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

Hypokalaemia

Electrolytes should be monitored during treatment as continued or intensive use of bendroflumethiazide may result in hypokalaemia. This effect may be enhanced with concomitant use of medicines that can also cause hypokalaemia such as other diuretics or beta-2 agonists. Hypokalaemia can increase the risk of cardiac arrhythmia particularly when the patient is also taking an anti-arrhythmic, anti-histamine, anti-malarial, anti-psychotic or digoxin (see section 4.5).

Potassium replacement or conservation may be necessary in patients at risk from the cardiac effects of hypokalaemia, such as those with prolonged QT intervals, severe heart disease, those taking digitalis preparations or high doses of diuretics and in patients with severe liver disease. If hypokalaemia (< 3.4 mmol potassium) is detected, it must be corrected and it should be prevented in at-risk patients.

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.

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.

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.

Hypomagnesaemia

There is an increased risk of hypomagnesaemia in patients with alcoholic cirrhosis taking bendroflumethiazide. Hypomagnesaemia has been implicated as a risk factor for arrhythmias. Electrolyte levels including magnesium should be monitored during treatment of patients with alcoholic cirrhosis.

Hypercalcaemia

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.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Mild or moderate hepatic or renal impairment

Use with caution in renal impairment (severe renal insufficiency is a contraindication to use, see 4.3). Renal function should be monitored during bendroflumethiazide therapy. Thiazides can cause electrolyte imbalance which is more severe in patients with hepatic and renal impairment and in those receiving higher or prolonged doses.

Use with caution in hepatic impairment (severe hepatic impairment is a contraindication to use, see 4.3). In case of hepatic impairment, thiazide diuretics may precipitate hepatic encephalopathy, particularly in case of electrolyte imbalance. Administration of the diuretic must be stopped immediately if this occurs.

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

Concomitant use with lithium

Bendroflumethiazide inhibits the tubular elimination of lithium resulting in an elevated plasma lithium concentration and risk of toxicity. Both lithium and thiazide and related diuretics can cause hypokalaemia, increasing the risk of torsade de pointes. Avoid concurrent use unless lithium levels and potassium concentrations can be closely monitored and the lithium dose adjusted as necessary. Advise patients to report lithium adverse effects (tremor, dysarthria, ataxia, confusion) (see section 4.5).

Concomitant use with pimozide, sertindole or thioridazine

Diuretic-induced hypokalaemia increases the risk of ventricular arrhythmias with pimozide, sertindole and thioridazine therefore concomitant use should be avoided (see section 4.5).

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazides and thiazide-related diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Systemic lupus erythematosus

Thiazide diuretics can induce a cutaneous lupus-like adverse reaction. Thiazide diuretics may also exacerbate or activate systemic lupus erythematosus (SLE) in susceptible patients.

Pancreatitis

Pancreatitis has been reported during thiazide therapy. Thiazide therapy is associated with hypercalcaemia and hyperlipidaemia both of which are risk factors for pancreatitis.

Gout

Thiazide use may aggravate gout. Serum uric acid levels may be raised with or without gout in some patients.

Diabetes mellitus

Bendroflumethiazide may precipitate diabetes mellitus and may impair glycaemic control in patients with diabetes.

Hyperlipidaemia

Caution should be exercised when used in patients with hyperlipidaemia.

Lactose

This product contains the excipient 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

Pharmacodynamic interactions

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.

Antibacterials

Severe hyponatraemia may occur with concomitant administration of bendroflumethiazide and trimethoprim.

Anti-depressants

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 can act synergistically with chlorpropamide to increase the risk of hyponatraemia.

Anti-epileptics

There is a risk of hyponatraemia occurring when thiazide diuretics, such as bendroflumethiazide, are used concomitantly with carbamazepine.

Anti-fungals

Increased risk of hypokalaemia with concurrent use of thiazide diuretics and amphotericin.

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, 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.

Barbiturates

Postural hypotension associated with therapy may be enhanced by concomitant ingestion of barbiturates.

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.

Calcium-channel blockers and peripheral vasodilators

The hypotensive effect of calcium channel blockers and moxisylyte may be enhanced when co-administered with bendroflumethiazide.

Corticosteroids

Increased risk of thiazide-induced hypokalaemia, mainly with the naturally occurring corticosteroids such as cortisone and hydrocortisone. Adrenocorticotropic hormone (ACTH) can also exacerbate hypokalaemia associated with bendroflumethiazide use.

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

There is an increased risk of hypercalcaemia when thiazides are used concomitantly with toremifene. There is an increased risk of hyponatraemia when thiazides are used concomitantly with aminoglutethimide.

Nitrates

Enhanced hypotensive effect may occur when nitrates and thiazide diuretics are used concomitantly.

Opioids

Postural hypotension associated with therapy may be enhanced by concomitant ingestion of opioids.

Prostaglandins

Hypotensive effect may be potentiated by alprostadil.

Theophylline

Concomitant administration of xanthines such as theophylline and bendroflumethiazide increases the risk of hypokalaemia.

Sympathomimetics

Increased risk of hypokalaemia with thiazide diuretics and high doses of beta-2 sympathomimetics.

Ulcer healing drugs

Potential for severe hypokalaemia with carbenoxolone. Patients should be monitored and given potassium supplements when required.

Pharmacokinetic interactions

Anion exchange resins

Colestipol and colestyramine reduce absorption of thiazides. This can be prevented by leaving an interval of two hours between doses of bendroflumethiazide and the anion exchange resin.

Effect of other medicinal products on bendroflumethiazide

Analgesics

Non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin 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.

Oestrogens and progestogens

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

Effect of bendroflumethiazide on other medicinal products

General

Some electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia) may increase the toxicity of certain other drugs (e.g. digitalis preparations and drugs inducing QT interval prolongation syndrome).

Analgesics

Diuretics may increase the risk of nephrotoxicity of non-steroidal anti-inflammatory drugs (NSAIDs). The effects of concurrent use should be monitored and the dose of bendroflumethiazide modified if necessary.

Anti-arrhythmics (see section 4.4)

The cardiotoxicity of disopyramide, amiodarone, 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.

Antidiabetics

Bendroflumethiazide may antagonise the hypoglycaemic effects of antidiabetic drugs including insulin possibly necessitating adjustment of the dose of the antidiabetic agent.

Antigout agents

Potential for increased toxicity and hypersensitivity/allergic reactions with concomitant use of allopurinol and thiazide diuretics.

Antihistamines (see section 4.4)

Bendroflumethiazide-induced hypokalaemia may increase the risk of arrhythmias with drugs that prolong the QT interval, such as astemizole and terfenadine.

Antihypertensives

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 (see section 4.4)

Bendroflumethiazide -induced hypokalaemia may increase the risk of arrhythmias with drugs that prolong the QT interval, such as halofantrine.

Antipsychotics (see section 4.4)

Diuretic-induced hypokalaemia increases the risk of ventricular arrhythmias with pimozide, sertindole and thioridazine therefore concomitant use should be avoided. Enhanced hypotensive effect may occur when phenothiazines and thiazide diuretics are used concomitantly.

Ciclosporin

Increased risk of nephrotoxicity and/or hypermagnesaemia with concomitant use of ciclosporin and thiazide diuretics, such as bendroflumethiazide.

Cytotoxics

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

Digoxin (see section 4.4)

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, treatment with cardiac glycosides may have to be temporarily suspended and a potassium supplement given to restore stability.

Lithium (see section 4.4)

Bendroflumethiazide inhibits the tubular elimination of lithium resulting in an elevated plasma lithium concentration and risk of toxicity. Both lithium and thiazide and related diuretics can cause hypokalaemia, increasing the risk of torsade de pointes. Avoid concurrent use unless lithium levels and potassium concentrations can be closely monitored and the lithium dose adjusted as necessary. Advise patients to report lithium adverse effects (tremor, dysarthria, ataxia, confusion).

Muscle relaxants

Diuretic-induced hypokalaemia may enhance the neuromuscular blocking activity of non-depolarising muscle relaxants, such as tubocurarine, gallamine, alcuronium and pancuronium. An enhanced hypotensive effect may occur with tizanidine.

Interference with tests for parathyroid function

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

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

Summary of safety profile

The safety profile of bendroflumethiazide includes a degree of electrolyte imbalance. Serious adverse reactions include pancreatitis, hypersensitivity reactions, serious skin reactions and blood dyscrasias.

Adverse reactions listed below are based on available data for bendroflumethiazide and classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: 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), and not known (cannot be estimated from the available data).

Table 1. Adverse reactions

System organ class

Very common

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

Blood dyscrasias, including neutropenia, agranulocytosis, aplastic anaemia,

thrombocytopenia and leucopenia

Immune system disorders

Hypersensitivity reactions

Endocrine disorders

Thiazides may cause hyperglycaemia and aggravate or unmask diabetes mellitus.

Nervous system disorders

Headache

Dizziness

Paraesthesia

Drowsiness

Eye disorders

Choroidal effusiona

Vascular disorders

Postural hypotension

Vasculitis

Respiratory, thoracic and mediastinal disorders

Pneumonitis and

pulmonary oedema (as part of hypersensitivity reaction)

Gastrointestinal disorders

Pancreatitis

Nausea

Vomiting

Diarrhoea

Constipation

Gastric irritation

Dry Mouth

Thirst

Hepatobiliary disorders

Cholestasis

Cholecystitis

Skin and

subcutaneous tissue disorders

Rashes (including

exfoliative dermatitis)

Photosensitivity

Skin eruptions resembling lichen planus and subacute cutaneous lupus erythematosus

Erythema multiforme

Pseudoporphyria

Musculoskeletal and connective tissue disorders

Systemic lupus erythematosus

Renal and urinary disorders

Acute interstitial nephritis

Non-opaque urate calculi

Oliguria

Reproductive system and breast disorders

Impotence (reversible on discontinuing the drug)

Investigations

Increased triglyceride, total cholesterol, low-density and very-low density

lipoprotein cholesterol concentrations

Hypokalaemia.

Hypomagnesaemia

Hyponatraemia

Hypercalcaemia

Hypochloraemic alkalosis

Hyperuricaemia with/without gout

a see subsection below for additional information

Description of selected adverse reactions

Choroidal effusion

Cases of choroidal effusion with visual field defect have been reported after the use of thiazide and thiazide-like diuretics.

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

Signs and symptoms

Symptoms of overdosage include anorexia, nausea, vomiting, diarrhoea, dehydration, hypotension, dizziness, weakness, muscle cramps, convulsions, increased frequency of micturition with polyuria and thirst, paraesthesia, and tetany.

Extreme cases may show depletion of intravascular volume, hypotension and peripheral circulatory failure.

Hypokalaemia can occur and is especially important in patients with pre-existing cardiac disease. Hyponatraemia, hypomagnesaemia, hypercalcaemia, hypo- or hyperglycaemia and metabolic alkalosis are also possible. Electrolyte abnormalities can lead to arrhythmias.

CNS depression (e.g. drowsiness, lethargy and coma) may occur without cardiovascular or respiratory depression.

Management of overdose

Treatment should be supportive and directed at fluid and electrolyte replacement which should be monitored together with blood pressure, blood glucose, ECGs and renal function. Cathartics should be avoided.

There is no specific antidote.

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

11/12/2020