Bendroflumethiazide 2.5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bendroflumethiazide 2.5mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Bendroflumethiazide 2.5 mg per tablet.
For excipients, see 6.1.
3. PHARMACEUTICAL FORM
Tablet.
Bendroflumethiazide 2.5 mg tablets are presented as white flat bevelled edge tablets engraved with the company logo on one side and A268 on the other side.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Oedema:
Bendroflumethiazide is indicated in the treatment of oedema associated with conditions such as congestive heart failure, nephrotic syndrome, cirrhosis of the liver.
Essential hypertension:
Bendroflumethiazide may be used as the sole antihypertensive agent or used concurrently with other specific hypotensive agents whose action it potentiates.
4.2. Posology and method of administration
Route of administration: Oral
ADULTS:
Oedema:
5.0 - 10.0 mg once daily or on alternate days Maintenance:
2.5 - 5.0 mg two or three times a week Essential hypertension:
2.5 mg in the morning, alone or in conjunction with other antihypertensive agents in more severe hypertension.
The dosage should be reduced in the elderly with impaired renal function. CHILDREN:
Diuretic - Initial: 0.4 mg per kg of body-weight per day.
Maintenance: 0.05 to 0.1 mg per kg of body-weight per day.
Antihypertensive: 0.05 to 0.4 mg/kg body-weight per day as a single dose or in two divided daily doses, adjusted according to response.
4.3. Contraindications
Bendroflumethiazide is contra-indicated in patients hypersensitive to this drug or any of the excipients and in patients with severe renal insufficiency, Addison’s disease, refractory hypokalaemia, hyponatraemia, hypercalcaemia, serious hepatic disorders, symptomatic hyperuricaemia and acute porphyria.
4.4. Special warnings and precautions for use
When doses higher than those stated in Section 4.2 Posology and method of administration are given to patients being treated for hypertension, more marked changes in plasma potassium, uric acid, glucose and lipids may be experienced. There is also no advantage in the control of blood pressure at higher doses and therefore should not be used.
Patients receiving thiazides should be checked regularly for potassium deficiency. Thiazides may aggravate gout, Systemic Lupus Erythematosus (SLE), existing diabetes mellitus and cause symptoms in patients with latent diabetes.
Caution is required in treating patients with alcoholic cirrhosis as there is an increased risk of hypomagnesaemia with bendroflumethiazide.
Particular caution is required in patients with severe asthma who are taking bendroflumethiazide and beta2 agonist therapy concomitantly because potentially serious hypokalaemia associated with beta2 agonist therapy may be potentiated.
Particular caution is needed in the elderly because of their susceptibility to electrolyte imbalance. Electrolytes should be monitored regularly.
Renal function should also be monitored at regular intervals.
There is a risk of precipitating hepatic encephalopathy in patients with cirrhosis. Caution should be exercised when used in patients with diabetes, gout, SLE, hepatic impairment and renal impairment, porphyria, hyperlipidaemia, pancreatitis, cirrhosis and prostatic hypertrophy. ECG should be monitored in patients receiving cardiac glycosides.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5. Interactions with other medicinal products and other forms of interaction
Analgesics: Diuretics such as bendroflumethiazide increase the risk of nephrotoxicity associated with non-steroidal anti-inflammatory analgesics (NSAIDs). NSAIDs, particularly indometacin and ketorolac may antagonise the natriuresis and increase in plasma renin activity caused by thiazide diuretics. It may also reduce the antihypertensive effect and increase in urine volume caused by thiazide diuretics, possibly by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention. There have been occasional reports of decreased renal function when indometacin is given with triamterene. Concomitant use should therefore be avoided. There is an increased risk of ventricular arrythmias with levacetylmethadol. Concomitant use with opiates leads to an increased risk of postural hypotension.
Anion-exchange resins: colestyramine and colestipol lead to decreased absorption of thiazides. It has been recommended that administration is at least 2 hours apart.
Antidiabetics: Concurrent administration of bendroflumethiazide in patients receiving sulphonylureas may impair control of diabetes by antagonising the hypoglycaemic effect. Chlorpropamide increases the risk of hyponatraemia associated with taking thiazides such as bendroflumethiazide in combination with potassium-sparing diuretics.
Antiepileptics: There is an increased risk of hyponatraemia with
carbamazepine.
Antifungals: There is an increased risk of hypokalaemia if thiazides are given with amphotericin.
Antihistamines: Patients with hypokalaemia or other electrolyte imbalance have an increased risk of ventricular arrhythmias with terfenadine.
Antihypertensives: Concurrent use of bendroflumethiazide with
antihypertensives enhances the hypotensive effect. There is an increased risk of first-dose hypotensive effect of post-synaptic alpha-blockers such as prazosin.
Antipsychotics: Patients with hypokalaemia have an increased risk of
ventricular arrhythmias with pimozide. Concomitant use should be avoided.
Alprostadil: Concomitant use with alprostadil enhances the hypotensive effect.
Anti-arrhythmics: The cardiac toxicity associated with amiodarone,
disopyramide, flecainide, and quinidine is increased if hypokalaemia occurs. The action of lidocaine and mexiletine is antagonised by hypokalaemia.
Antidepressants: There is a possible increased risk of postural hypotension with tricyclic antidepressants and of hypokalaemia if thiazides are given with reboxetine.
Beta-blockers: Use with bendroflumethiazide enhances the hypotensive effect. Patients with hypokalaemia have an increased risk of ventricular arrhythmias with sotalol.
Calcium salts: There is an increased risk of hypercalcaemia with thiazides such as bendroflumethiazide.
Calcium-channel blockers: Concomitant use with bendroflumethiazide enhances the hypotensive effect.
Cardiac glycosides: The concurrent use of cardiac glycosides with thiazide diuretics may enhance the possibility of cardiac toxicity associated with hypokalaemia, resulting in cardiac arrhythmias.
Corticosteroids: There is an increased risk of hypokalaemia with thiazides such as bendroflumethiazide and the diuretic effect is antagonised.
Cytotoxics: Concurrent use of diuretics such as bendroflumethiazide with cisplatin increases the risk of nephrotoxicity and ototoxicity.
Hormone Antagonists: There is an increased risk of hyponatraemia with aminoglutethimide. Thiazides such as bendroflumethiazide increase the risk of hypercalcaemia with toremifene.
Moxisylyte: Concomitant use with bendroflumethiazide enhances the
hypotensive effect.
Muscle relaxants: An enhanced hypotensive effect is associated with concomitant use with baclofen and tizanidine. Bendroflumethiazide interacts with nondepolarising neuromuscular blocking drugs leading to prolonged neuromuscular blockade.
Oestrogens and Progestogens: The diuretic effect is antagonised with oestrogens and combined oral contraceptives.
Other diuretics: There is an increased risk of hypokalaemia if thiazides such as bendroflumethiazide, loop diuretics or acetazolamide are taken together.
Sympathomimetics: There is an increased risk of hypokalaemia if thiazides are given with high doses of bambuterol, fenoterol, formoterol, reproterol, ritodrine, salbutamol, salmeterol, terbutaline and tulobuterol. Potentially serious hypokalaemia may result from beta2 agonist therapy.
Theophylline: There is an increased risk of hypokalaemia with thiazides such as bendroflumethiazide.
Ulcer-healing Drugs: There is an increased risk of hypokalaemia if thiazides are given with carbenoxolone. Carbenoxolone also antagonises the diuretic effect.
Other interactions: Interactions with lithium (leading to lithium toxicity due to reduced renal clearance of lithium), vitamin D (leading to increased risk of hypercalcaemia), alcohol, and barbiturates (leading to increased risk of postural hypotension) have also been reported.
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 hypovolaemia, increased blood viscosity and reduced placental perfusion.
There is inadequate evidence of safety in human pregnancy and some workers have described foetal bone marrow depression and blood disorders including neutropenia and thrombocytopenia. When given in late pregnancy, neonatal thrombocytopenia has been reported. Foetal and neonatal jaundice have also been described.
As diuretics pass into breast milk, they should be avoided in mothers who wish to breast-feed.
Bendroflumethiazide may suppress lactation.
4.7. Effects on ability to drive and use machines
None reported.
4.8. Undesirable effects
Impotence may occur and is reversible within a few weeks of stopping the treatment. Mild anorexia or indigestion which may occur occasionally can be avoided or reduced by taking the dose during or immediately after a meal.
Hypersensitivity reactions including pneumonitis, pulmonary oedema, and severe skin reactions have been reported.
Skin reactions have been reported in a few patients. Blood dyscrasias and pancreatitis have occurred rarely.
The intensive or continuous use of bendroflumethiazide may cause hypokalaemia and therefore potassium chloride supplements are strongly recommended in these circumstances. Higher doses cause more marked changes in plasma potassium.
Disturbances of electrolytes i.e. hypomagnesaemia, hyponatraemia, hypercalcaemia, hypochloraemic alkalosis, and acid/base balance, hyperglycaemia, lipids, hyperuricaemia, nausea, vomiting, diarrhoea, constipation, thirst and polyuria, weakness, dizziness, muscle cramps, loss of libido, precipitation of gout, postural hypotension, photosensitivity, intrahepatic cholestasis, and in cirrhosis, hepatic encephalopathy may occur.
4.9. Overdose
Signs and symptoms of overdosage are drowsiness, lethargy, coma, evidence of CNS depression with or without cardiovascular or respiratory depression and hypovolaemia.
Treatment should be symptomatic and aimed at fluid and electrolyte replacement. Gastric lavage should be carried out in the case of a recent excessive ingestion. Blood pressure monitoring is strongly advised.
During treatment, electrolyte and fluid status together with renal function should be carefully monitored. Hyponatraemia should be treated with water deprivation rather than salt addition. Cathartics should be avoided. There is no known specific antidote.
5.1. Pharmacodynamic properties
Pharmacotherapeutic classification : Low-Ceiling Diuretics Thiazides -
B endroflumethiazi de
ATC code : C03A A01
Bendroflumethiazide is a thiazide diuretic which reduces the reabsorption of electrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. Thiazides also reduce the carbonic anhydrase activity so that bicarbonate excretion is increased but this inhibitory action is weak as compared with the effect on chloride excretion and does not appreciably alter the pH of the urine. In response to the increased tubule load of sodium, the rate of tubular secretion of potassium and exchange with sodium is augmented and an increased amount of potassium is lost in the urine.
Diuresis is initiated after about 2 hours of bendroflumethiazide administration, the maximum diuresis occurs within 12 hours and a significant diuretic effect persists for 24 hours. In subjects with normal renal function; sodium and chloride output is increased twofold after 5 mg of bendroflumethiazide, 7.5 mg increases sodium output threefold and chloride output fourfold. 10 mg does not increase sodium and chloride output significantly more than 7.5 mg i.e. the dose response curve becomes flat. Potassium excretion is doubled after 5 mg of bendroflumethiazide, in normal subjects doubling this dose has no effect on potassium excretion.
Bendroflumethiazide has, like other thiazides, a lowering effect on blood pressure which is considered to be due to sodium depletion; and it also enhances the effects of other antihypertensive agents.
Bendroflumethiazide is used in oedema associated with congestive heart failure, renal and hepatic disorders.
In the treatment of oedema, the usual initial dose is 5 mg daily, reduced to a dose of 2.5 mg daily or 5 mg on alternative days. A suggested initial dose for children is up to
400 micrograms per kg body weight daily, reduced to 50 - 100 micrograms per kg for maintenance.
In the treatment for hypertension the usual dose is 2.5 mg to 10 mg daily either alone, or in conjunction with other antihypertensive agents.
5.2.
Pharmacokinetic properties
Bendroflumethiazide is more completely absorbed from the gastro-intestinal tract than chlorothiazide, reflecting its greater lipid solubility. Maximum diuresis occurs within 12 hours of bendroflumethiazide administration, although a significant diuretic effect persists for 24 hours.
Bendroflumethiazide is fairly extensively metabolised: about 30% is excreted unchanged in the urine. It is estimated to have plasma half-life of about 3 or 4 hours.
5.3. Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Lactose Maize starch
Pregelatinised maize starch Magnesium stearate Starch 1500 Potable water
6.2. Incompatibilities
Bendroflumethiazide preparations should not be administered concurrently with lithium carbonate.
6.3. Shelf life
As packaged for sale:
3 years for opaque plastic containers. 2 years for blister packaging.
6.4. Special precautions for storage
Blister Packs: Do not store above 25°C, store in original package.
Plastic Containers: Do not store above 25°C, keep container tightly closed.
6.5. Nature and contents of container
Bendroflumethiazide tablets are packed in the following containers and closures.
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1. |
Opaque plastic containers composed of polypropylene tubes and polyethylene-made tamper-evident closures for pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1000 tablets. |
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2. |
Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper-evident or child-resistant tamper-evident closure composed of high density polyethylene with a packing inclusion of standard polyether foam or polyethylene or polypropylene made filler in pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1000 tablets. |
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3. |
Blister packs of aluminium/opaque PVC. It is subsequently packed in printed boxboard cartons in pack sizes of 28, 30, 42, 56, 60, 84, 90 and 112 tablets. |
Not all pack sizes may be marketed.
6.6. Instructions for Use, Handling and Disposal
No special instructions for use/handling.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR,
United Kingdom.
8. MARKETING AUTHORISATION NUMBER
PL 04416 / 0529
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/06/2006
10 DATE OF REVISION OF THE TEXT
08/02/2011