This information is intended for use by health professionals

1. Name of the medicinal product

AmBisome Liposomal 50 mg Powder for dispersion for infusion

2. Qualitative and quantitative composition

Each vial contains 50 mg of amphotericin (50,000 units) encapsulated in liposomes. After reconstitution, the concentrate contains 4 mg/mL amphotericin B.

Excipient with known effect:

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Sterile, powder for dispersion for infusion.

Yellow lyophilised cake or powder.

4. Clinical particulars
4.1 Therapeutic indications

AmBisome is indicated in adults and children aged 1 month to 18 years old for:

• the treatment of severe systemic and/or deep mycoses

• 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.

AmBisome should not be used to treat the common clinically inapparent forms of fungal disease which show only positive skin or serologic tests.

4.2 Posology and method of administration

Non-equivalence of amphotericin products

Different amphotericin products (sodium deoxycholate, liposomal, lipid complex) are not equivalent in terms of pharmacodynamics, pharmacokinetics and dosing and so the products should not be used interchangeably without accounting for these differences. Both the trade name, common name and dose should be verified pre-administration.

There is a risk of under-dose if AmBisome is administered at a dose recommended for amphotericin B deoxycholate.

Posology

Administration of a test dose is advisable before a new course of treatment. A small amount of an AmBisome infusion (e.g. 1 mg) can be administered for about 10 minutes and then 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.

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.

Mucormycosis

The recommended starting dose is 5 mg/kg/day. The duration of therapy should be determined on an individual basis. Courses of up to 6 – 8 weeks are commonly used in clinical practice; longer durations of therapy may be required for deep seated infections or in cases of prolonged courses of chemotherapy or neutropenia.

Although doses greater than 5 mg/kg and up to a maximum of 10 mg/kg have been used in clinical trials and clinical practice, data on the safety and efficacy of AmBisome for the treatment of mucormycosis at these higher doses are limited. Therefore, a benefit:risk assessment should be made on an individual patient level to determine whether the potential benefits of treatment are considered to outweigh the known increased risk of toxicity at higher AmBisome doses (see section 4.4 ).

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 population

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. AmBisome has been studied in paediatric patients aged one month to 18 years old. Doses used in these clinical studies were the same as those used in adults on a mg/kg body weight basis.

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

Elderly patients

No alteration in dose or frequency of dosing is required.

Renal impairment

AmBisome has been 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 (See section 4.4).

Hepatic impairment

No data are available on which to make a dose recommendation for patients with hepatic impairment (See section 4.4).

Method of administration

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 (see section 4.4). The recommended concentration for intravenous infusion is 0.20 mg/ml to 2.00 mg/ml amphotericin B as AmBisome.

For instructions on reconstitution and dilution of the product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 unless, in the opinion of the physician, the condition requiring treatment is life-threatening and amenable only to AmBisome therapy.

4.4 Special warnings and precautions for use

Anaphylaxis and anaphylactoid reactions

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 (see section 4.8). Therefore, administration of a test dose is still advisable before a new course of treatment (see section 4.2). 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.

Infusion-related reactions

Other severe infusion-related reactions can occur during administration of amphotericin B-containing products, including AmBisome (see section 4.8). 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.

Renal toxicity

AmBisome has been shown to be substantially less toxic than conventional amphotericin B, particularly with respect to nephrotoxicity; however, 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 (see section 4.5). 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.

Pulmonary toxicity

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.

Diabetic patients

AmBisome contains approximately 900 mg of sucrose in each vial. This should be taken into account when treating diabetic patients.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed with AmBisome. However, the following medicinal products 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.

4.6 Fertility, pregnancy and lactation

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Pregnancy

The safety of AmBisome in pregnant women has not been established.

Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin B without obvious effect on the fetus, but the number of cases reported is insufficient to draw any conclusions on the safety of AmBisome in pregnancy.

AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks to the mother and fetus.

Breast-feeding

It is unknown whether AmBisome is excreted in human breast milk. A decision on whether to breastfeed while receiving AmBisome should take into account the potential risk to the child as well as the benefit of breast feeding for the child and the benefit of AmBisome therapy for the mother.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Some of the undesirable effects of AmBisome presented below may impact the ability to drive and use machines.

4.8 Undesirable effects

Summary of adverse reactions

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

Common

Uncommon

Very rare

(≥ 1/10)

(≥ 1/100 to < 1/10)

(≥ 1/1,000 to < 1/100)

(<1/10,000),