Drug Class Description

Generic Name

Drug Description

Presentation

Indications

AmBisome is indicated in:

• the treatment of severe systemic and/or deep mycoses where toxicity (particularly nephrotoxicity) precludes the use of conventional systemic amphotericin B in effective dosages.

• the treatment of visceral leishmaniasis in immunocompetent patients including both adults and children.

• the empirical treatment of presumed fungal infections in febrile neutropenic patients, where the fever has failed to respond to broad spectrum antibiotics and appropriate investigations have failed to define a bacterial or viral cause. Infections successfully treated with AmBisome include: disseminated candidiasis, aspergillosis, mucormycosis, chronic mycetoma, cryptococcal meningitis and visceral leishmaniasis. This drug should not be used to treat the common clinically inapparent forms of fungal disease which show only positive skin or serologic tests.

Adult Dosage

AmBisome should be administered by intravenous infusion over a 30 - 60 minute period. For doses greater than 5mg/kg/day, intravenous infusion over a 2 hour period is recommended. The recommended concentration for intravenous infusion is 0.20 mg/ml to 2.00 mg/ml amphotericin B as AmBisome. AmBisome therapy has been administered for as long as three months, with a cumulative dose of 16.8 g of amphotericin B as AmBisome without significant toxicity.

Adult Patients

Treatment of mycoses:

Therapy is usually instituted at a daily dose of 1.0 mg/kg of body weight, and increased stepwise to 3.0 mg/kg, as required. Data are presently insufficient to define total dosage requirements and duration of treatment necessary for resolution of mycoses. However, a cumulative dose of 1.0 - 3.0 g of amphotericin B as AmBisome over 3 - 4 weeks has been typical. Dosage of amphotericin B as AmBisome must be adjusted to the specific requirements of each patient.

Treatment of visceral leishmaniasis:

A total dose of 21.0 - 30.0 mg/kg of body weight given over 10-21 days may be used in the treatment of visceral leishmaniasis. Particulars as to the optimal dosage and the eventual development of resistance are as yet incomplete. The product should be administered under strict medical supervision.

Empirical treatment of febrile neutropenia:

The recommended daily dose is 3 mg/kg body weight per day. Treatment should be continued until the recorded temperature is normalised for 3 consecutive days. In any event, treatment should be discontinued after a maximum of 42 days.

Paediatric Patients: Both systemic fungal infections in children and presumed fungal infections in children with febrile neutropenia have been successfully treated with AmBisome, without reports of unusual adverse events. Paediatric patients have received AmBisome at doses comparable to those used in adults on a per kilogram body weight basis.

AmBisome is not recommended for use in children below 1 month old due to a lack of data on safety and efficacy.

Elderly Patients: No alteration in dose or frequency of dosing is required.

Renal Impairment: AmBisome has been successfully administered to a large number of patients with pre-existing renal impairment at starting doses ranging from 1-3 mg/kg/day in clinical trials and no adjustment in dose or frequency of administration was required.

Contra Indications

AmBisome is contraindicated in those patients who have shown hypersensitivity to the active substance or to any of the excipients unless, in the opinion of the physician, the condition requiring treatment is life-threatening and amenable only to AmBisome therapy.

Special Precautions

Anaphylaxis and anaphylactoid reactions have been reported in association with AmBisome infusion. Allergic type reactions, including severe infusion-related reactions can occur during administration of amphotericin-containing products, including AmBisome. Therefore, administration of a test dose is still advisable before a new course of treatment. For this purpose a small amount of an AmBisome infusion (e.g. 1 mg) can be administered for about 10 minutes, the infusion stopped and the patient observed carefully for the next 30 minutes. If there have been no severe allergic or anaphylactic/anaphylactoid reactions the infusion of AmBisome dose can be continued. If a severe allergic or anaphylactic/anaphylactoid reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusion of AmBisome.

Other severe infusion-related reactions can occur during administration of amphotericin B-containing products, including AmBisome. Although infusion-related reactions are not usually serious, consideration of precautionary measures for the prevention or treatment of these reactions should be given to patients who receive AmBisome therapy. Slower infusion rates (over 2 hours) or routine doses of diphenhydramine, paracetamol, pethidine and/or hydrocortisone have been reported as successful in their prevention or treatment.

AmBisome has been shown to be substantially less toxic than conventional amphotericin B, particularly with respect to nephrotoxicity; however, adverse reactions including renal adverse reactions, may still occur.

In studies comparing AmBisome 3 mg/kg daily with higher doses (5, 6 or 10 mg/kg daily, it was found that the incidence rates of increased serum creatinine, hypokalaemia and hypomagnesaemia were notably higher in the high dose groups.

In particular, caution should be exercised when prolonged therapy is required. Regular laboratory evaluation of serum electrolytes, particularly potassium and magnesium as well as renal, hepatic and haematopoietic function should be performed, at least once weekly. This is particularly important in patients receiving concomitant nephrotoxic medications. Renal function should be closely monitored in these patients. Due to the risk of hypokalaemia, appropriate potassium supplementation may be required during the course of AmBisome administration. If clinically significant reduction in renal function or worsening of other parameters occurs, consideration should be given to dose reduction, treatment interruption or discontinuation.

Acute pulmonary toxicity has been reported in patients given amphotericin B (as sodium deoxycholate complex) during or shortly after leukocyte transfusions. It is recommended that these infusions are separated by as long a period as possible and pulmonary function should be monitored.

In the Treatment of Diabetic Patients: It should be noted that AmBisome contains approximately 900 mg of sucrose in each vial.

Interactions

No specific interaction studies have been performed with AmBisome. However, the following drugs are known to interact with amphotericin B and may interact with AmBisome:

Nephrotoxic medications: Concurrent administration of AmBisome with other nephrotoxic agents (for example ciclosporin, aminoglycosides, polymixins, tacrolimus and pentamidine) may enhance the potential for drug-induced renal toxicity in some patients. However, in patients receiving concomitant ciclosporin and/or aminoglycosides, AmBisome was associated with significantly less nephrotoxicity compared to amphotericin B. Regular monitoring of renal function is recommended in patients receiving AmBisome with any nephrotoxic medications.

Corticosteroids, corticotropin (ACTH) and diuretics: Concurrent use of corticosteroids, ACTH and diuretics (loop and thiazide) may potentiate hypokalemia.

Digitalis glycosides: AmBisome-induced hypokalemia may potentiate digitalis toxicity.

Skeletal muscle relaxants: AmBisome-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g. tubocurarine).

Antifungals: No evidence of benefit from the use of flucytosine with AmBisome has been observed. Whilst synergy between amphotericin and flucytosine has been reported, concurrent use may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion.

Antineoplastic agents: Concurrent use of antineoplastic agents may enhance the potential for renal toxicity, bronchospasm and hypotension. Antineoplastic agents should be given concomitantly with caution.

Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients given amphotericin B (as sodium deoxycholate complex) during or shortly after leukocyte transfusions. It is recommended these infusions are separated by as long a period as possible and pulmonary function should be monitored.

Adverse Reactions

Fever and chills/rigors are the most frequent infusion-related reactions expected to occur during AmBisome administration. Less frequent infusion-related reactions may consist of one or more of the following symptoms: back pain, chest tightness or pain, dyspnoea, bronchospasm, flushing, tachycardia, and hypotension. These resolve rapidly on stopping the infusion and may not occur with every subsequent dose or when slower infusion rates (over 2 hours) are used. In addition, infusion-related reactions may also be prevented by the use of premedication. However, severe infusion-related reactions may necessitate the permanent discontinuation of AmBisome.

In two double-blind, comparative studies, AmBisome treated patients experienced a significantly lower incidence of infusion-related reactions, as compared to patients treated with conventional amphotericin B or amphotericin B lipid complex.

In pooled study data from randomised, controlled clinical trials comparing AmBisome with conventional amphotericin B therapy in greater than 1,000 patients, reported adverse reactions were considerably less severe and less frequent in AmBisome treated patients as compared with conventional amphotericin B treated patients.

Nephrotoxicity occurs to some degree with conventional amphotericin B in most patients receiving the drug intravenously. In a double-blind study involving 687 patients, the incidence of nephrotoxicity with AmBisome (as measured by serum creatinine increase greater than 2.0 times baseline measurement), was approximately half that for conventional amphotericin B. In another double-blind study involving 244 patients, the incidence of nephrotoxicity with AmBisome (as measured by serum creatinine increase greater than 2.0 times baseline measurement) is approximately half that for Amphotericin B lipid complex.

The following adverse reactions have been attributed to AmBisome based on clinical trial data and post-marketing experience. The frequency is based on analysis from pooled clinical trials of 688 AmBisome treated patients; the frequency of adverse reactions identified from post-marketing experience is not known. Adverse reactions are listed below by body system organ class using MedDRA and are sorted by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Frequencies are defined as:

Very common ( 1/10)

Common ( 1/100 to < 1/10)

Uncommon ( 1/1,000 to < 1/100)

Very rare (<1/10,000), not known (cannot be estimated from the available data)

CARDIAC DISORDERS

Common: tachycardia

Not known: cardiac arrest, arrhythmia

BLOOD AND LYMPHATIC SYSTEM DISORDERS

Uncommon: thrombocytopenia

Not known: anemia

NERVOUS SYSTEM DISORDERS

Common: headache

Uncommon: convulsion

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

Common: dyspnoea

Uncommon: bronchospasm

GASTROINTESTINAL DISORDERS

Very common: nausea, vomiting

Common: diarrhoea, abdominal pain

RENAL AND URINARY DISORDERS

Common: increased creatinine, blood urea increased

Not known: renal failure, renal insufficiency

SKIN AND SUBCUTANEOUS DISORDERS

Common: rash

Not known: angioneurotic oedema

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Common: back pain

METABOLISM AND NUTRITION DISORDERS

Very common: hypokalemia

Common: hypomagnesaemia, hypocalcemia, hyperglycemia, hyponatremia

VASCULAR DISORDERS

Common: vasodilatation, flushing, hypotension

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Very Common: pyrexia, rigors

Common: chest pain

IMMUNE SYSTEM DISORDERS

Uncommon: anaphylactoid reaction

Not known: anaphylactic reactions, hypersensitivity

HEPATOBILIARY DISORDERS

Common: liver function tests abnormal, hyperbilirubinaemia, alkaline phosphatase increased

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