Consumer medicine information

AmBisome powder for injection vial

Amphotericin B (liposomal)

BRAND INFORMATION

Brand name

AmBisome

Active ingredient

Amphotericin B (liposomal)

Schedule

What is in this leaflet

This leaflet answers some common questions about AmBisome.

The medicine your doctor has prescribed for you is called AmBisome for Injection. This is the brand name of a drug called liposomal amphotericin B (amphotericin).

All medicines have risks and benefits. Your doctor has weighed the risks of you having AmBisome against the benefits it is expected to have for you.

If you have any concerns about having this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What is AmBisome used for

AmBisome contains amphotericin B (amphotericin) which belongs to a group of medicines called antifungals.

It is used to help the body overcome serious fungal infections by either killing the fungus or stopping it spreading.

Amphotericin B (amphotericin) is also used to treat a disease which is rare in Australia called leishmaniasis.

Ask your doctor if you have any questions about why AmBisome has been prescribed for you. Your doctor may have prescribed AmBisome for another reason.

AmBisome is not addictive.

This medicine is available only with a doctor’s prescription.

Before you are given AmBisome

When you must not have it:

Do not have AmBisome if you are allergic to:

amphotericin B (amphotericin) or
any of the other ingredients in AmBisome listed at the end of this leaflet.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes. Tell your doctor if you have, or have had, any of the following medical conditions:

kidney disease
liver disease
diabetes

Tell your doctor if you are pregnant, or likely to become pregnant during your course of medication. Your doctor can discuss with you the benefits and risks of having AmBisome.

Tell your doctor if you are breastfeeding, or likely to breastfeed during your course of medication. AmBisome is not recommended during breastfeeding, as it may pass into breast milk.

If you have not told your doctor or pharmacist about any of the above, tell them before you are given AmBisome.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and AmBisome may interfere with each other. These include:

anticancer agents (chemotherapy)
digoxin (e.g. Lanoxin)
flucytosine (e.g. Ancotil)
cortisone-like medicine (e.g. hydrocortisone, betamethasone, dexamethasone, prednisolone, methylprednisolone)
corticotrophin (e.g. Acthargel)
dipyridamole (e.g. Persantin)

These medicines may be affected by AmBisome or may affect how well it works. You may need different amounts of the medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

How AmBisome is given

AmBisome is to be administered only by or under the supervision of your doctor.

AmBisome must be reconstituted using Water for Injection and then filtered using a 5-micron filter into the correct amount of 5% Glucose Injection. It is given as a long running infusion (e.g. a slow injection via a “drip” into a vein).

If you have too much (overdose)

As AmBisome is most likely to be given to you in hospital under the supervision of your doctor, it is very unlikely that you will receive an overdose.

Severe side effects due to AmBisome are more likely to occur at high doses, particularly if you receive an overdose. Symptoms of AmBisome overdose include the side effects listed, but are usually of a more severe nature.

However, if you experience any severe side effects after being given AmBisome, tell your doctor immediately.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are given AmBisome.

All medicines can have side effects. If they occur most are minor and temporary. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Tell your doctor if you notice any of the following and they worry you:

Common side effects:

nausea and vomiting
rash
mild headaches

Less common side effects. The following side effects have been reported:

back pain
joint pain and bone pain
fever, chills
chest tightness
kidney problems
liver problems

Check with your doctor or pharmacist if you experience or do not understand any of the side effects described above.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

After receiving AmBisome

Storage

AmBisome should be stored in the pharmacy or on the hospital ward.

Keep out of reach of children.

Do not keep or use the medicine after the expiry date marked on the packet.

Unopened vials of AmBisome should be stored below 25°C.

Product Description

Ingredients

Each injection contains amphotericin equivalent to 50 mg of amphotericin B (amphotericin) plus hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol (as the sodium salt), alpha tocopherol, sucrose and sodium succinate hexahydrate.

Manufacturer

AmBisome is supplied in Australia by:

Gilead Sciences Pty Ltd
Level 6, 417 St Kilda Road
Melbourne, Victoria 3004

AUST R 53783

AmBisome is supplied in New Zealand by:

Gilead Sciences (NZ)
c/- PricewaterhouseCoopers
Level 8 Pricewaterhousecoopers Tower
188 Quay Street
Auckland 1010

AmBisome® is a registered trademark licensed to Gilead Sciences Pty. Limited.

Date of Preparation: 30 March 2017

Published by MIMS July 2017

BRAND INFORMATION

Brand name

AmBisome

Active ingredient

Amphotericin B (liposomal)

Schedule

1 Name of Medicine

AmBisome (liposomal amphotericin B).

2 Qualitative and Quantitative Composition

AmBisome is available in vials as powder for injection. Each vial contains amphotericin B equivalent to 50 mg of amphotericin B encapsulated in the bilayer of liposomes consisting of approximately 213 mg hydrogenated soy phosphatidylcholine, 52 mg cholesterol, 84 mg distearoylphosphatidylglycerol (as the sodium salt), 0.64 mg alpha-tocopherol together with 900 mg sucrose, and 27 mg sodium succinate hexahydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

AmBisome is a sterile, lyophilised product for intravenous infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

AmBisome is indicated for: prophylaxis in liver transplant patients at risk of systemic Candida, Aspergillus and Cryptococcus infections, and for the treatment of systemic fungal infections caused by organisms susceptible to amphotericin B (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
AmBisome is indicated for empirical treatment of presumed fungal infections in febrile neutropaenic patients whose fever has failed to respond to broad spectrum antibiotic treatment.
AmBisome is indicated for the treatment of visceral leishmaniasis. Clinical studies of efficacy in visceral leishmaniasis are limited to Leishmania infantum.

4.2 Dose and Method of Administration

AmBisome should be administered by intravenous infusion over 30 to 60 minutes. The recommended concentration for intravenous infusion is 0.20 mg/mL to 2.00 mg/mL amphotericin as AmBisome. Dosage of amphotericin as AmBisome must be adjusted to the specific requirements of each patient.
a) For systemic mycoses, therapy is usually instituted at a daily dose of 3.0 mg/kg/day of body weight, and increased stepwise to 5.0 mg/kg/day, for a minimum of 14 days. Dosage of amphotericin B as AmBisome must be adjusted to the specific requirements of each patient.
AmBisome therapy has been administrated for as long as three months, with a cumulative dose of 16.8 g of amphotericin as AmBisome without significant toxicity.

Mucormycosis.

The recommended initial and maintenance dose is 5 to 10 mg/kg by intravenous infusion administered daily. In patients with brain involvement or solid-organ transplant, dose at 10 mg/kg, administered daily. Avoid slow escalation of doses. The duration of therapy should be determined on an individual basis. Courses of up to 56 days 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.
Doses greater than 5 mg/kg and up to 10 mg/kg have been used in clinical trials and clinical practice. For doses greater than 5 mg/kg, intravenous infusion over a 2 hour period is recommended. There are limited data on the safety and efficacy of AmBisome for the treatment of mucormycosis at these higher doses, 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 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Cryptococcal meningitis.

Single agent therapy: Initiate treatment with 3 to 6 mg/kg/day AmBisome for 14 days.
High-dose induction therapy in HIV-associated cryptococcal meningitis: Administer a single dose of 10 mg/kg AmBisome on day 1, in combination with daily flucytosine 100 mg/kg and daily fluconazole 1200 mg, both administered for 14 days.
After the 2-week induction period, patients should receive fluconazole 800 mg daily for 8 weeks and then at a dose of 200 mg daily thereafter at the treating physician's discretion.
b) For prophylaxis against invasive fungal infections in liver transplant recipients, AmBisome may be administered at a daily dose of 1 mg/kg/day for five successive days following transplantation.
c) In HIV associated disseminated cryptococcosis, a dose of 3 mg/kg/day for up to 42 days may be used. Because of the high frequency of relapses, chronic suppressive therapy with another agent may be necessary after completion of a treatment course with AmBisome.
d) In immunocompetent patients, a dose of 1.0 to 1.5 mg/kg/day for 21 days or alternatively a dose of 3.0 mg/kg/day for 10 days can be used for treatment of visceral leishmaniasis. In immunocompromised patients (e.g. HIV positive) with visceral leishmaniasis, a dose of 1.0 to 1.5 mg/kg/day for 21 days may be used.
e) For empirical treatment of presumed fungal infection of febrile neutropaenic patients, AmBisome therapy should be initiated at a daily dose of 3 mg/kg for 10 to 14 days, or until resolution of neutropenia. The daily dosage may be adjusted based on the clinical condition, as required.

Paediatric patients.

Candida, Aspergillus and visceral leishmaniasis infections have been treated with AmBisome in a limited number of paediatric patients, without reports of unexpected adverse events. Paediatric patients have received AmBisome at doses comparable to those used in adults on a per kilogram body weight basis.

Elderly patients.

There have been no systematic studies in elderly patients.

Hepatic patients.

No data are available on which to make a dose recommendation for patients with hepatic impairment.

Directions for reconstitution and dilution.

AmBisome must be reconstituted using water for injection (without a bacteriostatic agent) and then further diluted using 5% glucose injection.
AmBisome infusions are prepared as follows:
If you need to reconstitute more than one vial, complete the whole reconstitution and dispersion process for one vial before adding the sterile water to the next vial.
1. Add 12 mL of sterile water for injection to the AmBisome vial, to yield a preparation containing the equivalent of 4 mg/mL amphotericin B.
2. Immediately after the addition of water, shake the vial vigorously for at least 30 seconds to completely disperse the AmBisome. Visually inspect the vial for particulate matter and continue shaking until complete dispersion is obtained. Each vial should be reconstituted/ diluted in sequence.
3. Calculate the amount of reconstituted (4 mg/mL) AmBisome to be further diluted.
4. The infusion, providing the equivalent from 2 to 0.2 mg amphotericin B per mL, is obtained by dilution with the appropriate amount of 5% glucose injection.
5. Withdraw the calculated volume of reconstituted AmBisome into a sterile syringe. Attach the 5 micron filter provided to the sterile syringe and instill the AmBisome preparation into a sterile container with the correct amount of 5% glucose injection. Visually inspect the infusion for particulate matter.
Use only water for injections to reconstitute the powder/ cake. Use only 5% glucose injection to dilute the reconstituted product to the appropriate concentration for infusion.
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, as this may filter out the active ingredient.

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 5% glucose injection prior to infusion of AmBisome. If this is not feasible, AmBisome should be administered through a separate line.
Do not reconstitute the lyophilised powder/ cake with saline or add saline to the reconstituted concentrate, or mix with other drugs.
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 or foreign matter. Aseptic technique must be observed in all handling, since no preservative or bacteriostatic agent is present in AmBisome, or in the materials specified for reconstitution and dilution.

4.3 Contraindications

AmBisome is contraindicated in those patients who have shown hypersensitivity to any of its constituents.

4.4 Special Warnings and Precautions for Use

In studies in febrile neutropaenic patients AmBisome has been shown to be substantially less toxic than conventional amphotericin B, however, adverse reactions may still occur with AmBisome (see Section 4.8 Adverse Effects (Undesirable Effects)). In particular, caution should be exercised when prolonged therapy is required. Laboratory evaluation of renal, hepatic and haematopoietic function should be performed regularly, and at least once weekly. In addition, serum electrolytes, particularly potassium and magnesium should also be regularly monitored. Particular attention should be paid to patients receiving concomitant therapy with nephrotoxic drugs. Due to the risk of hypokalaemia, appropriate potassium supplementation may be required during the course of AmBisome administration. Renal function should be closely monitored in these patients.
AmBisome may be nephrotoxic despite being tolerated significantly better than other amphotericin B products. If clinically significant reduction in renal function or worsening of other parameters occurs during AmBisome therapy, consideration should be given to dose reduction, treatment interruption or discontinuation.
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.
Anaphylaxis and anaphylactoid reactions have been reported in association with AmBisome infusion. If a severe anaphylactic/ anaphylactoid reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusion of AmBisome. 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 measures for prevention or treatment of these reactions should be given to patients who receive AmBisome therapy.
Do not reconstitute the lyophilised powder/ cake with saline or add saline to the reconstituted concentrate, or mix with other drugs.

Leucocyte transfusions.

In the treatment of diabetic patients.

It should be noted that AmBisome contains approximately 900 mg of sucrose in each vial.

In the treatment of renal dialysis patients.

The administration of AmBisome should commence only when dialysis is completed. Levels of serum potassium and magnesium should be monitored regularly.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Formal studies of interactions between AmBisome and other drugs have not been conducted. Interactions between amphotericin B and other drugs have been reported, patients given concomitant drug therapy should be monitored closely. Conventional amphotericin has been reported to interact with the following drugs: antineoplastic agents (cisplatin and nitrogen mustards, see below), corticosteroids, corticotropin (ACTH), diuretics (e.g. loop and thiazide), digitalis glycosides and skeletal muscle relaxants (tubocurarine, see below).
Antineoplastic agents such as cisplatin and the nitrogen mustard compounds may enhance the potential for renal toxicity, bronchospasm and hypotension in patients receiving amphotericin B; such concomitant therapy should be used with caution.
Amphotericin B can induce hypokalaemia which in turn may enhance the effects of nondepolarising skeletal muscle relaxants (tubocurarine) and digitalis glycosides. To date, there have not been reports of this enhancement attributed to amphotericin B; but such concomitant therapy should be used with caution.

Leucocyte transfusions.

Acute pulmonary toxicity has been reported in patients given amphotericin B (as sodium deoxycholate complex) during or shortly after leucocyte transfusions. It is recommended these infusions are separated by as long a period as possible and pulmonary function should be monitored.
Adequate clinical studies of the use of the combination of flucytosine with AmBisome have not been conducted. Whilst synergy between flucytosine and amphotericin has been reported, amphotericin B may enhance the toxicity of flucytosine by increasing its cellular uptake and impeding its renal excretion.
Concurrent administration of AmBisome with other nephrotoxic agents, for example cyclosporin, aminoglycosides and pentamidine, may increase the risk of nephrotoxicity in some patients. Regular monitoring of renal function is recommended in patients receiving AmBisome with any nephrotoxic medications. However, a pivotal study in FUO (94-0-002) has demonstrated that patients receiving concomitant cyclosporin and/or aminoglycosides experienced significantly less nephrotoxicity when receiving AmBisome as compared to conventional amphotericin B (see Section 4.8 Adverse Effects (Undesirable Effects)).
It should be noted that this finding is based upon a retrospective analysis of the data from this study. To date no other studies, either prospectively or retrospectively, have analysed the interaction between AmBisome and concomitantly administered cyclosporin and/or aminoglycosides. Also this reported difference was not observed in the paediatric population under the age of 13 years, possibly because of better tolerance of the nephrotoxic effects of conventional amphotericin B in that population.
There have been reports of patients experiencing headache, malaise, hypotension and dizziness during concomitant therapy of AmBisome with dipyridamole, but the contribution of an interaction between the two drugs to the causation of these events is unclear.

4.6 Fertility, Pregnancy and Lactation

(Category B3)
Safety for use of AmBisome in pregnant women has not been established. No reproductive toxicity studies have been conducted with AmBisome or conventional amphotericin. 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 have been small. Therefore, AmBisome should only be used during pregnancy if the possible benefits outweigh the potential risks.
In embryofetal development studies in rats an increased incidence of visceral variations (thymic remnant in the neck) at 15 mg/kg/day (4 times the clinical exposure at the MRCD based on AUC), in the presence of maternal toxicity (decreased bodyweight gain, bodyweight loss and reduced food consumption). No effects on embryofetal development were seen in rabbits at up to 16 mg/kg/day (3.4 times the clinical exposure at the MRCD).
Embryofetal development studies in both rats and rabbits concluded that AmBisome has no teratogenic potential in these species.

Effects on fertility.

In a fertility study in rats, prolonged dioestrus and decreased number of corpora lutea and implantations were observed in female rats at doses of 10 and 15 mg/kg/day, associated with maternal toxicity (significantly decreased bodyweight gain and food consumption). A small reduction in the fertility index was also observed at maternally toxic dose of 15 mg/kg/day. Systemic exposures at 10 and 15 mg/kg/day in rats were 2.7 and 4 times the clinical exposure at the maximum recommended clinical dose (MRCD) based on AUC.
It is not known whether AmBisome is excreted into breast milk. It is therefore recommended that breastfeeding be discontinued during treatment.

4.7 Effects on Ability to Drive and Use Machines

The effects of AmBisome on the ability to drive and/or use machines have not been investigated. Some of the undesirable effects of AmBisome presented below may impact the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
In general, patients should be monitored for any type of adverse event associated with the use of amphotericin B. In particular, caution should be exercised when prolonged therapy is required.
Patients who have experienced acute toxicity with conventional amphotericin B generally did not experience acute toxicity when AmBisome was substituted.

Infusion related reactions.

AmBisome is generally well tolerated. The most frequent infusion related reactions of AmBisome are fever, rigors and chills.
Less frequent infusion related reactions may consist of one or more of the following symptoms: chest tightness or pain, dyspnea, bronchospasm, flushing, tachycardia, hypotension, and musculoskeletal pain (described as arthralgia, back pain, or bone pain). 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. Back pain has been reported to be moderate to severe back pain, with or without chest tightness or pain. In some instances this was associated with tachycardia or hypotension. Characteristically, a patient develops low back pain within a few minutes after the start of an infusion. The symptoms cease rapidly when the infusion is stopped. The back pain does not occur with every dose and it usually does not recur when the infusion rate is slowed.
The following is a listing by body system of all adverse reactions (causality of related, probably related or possibly related) and their incidences reported during nine clinical trials involving 834 patients. Adverse events with a causality of not related have not been included.

Body as a whole.

Abdominal pain (1.0%); headache (1.0%).
Rigors and pyrexia have been very commonly reported (≥ 10%).
Chest pain has commonly been reported (≥ 1% and < 10%). The following have all been reported with an incidence less than 1%: allergic reaction, asthenia, burning sensation, death, face oedema, fungal infection, influenza-like symptoms, injection site pain, leg pain, malaise and pain.

Cardiovascular system.

Tachycardia and vasodilatation have been commonly reported (≥ 1% and < 10%). The following have all been reported with an incidence less than 1%: cardiac failure, extrasystoles, hypotension and thrombophlebitis. There are postmarketing reports of bradycardia, cardiac arrest and arrhythmia.

Digestive system.

Nausea (1.9%); vomiting (1.3%).
Diarrhoea has been commonly reported (≥ 1% and < 10%). The following have all been reported with an incidence less than 1%: constipation, dyspepsia, hepatic enzymes increased, hepatic function abnormal, hepatitis cholestatic, hepatocellular damage, hepatomegaly, jaundice, pancreatitis (on occasions severe), pruritus ani and veno-occlusive liver disease.
Normally, abnormalities in liver function tests do not progress with an increase in the cumulative dose of AmBisome. Liver transplant recipients can have a significantly higher alkaline phosphatase postoperatively with AmBisome prophylaxis.

Immune system disorders.

Anaphylactoid reactions have been uncommonly reported (≥ 0.1% to < 1%). Anaphylactic reactions and hypersensitivity have also been reported (incidence not known).

Haemic and lymphatic system.

The following have all been reported with an incidence less than 1%: anaemia, granulocytopaenia, leucopaenia, splenomegaly and thrombocytopaenia.

Musculoskeletal and connective tissue disorders.

Common: back pain.
Not known: rhabdomyolysis (associated with hypokalaemia) has been reported, musculoskeletal pain (described as arthralgia or bone pain).

Metabolic and nutritional disorders.

Increased alkaline phosphatase (1.6%); hypokalaemia (5.2%).
Abnormal liver function tests, hyponatraemia and hyperbilirubinaemia have been commonly reported (≥ 1% and < 10%). The following have all been reported with an incidence less than 1%: bilirubinaemia, increased creatine phosphokinase, cyanosis, hyperglycaemia, hyperkalaemia, hypernatraemia, hyperuricaemia, hypoalbuminaemia, hypocalcaemia, hypomagnesaemia, increased LDH, leg oedema, increased SGOT, increased SGPT, leg cramps and tendon disorder.

Nervous system.

Flushing has been commonly reported (≥ 1% and < 10%). The following have all been reported with an incidence less than 1%: anxiety, coma, convulsions, depression, dizziness, dystonia, hypertension, neuropathy, neurosis, paraesthesia, sensory disturbance and tremor.

Respiratory system.

Dyspnoea has been commonly reported (≥ 1% and < 10%). The following have all been reported with an incidence less than 1%: bronchospasm, coughing, dysphonia, epistaxis, hypoxia, pulmonary haemorrhage, respiratory disorder and respiratory insufficiency.

Skin and appendages.

Rash, on occasions severe (2.0%).
The following have all been reported with an incidence less than 1%: folliculitis, erythematous rash, follicular rash, maculopapular rash, increased sweating and acute urticaria. Angioneurotic oedema has also been reported (incidence not known).

Urogenital system.

Toxic nephropathy (1.1%).
Increased creatinine and blood urea have been commonly reported (≥ 1% and < 10%). The following have all been reported with an incidence less than 1%: albuminuria, nephrosis, renal abscess, acute renal failure, abnormal renal function and uraemia. Renal insufficiency and renal failure have also been reported (incidence not known).

Interference with phosphorus chemistry assay.

False elevations of serum phosphate may occur when samples from patients receiving AmBisome are analyzed using the PHOSm assay (e.g. used in Beckman Coulter analyzers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples.
In studies in patients with febrile neutropaenia unresponsive to broad spectrum antibiotic therapy, the adverse event response is represented by the following: see Tables 1, 2, 3 and 4.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Symptoms.

There have been no reports of patients who have been given overdoses of AmBisome. The symptoms of overdosage are likely to be an extension of the adverse reactions to AmBisome.

Management.

If overdosage should occur, cease administration immediately. Symptomatic supportive measures should be instituted. Carefully monitor clinical status including renal and hepatic function, serum electrolytes and haematologic status. Haemodialysis or peritoneal dialysis does not appear to affect the elimination of AmBisome.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Amphotericin is a mixture of antifungal polyenes produced by the growth of Streptomyces nodosus. The major component of amphotericin, amphotericin B, is fungistatic or fungicidal, depending on the drug concentration attained in body fluids and the susceptibility of the fungus. Its mechanism of action is partly due to its binding to a sterol (ergosterol) present in the membrane of sensitive fungi. This results in a change in membrane permeability allowing leakage of cell components. Mammalian cell membranes also contain sterols such as cholesterol, to which amphotericin B has less binding affinity than to ergosterol. It has been suggested that damage to human cells and fungal cells caused by amphotericin B may share common mechanisms.
AmBisome contains liposomal amphotericin B. Liposomes are closed, spherical vesicles formed when certain polar lipids, such as phospholipids and cholesterol, are dispersed in water. Phospholipids arrange themselves into single or multiple concentric bilayer membranes when exposed to and homogenised in aqueous solutions. AmBisome contains single bilayer liposomes with the drug held in the membrane as a charge complex with distearoylphosphatidylglycerol. The liposomes are less than 100 nanometre in diameter.
AmBisome can remain intact in the circulation for prolonged periods and distributes as intact liposomes to tissues where fungal infections may occur. Both AmBisome and liposomes with the same lipid composition preferentially associate with the outer surface of fungal cell walls. AmBisome acts by liposome binding to the outer wall of fungi, followed by drug release. On release, the drug is thought to transfer to the ergosterol rich fungal cell membrane for which it has high affinity. Interaction with fungi occurs both within and outside macrophages and is believed to be enzymatically mediated.

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 ranging from 0.03 to 1.0 microgram/mL in vitro. Amphotericin B has minimal or no effect on bacteria and viruses.

Clinical trials.

The efficacy of AmBisome has been established in a number of clinical trials for the treatment of systemic mycotic infections, as empirical therapy for fever of unknown origin in neutropenic patients, for the treatment of visceral leishmaniasis, and for the treatment of cryptococcal meningitis. These studies include comparative randomized studies of AmBisome versus conventional amphotericin B in confirmed Aspergillus and Candida infections where the efficacy of both medicinal products was equivalent. In both adult and paediatric febrile neutropenic patients presumed to have fungal infection, the results of a randomized, double-blind clinical trial demonstrated that AmBisome administered at 3 mg/kg is as effective as conventional amphotericin B. The efficacy of AmBisome in the treatment of visceral leishmaniasis has been demonstrated in a large population of immunocompetent and immunocompromised patients.
Invasive filamentous fungal infections (IFFI).

Invasive filamentous fungal infections (IFFI) including Aspergillus spp.

The efficacy of AmBisome has been demonstrated in a large-scale prospective, randomised, multicenter study as first line treatment in immunocompromised, mainly neutropenic adults and children (> 30 days old) with proven or probable IFFIs (AmBiLoad Study). Patients were monitored for 12 weeks. A standard-dose regimen of 3 mg/kg (N=107) was compared to a loading dose regimen of 10 mg/kg (N=94) for the first 14 days of treatment followed by 3 mg/kg in both groups according to clinical need. The favourable overall response rates were 50% of subjects in the standard-dose group and 46% of the subjects in the loading-dose group in the modified intent-to-treat analysis set. Differences were not statistically significant. The median time to resolution of fever was similar in the standard-dose and loading-dose groups (6 and 5 days, respectively). Twelve weeks after the first dose of AmBisome, survival was 72% in the standard-dose group and 59% in the loading-dose group, a difference that was not statistically significant.
Treatment of Candida, Aspergillus and Cryptococcus systemic infections. AmBisome was studied in an open uncontrolled compassionate use study in patients with systemic fungal infections for whom no effective alternative therapy was available. Patient recruitment involved 138 infectious episodes in 128 patients: 79 males; 49 females. The mean age was 38.5 years (range 4 to 87). The mean weight was 61.00 kg (range 16.5 to 87.0). Hospitalised patients with evidence of severe or life threatening invasive systemic fungal infection were enrolled for the following reasons:
(i) prior amphotericin B toxicity (50 cases);
(ii) failure of previous antifungal therapy (37 cases);
(iii) renal insufficiency (34 cases);
(iv) other reasons (7 cases);
(v) no reason stated (10 cases).
AmBisome was given as an intravenous infusion of 0.5 g/L in 5% dextrose over 30-60 minutes. The following initial doses were used:

(i) Patients with a history of amphotericin B nephrotoxicity.

Start at 0.2 mg/kg/day below previous daily dose of amphotericin B.

(ii) Patients with failure to respond to amphotericin B alone or in combination.

AmBisome dose same as previous amphotericin B dose.

(iii) Renal insufficiency not related to amphotericin B.

0.25 mg/kg/day initially.
In all cases, the AmBisome dose could be increased by 0.2 mg/kg/day to 3.0 mg/kg/day or higher with approval of the sponsor.
Duration of treatment: Range: 1 to 97 days.
Three categories of patients were treated:

(i) Definitive diagnosis of systemic infection.

Positive culture or microscopic identification of a fungus from tissue or blood where the fungus or colonisation/ contamination were not normally found.
There were 60 definite fungal infections in 58 patients. One patient had two forms of pulmonary disease (aspergillosis pneumonia and aspergilloma). One patient had two different fungal infections (Trichosporon capitatum and Aspergillus fumigatus).

(ii) Presumptive systemic infection.

(a) Patients with positive serology and consistent clinical evidence (7 infections in 7 patients).
(b) Patients with positive Candida cultures of bronchial lavage, with consistent clinical evidence (14 infections in 14 patients).
(c) Patients with presumptive diagnosis only (clinical evidence only) (10 cases from 9 patients).
One patient had two separate presumptive fungal infections.

(iii) Refractory superficial infections.

Definitive diagnosis restricted to superficial tissues, which failed to respond to available therapies (8 cases in 8 patients).
Patients were excluded from the efficacy analysis if:
(a) less than 8 days of therapy was administered (26 cases);
(b) sufficient data were not available (13 cases).
Clinical and mycological efficacy were evaluated 48 hours after completion of AmBisome therapy.

Definitive group.

Clinical cure occurred in 19 (79%) of Candida cases, 7 (27%) of 26 Aspergillus cases, 6 (86%) of 7 Cryptococcus meningitis patients with AIDS.
In 56 mycologically evaluable cases, eradication occurred in 19 (83%) of 23 Candida cases, 9 (37.5%) of 24 Aspergillus cases, 5 (71.4%) of 7 patients with Cryptococcus meningitis with AIDS.

Presumptive group.

Clinical cure occurred in 12 of 22 cases with presumed Candida infection. There were 3 improvements, 5 failures and 2 nonevaluable cases. Cure occurred in 2 of 5 aspergillosis cases, 2 cases improved and one was not evaluable.
Thirteen cases were mycologically evaluable, all Candida cases. Eradication occurred in 9 cases; persistence in 4 cases.

Superficial group.

There were 8 cases. Four Candida infections and one case of pulmonary aspergillosis were cured.
Mycological evaluation was possible in only 3 cases. Two cases of Candida were eradicated.
Of the 138 episodes of fungal infection, the reason for enrollment was prior amphotericin B toxicity (50 cases) or renal insufficiency (34 cases). Among cases treated with AmBisome for greater or equal to 8 days enrolled with prior amphotericin B toxicity, 21/37 (57%) cases had a clinical cure as well as mycological eradication. For cases enrolled with renal insufficiency and treated for greater than or equal to 8 days, 13/21 (62%) cases had clinical cure and mycological eradication. Among the 13 cases enrolled with prior amphotericin B toxicity who were not evaluable, the reason for receiving less than 8 days of AmBisome therapy were: death unrelated to study drug (5 cases), investigator decision (2 cases), resolution of infection (2 cases) and one case each of patient request, intercurrent illness, an adverse event, and other reasons. For the 13 cases enrolled with renal insufficiency who received less than 8 days of AmBisome therapy, the reasons for study drug discontinuation were: death unrelated to study drug (9 cases), resolution of infection (2 cases), investigator decision (1 case) and unknown (1 case).
AmBisome may be safe and effective therapy for some patients with systemic fungal infections who have preexisting renal insufficiency or have experienced prior amphotericin B toxicity.
Prophylaxis in liver transplant patients. AmBisome was evaluated in a randomised placebo controlled double blind study as prophylaxis of fungal infections in liver transplant patients. The study compared 5 days of therapy with either AmBisome (1 mg/kg/day) or placebo as prophylaxis against fungal infections in patients undergoing liver transplantation.

Proven infection.

Positive blood cultures from sterile body sites or deep organ biopsy during life. In addition, for Aspergillus species, preliminary X-ray findings and positive culture or microscopy in bronchoscopic lavage fluid or bronchoscopic biopsy. At autopsy, positive culture or microscopy from deep organ tissue.

Suspected infection.

Clinically ill patients without positive serological or fungal antigen findings.
For analysis of efficacy of prophylaxis, patients must have completed the full five day course of treatment. Cut off for analysis was 30 days post-transplantation.
There were 23 males in the placebo group and 15 males in the AmBisome group. All received orthotopic liver grafts. There was a larger proportion of placebo patients (27/37) with fungal colonisation prior to treatment than AmBisome patients (20/40). In other respects, patient characteristics did not differ between the groups. There was no difference between groups in a number of risk factors.
Eight of the 85 patients were not evaluated for efficacy (3 AmBisome; 5 placebo). The sole significant difference in outcomes was in proven fungal infections. There were six proven fungal infections in the placebo group (16%) (5 Candida spp; one Aspergillus niger), and none with the AmBisome treated group (0%) during the 30 day assessment period (p < 0.01). Onset was 12 ± 5 (mean ± SE) days, range 6-20 days. Suspected fungal infections occurred in two AmBisome patients and no placebo patients. In both cases, suspicion was based on positive Cand-Tech test (day 11 and day 15, respectively).
Invasive mucormycosis (zygomycosis). Invasive mucormycosis (zygomycosis): There are no large-scale randomised clinical trials in mucormycosis. A pilot study of 20 patients compared AmBisome (doses ≥ 5 mg/kg) alone versus AmBisome plus deferasirox. Global success (alive, clinically stable, radiographically improved) at 30 days and 90 days was 6/9 (67%) and 5/9 (56%) in the group receiving AmBisome alone as compared to AmBisome plus deferasirox (2/11 (18%) at days 30 and 90). A retrospective study over a 15-year period included 59 haematological patients with proven or probable mucormycosis. Therapy was successful in 18 patients (37%): nine of 39 patients who received conventional amphotericin B (23%) and 7 of the 12 patients who received AmBisome (58%) responded to therapy. A prospective pilot study using high-dose (10 mg/kg/day) AmBisome and surgery (performed in 71% of patients) was associated with an overall response rate of 36% at week 4 and 45% at week 12 and creatinine level doubling in 40% of patients (transient in 63%).
Visceral leishmaniasis. AmBisome was studied in three small open multicentre trials for treatment of visceral leishmaniasis. Leishmania infantum was the organism most commonly isolated as all patients were infected in Italy or nearby islands. Initially, two dose regimens were studied in immunocompetent patients. In the first study, 10 patients (4 adults; 6 children), including four with a history of relapse after previous alternative treatments, were given 1.0 to 1.5 mg/kg/day for 21 days. Clearance of parasites from splenic or bone marrow aspirates on microscopy was documented in 8/8 patients tested and from culture of the aspirate in 6/6 patients. Fever was present in 9/10 prior to treatment and eradicated from 10 patients.
In light of these results, a second group of immunocompetent patients (9 children, one adult) were treated with AmBisome 3 mg/kg/day for 10 days. Clearance from aspirate on microscopy occurred in 10/10 patients following therapy and from 3/3 aspirate cultures performed. Relapses in immunocompetent patients were not documented, but follow-up may have been incomplete.
The third study was performed in eleven immunocompromised subjects: 8 HIV positive patients and 3 HIV negative patients using a dose of 1.0 to 1.5 mg/kg/day for 21 days. Of the 8 HIV patients, all had clinical and parasitological eradication, but there was relapse in 3 of 8 within follow-up periods of up to 5 months. The eighth patient died of AIDS related cerebral toxoplasmosis at 2 months. Among the 3 HIV negative patients, one died during treatment (not AmBisome related) and one relapsed at 5 months.
Febrile neutropaenic patients unresponsive to broad spectrum antibiotic agents. AmBisome was studied in four randomised, comparator trials in neutropaenic patients unresponsive to broad spectrum antibiotic therapy for at least three days including:
One double blind trial (94-0-002) comparing 343 AmBisome treated patients to 344 conventional amphotericin B treated patients. AmBisome was dosed at 3 mg/kg daily and conventional amphotericin B at 0.6 mg/kg daily. The doses could be increased by 50% or 100% or decreased by 50%, or interrupted, based on clinical response or toxicity.
One double blind trial (97-0-034) comparing AmBisome 3 mg/kg daily or 5 mg/kg daily to amphotericin B lipid complex (ABLC) 5 mg/kg daily in 85, 81, and 78 patients, respectively.
Two open label dose finding trials evaluating AmBisome at 1 mg/kg or 3 mg/kg, or amphotericin B at 1 mg/kg daily. Trial 104-10 enrolled 134 adults and trial 104-14 enrolled 205 children with FUO. Patients in each study were equally distributed among the treatment arms.
Treatment was continued until resolution of fever for three days in the open label trials, and until neutrophil recovering in the two double blind trials. Mean treatment duration ranged from 7-16 days.
In the two double blind trials, the definition of clinical success included: survival for 7 days post study drug; resolution of fever during neutropaenia; resolution of microbiologically confirmed baseline fungal infection, if applicable; no emergent fungal infection; no premature discontinuation of study drug due to toxicity or lack of efficacy. In the two open labeled trials, clinical success was defined as: afebrile for ≥ 3 days until study end; no emergent fungal infection; no concomitant antifungal therapy.
In the study 94-0-002, clinical success, based on a composite endpoint in a modified intent to treat analysis, was reported in 50.1% in the AmBisome 3 mg/kg group and 49.4% in the conventional amphotericin B group. The 95% CI of the difference in overall success rates were -6.8% and +8.2%.
Clinical success in each of the studies is presented in the following (see Table 5).

In study 94-0-002, there were significantly more emergent proven infections in conventional amphotericin B treated patients compared to AmBisome treated patients (7.8% vs. 3.2%, respectively, p = 0.009).
Overall in study 94-0-002, AmBisome and conventional amphotericin B showed equivalent efficacy by the primary composite endpoint success.
Likewise, in study 97-0-034 there were no statistically significant differences between AmBisome and amphotericin B lipid complex (ABLC) in terms of overall success rate. However, this trial was not adequately powered to enable a conclusion to be drawn about the efficacy equivalence of AmBisome and ABLC.
Cryptococcal meningitis. A randomized, phase III, open-label, multi-centre trial evaluated single, high-dose AmBisome-based treatment compared to the control group (7-day amphotericin B deoxycholate-based treatment) for HIV-associated cryptococcal meningitis. The study enrolled and randomized a total of 844 adult patients with HIV who had a first episode of cryptococcal meningitis, as diagnosed on the basis of a positive India ink stain or cryptococcal antigen test (CrAg lateral flow assay) of a cerebrospinal fluid sample.
Patients were randomized (1:1) to receive either a single dose (10 mg/kg) of AmBisome plus 14 days of flucytosine (100 mg/kilogram/day) and fluconazole (1200 mg/day) or amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg/kg/day) for 7 days, followed by fluconazole (1200 mg/day) on days 8 through 14. After the 2-week induction period, all patients received fluconazole at a dose of 800 mg per day for 8 weeks and then at a dose of 200 mg per day thereafter. Antiretroviral therapy was initiated, reinitiated, or switched to a new antiretroviral therapy with a different agent during weeks 4 to 6 and was chosen in accordance with national guidelines.
The primary analysis was performed in the intention-to-treat population (n=814), which included all randomized patients that had not met any late-exclusion criteria. The primary endpoint was death from any cause at 10 weeks after randomization; the trial was powered to show noninferiority at a 10-percentage-point margin. At 10 weeks, deaths were reported in 101 patients (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the AmBisome group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P < 0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log₁₀ colony forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log₁₀ CFU per milliliter per day in the control group.

HIV-associated cryptococcal meningitis.

A randomized phase III study assessed a single 10 mg/kg dose of AmBisome with a backbone of 14 days flucytosine and fluconazole, compared to the control group (1-week conventional amphotericin B plus flucytosine followed by 1 week of fluconazole) in the treatment of HIV-associated cryptococcal meningitis. The AmBisome treated patients experienced fewer grade 3 or 4 adverse events compared to the control group. The safety profile observed in this patient population was consistent with the overall safety profile for AmBisome.

5.2 Pharmacokinetic Properties

Pharmacokinetic data from animal studies demonstrated that higher peak plasma levels and greater total area under the curve values for amphotericin B were achieved after AmBisome administration, as compared to conventional intravenous amphotericin B. Higher levels of amphotericin were achieved in hepatic and splenic tissues with AmBisome in biodistribution studies in mice and rats. However, in rats, amphotericin levels in renal tissue were 5 to 6 fold lower for a given dose of AmBisome, compared to conventional drug after repeated administration for 28 days. For other organs, tissue levels of amphotericin were similar following dosing with AmBisome or with the conventional drug.
AmBisome has a pharmacokinetic profile significantly different from that of conventional amphotericin B. In phase I pharmacokinetic studies in patients, a dose dependent increase in peak serum concentrations was observed between daily doses of 2 mg/kg to 5 mg/kg. The peak serum concentrations achieved with AmBisome are 6 to 10-fold greater than those reported for the conventional formulation. A dose dependency was observed for AmBisome serum trough levels obtained 24 hours postdosing. The apparent volume of distribution ranged from 18.9 L to 49.1 L, with mean values of 29.5 L, 28.6 L and 24.1 L for daily doses of 3, 4, and 5 mg/kg, respectively. Conventional amphotericin B has an apparent volume of distribution of 280 L and so the volume of distribution of AmBisome is approximately 1 to 18% that of amphotericin B.

Distribution.

Detailed human tissue distribution and possible metabolic pathways of conventional amphotericin are not fully understood and have not been established for AmBisome.

Excretion.

In all the pharmacokinetic studies, the total body clearance of AmBisome ranged from 0.5 to 1.3 L/hr. The total body clearance for amphotericin B is approximately 1.8 L/hr. In a single patient who received both conventional amphotericin B and AmBisome at equivalent doses, the area under the serum concentration curve (AUC) increased 13-fold for AmBisome relative to the conventional drug. Amphotericin B tissue concentrations were determined in autopsy material from three patients. Drug concentrations following AmBisome were highest in the liver and spleen, confirming data obtained from animal studies. Concentrations in the lungs, kidneys, brain, and heart were comparatively low.
Table 6 shows the results of a study in patients with AmBisome at doses of 3.0, 4.0, and 5.0 mg/kg/day. Some variability of the data in patients has been observed.

The values in Table 6 were determined by pooling serial measurements of serum data at each dose level, generating a curve fit and calculating the pharmacokinetic parameters from that curve. Patient numbers were small and the number of measurements pooled was not constant across all patients at each dose level.

5.3 Preclinical Safety Data

Carcinogenicity, genotoxicity and impairment of fertility.

No long-term studies in animals have been performed to evaluate the carcinogenic potential of AmBisome or of conventional amphotericin B. There have been no studies to evaluate genotoxicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Amphotericin B is encapsulated in the bilayer of liposomes consisting of approximately 213 mg hydrogenated soy phosphatidylcholine, 52 mg cholesterol, 84 mg distearoylphosphatidylglycerol (as the sodium salt), 0.64 mg alpha-tocopherol, 900 mg sucrose and 27 mg sodium succinate hexahydrate.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Unopened vials of lyophilised material should be stored below 25°C.

Storage of reconstituted product concentrate.

Storage of diluted product.

As AmBisome contains no bacteriostatic agent, from a microbiological point of view, the reconstituted/ diluted product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2-8°C. Infusions should be completed within this 24 hour timeframe. AmBisome is provided as a unit dose product. Product is for one dose in one patient only; discard any remaining contents. Do not store partially used vial for future patient use.

6.5 Nature and Contents of Container

AmBisome is presented in single use vials and supplied in ten pack bulk cartons. Each carton presentation includes the directions for use and 5 micron filter(s) for use during dilution. Each vial contains amphotericin B.P. equivalent to 50 mg of amphotericin B (amphotericin).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The chemical structure of amphotericin B (amphotericin) is shown below.

CAS number.

1397-89-3.

7 Medicine Schedule (Poisons Standard)

S4.

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