LEO Pharma

Burinex^® 5 mg Tablets

Each tablet contains 5 mg of Bumetanide.

Excipients: Each tablet contains 92 mg lactose monohydrate.

For a full list of excipients, see section 6.1

Tablet

A white, flat, circular, uncoated, bevelled-edge tablet marked with a score line and '5 mg' on one face.

The scoreline is only to facilitate breakup for ease of swallowing and not to divide into equal doses.

In the management of oedema due to congestive heart failure, hepatic cirrhosis and renal disease, including nephrotic syndrome, where high dose diuretic is required.

The dose should be carefully adjusted according to response. As a general rule, dosage should be started at 5 mg daily and then increased by 5 mg every 12-24 hours until the required response is obtained or side effects appear. Consideration should be given to a twice daily dosage, rather than a once daily dosage.

Children:

Not recommended as no clinical trials have been carried out in children.

Elderly:

The dosage recommendations for adults apply, but in the elderly bumetanide is generally eliminated more slowly. Dosage should be titrated until the required response is achieved.

Patients with liver or renal insufficiency

Depending on the liver or renal function, the dose should be titrated according to the patient's response and required therapeutic effect (see section 4.4).

Hypersensitivity to active substance or any of the excipients

Severe electrolyte depletion

Persisting anuria

Hepatic encephalopathy including coma

Caution is advised if bumetanide is to be administered to patients with severe hepatic impairment.

Caution should be exercised when bumetanide is used in patients with hypotension.

Electrolyte and fluid imbalance may occur and replacement therapy should be instituted where indicated. Serum potassium concentrations should be monitored regularly.

As with other diuretics, bumetanide may cause an increase in blood uric acid.

Burinex^® should be used with caution in patients with potential obstruction of the urinary tract.

In patients with severe chronic renal failure treated with high doses of Burinex^®, there have been reports of severe generalised musculoskeletal pain sometimes associated with muscle spasm, occurring one or two hours after administration and lasting for up to 12 hours. Occasionally analgesic medication has been required to treat the pain. All patients recovered fully and there was no deterioration in their renal function. The cause of this pain is uncertain but may be a result of varying electrolyte gradients at the cell membrane level. Experience suggests that the incidence of such reactions is reduced by initiating treatment at 5-10 mg daily and titrating upwards, using a twice daily dosage regimen at doses of 20 mg per day or more. When using more than 10 mg per day expert advice should be sought. Patients with chronic renal failure on high doses of bumetanide should remain under constant hospital supervision.

Caution is advised if bumetanide is to be administered to patients with severe or progressive renal impairment or with elevated urea/Blood Urea Nitrogen (BUN) or creatinine.

Periodic monitoring of urine and blood glucose should be made in diabetics and patients suspected of latent diabetes since this preparation may induce hyperglycaemia (see sections 4.5 and 4.8).

If known hypersensitivity to sulphonamides there may be a potential risk of hypersensitivity to bumetanide.

Bumetanide found in urine by doping test is cause for disqualification of athletes.

Burinex^® tablets contains lactose as an excipient and patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Dose adjustment of hypoglycaemic agents may be necessary in patients with diabetes mellitus.

Digitalis glycosides

Hypokalaemia increases the sensitivity to digitalis glycosides which might result in digitalis toxicity (nausea, vomiting, and arrhythmias). Potassium level and signs for digitalis toxicity should be monitored. Potassium supplementation and lower digitalis glycoside dose should be considered.

Non-depolarising neuromuscular blocking agents

Hypokalaemia increases the sensitivity to non-depolarising neuromuscular blocking agents.

Lithium

Bumetanide reduces lithium clearance resulting in high serum levels of lithium, therefore concomitant therapy requires close monitoring of serum lithium levels. Lower lithium doses may be required.

Antiarrhythmics

Concomitant use of bumetanide and class III antiarrhythmic drugs may result in increased risk of electrolyte imbalance and subsequent cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest). Patients' electrolyte levels should be monitored as should symptoms of arrhythmias.

NSAIDs

Non-steroidal anti-inflammatory drugs (NSAID) inhibit the effect of bumetanide. The effects of concurrent use should be monitored (e.g. blood pressure, signs of renal failure). Diuretics may enhance the nephrotoxicity of NSAIDs.

Antihypertensive agents and medicinal products inducing postural hypotension.

Bumetanide may potentiate the effect of antihypertensive agents including diuretics and drug inducing postural hypotension (e.g. tricyclic antidepressants). First-dose hypotension may occur.

Potassium depleting agents

The potassium depleting effect of bumetanide may be increased by other potassium depleting agents.

Aminoglycosides

The ototoxic effects of aminoglycosides may be increased by concomitant administration of potent diuretics such as bumetanide.

Probenecid

Probenecid inhibits the renal tubular secretion of bumetanide leading to a diminished natriuresis

Pregnancy

Bumetanide may cause harmful pharmacological effects during pregnancy, to the foetus or to the newborn child. Burinex^® should not be used during pregnancy unless the clinical condition of the woman requires treatment with bumetanide. It may be used only in case of heart failure when the potential benefit justifies the potential risk to the foetus.

Breastfeeding

Bumetanide should not be used during breastfeeding.

Fertility

There are no clinical studies with bumetanide regarding fertility

Bumetanide has no or negligible direct influence on the ability to drive and use machines. However, the patient should be informed that dizziness may occur during treatment and take this into account while driving or using machines.

The estimation of the frequency of undesirable effects is based on a pooled analysis of data from clinical studies and spontaneous reporting.

Based on pooled data from clinical studies including more than 1000 patients who received bumetanide, approximately 12% of patients can be expected to experience an undesirable effect.

The most frequently reported adverse reactions during treatment are headache and electrolyte imbalance (including hypokalaemia, hyponatraemia, hypochloraemia and hyperkalaemia) occurring in approximately 4% of the patients, followed by dizziness (including orthostatic hypotension and vertigo) and fatigue occurring in approximately 3% of patients.

Electrolyte disturbances can occur especially during long term treatment.

Renal failure has been reported in post-marketing safety surveillance.

Undesirable effects are listed by MedDRA system organ class (SOC) and the individual undesirable effects are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Very common 1/10

Common 1/100 and < 1/10

Uncommon 1/1,000 and <1/100

Rare 1/10,000 and <1/1,000

Very rare <1/10,000

Paediatric population

The safety profile of Burinex^® has not been established in the paediatric population.

In high doses and during long-term treatment loop diuretics may cause electrolyte imbalance, dehydration and polyuria.

Symptoms of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, confusion, gastrointestinal disturbances, restlessness, muscle pain and cramps and seizures.

Treatment is adjustment of the fluid and electrolyte imbalance.

ATC Code: C03CA 02

Bumetanide is a potent loop diuretic.

Bumetanide exerts an inhibiting effect on the reabsorption mechanism of salts in the ascending limb of the loop of Henle and in the renal proximal tubules. Bumetanide thereby causes the diuretic and natriuretic action observed.

Bumetanide is nearly totally absorbed from the gastro-intestinal tract. After peroral administration, a bioavailability of between 80-95% is observed. Diuresis begins within ½-1 hour with a peak effect between one and two hours. The diuretic effect lasts up to about 4 hours. Bumetanide is eliminated with half-life ranging from between 1 to 2 hours after oral administration of a dose of 0.5-2 mg. It is strongly bound to plasma proteins and renal excretion of unchanged drug accounts for about half of the total clearance. The hepatic metabolism and biliary excretion accounts for the other half. The primary metabolites are conjugated alcohols of bumetanide. No active metabolites have been found. Burinex^® has a steep dose response curve.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

maize starch

lactose monohydrate

povidone

polysorbate 80

colloidal anhydrous silica

agar powder

talc

magnesium stearate

Not applicable

3 years

Keep the blister in the outer carton in order to protect from light.

PVC/aluminium blister packs of 14 (physician's sample), 28 and 56 tablets.

Not all pack sizes may be marketed.

No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

LEO Laboratories Ltd., Cashel Road, Dublin 12.

PA 46/16/3

Date of first authorisation: 01 April 1978

Date of last renewal: 01 April 2008

January 2012

Product subject to prescription which may be renewed (B)