AmBisome 50 mg Powder for solution for infusion.

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

For a full list of excipients, see section 6.1.

AmBisome is a sterile, Powder for solution for infusion. AmBisome is a yellow lyophilised cake or powder. After reconstitution, the product is an injectable intended to be administered by intravenous infusion.

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.

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. 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.

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.

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. 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 (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.

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 (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.

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.

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.

Pregnancy

Teratogenicity studies in both rats and rabbits have concluded that AmBisome had no teratogenic potential in these species (See also section 5.3).

The safety of AmBisome in pregnant women has not been established. AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks to the mother and foetus.

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

Lactation

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.

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.

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 (see section 4.4).

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

The toxicity of AmBisome due to acute overdose has not been defined. If overdose should occur, cease administration immediately. Carefully monitor clinical status including renal and hepatic function, serum electrolytes and haematological status. Haemodialysis or peritoneal dialysis does not appear to affect the elimination of AmBisome.

Pharmacotherapeutic group: Antimycotics for systemic use, antibiotics; ATC code: J02AA01.

Amphotericin B is a macrocyclic, polyene antifungal antibiotic produced by Streptomyces nodosus. Liposomes are closed, spherical vesicles formed from a variety of amphiphilic substances such as phospholipids. Phospholipids arrange themselves into membrane bilayers when exposed to aqueous solutions. The lipophilic moiety of amphotericin allows the drug to be integrated into the lipid bilayer of the liposomes.

Amphotericin B is fungistatic or fungicidal depending on the concentration attained in body fluids and the susceptibility of the fungus. The drug is thought to act by binding to sterols in the fungal cell membrane, with a resulting change in membrane permeability, allowing leakage of a variety of small molecules. Mammalian cell membranes also contain sterols, and it has been suggested that the damage to human cells and fungal cells caused by amphotericin B may share common mechanisms.

Microbiology

Amphotericin B, the antifungal component of AmBisome, shows a high order of in vitro activity against many species of fungi. Most strains of Histoplasma capsulatum, Coccidioides immitis, Candida spp., Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenkii, Mucor mucedo and Aspergillus fumigatus, are inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/ml in vitro. Amphotericin has minimal or no effect on bacteria and viruses.

The pharmacokinetic profile of AmBisome, based upon total plasma concentrations of amphotericin B, was determined in cancer patients with febrile neutropenia and bone marrow transplant patients who received 1 hour infusions of 1.0 to 7.5mg/kg/day AmBisome for 3 to 20 days. AmBisome has a significantly different pharmacokinetic profile from that reported in the literature for conventional presentations of amphotericin B, with higher amphotericin B plasma concentrations (Cmax) and increased exposure (AUC_0-24) following administration of AmBisome as compared to conventional amphotericin B. After the first dose and last dose, the pharmacokinetic parameters of AmBisome (mean ± standard deviation) ranged from:

Minimum and maximum pharmacokinetic values do not necessarily come from the lowest and highest doses, respectively. Following administration of AmBisome steady state was reached quickly (generally within 4 days of dosing). AmBisome pharmacokinetics following the first dose appear non-linear such that serum AmBisome concentrations are greater than proportional with increasing dose. This non-proportional dose response is believed to be due to saturation of reticuloendothelial AmBisome clearance. There was no significant drug accumulation in the plasma following repeated administration of 1 to 7.5mg/kg/day. Volume of distribution on day 1 and at steady state suggests that there is extensive tissue distribution of AmBisome. After repeated administration of AmBisome, the terminal elimination half-life (t_½β) for AmBisome was approximately 7 hours. The excretion of AmBisome has not been studied. The metabolic pathways of amphotericin B and AmBisome are not known. Due to the size of the liposomes, there is no glomerular filtration and renal elimination of AmBisome, thus avoiding interaction of amphotericin B with the cells of the distal tubuli and reducing the potential for nephrotoxicity seen with conventional amphotericin B presentations.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of AmBisome has not been formally studied. Data suggest that no dose adjustment is required in patients undergoing haemodialysis or filtration procedures, however, AmBisome administration should be avoided during the procedure.

In subchronic toxicity studies in dogs (1 month), rabbits (1 month) and rats (3 months) at doses equal to or, in some species, less than the clinical therapeutic doses of 1 to 3 mg/kg/day, the target organs for AmBisome toxicity were the liver and kidneys with thrombocytopenia also observed. All are known targets for amphotericin B toxicity.

AmBisome was found to be non-mutagenic in bacterial and mammalian systems.

Carcinogenicity studies have not been conducted with AmBisome.

No adverse effects on male or female reproductive function were noted in rats.

Hydrogenated soy phosphatidylcholine

Cholesterol

Distearoylphosphatidylglycerol

Alpha tocopherol

Sucrose

Disodium succinate hexahydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

AmBisome is incompatible with saline solutions and may not be mixed with other drugs or electrolytes.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

3 years

Shelf –life of AmBisome after first opening

As AmBisome does not contain any bacteriostatic agent, from a microbiological point of view, the reconstituted or diluted product should be used immediately.

In-use storage times and conditions prior to administration are the responsibility of the user and would normally not be longer than 24 hours at 2-8˚C, unless reconstitution has taken place in controlled and validated aseptic conditions.

However, the following chemical and physical in-use stability data for AmBisome has been demonstrated:

Shelf-life after reconstitution:

Glass vials for 24 hours at 25±2˚C exposed to ambient light

Glass vials and polypropylene syringes up to 7 days at 2-8˚C

Do not freeze

DO NOT STORE partially used vials for future patient use.

Shelf-life after dilution with Dextrose:

PVC or Polyolefin infusion bags: 25±2˚C exposed to ambient light or at 2-8˚C. Do not freeze. See table below for recommendations.

AmBisome: Unopened vials; Do not store above 25°C. Do not freeze. Keep container in the outer carton.

For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.

AmBisome is presented in 15 ml or 30ml sterile, Type I glass vials. The closure consists of a grey butyl rubber stopper and aluminium ring seal fitted with a removable plastic cap. Single-dose vials are packed ten per carton with 10 filters. Not all pack sizes may be marketed.

READ THIS ENTIRE SECTION CAREFULLY BEFORE BEGINNING RECONSTITUTION

AmBisome Must Be Reconstituted By Suitably Trained Staff.

AmBisome must be reconstituted using Sterile Water for Injection (without a bacteriostatic agent). After reconstitution with water for injections the concentrate is a translucent, yellow dispersion.

Vials of AmBisome Containing 50 mg of Amphotericin are Prepared as Follows:

Do not reconstitute the lyophilized powder/cake with saline or add saline to the reconstituted concentrate, or mix with other drugs.

Use only Water for Injection to reconstitute the powder/cake. Use only Dextrose Injection to dilute the reconstituted product to the appropriate concentration for infusion.

Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in AmBisome, or in the materials specified for reconstitution and dilution. The use of any solution other than those recommended, or the presence of a bacteriostatic agent (e.g. benzyl alcohol) in the solution, may cause precipitation of AmBisome. Do not use material if there is any evidence of precipitation of foreign matter.

An in-line membrane filter may be used for intravenous infusion of AmBisome. However, the mean pore diameter of the filter should not be less than 1.0 micron.

NOTE: AMBISOME IS NOT PHYSICALLY COMPATIBLE WITH SALINE SOLUTIONS AND SHOULD NOT BE MIXED WITH OTHER DRUGS OR ELECTROLYTES. AN EXISTING INTRAVENOUS LINE MUST BE FLUSHED WITH DEXTROSE INJECTION PRIOR TO INFUSION OF AMBISOME. IF THIS IS NOT FEASIBLE, AMBISOME SHOULD BE ADMINISTERED THROUGH A SEPARATE LINE.

Any unused product or waste material should be disposed of in accordance with local requirements.

Gilead Sciences International Limited,

Granta Park,

Abington,

Cambridge,

CB21 6GT.

PL: 16807/0001

11 September 1998/24 September 2004.

21/01/2009