Bumetanide/Amiloride 1mg/5mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Bumetanide PhEur 1mg and Amiloride Hydrochloride BP 5mg

Contains lactose

For a full list of excipients see Section 6.1.

3 PHARMACEUTICAL FORM

Tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Bumetanide/Amiloride 1mg/5mg Tablets are indicated where a prompt diuresis is required. It is particularly of value in conditions where potassium conservation is important.

4.2 Posology and method of administration

For oral administration:

Adults: The normal adult dose is 1 to 2 tablets daily. The dose may be

adjusted according to response.

Elderly: The dose should be adjusted according to needs and serum

electrolytes and urea should be monitored carefully.

Children and adolescents under the age of 18 years: Not recommended.

4.3 Contraindications

Hyperkalaemia (serum potassium >5.3mmol/litre), severe electrolyte imbalance, acute renal insufficiency, severe progressive renal disease, anuria, severe liver disease, adrenocortical insufficiency (Addison's Disease), precomatose states associated with cirrhosis, known sensitivity to bumetanide or amiloride or to Bumetanide/ Amiloride 1mg/5mg Tablets. Bumetanide/Amiloride 1mg/5mg Tablets should not be given concurrently with potassium supplements or potassium-sparing agents.

Bumetanide/Amiloride 1mg/5mg Tablets are contra-indicated in children as safety in this age group has not been established.

Bumetanide/Amiloride 1mg/5mg Tablets are contra-indicated in hepatic coma and care should be taken in states of severe electrolyte depletion.

As with other diuretics, bumetanide/amiloride should not be administered concurrently with lithium salts. Diuretics can reduce lithium clearance resulting in high serum levels of lithium.

4.4 Special warnings and precautions for use

Serum uric acid levels may be increased and acute attacks of gout may be precipitated. Patients with prostatic hypertrophy or impaired micturition may be at risk of developing acute retention.

To minimise risk of hyperkalaemia, caution is advised if bumetanide/amiloride tablets are administered to patients with known/suspected diabetes mellitus (see section 4.5).

Bumetanide/Amiloride 1mg/5mg Tablets should be discontinued before a glucose tolerance test. The tablets may cause latent diabetes to become manifest. It may be necessary to increase the dose of hypoglycaemic agents in diabetic patients.

Bumetanide/Amiloride 1mg/5mg Tablets should be used with caution in patients already receiving nephrotoxic or ototoxic drugs.

Patients who are being treated with this preparation require regular supervision with monitoring of fluid and electrolyte status to avoid excessive fluid loss.

In common with other potent diuretics, Bumetanide/Amiloride 1mg/5mg Tablets should be used with caution in elderly patients or those with disorders rendering electrolyte balance precarious. Hyponatraemia, hypochloraemia and raised blood urea may occur during vigorous diuresis especially in seriously ill patients. Careful monitoring of serum electrolytes and urea should be undertaken in these patients.

Caution is advised when used in patients with hypotension and in patients with porphyria.

Caution should be exercised when used in patients with hepatic impairment as there may be increased risk of encephalopathy.

In patients with known hypersensitivity to sulfonamides or thiazides there may be a potential risk of hypersensitivity to bumetanide.

Bumetanide and/or amiloride found in urine by doping test is cause for disqualification of athletes.

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

In common with other diuretics serum lithium levels may be increased when lithium is given concurrently with Bumetanide/Amiloride 1mg/5mg Tablets. Concomitant use is contraindicated (see section 4.3).

Hyperkalaemia has been observed in patients receiving amiloride and therefore concurrent use of Bumetanide/Amiloride 1mg/5mg Tablets with potassium conserving diuretics is not recommended.

As ACE Inhibitors, angiotensin II receptor antagonists, ciclosporin and trilostane may elevate serum potassium levels, especially in the presence of renal impairment, combination with Bumetanide/Amiloride 1mg/5mg Tablets is best avoided in elderly patients or in those in whom renal function may be compromised. If use of the combination is considered essential the clinical condition and serum electrolytes must be carefully and continuously monitored.

Bumetanide can cause hypokalaemia, which can increase the sensitivity to digitalis glycosides and non-depolarising neuromuscular blocking agents.

The dose of cardiac glycosides or hypotensive agents may require adjustment.

Bumetanide/Amiloride may potentiate the effect of antihypertensive agents including diuretics and drugs inducing postural hypotension e.g. tricyclic antidepressants. Therefore the dose of these drugs may need adjustment when bumetanide/amiloride tablets are used to treat oedema in hypertensive patients. Certain non-steroidal anti-inflammatory drugs have been shown to antagonise the action of diuretics, increase the risk of nephrotoxicity and increase the risk of hyperkalaemia.

The toxic effects of nephrotoxic drugs may be increased by concomitant administration of potent diuretics such as bumetanide.

Impairment of renal function may develop in patients receiving treatment with bumetanide and high doses of certain cephalosporins.

Concurrent use of tetracyclines and diuretics should be avoided because of their association with rises in blood urea nitrogen levels.

Bumetanide may potentiate the ototoxicity of aminoglycosides and other ototoxic drugs. Since this may lead to irreversible damage, these drugs must not be used with Bumetanide/Amiloride unless there are compelling medical reasons. In such situations, careful medical supervision is required.

As would be expected, the use of an alpha blocker with a diuretic may result in an additive hypotensive effect, but aside from first-dose hypotension, this usually seems to be a beneficial interaction in patients with hypertension. The effects in patients with congestive heart failure may be more severe.

Bumetanide/Amiloride may antagonise hypoglycaemic effect of antidiabetic drugs. Adjustment of the dose of antidiabetic drugs may be needed in concomitant use (see section 4.4).

Probenecid, when administered concomitantly with bumetanide, may lead to diminished natriuresis. Increased natriuresis may be observed when administered concomitantly with amiloride. The effect on natriuresis may therefore be cancelled out when co-administering probenecid and Bumetanide/Amiloride.

4.6 Pregnancy and lactation

Pregnancy: There are no adequate data from the use of Bumetanide/Amiloride in pregnant women. Bumetanide/Amiloride should not be used during pregnancy unless clearly necessary. It may be used only when the potential benefit justifies the potential risk to the foetus.

Lactation: There is insufficient information on the excretion of Bumetanide/Amiloride in human or animal breast milk. Therefore Bumetanide/Amiloride should not be taken by nursing mothers.

4.7 Effects on ability to drive and use machines

Patients who experience dizziness or fatigue should not drive or operate machinery.

4.8 Undesirable effects

The following side effects, listed below by system organ class, have been reported to be associated with bumetanide or amiloride use, which should be considered as potential adverse effects of Bumetanide/Amiloride 1mg/5mg Tablets. Since only post marketing data are available, the frequency for these side effects is unknown.

Bumetanide-related effects:

Blood and lymphatic system disorders

Thrombocytopenia, leukopenia, bone marrow failure, agranulocytosis

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Electrolyte imbalance, for example:

Hypokalaemia, hyponatraemia, dehydration, hypomagnesaemia, gout, hyperuricaemia, alkalosis hypochloraemic, hyperglycaemia, hypocalcaemia, hyperlipidaemia.

Nervous system disorders

Headache, dizziness

Ear and labyrinth disorders

Tinnitus, deafness

Vascular disorders

Orthostatic hypotension, hypotension

Gastrointestinal disorders

Gastrointestinal disorder, for example:

Nausea, vomiting, diarrhoea, abdominal pain

Hepatobiliary system disorders

Cholestasis, jaundice

Skin and subcutaneous tissue disorders

Rash*, urticaria, dermatitis, photosensitivity reaction, pruritus

*Various types of rash reactions such as erythematous, maculo-papular and pustular have been reported

Musculoskeletal, connective tissue and bone disorders

Myalgia, muscle spasm, arthralgia

Renal and urinary disorders

Renal failure acute

Reproductive system and breast disorders

Gynaecomastia, breast pain

General disorders and administrative site conditions

Fatigue

Investigations

Blood creatinine increased

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 or two hours after administration and lasting up to 12 hours. The lowest reported dose causing this type of adverse reaction was 5 mg by intravenous injection and the highest was 75 mg 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 5-10 mg daily and titrating upwards using a twice daily dosage regimen at doses of 20 mg per day or more.

Metabolism and nutrition disorders

Hyperkalaemia, hyperuricaemia, hyponatraemia

Psychiatric Disorders Psychiatric symptoms, for example:

Confusion, libido decreased

Nervous system disorders

Headache, dizziness, paraesthesia, encephalopathy

Ear and labyrinth disorders

Tinnitus, vertigo

Cardiac disorders

Arrhythmia, atrioventricular block complete (one patient with partial heart block developed complete heart block), angina pectoris, palpitations

Vascular disorders

Orthostatic hypotension

Gastrointestinal disorders

Gastrointestinal disorder, for example:

Nausea, abdominal pain, diarrhoea, constipation, vomiting, dyspepsia, flatulence

Hepatobiliary system disorders

Jaundice

Skin and subcutaneous tissue disorders

Rash, pruritus

Musculoskeletal, connective tissue and bone disorders

Muscle spasm

Reproductive system disorders

General disorders and administrative site conditions

Thirst

Investigations

Hepatic enzyme abnormal

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

Symptoms would be those caused by excessive diuresis such as dehydration, electrolyte imbalance, particularly hyperkalaemia, and hypotension and treatment should be aimed at reversing these. No specific antidote is available. Treatment is symptomatic and supportive. If hyperkalaemia is present appropriate measures must be instituted to reduce serum potassium.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Bumetanide/Amiloride 1mg/5mg Tablets combine the potent loop diuretic bumetanide with the potassium sparing diuretic amiloride.

The action of bumetanide starts within 30 minutes and is virtually complete within 3 hours. The addition of amiloride will reduce any tendency towards hypokalaemia and its mild natriuretic effect will be additive to that of bumetanide.

5.2 Pharmacokinetic properties

The product contains a short acting diuretic and a potassium sparing diuretic with a more prolonged action.

After administration of one tablet containing bumetanide 1mg and amiloride hydrochloride 5mg to healthy volunteers, a Cmax of 48.60 ± 19.08ng/ml was found for bumetanide at Tmax 0.91 ± 0.31 hours.

The corresponding data for amiloride hydrochloride was Cmax 10.47 ± 4.02ng/ml at Tmax 2.92 ± 0.78 hours.

5.3 Preclinical safety data

There are no preclinical 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

Microcrystalline cellulose, lactose, magnesium stearate, maize starch

6.2 Incompatibilities

None known

6.3 Shelf life

3 years

6.4 Special precautions for storage

None

6.5 Nature and contents of container

Glass bottles of 50 and 100 tablets. Blister packs of 14, 28 and 56 tablets.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Chemidex Pharma Limited Trading as: Essentials Generics 7 Egham Business Village Crabtree Road Egham Surrey TW20 8RB

8 MARKETING AUTHORISATION NUMBER

PL 17736/0122

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/09/1990

10 DATE OF REVISION OF THE TEXT

29/10/2015