Amphotericin B

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:

• Potentially life-threatening fungal infections, such as cryptococcosis (torulosis); North American blastomycosis; the disseminated forms of moniliasis (candidiasis), coccidioidomycosis and histoplasmosis; mucormycosis (phycomycosis) caused by susceptible species of the genera Mucor, Rhizopus, Absidia, Entomophthora and Basidiobolus; sporotrichosis (Sporothrix schenckii); aspergillosis (Aspergillus fumigatus)
• American mucocutaneous leishmaniasis (not the medicine of choice in primary therapy)

Contraindications

• Hypersensitivity to the active ingredient or to any of its excipients (unless, in the opinion of the physician, the condition requiring treatment is life-threatening and amenable only to such therapy)

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Rapid infusion rate
• Large cumulative doses
• Accidental overdose
• Patients who received total body irradiation
• Intrathecal administration
• Coadministration with corticosteroids (unless necessary to control drug reactions)
• Coadministration with nephrotoxic antibiotics and neoplastic agents
• Coadministration with diuretics

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

Dosages below include:

• General range dosing
• South African Standard Treatment Guidelines indications and dosages
• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

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: 0.3-1mg/kg, dly, as a single infusion

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

South African Standard Treatment Guidelines indications and dosages

Febrile neutropenia (Additional agent required)

• IV: 1mg/kg, given over 4hrs, dly; Treatment duration: 2-7 days after fever has settled
  (STG, Adult 2019)

Intravascular catheter-associated candidaemia

• IV: 0.7mg/kg, dly; Treatment duration: 2 weeks after first negative blood culture 
  (STG, Adult 2019)

Cryptococcosis meningitis - induction phase
- If flucytosine is available (Additional agent required)

• IV: 1mg/kg, given over 4hrs, dly; Treatment duration: 7 days
  (STG, Adult 2023)

- If flucytosine is not available (Additional agent required)

• IV: 1mg/kg, given over 4hrs, dly; Treatment duration: 14 days 
  (STG, Adult 2023)

Cryptococcal meningitis, HIV uninfected (Additional agent required)

• IV: 1mg/kg, dly; Treatment duration: 4-6 weeks
  (STG, Adult 2019)

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South African registered indications and dosages

Patients with progressive, potentially fatal infections 
- Cryptococcosis (torulosis)
- North American blastomycosis
- Disseminated forms of moniliasis (candidiasis), coccidioidomycosis and histoplasmosis
- Mucormycosis (phycomycosis) caused by species of the genera Mucor, Rhizopus, Absidia, Entomophthora, and Basidiobolus sporotrichosis (Sporotrichum schenckii), Aspergillosis (Aspergillus fumigatus) 
American mucocutaneous leishmaniasis (not the medicine of choice in primary therapy) 

• IV: Initial: 0.25mg/kg, as an infusion over 2-6hrs; Titrate gradually as tolerance permits

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The recommended concentration for IV infusion is 0.1mg/ml (1 mg/10ml)

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Dosage must be adjusted to the specific requirements of each patient since tolerance to amphotericin B intravenous varies individually

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Though not proven to be a reliable predictor of intolerance, an initial test dose (1mg in 20ml of 5% dextrose solution) administered IV over 20-30 mins may be preferred

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The patient's temperature, pulse, respiration, and blood pressure should be recorded every 30mins for 2-4hrs

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Severe and rapidly progressing fungal infection 
- With good cardiopulmonary function and who tolerates the test dose without a severe reaction

• IV: 0.3mg/kg, as an infusion over 2-6hrs; Titrate gradually in dose increments of 5-10mg/day; Final dose: 0.5-0.7mg/kg/day

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For patients with cardiopulmonary impairment or severe reaction to the test dose, therapy should be initiated with smaller daily doses (i.e. 5-10 mg)

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There are insufficient data presently available to define total dosage requirements and duration of treatment necessary for eradication of mycoses such as mucormycosis. The optimal dose is unknown

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Total daily dosage may range up to 1mg/kg per day, or up to 1.5mg/kg on alternate days, in severe infections caused by less susceptible pathogens. Several months of therapy are usually necessary; a shorter period of therapy may produce an inadequate response and lead to relapse

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Under no circumstances should a total daily dosage of 1.5mg/kg be exceeded. Amphotericin B intravenous overdoses can result in potentially fatal cardiac or cardio-respiratory arrest

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The duration of treatment for deep-seated mycoses may be 6-12 weeks or longer

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Rhinocerebral mucormycosis

• IV: 0.7-1.5mg/kg, as an infusion over 2-6hrs

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Rhinocerebral mucormycosis, a fulminating disease, generally occurs in association with diabetic ketoacidosis. It is imperative that rapid restoration of diabetic control be achieved in order for treatment with amphotericin B intravenous to be successful

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Since rhinocerebral mucormycosis usually follows a rapidly fatal course, the therapeutic approach must necessarily be more aggressive than that used in more indolent mycoses

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Indications and dosages registered in other jurisdictions

Note: 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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Under no circumstances should a total daily dose of 1.5mg/kg be exceeded. Amphotericin B overdoses can result in potentially fatal cardiac or cardiorespiratory arrest

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Patients with progressive, potentially fatal infections 
- Cryptococcosis (torulosis)
- North American blastomycosis
- Disseminated forms of candidosis, coccidioidomycosis and histoplasmosis  
- Mucormycosis (phycomycosis) caused by species of the genera Mucor, Rhizopus, Absidia, Entomophthora and Basidiobolus sporotrichosis (Sporotrichum schenckii), Aspergillosis (Aspergillus fumigatus) 

• IV: Initial: 0.25mg/kg, as an infusion over 2-6hrs; Titrate gradually to 1mg/kg depending on individual response and tolerance

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The daily dose should be maintained within the range of 0.25-1mg/kg at the highest level which is not accompanied by unacceptable toxicity

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Reduction of the infusion rate may reduce the incidence of side effects

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In seriously ill patients, the daily dose may be gradually increased up to a total of 1.5mg/kg

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Since amphotericin B is excreted slowly, therapy may be given on alternate days in patients on the higher dosage schedule

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Several months of therapy are usually necessary; a shorter period of therapy may produce an inadequate response and lead to relapse

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When commencing all new courses of treatment, it is advisable to administer a test dose immediately preceding the first dose

A volume of the infusion containing 1mg (i.e. 10ml) should be infused over 20-30mins and the patient carefully observed for at least a further 30mins. It should be noted that patient responses to the test dose may not be predictive of subsequent severe side effects

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Severe and rapidly progressing fungal infection 
- With good cardiopulmonary function and who tolerates the test dose without a severe reaction

• IV: 0.3mg/kg, as an infusion over 2-6hrs; Titrate gradually in dose increments of 5-10mg/day; Final dose: 0.5-1mg/kg/day

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For patients with cardiopulmonary impairment or severe reaction to the test dose, a lower dose (i.e. 5-10mg) is recommended

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Whenever medication is interrupted for a period longer than 7 days, therapy should be resumed by starting with the lowest dosage level, i.e. 0.25mg/kg of body weight and increased gradually

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The recommended concentration for IV infusion is 10mg/100ml

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

Paed. dosages below include:

• General dosing range
• South African Standard Treatment Guidelines indications and dosages

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: 0.5-1mg/kg, dly, as a single infusion

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

South African Standard Treatment Guidelines indications and dosages

Systemic candidiasis

• IV: 1mg/kg, given over 4hrs, dly; Treatment duration: 2-3 weeks; Max cumulative dose: 30-35mg/kg over 4-8 weeks
  (STG, Paed. 2017)

Cryptococcal meningitis (Additional agent required)

• IV: 1mg/kg, given over 4hrs, dly; Treatment duration: 2 weeks
  (STG, Paed. 2017)

Fungal pneumonia

• IV: 0.6-1mg/kg, given over 4hrs, dly; Treatment duration: ≥14 days 
  (STG, Paed. 2023)

Fungal septicaemia of the newborn

• IV: 1-1.5mg/kg, given over 4hrs, dly; Treatment duration: 14 days 
  (STG, Paed. 2017)

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Not established for use in paediatric patients according to international manufacturer recommendations

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Not established for use in paediatric patients according to South African manufacturer recommendations

Pregnancy

• Caution
• Safety for use in pregnancy has not been established; therefore it should be used during pregnancy only if the possible benefits to be derived outweigh the potential risks involved

Breastfeeding

• Caution
• It is not known whether amphotericin B is excreted in human milk. As excretion of amphotericin B in human milk is possible and considering its potential toxicity, it should be used in breastfeeding mothers only if the possible benefits to be derived outweigh the potential risks involved. In addition, it is prudent to advise a breastfeeding mother to discontinue breastfeeding

Renal Impairment

• Caution; no dose adjustment recommended
  For high-risk patients with CKD/CRF, and on concomitant nephrotoxic agents:
  Ensure 'aggressive' rehydration prior to a conventional amphotericin B administration
  If required, no adjustment is needed for loading doses
  Maintenance dosage should not exceed 1.5mg/kg/day (or 150mg/24hrs)
  Consider liposomal amphotericin B in case of a deteriorated renal function (or high-risk patients)  

Hepatic Impairment

• Caution; no information available

Elderly

• Caution; no dose adjustment recommended
  For high-risk patients, such as the elderly:
  Ensure 'aggressive' rehydration prior to a conventional amphotericin B administration
  If required, no adjustment is needed for loading doses
  Maintenance dosage should not exceed 1.5mg/kg/day (or 150mg/24hrs)
  Consider liposomal amphotericin B in case of a deteriorated renal function (or high-risk patients)  

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Seizures
• Peripheral neuropathy
• Encephalopathy
• Malaise

Cardiovascular Disorders

• Arrhythmias, including ventricular fibrillation
• Cardiac arrest
• Cardiac failure
• Hypertension
• Hypotension
• Shock

Respiratory Disorders

• Dyspnoea
• Cardiorespiratory arrest
• Bronchospasm
• Allergic alveolitis
• Non-cardiogenic pulmonary oedema

Gastrointestinal Disorders

• Nausea and vomiting
• Upper abdominal pain
• Diarrhoea
• Dyspepsia
• Haemorrhagic gastroenteritis
• Melaena

Hepatobiliary Disorders

• Abnormal hepatic function (and abnormal hepatic function test results)
• Jaundice
• Acute hepatic failure

Genitourinary Disorders

• Renal impairment
• Abnormal renal function tests
• Azotemia
• Hyposthenuria
• Renal tubular acidosis
• Nephrocalcinosis
• Acute renal failure
• Anuria
• Nephrogenic diabetes insipidus
• Oliguria
• Increased blood creatinine

Endocrine and Metabolic Disorders

• Hypokalaemia
• Hypomagnesemia
• Decreased appetite
• Hyperkalaemia
• Decreased weight

Musculoskeletal Disorders

• Myalgia
• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Maculopapular rash
• Pruritus
• Skin exfoliation
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Flushing

Immune, Blood and Lymphatic System Disorders

• Anaphylactoid reactions
• Anaphylactic reactions
• Anaemia
• Agranulocytosis
• Leukopenia
• Thrombocytopenia
• Coagulopathy
• Eosinophilia
• Leucocytosis
• Fever
• Chills

Sensory Disorders

• Blurred vision
• Diplopia
• Deafness
• Tinnitus
• Vertigo

Others

• Injection site pain (with or without phlebitis or thrombophlebitis)
• Pain

• Nephrotoxic agents
• Antineoplastics
• Muscle relaxants
• Digitalis glycosides
• Corticosteroids
• Corticotrophin
• Flucytosine
• Leukocyte transfusions

• Blood urea nitrogen (BUN)
• Serum creatinine
• Electrolytes (especially potassium and magnesium)
• Renal function
• Hepatic function
• Temperature
• Prothrombin time (PT)  
• Partial thromboplastin time (PTT)
• Full blood count

Specific cases may require

• Cardiopulmonary function

Additional observations

• Signs of hypokalemia
  - Muscle weakness
  - Cramping
  - Drowsiness
  - ECG changes

Accidental overdose

• 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
• Care must be taken when administering amphotericin B to prevent overdose, which can result in potentially fatal cardiac or cardiorespiratory arrest
• Verify the product name and dosage pre-administration, especially if the dose prescribed exceeds 1.5mg/kg

Avoidance of rapid infusion rate

• Rapid intravenous infusion, over less than one hour, particularly in patients with renal insufficiency, has been associated with hyperkalaemia and arrhythmias and should therefore be avoided
• Reduction of the infusion rate may reduce the incidence of side-effects

Incompatibility with saline solutions

• Do not reconstitute with saline solutions. The use of any diluent other than the ones recommended or the presence of a bacteriostatic agent in the diluent may cause precipitation of the amphotericin B

Amphotericin B is a polyene antifungal antibiotic active against a wide range of yeasts and yeast-like fungi, including Candida albicans.  Amphotericin B is fungistatic rather than fungicidal in concentrations obtainable in body fluids. It probably acts by binding to sterols in the fungal cell membrane with a resultant change in membrane permeability which allows leakage of intracellular components. Mammalian cell membranes also contain sterols and it has been suggested that the damage to human and fungal cells may share common mechanisms. No strains of Candida resistant to amphotericin B have been reported in clinical use, and although in vitro testing does produce a small number of resistant isolates this occurs only following repeated subcultures.

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

• Fungizone (Bristol-Myers) originator