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BENDROFLUMETHIAZIDE TABLETS 5.0MG

Active substance(s): BENDROFLUMETHIAZIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Bendroflumethiazide Tablets 5.0 mg

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Bendroflumethiazide 5.0 mg per tablet
For excipients, see 6.1.

3

PHARMACEUTICAL FORM
Tablet.
White flat bevelled edge tablets engraved with the company logo on one side
and A269 on the other.

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 alternative 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
Hypersensitivity to Bendroflumethiazide or any of the excipients.
Bendroflumethiazide is contra-indicated in patients with:









4.4

severe renal insufficiency
Addison’s disease
refractory hypokalaemia
hyponatraemia
hypercalcaemia
serious hepatic disorders
symptomatic hyperuricaemia and
acute porphyria.

Special warnings and precautions for use
Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this
medicine.
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 Erythematous
(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.

4.5

Interaction 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:
carbamazepine.

There is an increased risk of hyponatraemia with

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:
effect.

Concomitant use with alprostadil enhances the hypotensive

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.
Estrogens and Progestogens: The diuretic effect is antagonised with estrogens
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

Fertility, 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
When driving vehicles or operating machines it should be taken into account
that occasionally dizziness may occur.

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.

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
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

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic classification : Low-Ceiling Diuretics Thiazides Bendroflumethiazide
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 starch
Magnesium stearate

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
Do not store above 25°C.

6.5

Nature and contents of container
1. Opaque plastic containers composed of polypropylene tubes and polyethylene
tamper-evident closures for pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100,
112, 250, 500 and 1000 tablets.
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 polyether foam or polyethylene or polypropylene filler in pack
sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1000 tablets.

3.

Blister packs of aluminium/opaque PVC subsequently packed in printed
cartons in pack sizes of 28, 30, 42, 56, 60, 84, 90 and 112 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special instructions for use/handling.

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Ltd
Units 3 and 4, Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0218

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/11/2003

10

DATE OF REVISION OF THE TEXT
12/04/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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