Amphotericin B Liposomal

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Empirical therapy for presumed fungal infection in febrile neutropenic adults and children unresponsive to anti-bacterial treatment
• Severe systemic and/or deep mycoses in adults and children in whom toxicity (particularly nephrotoxicity) precludes the use of conventional systemic amphotericin B, or in patients who are resistant to conventional amphotericin B (such as in disseminated candidiasis, aspergillosis, mucormycosis, chronic mycetoma and cryptococcal meningitis)
• Cryptococcal meningitis in HIV-infected patients
• Primary therapy of visceral leishmaniasis in immunocompetent adults and children and immunocompromised adults (e.g. HIV positive)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients 
  - Unless, in the opinion of the physician, the condition requiring treatment is life-threatening and amenable only to liposomal amphotericin B therapy 

Cautions

• Pregnancy 
• Breastfeeding 
• Renal impairment 
• Hepatic impairment 
• Porphyria 
• Infusion rate 
• High doses 
• Prolonged therapy 
• Diabetes mellitus 
• Coadministration with leukocyte transfusions 
• Coadministration with nephrotoxic agents 
• May impair ability to drive and operate machinery 

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• General dosing range
• International manufacturer recommendations
• South African manufacturer recommendations

Infections caused by: Candida albicans, Candida dubliniensis, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Mucorales (e.g., Absidia, Rhizomucor, Rhizopus), Blastomyces dermatitidis, Coccidioides immitis/posadasii, Histoplasma capsulatum, Sporothrix schenckii, Aspergillus sp (except A. terreus)

General dosing range

• IV: 3-5mg/kg/day, as an infusion over 120min

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

International manufacturer recommendations

Treatment of severe systemic and/or deep mycoses

• IV: Initial: 1mg/kg/day, as an infusion over 30-60min; Titrate stepwise to 3mg/kg/day, as needed; Treatment duration: 3-4 weeks

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Data are presently insufficient to define total dosage requirements and duration of treatment necessary for resolution of mycoses. However, a cumulative dose of 1.0-3.0g of liposomal amphotericin B over 3-4 weeks has been typical. Dosage of amphotericin B as liposomal amphotericin B must be adjusted to the specific requirements of each patient

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Mucormycosis 

• IV: Recommended starting dose: 5mg/kg/day, as an infusion over 30-60min; Treatment duration: 6-8 weeks (duration of therapy should be determined on an individual basis)

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Although doses greater than 5mg/kg and up to a maximum of 10mg/kg have been used in clinical trials and clinical practice, data on the safety and efficacy of liposomal amphotericin B 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 liposomal amphotericin B doses

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For doses greater than 5mg/kg/day, intravenous infusion over a 2hr period is recommended. The recommended concentration for intravenous infusion is 0.20mg/ml to 2.00mg/ml amphotericin B as liposomal amphotericin B 

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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

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Treatment of visceral leishmaniasis in immunocompetent patients 

• IV: 21-30mg/kg, over 10-21 days

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Liposomal amphotericin B should be administered by intravenous infusion over a 30-60min period. For doses greater than 5mg/kg/day, intravenous infusion over a 2hr period is recommended. The recommended concentration for intravenous infusion is 0.20mg/ml to 2.00mg/ml amphotericin B as liposomal amphotericin B

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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

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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 

• IV: 3mg/kg/day, as an infusion over 30-60min; Treatment duration: Continued until the recorded temperature is normalised for 3 consecutive days; Max duration: 42 days

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Administration of a test dose is advisable before a new course of treatment. A small amount of an amphotericin B liposomal infusion (e.g. 1mg) can be administered for about 10mins and then stopped and the patient observed carefully for the next 30mins. If there have been no severe allergic or anaphylactic/anaphylactoid reactions the infusion of amphotericin B liposomal dose can be continued

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All indications: 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

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All indications: There is a risk of under-dose if amphotericin B liposomal is administered at a dose recommended for amphotericin B deoxycholate

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All indications: Liposomal amphotericin B should not be used to treat the common clinically inapparent forms of fungal disease which show only positive skin or serologic tests

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South African manufacturer recommendations

Empirical therapy for presumed fungal infection in febrile neutropenic adults and children unresponsive to anti-bacterial treatment 

• IV: 3mg/kg/day, as an infusion over 30-60min 

Severe systemic and/or deep mycoses where toxicity (particularly nephrotoxicity) precludes the use of conventional systemic amphotericin B, or in patients who are resistant to conventional amphotericin B 
- Aspergillus*
- Candida
- Cryptococcus

• IV: 3-5mg/kg/day, as an infusion over 30-60min 

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*A large randomised controlled study of liposomal amphotericin B showed that a dose of 3mg/kg/day was optimal for invasive pulmonary aspergillosis 

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Cryptococcal meningitis in HIV-infected patients 

• IV: 6mg/kg/day, as an infusion over 120min 

Visceral leishmaniasis (Immunocompetent patients) 

• IV: 3mg/kg/day on days 1-5, day 14 and day 21 

Visceral leishmaniasis (Immunocompromised patients) 

• IV: 4mg/kg/day on days 1-5, day 10, day 17, day 24, day 31 and day 38 

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Liposomal amphotericin B should be administered by intravenous infusion over a 30-60min period. For doses greater than 5mg/kg/day, intravenous infusion over a 2hr period is recommended. The recommended concentration for intravenous infusion is 0.20mg/ml to 2.00mg/ml amphotericin B as liposomal amphotericin B 

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See additional prescribing points for reconstitution

Paed. forms avail. in SA and covered in this monograph: inj

Paed. dosages below include:

• General dosing range
• International manufacturer recommendations
• South African manufacturer recommendations

Infections caused by: Candida albicans, Candida dubliniensis, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Mucorales (e.g., Absidia, Rhizomucor, Rhizopus), Blastomyces dermatitidis, Coccidioides immitis/posadasii, Histoplasma capsulatum, Sporothrix schenckii, Aspergillus sp (except A. terreus)

General dosing range

• IV: 3-5mg/kg/day, as an infusion over 120min

International manufacturer recommendations

Treatment of severe systemic and/or deep mycoses
Mucormycosis 
Treatment of visceral leishmaniasis in immunocompetent patients 
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 

Younger than 1 month

• Not established for use

Older than 1 month

• See adult dosage

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South African manufacturer recommendations

Empirical therapy for presumed fungal infection in febrile neutropenic adults and children unresponsive to anti-bacterial treatment 
Severe systemic and/or deep mycoses where toxicity (particularly nephrotoxicity) precludes the use of conventional systemic amphotericin B, or in patients who are resistant to conventional amphotericin B
Cryptococcal meningitis in HIV-infected patients
Visceral leishmaniasis (Immunocompetent patients)
Visceral leishmaniasis (Immunocompromised patients)

Younger than 1 month

• Not established for use 

Older than 1 month

• See adult dosage 

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See additional prescribing points for reconstitution

Pregnancy

• Caution
• The safety of liposomal amphotericin B 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 foetus, but the number of cases reported is insufficient to draw any conclusions on the safety of liposomal amphotericin B in pregnancy
• Liposomal amphotericin B should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks to the mother and foetus

Breastfeeding

• Caution; not recommended
• It is unknown whether liposomal amphotericin B is excreted in human breast milk 
• A decision on whether to breastfeed while receiving liposomal amphotericin B should take into account the potential risk to the child as well as the benefit of breastfeeding for the child and the benefit of liposomal amphotericin B therapy for the mother

Fertility

• Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity 

Renal Impairment

• Caution; no dose adjustment recommended
  Liposomal amphotericin B has been shown to be substantially less toxic than conventional amphotericin B, particularly with respect to nephrotoxicity; however, renal adverse reactions may still occur 
  Caution should be exercised when prolonged therapy is required 

Hepatic Impairment

• Caution; no information available 

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Seizures

Cardiovascular Disorders

• Tachycardia
• Arrhythmias
• Cardiac arrest
• Hypotension
• Vasodilation
• Flushing
• Chest pain

Respiratory Disorders

• Dyspnoea
• Bronchospasm

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea

Hepatobiliary Disorders 

• Abnormal hepatic function tests
• Hyperbilirubinaemia
• Increased alkaline phosphatase

Genitourinary Disorders 

• Increased creatinine
• Increased blood urea
• Renal failure
• Renal insufficiency
• Nephrotoxicity

Endocrine and Metabolic Disorders 

• Hypokalaemia
• Hyponatremia
• Hypocalcaemia
• Hypomagnesaemia
• Hyperglycemia

Musculoskeletal Disorders

• Back pain
• Rhabdomyolysis (associated with hypokalaemia)
• Arthralgia
• Bone pain

Skin and Subcutaneous Tissue Disorders

• Rash
• Angioneurotic oedema

Immune, Blood and Lymphatic System Disorders 

• Thrombocytopenia
• Anaemia
• Anaphylactoid reaction
• Anaphylactic reactions
• Hypersensitivity
• Infusion-related reactions
  - Fever
  - Rigors
  - Chest tightness
  - Pain
  - Dyspnoea
  - Bronchospasm
  - Flushing
  - Tachycardia
  - Hypotension
  - Musculoskeletal pain

• Nephrotoxic agents
• Ciclosporin
• Aminoglycosides
• Polymixins
• Tacrolimus
• Pentamidine
• Antineoplastic agents
• Corticosteroids
• Corticotrophin (ACTH)
• Loop diuretics
• Thiazide diuretics
• Digitalis glycosides
• Muscle relaxants
• Tubocurarine
• Antifungals
• Flucytosine
• Leukocyte transfusions (See additional prescribing points)

Other interactions

• Phosphorus chemistry assay (See additional prescribing points)

• Renal function
• Hepatic function
• Electrolytes
• Temperature
• Electrocardiogram
• Full blood count

Some cases may require

• Cardiac function

Additional observations

• Signs of hypokalemia (muscle weakness, cramping, drowsiness)

Reconstitution directions

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Liposomal amphotericin B must be reconstituted using sterile water for injection (without a bacteriostatic agent) and diluted in dextrose solution (5%, 10% or 20%) for infusion only

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• 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 liposomal amphotericin B
• Liposomal amphotericin B is NOT compatible with saline and must not be reconstituted or diluted with saline or administered through an intravenous line that has previously been used for saline unless first flushed with dextrose solution (5%, 10% or 20%) for infusion. If this is not feasible, liposomal amphotericin B should be administered through a separate line
• Do NOT mix liposomal amphotericin B with other medicinal products or electrolytes
• Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in liposomal amphotericin B, or in the materials specified for reconstitution and dilution
• Liposomal amphotericin B must be reconstituted by suitably trained staff
• 50mg vials of amphotericin are prepared as follows:

1. Add 12ml of sterile water for injection to each vial, to yield a preparation containing 4mg/ml amphotericin
2. Immediately after the addition of water, shake the vial vigorously for 30secs to completely disperse the contents. After reconstitution, the concentrate is a translucent, yellow dispersion. Visually inspect the vial for particulate matter and continue shaking until complete dispersion is obtained. Do not use if there is any evidence of precipitation of foreign matter
3. Calculate the amount of reconstituted (4mg/ml) liposomal amphotericin B to be further diluted (see table below)
4. The infusion solution is obtained by dilution of the reconstituted amphotericin B liposomal with between one (1) and nineteen (19) parts dextrose solution (5%, 10% or 20%) for infusion by volume, to give a final concentration in the recommended range of 2.00 mg/ml to 0.20 mg/ml amphotericin B (see table below)
5. Withdraw the calculated volume of reconstituted liposomal amphotericin B into a sterile syringe. Using the 5 micron filter provided, instill the liposomal amphotericin B preparation into a sterile container with the correct amount of dextrose solution (5%, 10% or 20%) for infusion

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

Example of the preparation of liposomal amphotericin B dispersion for infusion at a dose of 3mg/kg/day in dextrose 5% solution for infusion

Weight (kg)	Number of vials	Amount of liposomal amphotericin B (mg) to be withdrawn for further dilution	Volume of reconstituted liposomal amphotericin B (ml)*	To make up a 0.2mg/ml concentration (1 in 20 dilution)		To make up a 2.0mg/ml concentration (1 in 2  dilution)
				Volume of 5% dextrose needed (ml)	Total volume (ml; liposomal amphotericin B plus 5% dextrose)	Volume of 5% dextrose needed (ml)	Total volume (ml; liposomal amphotericin B plus 5% dextrose)
10	1	30	7.5	142.5	150	7.5	15
25	2	75	18.75	356.25	375	18.75	37.5
40	3	120	30	570	600	30	60
55	4	165	41.25	783.75	825	41.25	82.5
70	5	210	52.5	997.5	1050	52.5	105
85	6	255	63.75	1211.25	1275	63.75	127.5

*Each vial of liposomal amphotericin B (50mg) is reconstituted with 12ml water for injection to provide a concentration of 4mg/ml amphotericin B

Infusion-related reactions

• Other severe infusion-related reactions can occur during administration of amphotericin B-containing products, including liposomal amphotericin B. 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 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

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

Interference with phosphorus chemistry assay

• False elevations of serum phosphate may occur when samples from patients receiving liposomal amphotericin B 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

Amphotericin B is a macrocyclic, polyene antifungal antibiotic produced by Streptomyces nodosus. Amphotericin B is fungistatic or fungicidal depending on the concentration attained in body fluids and the susceptibility of the fungus. The molecule 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. The lipophilic moiety of amphotericin allows the molecule to be integrated into the lipid bilayer of the liposomes. 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. 

Spectrum of activity: Candida albicans, Candida dubliniensis, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Mucorales (e.g., Absidia, Rhizomucor, Rhizopus), Blastomyces dermatitidis, Coccidioides immitis/posadasii, Histoplasma capsulatum, Sporothrix schenckii, Aspergillus sp (except A. terreus) 

Injection (per vial) 50mg

• AmBisome (Key Oncologics) originator