as an adjunct to other drugs whose action it potentiates. In non-oedematous patients, there may be little noticeable diuretic effect.

4.2 Posology and method of administration

Posology

It is recommended that the tablets should be taken in the morning to avoid nocturia.

Adults and children aged 12 years and over:

Oedema:

Initially 5-10mg in the morning, daily or on alternate days.

Maintenance dose 5-10mg one to three times weekly.

Hypertension: The usual dose is 2.5mg taken in the morning. Higher doses are rarely necessary.

Paediatric population

Children under 12 years: Dosage in children may be up to 400micrograms/kg of body weight initially, reducing to 50-100micrograms/kg of body weight daily for maintenance.

Elderly: The dosage of thiazide diuretics may need to be reduced in the elderly, particularly when renal function is impaired, because of the possibility of electrolyte imbalance.

Method of Adminstration

For oral administration.

4.3 Contraindications

• Hypersensitivity to the active substance, to thiazides or to any of the excipients listed in section 6.1.

• Severe renal or hepatic insufficiency.

• Hypercalcaemia; refractory hypokalaemia; hyponatraemia; symptomatic hyperuricaemia.

• Addison's disease.

4.4 Special warnings and precautions for use

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 (SLE) in susceptible patients.

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.

Aggravates diabetes and gout; increased risk of hypomagnesaemia in alcoholic cirrhosis.

Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

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

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

4.5 Interaction with other medicinal products and other forms of interaction

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

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.

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

Antidepressants: 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 MAOIs may result in an enhanced hypotensive effect.

Antiepileptics: Concomitant use of carbamazepine may increase the risk of hyponatraemia.

Antifungals: There is an increased risk of hyponatraemia if thiazides are given with amphotericin.

Antihypertensives: Thiazides may enhance the effects of antihypertensive agents, such as ACE inhibitors and angiotensin-II antagonists, while postural hypotension associated with therapy may be enhanced by concomitant ingestion of alcohol, barbiturates or opioids. There is an increased risk of first-dose hypotensive effect of post-synaptic alpha-blockers such as prazosin.

Antipsychotics: 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.

Calcium salts: The risk of hypercalcaemia is increased by the concomitant intake of calcium salts. Calcium channel blockers and peripheral vasodilators: Calcium channel blockers and moxisylyte can cause an enhanced hypotensive effect.

Corticosteroids: Corticosteroids may exacerbate the hypokalaemia associated with thiazide use.

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

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.

Hormone antagonists: There is an increased risk of hyponatraemia when thiazides are used concomitantly with aminoglutethamide. Thiazides can cause an increased risk of hypercalcaemia with toremifene.

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

Lithium: Serum lithium concentrations may be increased by concurrent use of thiazide diuretics.

Muscle relaxants: Thiazide diuretics may enhance the neuromuscular blocking effects of the non-depolarising muscle relaxants, e.g. tubocurarine. Baclofen or tizanidine may also give an increased hypotensive effect.

NSAIDs: Non-steroidal anti-inflammatory agents may blunt the diuretic and hypertensive effects of thiazide diuretics. Diuretics may increase the risk of nephrotoxicity of NSAIDs, e.g. indomethacin, ketorolac, ibuprofen, piroxicam, naproxen.

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

Sympathomimetics: Beta-agonists may exacerbate the hypokalaemia associated with thiazide use. The risk of serious heart arrhythmias in asthmatic patients may be increased if bendroflumethiazide is added to their medication.

Theophylline: Concomitant administration of xanthines, such as theophylline and thiazides may increase the risk of hypokalaemia.

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

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Bendroflumethiazide is best avoided for the management of oedema or hypertension in pregnancy as it crosses the placenta and its use may be associated with hypokalaemia, increased blood viscosity and reduced placental perfusion.

There is insufficient evidence of safety in human pregnancy and foetal bone marrow depression, thrombocytopenia and neonatal jaundice have been described.

Breast-feeding

Bendroflumethiazide suppresses lactation and, although the amounts passing into breast milk are small, it should be avoided in breast feeding mothers.

4.7 Effects on ability to drive and use machines

As bendroflumethiazide can cause dizziness, patients should make sure they are not affected before driving or operating machinery.

4.8 Undesirable effects

The following undesirable effects have been divided into the following categories: Very common: ≥1/10, Common: ≥1/100 to <1/10, Uncommon: ≥1/1,000 to<1/100 Rare: ≥1/10,000 to <1/1,000, Very rare: <1/10,000, not known (cannot be estimated from the available data)

Blood and the lymphatic system disorders

Rare

Blood dyscrasias, including agranulocytosis, aplastic anaemia, neutropenia, thrombocytopenia and leucopenia

Immune system disorders

not known

Rashes (including exfoliative dermatitis), photosensitivity, hypersensitivity reactions (including pneumonitis, severe skin reactions, pulmonary oedema) have been reported occasionally.

Metabolism and nutrition disorders

not known

Bendroflumethiazide may lower carbohydrate tolerance causing hyperglycaemia1. Bendroflumethiazide may raise serum uric acid levels (hyperuricaemia) and exacerbate gout in susceptible individuals. Plasma lipids may be altered in patients taking bendroflumethiazide.

Bendroflumethiazide administration may cause hypokalaemia2, hypomagnesaemia, hyponatraemia, hypercalcaemia and hypochloraemic alkalosis.

Nervous system disorders

not known

Dizziness

Vascular disorders

not known

Postural hypotension.

Gastrointestinal disorders

not known

Nausea, vomiting, diarrhoea, constipation and gastric irritation.

Hepatobiliary disorders

not known

Pancreatitis, intrahepatic cholestasis

Reproductive system and breast disorders

not known

impotence (reversible on discontinuing the drug)

1 insulin dosage of some diabetic patients may require adjustment. Care is required when Bendroflumethiazide is administered to patients with a known predisposition to diabetes.

2 hypokalaemia may result in polyuria, malaise, muscle weakness or cramp, dizziness, nausea, anorexia or vomiting.

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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms: Anorexia, nausea, vomiting, diarrhoea, diuresis, dehydration, hypotension, dizziness, weakness, muscle cramps, , paraesthesia, tetany, gastrointestinal bleeding, hyponatraemia, hyperglycaemia, hypokalaemia and metabolic alkalosis. CNS depression (eg drowsiness, lethargy and coma) may occur without cardiovascular or respiratory depression.

Treatment: Initial treatment consists of either emesis or gastric lavage, if appropriate. Activated charcoal may help reduce absorption of substantial amounts if given within one hour of ingestion. Treatment should be symptomatic and supportive including the correction of fluid and electrolyte imbalance. Hyponatraemia should be treated with water deprivation rather than by the administration of sodium chloride. Cathartics should be avoided.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: low-ceiling diuretics, thiazides. ATC code: C03AA01

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

Absorption:

Bendroflumethiazide has been reported to be completely absorbed from the gastrointestinal tract. Diuresis is initiated in about 2 hours and lasts for 12-18 hours or longer.

Distribution:

Bendroflumethiazide is more than 90% bound to plasma proteins.

Biotransformation:

There are indications that it is fairly extensively metabolised. Peak plasma levels are reached in 2 hours and a plasma half- life of between 3 and 8.5 hours on average.

Elimination:

About 30% is excreted unchanged in the urine with the remainder excreted as uncharacterized metabolites.

5.3 Preclinical safety data

Not applicable.

6. Pharmaceutical particulars
6.1 List of excipients

Also contains: lactose, magnesium stearate, maize starch, pregelatinised maize starch, stearic acid, water.

6.2 Incompatibilities

None known.

6.3 Shelf life

Shelf-life

Four years from the date of manufacture (PVC blister packs).

Three years from the date of manufacture (polypropylene containers; polyethylene containers; amber glass bottles.

6.4 Special precautions for storage

Store below 25°C in a dry place.

6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps and polyfoam wad or cotton wool.

Pack sizes: 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special precautions for disposal and other handling

Not applicable.

Administrative Data

7. Marketing authorisation holder

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS

8. Marketing authorisation number(s)

PL 0142/0380

9. Date of first authorisation/renewal of the authorisation

27.6.94

10. Date of revision of the text

15/04/2020