Bumetanide 1mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Bumetanide 1mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains: 1mg Bumetanide Ph.Eur.
3 PHARMACEUTICAL FORM
White uncoated tablet.
White, biconvex uncoated tablet impressed “C” on one face and the identifying letters “BU” on either side of a central division line on the reverse.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Bumetanide Tablets are indicated for use when diuretic therapy is required in the treatment of oedema, for example:
• oedema associated with congestive heart failure.
• oedema associated with cirrhosis.
• oedema associated with renal disease, including the nephrotic syndrome.
4.2 Posology and Method of Administration
For all listed indications use the following dosge regimen
Posology
Adults: Most patients require a daily dose of 1mg which can be given as a single morning or early evening dose. Depending upon the patient’s therapeutic response a second dose can be given 6 to 8 hours later. In refractory cases the dose can be increased until satisfactory diuresis is obtained.
Children: Not recommended for children under 12 years.
Elderly: The dosage should be adjusted according to therapeutic response. A dose of 0.5mg may be sufficient in some elderly patients.
Method of Administration For oral administration.
4.3 Contra-Indications
Bumetanide tablets should not be given in the following situations:
• Hypersensitivity to bumetanide or any of the other ingredients in the tablet.
• Hypersensitivity to sulphonamides as there is a risk of cross-sensitivity to bumetanide.
• Hepatic coma.
• Renal failure associated with hepatic coma.
• Renal failure caused by poisoning by hepatotoxic agents.
• Severe electrolyte depletion.
• Concurrently with lithium salts.
• If there is a marked increase in blood urea or the development of oliguria or anuria during treatment for severe progressive renal disease.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.4 Special Warnings and Special Precautions for Use
Care should be taken and the risk/benefit of treatment determined prior to
administration of bumetanide in the following situations:
• Caution in hypotension, prostatic enlargement (because of risk of developing acute retention) and porphyria.
• Gout as bumetanide may cause an increase in blood uric acid.
• Diabetes or suspected latent diabetes.
• Pre-existing hepatic impairment as there is a risk of encephalopathy.
• In elderly patients or those on a high dose treatment regimen. Excessively rapid mobilisation of oedema, particularly in elderly patients, 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.
• In patients with chronic renal failure on a high dose regimen of bumetanide constant hospital supervision is necessary.
• Bumetanide treatment can result in electrolyte disturbances. Patients on a low salt diet may be at an increased risk of electrolyte disturbances. Electrolyte levels especially sodium, potassium, chloride and bicarbonate should be monitored regularly and patients instructed to seek medical help if they develop and signs or symptoms of electrolyte imbalance, such as faintness, weakness, dizziness, fatigue, mental confusion, lassitude, muscle cramps, headache, paraesthesia, thirst, anorexia, nausea and/or vomiting.
4.5 Interaction with other Medicinal Products and other Forms of Interaction
Bumetanide can interact with the following drugs or groups of drugs:
• Alcohol: Co-administration may potentiate postural hypotension.
• Lithium. Bumetanide should not be administered concurrently with lithium salts as diuretics can reduce lithium clearance resulting in high serum levels of lithium.
• Cardiac glycosides. Bumetanide increases the excretion of potassium which can lead to an increase in the sensitivity of the myocardium to the toxic effects of digitalis. Thus dosage adjustment may be necessary.
• Antihypertensive medication (e.g. ACE inhibitors, calcium channel blockers, beta blockers, angiotensin II antagonists). Bumetanide may enhance the hypotensive effects of these medicines. Increased risk of first-dose hypotensive effect of post-synaptic alpha-blockers such as prazosin.
• Non-steroidal anti-inflammatory agents. Bumetanide may increase the nephrotoxicity of NSAIDs and NSAIDs may antagonise the action of bumetanide.
• Antiarrhythmic drugs. The toxicity of amiodarone, disopyramide, flecainide and quinidine is increased if hypokalaemia occurs and the action of lidocaine and mexiletine is antagonised by hypokalaemia.
• Ototoxic medicines. Bumetanide may increase the ototoxicity of the antibacterial agents aminoglycosides, colistimethate colistin and vancomycin.
• Antibacterials. Loop diuretics may increase the nephrotoxicity of cephalosorins.
• Nephrotoxic medicines (e.g. NSAIDs, cisplatin).
• Antidepressant drugs. Bumetanide increases the risk of postural hypotension with tricyclics.
Possible increased risk of hypokalaemia if given with reboxetine. MAOI’s enhance the hypotensive effect.
• Antidiabetic agents. Bumetanide antagonises the hypoglycaemic effects.
• Probenecid. Probenecid may reduce the natriuretic and diuretic effects of bumetanide.
• Antiepileptic drugs (e.g. carbamazepine). Bumetanide increases the risk of hyponatraemia with carbamazepine treatment.
• Cisapride. Avoid in patients with uncorrected electrolyte disturbance such as seen in patients taking potassium depleting diuretics.
• Alprostadil. Enhanced hypotensive effect.
• Antifungal Drugs (e.g. amphotericin). There is an increased risk of hypokalaemia if bumetanide is given concurrently with amphotericin.
• Antihistamine Drugs (e.g terfenadine). Bumetanide-induced hypokalaemia increases the risk of ventricular arrhythmias with terfenadine.
• Antipsychotics The risk of arrhythmias induced by pimozide and thioridazine is increased by hypokalaemia which may be induced by the administration of bumetanide and concomitant use should be avoided.. Hypokalaemia increases risk of ventricular arrythmias with amisulpiride and sertindole.
• Corticosteroids. Increased risk of hypokalaemia and may antagonise diuretic effect.
• Cytotoxics (e.g. cisplatin). Bumetanide increases the risk of nephrotoxicity and ototoxicity with cisplatin.
• Other diuretic drugs. Increased risk of hypokalaemia.
• Hormone antagonists (e.g. aminoglutethimide). Increased risk of hyponatraemia.
• Oestrogens &progestogens._May antagonise bumetanide diuretic effect.
• Sympathomimetics. Increased risk of hypokalaemia.
• Ulcer healing drugs. Increased risk of hypokalaemia.
• Neuromuscular blocking agents (e.g.. tubocurarine). Toxic effects of tubocurarine potentiated by bumetanide-induced hypokalaemia.
• Muscle relaxants. Enhanced hypotensive effect with baclofen and tizanidine.
• Theophylline. Increased risk of hypokalaemia.
4.6 Pregnancy and Lactation
Teratogenic effects have not been demonstrated in four animal species, however, there is insufficient evidence of safety of bumetanide in man. Use of bumetanide in the first trimester of pregnancy should be avoided. Diuretics are not recommended for the treatment of pregnancy-induced hypertension because of the maternal hypovolemia characteristics of this disease.
It is not known whether bumetanide is distributed in breast milk. If treatment is necessary in a lactating woman breast feeding should be stopped or the infant observed for any adverse effects. Bumetanide and other diuretics should be used cautiously during nursing because they may suppress lactation.
4.7 Effects on Ability to Drive and Use Machines
Bumetanide treatment can cause dizziness or blurred vision. Patients should make sure they are not affected before driving or operating machinery.
4.8 Undesirable Effects
Adverse effects of bumetanide which have been reported include:
• Effects on the gastro-intestinal system: Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea, stomach cramps, anorexia, abnormalities of liver enzymes, pancreatitis.
• Effects on the central nervous system: Dizziness, fatigue, headache, encephalopathy (in patients with pre-existing hepatic disease).
• Effects on the sensory systems: Blurred vision, hearing disturbances are rare and are usually reversible.
• Effects on the cardiovascular system: Hypotension, chest pain.
• Effects on the blood: Thrombocytopenia, bone marrow depression has been reported rarely.
• Effects on fluid and electrolyte balance: Dehydration, fluid and electrolyte depletion, hyperuricaemia, raised blood urea and creatinine, increased serum cholesterol and hyperglycaemia.
• Effects on the musculoskeletal system: Arthralgia, muscle cramps, gouty arthritis, severe muscle pain (see under high dose therapy).
• Effects on the skin: Skin rashes, pruritus, urticaria, sweating.
• Other effects: Gynaecomastia, painful breasts, premature ejaculation, erectile impotence.
• 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 1-2 hours after administration and lasting up to 12 hours. The lowest reported dose causing this type of adverse effect was 5mg by intravenous injection and the highest was 75mg orally in a single dose. All patients recovered fully with no further deterioration in renal function. The cause of the pain is unknown but may be a result of varying electrolyte gradients at the cell membrane level. The incidence of this reaction is reduced by initiating treatment at 5-10mg daily and titrating upwards using a twice daily dosage regimen at doses of 20mg per day or more.
4.9 Overdose
Symptoms of overdosage are those caused by excessive diuresis. The stomach should be emptied by gastric lavage or emesis. General supportive measures should be taken to restore blood volume, maintain blood pressure and correct electrolyte disturbances.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic Properties
ATC CODE - C03CA02 High Ceiling Diuretic
Bumetanide is a potent loop diuretic, the pharmacological effects of bumetanide are similar to those of furosemide. Bumetanide produces a diuresis and natriuresis which is ten times greater than control values in healthy subjects. Bumetanide acts directly on the ascending limb of the loop of Henle to inhibit sodium and chloride reabsorption. Bumetanide also appears to inhibit electrolyte reabsorption in the proximal renal tubule. Bumetanide may produce hypotensive effects resulting from decreased plasma volume.
5.2 Pharmacokinetic Properties
Bumetanide is almost completely and fairly rapidly absorbed from the gastrointestinal tract: the bioavailability is reported to be about 80-95%. The oral availability of bumetanide in patients with impaired renal or hepatic function does not appear to differ substantially from that in healthy individuals. The onset of action is approximately 30-60 minutes and the time to peak plasma level approximately 1-2 hours. Bumetanide has a plasma elimination half-life of about 1 to 1/ hours. The diuretic effect is virtually complete in 3 hours after a 1mg dose. Steady state volume of distribution may be decreased in patients with hepatic impairment and may be increased in patients with renal impairment. Bumetanide is about 95% bound to plasma proteins. Protein binding may be decreased in patients with renal impairment as binding appears to be correlated to plasma albumin concentration in these patients. It has been shown that bumetanide binding capacity to albumin is decreased in partially purified albumin from renal failure patients as compared to albumin derived from healthy volunteers. Bumetanide is partially metabolised in the liver to at least five metabolites. Metabolism occurs by oxidation of the N-butyl side chain of the bumetanide molecule, the phenyl ring is not metabolised. The major urinary metabolite is the 3’-alcohol derivative and the major metabolite in bile/faeces is the 2’-alcohol derivative. Minor metabolites include the 4’-alcohol, N-desbutyl and 3’-acid derivatives. Bumetanide metabolites in urine and bile are present as conjugates, principally glucoronide conjugates, conjugates do not appear in faeces. Bumetanide and its metabolites are primarily excreted in urine. Serum concentrations of bumetanide may be higher and half life prolonged in patients with impaired renal and/or hepatic function.
Half of the total drug is excreted unchanged via the renal route, and the remainder via the bile into the faeces.
5.3 Pre-clinical 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
Also contains:
IMS 740P
lactose monohydrate Magnesium stearate Polysorbate 80 Povidone K25 sodium starch glycollate Microcrystalline cellulose (E460)
6.2 Incompatibilities
Not applicable.
6.3 Shelf-Life
Shelf-life
Two years from the date of manufacture.
Shelf-life after dilution/reconstitution Not applicable.
Shelf-life after first opening Not applicable.
6.4 Special Precautions for Storage
Store below 25°C in a dry place. Protect from light.
6.5 Nature and Contents of Container
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids.
The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250pm white rigid PVC. (ii) Surface printed 20pm hard temper aluminum foil with 5-7g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.
Pack sizes: 28, 30, 56, 60, 84, 100, 112 (blisters) Pack sizes: 250, 500, 1000, 5000 (securitainers)
6.6 Instructions for Use/Handling
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis) Whiddon Valley BARNSTAPLE N Devon EX32 8NS
8 MARKETING AUTHORISATION NUMBER(S)
PL 00142/0445
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10/02/2009
10 DATE OF REVISION OF THE TEXT
06/06/2007