Bendroflumethiazide Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bendroflumethiazide Tablets BP 5 mg.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Bendroflumethiazide 5.0 mg.
For excipients, see 6.1
3. PHARMACEUTICAL FORM
Tablet.
Flat, white uncoated tablets with bevelled edge.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
The tablets are intended solely for oral administration as a diuretic in the treatment of essential hypertension and oedema.
They may also be used in the suppression of unwanted lactation.
4.2. Posology and method of administration
For oral administration.
Adults
Hypertension:
2.5mg in the morning. Higher doses are rarely necessary. The tablets may be used in conjunction with other anti-hypertensive agents (see BNF).
Oedema: 5 - 10 mg daily in the morning initially and a maintenance dose of 2.5 - 10mg up to three times a week.
Suppression of lactation:
5mg to be taken morning and midday for about five days.
Elderly
The dosage may need to be reduced particularly when renal function is impaired because of the possibility of electrolyte imbalance.
Children
Dosage can be up to 400pg/kg body weight daily initially with a maintenance dose of 50 - 100pg/kg daily.
4.3 Contra-indications
Severe renal insufficiency, refractory hypokalaemia, hyponatraemia and hypercalcaemia, symptomatic hyperuricaemia, hypersensitivity to any of the ingredients, hepatic failure, Addison’s disease and concurrent lithium therapy.
4.4. Special warnings and precautions for use
Electrolyte disturbances:
Particular caution is needed in the elderly because of their susceptibility to electrolyte imbalance. Periodic blood tests should be performed on patients on long term treatment and in the elderly.
Potassium depletion is a particular risk in digitalized patients, or in patients with hepatic cirrhosis and/or ascites and in patients with latent or overt diabetes. The dose of hypoglycaemic agents may need to be increased, and when added to anti-hypertensive agents such as beta-blockers the combined hypotensive effect may require reduction in the dose of the anti-hypertensive agents.
Use in patients with diabetes mellitus or predisposition to diabetes mellitus
The product may sometimes lower carbohydrate tolerance so that the insulin dosage of the diabetic patient may require adjustment. Care is therefore necessary when bendroflumethiazide is administered to those with a known predisposition of diabetes.
Potassium depletion is a risk in patients with latent or overt diabetes (see above - Electrolyte disturbances)
Patients with renal and/or hepatic impairment
Caution in patients with hepatic or renal impairment.
Renal function should be monitored periodically during treatment Potassium depletion is a risk in patients with hepatic cirrhosis and/or ascites (see above - Electrolyte disturbances)
Patients with systemic lupus erythematosus
May cause exacerbation or activation of systemic lupus erythematosus in susceptible individuals.
Patients with rare hereditary problems of fructose or galactose intolerance, the LAPP lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take these tablets as they contain lactose and sucrose.
4.5 Interaction with other medicinal products and other forms of interactions
Concomitant use with lithium is contraindicated (see Section 4.3). Thiazides reduce the excretion of lithium. Lithium blood levels and the risk of toxicity may be increased. Concomitant use is contraindicated.
Medicines used to treat cardiac arrhythmias including amiodarone, digoxin, digitoxin, disopyramide, flecainide, lidocaine, mexiletine, quinidine and sotalol. Increased sensitivity to digitalis glycosides by the hypokalaemic effect of concurrent bendroflumethiazide. Observe patients for digitalis intoxication, in particular if arrhythmias are observed the dose of the glycoside should be reduced temporarily and a potassium supplement given. Hypokalaemia increases the risk of ventricular arrhythmias with sotalol. The cardiac toxicity of disopyramide, amiodarone, flecainide and quinidine is increased if hypokalaemia occurs. The action of lidocaine and mexiletine is antagonized by hypokalaemia.
Medicines to treat diabetes such as chlorpropamide, sulphonylureas and insulin. Thiazide diuretics antagonize the hypoglycaemic effect of antidiabetics and therefore impair control of diabetes. There is an increased risk of hyponatraemia when a thiazide plus a potassium-sparing diuretic are given with chlorpropamide.
Thiazides may enhance the effects of anti-hypertensive agents e.g. beta-blockers, ACE inhibitors, angiotensin-II antagonists, alpha blockers and calcium channel blockers.
Other diuretics. There is an increased risk of hypokalaemia when thiazides are given with loop diuretics.
The vasodilator moxisylyte may enhance the hypotensive effect.
Non steroidal anti-inflammatory drugs (NSAIDs) used for relief of pain and inflammation (e.g. ibuprofen, indometacin, ketorolac) may blunt the diuretic and anti-hypertensive effects of thiazide diuretics. Diuretics may increase the risk of nephrotoxicity of NSAIDs
Medicines taken for depression including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs) and reboxetine. There is an increased risk of postural hypotension with tricyclic antidepressants, an increased risk of hypokalaemia with reboxetine and increased hypotensive effect with MAOIs.
Hypokalaemia increases the risk of ventricular arrhythmias with the CNS stimulant atomoxetine. The anticonvulsant carbamazepine may increase the risk of hyponatraemia.
Increased risk of hypokalaemia when give with medicines used to treat asthma such as theophylline and beta-agonists e.g. salbutamol.
There is an increased risk of hypersensitivity when given with allopurinol, used in the treatment of gout, especially in renal impairment.
There is an enhanced hypotensive effect when given with alprostadil, used to treat male impotence and neonatal congenital heart defects.
An increased risk of hypokalaemia with amphotericin (given by injection), used to treat fungal infections.
Avoidance of diuretics is advised by the manufacturer of the antibiotic lymecycline.
Calcium salts or vitamin D, used as dietary supplements increase the risk of hypercalcaemia.
Colestyramine and colestipol, used to treat high blood cholesterol may reduce the absorption of thiazide diuretics and should therefore be given at least 2 hours apart.
Medicines used in the treatment of mental illness e.g. amisulpride, phenothiazines, pimozide, sertindole, anxiolytics and hypnotics.
Hypokalaemia caused by diuretics increases the risk of ventricular arrhythmias with pimozide (avoid concomitant use), amisulpride and sertindole. There is an enhanced hypotensive effect when diuretics given with phenothiazines, anxiolytics and hypnotics.
Hypokalaemia or other electrolyte imbalance increases the risk of ventricular arrhythmias with terfenadine, taken for allergies.
There may be an increased hypotensive effect with medicines to treat muscle spasm and Parkinson’s disease e.g. baclofen, levodopa, tizanidine. Thiazide diuretics may enhance the neuro-muscular blocking effects of the nondepolarising muscle relaxants, e.g. atracurium.
Increased risk of hypercalcaemia with toremifene, used in the treatment of breast cancer.
Cytotoxic platinum compounds such as cisplatin can lead to an increased risk of nephrotoxicity and ototoxicity.
Immunosuppressant medicines. There is an increased risk of nephrotoxicity and possibly hypermagnesaemia when given with ciclosporin.
Enhanced hypotensive effect when given with aldesleukin.
Postural hypotension associated with thiazide therapy may be enhanced by concomitant ingestion of alcohol, barbiturates or opioids.
Hypotensive effect enhanced when given with general anaesthetics.
ACTH, corticosteroids, acetazolamide and carbenoxolone may exacerbate the hypokalaemic effect.
Oestrogens may antagonize the diuretic effect of thiazides.
Like all thiazides, it may interfere with a number of laboratory tests, including estimation of serum protein-bound iodine and tests of parathyroid function.
4.6. Pregnancy and lactation
Diuretics are best avoided for the management of oedema of pregnancy or hypertension in pregnancy, as their use may be associated with hypokalaemia, increased blood viscosity and reduced placental perfusion.
There is inadequate evidence of safety in human pregnancy and some have described foetal bone marrow depression and thrombocytopenia. Foetal and neonatal jaundice have also been described.
As diuretics pass into breast milk and bendroflumethiazide can suppress lactation, avoid in mothers who wish to breast feed.
4.7 Effects on ability to drive and use machines
May cause dizziness or visual disturbances, if affected do not drive or operate machinery.
4.8 Undesirable effects
The undesirable effects listed below are class effects for thiazides and related diuretics, they are not specific to bendroflumethiazide.
The following convention has been utilised for the classification of frequency: Very common > 1/10; common > 1/100 and < 1/10; uncommon > 1/1000 and < 1/100; rare >1/10,000 to < 1,1000; 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, thrombocytopenia and leucopenia.
Immune system disorders:
Not known: hypersensitivity reactions (including pneumonitis, pulmonary oedema and severe skin reactions.
Metabolism and nutrition disorders:
Not known: altered plasma lipid concentration; increase in blood urea nitrogen; metabolic and electrolyte disturbances e.g. hypokalaemia, hypomagnesaemia, hyponatraemia, hypercalcaemia, hyperglycaemia (diabetes may be precipitated or aggravated), hypochloraemic alkalosis, hyperuricaemia; gout in susceptible subjects.
Nervous system disorders:
Not known: headache, dizziness, paraesthesia.
Eye disorders:
Not known: transient blurred vision, aggravation of pre-existing myopia.
Cardiac disorders:
Not known: cardiac arrhythmias.
Vascular disorders:
Not known: postural hypotension.
Gastrointestinal disorders:
Rare: pancreatitis.
Not known: mild gastrointestinal disturbances such as loss of appetite, diarrhoea, constipation, nausea, vomiting.
Hepato-biliary disorders:
Not known: intrahepatic cholestasis.
Skin and subcutaneous tissue disorders:
Not known: skin rashes, photosensitivity, necrotising vasculitis.
Reproductive system and breast disorders:
Not known: impotence.
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 include anorexia, nausea, vomiting, diarrhoea, diuresis, dehydration, hypotension, dizziness, weakness, muscle cramps, paraesthesia, tetany, gastrointestinal bleeding, hyponatraemia, hypo- or hyperglycaemia, hypokalaemia and metabolic alkalosis.
If appropriate treat either by emesis or gastric lavage initially, otherwise treatment should be symptomatic and aimed at fluid and electrolyte replacement. Blood pressure should be monitored following the overdose and throughout treatment. There is no specific antidote.
5 PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
C03A A01 - Low ceiling diuretics, thiazides. Thiazides, plain
Bendroflumethiazide is a thiazide diuretic which acts by reducing reabsorption of electrolytes from renal tubules leading to increased excretion of sodium and chloride and hence water. Potassium is less affected but hypokalaemia must be checked in prolonged treatment.
It reduces carbonic anhydrase activity and bicarbonate excretion may be increased but unlikely to be a problem.
Bendroflumethiazide has a slight direct hypotensive action and tends to potentiate effect of other antihypertensive drugs.
Diuresis is initiated in about 2 hours and lasts for 12-18 hours.
5.2.
Pharmacokinetic Properties
Bendroflumethiazide is readily absorbed from the gastro-intestinal tract and about 30% is excreted unchanged in the urine and has a plasma half life of about 4 hours.
5.3. Preclinical Safety Data
No data of relevance which is additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1. List of excipients
Lactose
Pregelatinised Maize Starch Sucrose (as syrup)
Stearic Acid Magnesium Stearate
6.2. Incompatibilities
None known.
6.3. Shelf Life
3 years.
6.4. Special Precautions for Storage
Tablet containets: Do not store above 25°C. Store in the original container. Keep the container tightly closed.
Blister packs: Do not store above 25°C. Store in the original package. Keep blister in the outer carton.
6.5. Nature and contents of container
HDPE tablet containers with PP caps of 500 and 1000 tablets.
PP tablet containers with LDPE caps of 500 and 1000 tablets. Al/PVC/PVDC blister packs containing 28 or 56 tablets.
Not all pack sizes may be marketed.
6.6. Instruction for Use/Handling Not applicable.
7. MARKETING AUTHORISATION HOLDER
Dalkeith Laboratories Ltd
2 Park Street
Woburn
Bedfordshire
MK17 9PG
8. MARKETING AUTHORISATION NUMBER
PL 17496/0005
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19/02/2007
10 DATE OF REVISION OF THE TEXT
08/07/2015