SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bumetanide 1mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 1mg Bumetanide For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Tablet for oral use.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Bumetanide is indicated whenever diuretic therapy is required in the treatment of oedema, for example when associated with congestive heart failure, cirrhosis of the liver and renal disease including the nephrotic syndrome.

Bumetanide 5mg tablets may be used in oedema of cardiac or renal origin where high doses of a potent, short acting diuretic are required.

4.2 Posology and method of administration

Adults: The dose should be carefully titrated in each patient according to the patient’s response and the required therapeutic activity. Most patients require a daily dose of 1mg which can be given as a single morning or early evening dose.

Depending on the patient’s response, a second dose can be given six to eight hours later. In refractory cases, the dose can be increased until a satisfactory diuretic response is obtained or infusions of bumetanide can be given.

Children: Not recommended for children under 12 years of age.

Elderly: Adjust dosage according to response; a dose of 0.5mg bumetanide each day may be sufficient in some elderly patients.

4.3 Contraindications

Hypersensitivity to bumetanide.

Precomatose states associated with liver cirrhosis, hepatic coma, renal failure with anuria.

4.4 Special warnings and precautions for use

Excessively rapid mobilisation of oedema, particularly in elderly patients, who are sensitive to fluid and electrolyte changes, may give rise to sudden changes in cardiovascular pressure flow relationships with circulatory collapse. This should be considered when bumetanide is given in high doses either intravenously or orally. Electrolyte disturbances may occur particularly in those patients taking a low salt diet. Regular checks of serum electrolytes, in particular sodium, potassium, chloride and bicarbonate should be performed and replacement therapy instituted where indicated. Care should be taken in patients with severe electrolyte depletion.

Although bumetanide can be used to induce diuresis in renal insufficiency, any marked increase in blood urea or the development of oliguria or anuria during treatment of severe progressing renal disease are indications for stopping treatment with bumetanide.

Hypovolaemia should be corrected before using in oliguria.

Use may aggravate diabetes mellitus and gout (see 4.8 Undesirable Effects, Endocrine and Metabolic subsections).

Patients with chronic renal failure who are receiving high doses of bumetanide should remain under constant hospital supervision.

Particular caution is required in severe asthma, where hypokalaemia associated with beta₂ agonist therapy may be potentiated by diuretics (see 4.5 Interactions with Other Medicaments). Plasma potassium concentration should therefore be monitored in severe asthma.

Caution should be observed in hypotension, prostatic enlargement (because of the risk of developing acute retention) and porphyria.

Bumetanide should not be administered concurrently with lithium (risk of lithium toxicity) (see section 4.5 Interactions).

Encephalopathy may be precipitated by hypokalaemia in patients with pre-existing hepatic impairment (See also 4.3 Contraindications).

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Co-administration of alcohol may potentiate postural hypotension.

Analgesics: diuretics increase the risk of nephrotoxicity of non-steroidal antiinflammatory drugs (NSAIDs).

Certain NSAIDs, notably indometacin and ketorolac, have been shown to antagonise the action of diuretics.

Anti-arrhythmics: Cardiac toxicity of amiodarone, disopyramide, flecainide, and quinidine is increased if hypokalaemia occurs. The action of lidocaine and mexiletine is antagonised by hypokalaemia.

Antibacterials: Bumetanide should be used with caution in patients already receiving nephrotoxic drugs, such as cephalosporins, or ototoxic drugs, such as aminoglycosides, colistin, and vancomycin.

Antidiabetics: The hypoglycaemic effect of antidiabetics may be antagonised by loop diuretics.

Antidepressants: Increased risk of postural hypotension with tricyclics; possibly an increased risk of hypokalaemia if loop diuretics are given with reboxetine. Enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs)

Antiepileptics: Increased risk of hyponatraemia with carbamazepine.

Antifungals: Increased risk of hypokalaemia if loop diuretics are given with parenteral amphotericin.

Antihistamines: Hypokalaemia or other electrolyte imbalance increases the risk of ventricular arrhythmias with terfenadine.

Antihypertensives: Bumetanide may potentiate the effects of antihypertensive drugs, including calcium channel blockers and beta blockers. Particular care should be taken with ACE inhibitors and Angiotensin-II antagonists since the enhanced hypotensive effect may be extreme. The dose of antihypertensive may need adjustment when bumetanide is used to treat oedema in hypertensive patients. In addition, there is an increased risk of the first-dose hypotensive effect when used with post-synaptic alpha blockers such as prazosin.

Antipsychotics: In hypokalaemia increased risk of ventricular arrhythmias with pimozide and sertindole. Concomitant use should be avoided.

Cardiac glycosides: Like other diuretics, bumetanide shows a tendency to increase the excretion of potassium and if hypokalaemia occurs this can lead to an increase in the sensitivity of the myocardium to the toxic effects of digitalis and other cardiac glycosides. The dose may need adjustment when given in conjunction with cardiac glycosides.

Corticosteroids: Increased risk of hypokalaemia and antagonism of the diuretic effect.

Cytotoxics: Increased risk of nephrotoxicity and ototoxicity with cisplatin.

Diuretics: Increased risk of hypokalaemia if loop diuretics, thiazides or acetazolamide are given together.

Lithium: Diuretics can reduce lithium clearance resulting in high serum levels of lithium. Bumetanide should not be administered concurrently with lithium salts.

Muscle Relaxants: Enhanced hypotensive effect with baclofen and tizanidine.

Oestrogens and progestogens: Oestrogens and combined oral contraceptives may antagonise the diuretic effect.

Peripheral vasodilators: enhanced hypotensive effect with thymoxamine (moxisylyte).

Prostaglandins: Hypotensive effect may be potentiated by alprostadil.

Sympathomimetics (Beta-2 agonists): Increased risk of hypokalaemia if loop diuretics are given with high doses of bambuterol, fenoterol, formoterol, reproterol, ritodrine, salbutamol, salmeterol, terbutaline, and tulobuterol (see 4.4, Special Warnings and Precautions for Use).

Theophylline: Increased risk of hypokalaemia with loop diuretics.

Ulcer-healing drugs: Increased risk of hypokalaemia when loop diuretics are given with carbenoxolone; carbenoxolone antagonises the diuretic effect

4.6 Pregnancy and lactation

Tests in four animal species have shown no teratogenic effects. However, the ordinary precaution of avoiding use of bumetanide in the first trimester of pregnancy should be observed.

It is not known whether bumetanide is distributed into breast milk. Nursing mothers should either stop breast feeding or, if the drug is absolutely necessary for the mother, the infant should be observed for any adverse effects.

4.7 Effects on ability to drive and use machines

Reduced mental alertness may impair ability to drive or operate dangerous machinery.

4.8 Undesirable effects

Fluid and electrolyte imbalance including hypokalaemia, hyponatraemia, hypochloraemic alkalosis, and increased calcium excretion have been reported. Signs and symptoms of electrolyte imbalance include muscle cramps, dizziness, hypotension (including postural), headache, dry mouth, thirst, dehydration, weakness, drowsiness, fatigue, restlessness, oliguria and cardiac arrhythmias

Other reported reactions include the following:

Disorders of the ear: Tinnitus and deafness may rarely occur, usually in association with renal function impairment or during rapid high-dose parenteral therapy. It is usually transient but permanent deafness has occurred, especially in patients receiving other ototoxic drugs.

Disorders of the eye: Blurred vision.

Disorders of the immune system: Rarely allergic reactions including skin rashes, pruritus, urticaria, photosensitivity, vasculitis, interstitial nephritis and fever (see also under ‘Skin’ ).

Endocrine: Bumetanide may provoke hyperglycaemia and glycosuria. Periodic checks on urine and blood glucose should be made in diabetes and patients suspected of latent diabetes.

Gastro-intestinal: abdominal pain, nausea, vomiting, dyspepsia, diarrhoea, stomach cramps; Pancreatitis has been reported in association with the loop diuretics but may be more likely to occur with high doses and/or parenteral therapy.

Haematopoietic: Thrombocytopenia and bone marrow depression, including agranulocytosis and leucopenia, associated with the use of bumetanide has been reported rarely but it has not been proven to be attributed to the drug.

Hepatic: Abnormalities of serum levels of hepatic enzymes.

Metabolic: gynaecomastia and painful breasts. Bumetanide may cause an increase in blood uric acid and gout may be precipitated.

Skin: Rarely allergic reactions including skin rashes, pruritus, urticaria, and (see also ‘Disorders of the immune system’ above).

High dose therapy: In patients with severe, chronic renal failure given high doses of bumetanide there have been reports of severe, generalised, musculoskeletal pain sometimes associated with muscle spasm occurring one to two hours after administration and lasting up to 12 hours. The lowest reported dose causing this type of adverse reaction was 5mg by intravenous injection and the highest was 75mg orally in a single dose. All patients recovered fully and there was no deterioration in their renal function. The cause of this pain is uncertain but it 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 5-10mg daily and titrating upwards using a twice daily dosage regimen at doses of 20mg each day or more.

4.9 Overdose

Symptoms would be those caused by excessive diuresis. The stomach should be emptied by gastric lavage or emesis. General measures should be taken to restore blood volume, maintain blood pressure and correct electrolyte disturbance.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Bumetanide is a potent, high ceiling, loop diuretic with a rapid onset and a short duration of action. The primary site of action is the ascending limb of the loop of

Henle where it exerts inhibiting effects on electrolyte reabsorption causing the diuretic and natiuretic action observed.

After oral administration of 1mg bumetanide, diuresis begins within 30 minutes with a peak effect between one and two hours. The diuretic effect is virtually complete three hours after a 1mg dose.

5.2 Pharmacokinetic properties

Bumetanide is well absorbed after oral administration with the bioavailability reaching between 80 and 95%. The elimination half life ranges from between 0.75 to 2.6 hours. No active metabolites are known. Renal excretion accounts for approximately half the clearance with hepatic excretion responsible for the other half. There is an increase in half life and a reduced plasma clearance in the presence of renal or hepatic disease. In patients with chronic renal failure the liver takes more importance as an excretory pathway although the duration of action is not markedly prolonged.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to those already included in other sections.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Maize Starch Lactose

Polyvidone K25

Polysorbate 80

Colloidal Anhydrous Silica

Agar

Talc

Magnesium Stearate

6.2    Incompatibilities

None known.

6.3 Shelf life

Five years

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original container.

6.5 Nature and contents of container

Glass tablet containers containing 10, 100 and 1000 tablets.

250 pm PVC/20pm aluminium strips in packs containing 14, 28 and 56 tablets.

6.6 Special precautions for disposal

None.

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited Ash Road North Wrexham LL13 9UF United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0326

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

18/02/1997 / 04/08/2003

10 DATE OF REVISION OF THE TEXT

23/11/2011