Bristol-Myers Squibb Pharmaceutical Limited

Fungizone 50mg Powder for sterile concentrate.

Each vial contains 50mg of amphotericin.

For a full list of excipients, see section 6.1.

Powder for Concentrate for Solution for Infusion. (Powder for sterile concentrate)

Yellow to orange, fine, fluffy powder.

Fungizone should be administered primarily to patients with progressive, potentially fatal infections. This potent drug should not be used to treat the common forms of fungal disease which show only positive skin or serological tests.

Fungizone is specifically intended to treat cryptococcosis (torulosis); North American blastomycosis; the disseminated forms of candidosis, coccidioidomycosis and histoplasmosis; mucormycosis (phycomycosis) caused by species of the genera Mucor, Rhizopus, Absidia, Entomophthora, Conidiobolus and Basidiobolus sporotrichosis (Sporotrichum schenckii), aspergillosis (Aspergillus fumigatus).

Amphotericin may be helpful in the treatment of American mucocutaneous leishmaniasis but is not the drug of choice in primary therapy.

Adults and children:

When commencing all new courses of treatment, it is advisable to administer a test dose immediately preceding the first dose. A volume of the infusion containing 1mg (i.e. 10ml) should be infused over 20-30 minutes and the patient carefully observed for at least a further 30 minutes. It should be noted that patient responses to the test dose may not be predictive of subsequent severe side effects.

Fungizone should be administered by intravenous infusion over a period of 2-4 hours. Reduction of the infusion rate may reduce the incidence of side-effects. In rare instances infusion times of up to 6 hours may be necessary. Initial daily dose should be 0.25mg/kg of body weight gradually increasing to a level of 1.0mg/kg of body weight depending on individual response and tolerance. Within the range of 0.25-1.0mg/kg the daily dose should be maintained at the highest level which is not accompanied by unacceptable toxicity.

In seriously ill patients the daily dose may be gradually increased up to a total of 1.5mg/kg. Since amphotericin is excreted slowly, therapy may be given on alternate days in patients on the higher dosage schedule. Several months of therapy are usually necessary; a shorter period of therapy may produce an inadequate response and lead to relapse.

Whenever medication is interrupted for a period longer than seven days, therapy should be resumed by starting with the lowest dosage level, i.e. 0.25mg/kg of body weight and increased gradually.

CAUTION:

Under no circumstances should a total daily dose of 1.5mg/kg be exceeded. Amphotericin B overdoses can result in potentially fatal cardiac or cardiorespitatory arrest. The recommended concentration for intravenous infusion is 10mg/100ml.

Amphotericin B may be the only effective treatment available for potentially life-threatening fungal disease. In each case, its possible life-saving benefit must be balanced against its untoward and dangerous side effects.

Elderly:

No specific dosage recommendations or precautions.

The use of Fungizone by other routes has been documented in the published literature:

Bladder irrigation/instillation (e.g. candiduria): Continuous irrigation with 50mg Fungizone in 1 litre sterile water each day until urinary cultures are negative. Intermittent use of volumes of 100-400ml (concentrations of 37.5-200mcg/ml) has also been reported. The urine should be alkalinized (with potassium citrate) and antifungal ointment applied to the perineal area.

Lung inhalation (e.g. pulmonary aspergillosis): 8-40mg amphotericin (nebulized in sterile water or 5% Glucose) has been given daily in divided doses. Concurrent eradication of oral and intestinal yeast reservoirs is recommended.

Intrathecal (e.g. coccidiodal meningitis): Current published dosage recommendations are for maintenance 0.25-1.0mg amphotericin 2-4 times weekly following initiation with a low dose (0.025mg) and cautious increases. Amphotericin is irritating when injected into the CSF.

Other: Other uses of solutions prepared using Fungizone include local instillations for the treatment of fungal infections of the ear, eye, peritoneum, lung cavities and joint spaces.

Those patients who are hypersensitive to amphotericin, unless, in the opinion of the physician, the condition requiring treatment is life-threatening and amenable only to such therapy.

To detect idiosyncratic anaphylactic reactions and to minimise the dose administered if such a reaction occurs, a test dose should be administered initially.

Prolonged therapy with amphotericin is usually necessary. Unpleasant reactions are quite common when the drug is given parenterally at therapeutic dosage levels. Some of these reactions are potentially dangerous. Hence amphotericin should be used parenterally only in hospitalised patients, or those under close clinical observation. The drug is nephrotoxic. If the serum creatinine exceeds 260 micromol/l the drug should be discontinued or the dosage markedly reduced until renal function is improved. Weekly blood counts and serum potassium determinations are also advisable and renal and hepatic function should also be monitored regularly during treatment. If any deterioration occurs in these parameters administration of the drug should cease immediately. Low serum magnesium levels have also been noted during treatment with amphotericin. Therapy should be discontinued if liver function test results (elevated bromsulphalein, alkaline phosphatase and bilirubin) are abnormal.

Leucoencephalopathy has been reported very occasionally following the use of amphotericin injection in patients who received total body irradiation. Most of these patients received high cumulative doses of amphotericin.

Rapid intravenous infusion, over less than one hour, particularly in patients with renal insufficiency, has been associated with hyperkalaemia and arrhythmias and should therefore be avoided.

Corticosteroids should not be administered concomitantly unless they are necessary to control drug reactions. Other nephrotoxic antibiotics and antineoplastic agents should not be given concomitantly except with great caution.

Safety and effectiveness in paediatric patients have not been established through adequate and well-controlled studies.

Care must be taken when administering Fungizone to prevent overdose, which can result in potentially fatal cardiac or cardiorespiratory arrest. Verify the product name and dosage pre-administration, especially if the dose prescribed exceeds 1.5mg/kg (See section 4.2 Posology and Method of Administration and Section 4.9 Overdose Symptoms, Emergency Procedures and Antidotes).

Concomitant administration of nephrotoxic drugs or antineoplastics should be avoided if at all possible.

The hypokalaemia following amphotericin therapy may potentiate the effects or toxicity of agents such as digitalis glycosides, anti-arrhythmic agents and skeletal muscle relaxants.

Corticosteroids may increase the potassium loss due to amphotericin.

Flucytosine toxicity may be enhanced during concomitant administration, possibly due to an increase in its cellular uptake and/or impairment of its renal excretion.

Acute pulmonary reactions have occasionally been observed in patients given amphotericin during or shortly after leukocyte transfusions. It is advisable to separate these infusions as far as possible and to monitor pulmonary function.

Safety for use in pregnancy has not been established; therefore it should be used during pregnancy only if the possible benefits to be derived outweigh the potential risks involved.

It is not known whether amphotericin B is excreted in human milk. It is recommended that women taking amphotericin B do not breast-feed because of the potential for serious adverse reactions in nursing infants.

Not applicable.

While some patients may tolerate full intravenous doses of amphotericin without difficulty, most will exhibit some intolerance. In patients experiencing adverse reactions these may be made less severe by giving aspirin, antihistamines or anti-emetics. Febrile reactions may be decreased by the intravenous administration of small doses of adrenal corticosteroids, e.g. 25mg hydrocortisone. This may be administered just prior to or during amphotericin infusion. The dosage and duration of such corticosteroid therapy should be kept to a minimum. Administration of the drug on alternate days may decrease anorexia and phlebitis.

Addition of heparin (1000 units per infusion), rotation of the injection site, the use of a paediatric scalp-vein needle and alternate-day therapy may lessen the incidence of thrombophlebitis. Extravasation may cause chemical irritation. The adverse reactions that are most commonly observed are: fever (sometimes with shaking chills), headache, anorexia, weight loss, nausea and vomiting, malaise, muscle and joint pains, dyspepsia, cramping epigastric pain, diarrhoea, local venous pain at the injection site with phlebitis and thrombophlebitis, normochromic normocytic anaemia and hypokalaemia. Abnormal renal function (including renal impairment, renal insufficiency, acute renal failure and nephrogenic diabetes insipidus) including hypokalaemia, azotaemia, hyposthenuria, renal tubular acidosis or nephrocalcinosis, is also commonly observed and usually improves upon interruption of therapy; however, some permanent impairment often occurs, especially in those patients receiving large amounts (over 5g) of amphotericin.

The following adverse reactions occur less frequently or rarely; anuria (oliguria); cardiovascular toxicity including arrhythmias, ventricular fibrillation, cardiac arrest, hypotension, hypertension; coagulation defects; thrombocytopenia; leucopenia; agranulocytosis; eosinophilia; leucocytosis; melaena or haemorrhagic gastroenteritis; maculopapular rash and pruritus; hearing loss, tinnitus; transient vertigo; blurred vision, or diplopia; encephalopathy (see 4.4 Special Warnings and Special Precautions for Use); peripheral neuropathy, convulsions and other neurologic symptoms; anaphylactoid reactions, acute liver failure and flushing. Very rare reports of Stevens-Johnson syndrome have been received during post-marketing surveillance.

Under no circumstances should a total daily dose of 1.5mg/kg be exceeded. The recommended concentration for IV infusion is 10mg/100ml. Amphotericin overdoses can result in potentially fatal cardio-respiratory arrest. If an overdose is suspected, discontinue therapy and monitor the patient's clinical status (e.g., cardio-respiratory, renal and liver function, haematologic status serum electrolytes) and administer supportive therapy as required. Amphotericin is not haemodialysable. Prior to reinstituting therapy, the patient's condition should be stabilised (including correction of electrolyte deficiencies, etc.).

Amphotericin is a polyene antifungal antibiotic active against a wide range of yeasts and yeast-like fungi including Candida albicans. Crystalline amphotericin is insoluble in water; therefore, the antibiotic is solubilised by the addition of sodium desoxycholate to form a mixture which provides a colloidal dispersion for parenteral administration. Amphotericin is fungistatic rather than fungicidal in concentrations obtainable in body fluids. It probably acts by binding to sterols in the fungal cell membrane with a resultant change in membrane permeability which allows leakage of intracellular components.

Mammalian cell membranes also contain sterols and it has been suggested that the damage to human and fungal cells may share common mechanisms. No strains of Candida resistant to amphotericin have been reported in clinical use, and although in vitro testing does produce a small number of resistant isolates this occurs only following repeated subcultures.

Average peak plasma concentrations ranging from 0.5 to 2 mcg/ml are found in adults given repeated doses of approximately 0.5 mg/kg/day. Following a rapid initial fall, plasma concentrations plateau at about 0.5 mcg/ml. An elimination half-life of approximately 15 days follows an initial plasma half-life of about 24 hours. It has been reported that amphotericin is highly bound (more than 90%) to plasma proteins and is poorly dialysable.

Amphotericin is excreted very slowly by the kidneys with 2 to 5% of a given dose being excreted in biologically active form. After treatment is discontinued the drug can be detected in the urine for at least seven weeks. The cumulative urinary output over a seven day period amounts to approximately 40% of the amount of drug infused.

Excretion in the bile may represent an important route of elimination. Details of other metabolic pathways are not known. Blood levels are not affected by renal or hepatic disease.

No further relevant data.

Desoxycholic acid,

Disodium phosphate dodecahydrate,

Monosodium phosphate dihydrate,

Sodium hydroxide,

Concentrated Phosphoric acid.

Do not reconstitute with saline solutions. The use of any diluent other than the ones recommended or the presence of a bacteriostatic agent in the diluent may cause precipitation of the amphotericin.

Unopened: 2 years

Reconstituted: After reconstitution with 10 ml sterile Water for Injections the concentrate (5mg/ml) should be stored protected from light. Chemical and physical in-use stability has been demonstrated for 8 hours at up to 25 °C and 24 hours at 2-8 °C.

From a microbiological point of view, due to the absence of any microbial preservative, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. These would normally not be longer than 24 hours at 2-8 °C unless reconstitution has taken place in controlled and validated aseptic conditions. It is not intended as a multidose vial. Any unused material should be discarded. Solutions prepared for intravenous infusion (i.e. 10 mg or less amphotericin per 100 ml) should be used promptly after preparation.

Vials of powder for reconstitution should be stored in a refrigerator (2-8°C).

For storage of reconstituted product, see section 6.3.

Type I clear flint glass vials closed with a grey butyl rubber stopper. Vials of 50mg.

Preparation of solutions:

Reconstitute as follows: An initial concentrate of 5mg amphotericin per ml is first prepared by rapidly expressing 10ml sterile water for injection, without a bacteriostatic agent, directly into the lyophilized cake, using a sterile needle (minimum diameter: 20 gauge) and syringe. Shake the vial immediately until the colloidal solution is clear. The reconstituted product is a yellow solution. The infusion solution, providing 10mg/100ml is obtained by further dilution (1:50) with 5% Glucose Injection of pH above 4.2. The pH of each container of Glucose Injection should be ascertained before use. Commercial Glucose Injection usually has a pH above 4.2; however, if it is below 4.2 then 1 or 2 ml of buffer should be added to the Glucose Injection before it is used to dilute a concentrated solution of amphotericin. The recommended buffer has the following composition:

The buffer should be sterilised before it is added to the Glucose Injection, either by filtration through a bacterial filter, or by autoclaving for 30 mins at 15lb pressure (121°C).

CAUTION:

Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present. Do not use the initial concentrate or the infusion solution if there is any evidence of precipitation of foreign matter.

An in-line membrane filter may be used for intravenous infusion of amphotericin; however the mean pore diameter of the filter should not be less than 1.0 micron in order to assure passage of the amphotericin dispersion.

Other preparations for injection should not be added to the infusion solution or administered via the cannula being used to administer Fungizone.

Bristol-Myers Squibb Pharmaceuticals Ltd

Swords

County Dublin

Ireland

PA 2/6/1

1 April 1977/1 April 2008

February 2011