Drugs List

Therapeutic Indications

Uses

Treatment of severe systemic and/or deep mycoses where toxicity (particularly nephrotoxicity) precludes the use of conventional systemic amphotericin in effective doses.

Treatment of visceral leishmaniasis in immunocompetent patients (adults and children)

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 identify a bacterial or viral cause.

Types of infections treated successfully with amphotericin liposomal powder for solution for infusion include:
Disseminated candidiasis
Aspergillosis
Mucormycosis
Chronic mycetoma
Cryptococcal meningitis
Visceral leishmaniasis

Amphotericin liposomal powder for solution for infusion should not be used to treat the common clinically inapparent forms of fungal infection which show only positive skin or serologic tests.

Consideration should be given to official local guidance on the appropriate use of antifungal agents.

Administration

For intravenous infusion.

Following reconstitution, the solution should be administered by intravenous infusion over 30 - 60 minutes. Rapid infusion should be avoided as this increases the risk of arrhythmias. For doses greater than 5mg/kg/day, intravenous infusion over a 2 hour period is recommended.

An existing intravenous line must be flushed with glucose injection (5%, 10% or 20%) before infusion of amphotericin. If this is not feasible, amphotericin should be administered through a separate line.

Recommended concentration for intravenous infusion is 0.2 to 2 mg/ml amphotericin.

Handling

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 degrees C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Shelf life after reconstitution
Glass vials for 24 hours at 25 +/- 2 degrees C exposed to ambient light
Glass vials and polypropylene syringes up to 7 days at 2-8 degrees C

Shelf life after dilution with glucose (in PVC or Polyolefin infusion bags)
5% Glucose
A 1:2 dilution with concentration of amphotericin 2mg/ml may be stored for 7 days at 2-8 degrees C or for 48 hours at 25 +/- 2 degrees C
A 1:8 dilution with concentration of amphotericin 0.5mg/ml may be stored for 7 days at 2-8 degrees C or for 48 hours at 25 +/- 2 degrees C
A 1:20 dilution with concentration of amphotericin 0.2mg/ml may be stored for 4 days at 2-8 degrees C or for 24 hours at 25 +/- 2 degrees C
10% Glucose
A 1:2 dilution with concentration of amphotericin 2mg/ml may be stored for 48 hours at 2-8 degrees C or for 72 hours at 25 +/- 2 degrees C
20% Glucose
A 1:2 dilution with concentration of amphotericin 2mg/ml may be stored for 48 hours at 2-8 degrees C or for 72 hours at 25 +/- 2 degrees C

Reconstitution

Reconstitution
Reconstitution must only be carried out by suitably trained staff.
Amphotericin liposomal powder for solution for infusion must be reconstituted with Water for Injections (without a bacteriostatic agent).

Add 12ml of Water for injection to the vial. Immediately after addition of water, shake the vial vigorously for 30 seconds until dispersion is complete. After reconstitution the concentrate is a translucent, yellow dispersion.
Inspect the vial visually for particulate matter and continue shaking until complete dispersion is obtained. The concentration of this solution is 4mg/ml.

Further dilution
Calculate the amount of reconstituted amphotericin 4mg/ml to be further diluted. The infusion is obtained by dilution of the reconstituted solution with between 1 and 19 parts glucose injection (5%, 10% or 20%) to give a final concentration in the range of 0.2 to 2mg/ml amphotericin.
Withdraw the calculated volume of reconstituted amphotericin into a sterile syringe. Using the 5 micron filter provided, instil the amphotericin preparation into a sterile container with the correct amount of glucose solution (5%, 10% or 20%) for infusion.

Incompatibilities

Amphotericin liposomal powder for solution for infusion is not physically compatible with saline solutions and should not be mixed with other drugs or electrolytes.

Contraindications

None known

Precautions and Warnings

Different formulations of intravenous amphotericin are not interchangeable.
There is a risk of confusion between non-lipid formulations and lipid formulations of injectable amphotericin. Care should be taken in the selection and administration of intravenous amphotericin preparations especially with regard to dose calculations.

Consideration should be given to official local guidance on the appropriate use of antifungal agents.

May be used in hypersensitive patients only in life-threatening situations.

Allergic type reactions, including severe infusion-related reactions, can occur during administration of amphotericin containing products. Administration of a test dose before a new course of treatment is advisable (see Dosage for details ).
If there have been no severe allergic or anaphylactic reactions to the test dose, the infusion can be continued. If a severe allergic or anaphylactic reaction occurs, the patient should not receive further infusions of amphotericin liposomal powder for solution for infusion.

Consider precautionary measures to prevent or treat infusion-related reactions, such as slower infusion rates (over 2 hours) or routine doses of diphenhydramine, paracetamol, pethidine and/or hydrocortisone.

When treating diabetic patients, note that this formulation contains approximately 900mg sucrose per vial.

Caution should be exercised when prolonged therapy is required.

Laboratory evaluation of renal, hepatic and haematopoietic function should be performed at least once weekly.

Monitor serum electrolytes, particularly potassium and magnesium at least once a week. Due to the risk of hypokalaemia, appropriate potassium supplementation may be required during the course of amphotericin administration.

Monitor renal function closely. Although amphotericin (encapsulated in liposomes) is less nephrotoxic than conventional amphotericin preparations, renal adverse reactions may still occur. If clinically significant reduction in renal function or worsening of other parameters occur, consideration should be given to dose reduction, treatment interruption or discontinuation. Concurrent administration of amphotericin with other nephrotic drugs may enhance the potential for drug induced renal toxicity in some patients therefore regular monitoring of renal function is required in these patients. Use with caution in patients with renal impairment.

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.

May interfere with certain phosphorus chemistry assays. See Effects on Laboratory Tests section.

Pregnancy - see Pregnancy section

Breastfeeding - see Lactation section

Children under 1 month - see Dosage - Neonates

CSM Warnings

The CSM has advised that anaphylaxis occurs rarely with any intravenous amphotericin product and a test dose is advisable before the first infusion; the patient should be carefully observed for at least 30 minutes after the test dose. Prophylactic antipyretics or hydrocortisone should only be used in patients who have previously experienced acute adverse reactions (in whom continued treatment with amphotericin is essential).

Pregnancy and Lactation

Pregnancy

Should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks.

Safety of amphotericin B during human pregnancy has not been established. Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin without obvious effects on the foetus, but the number of cases reported has been small.

No reproductive toxicity studies have been conducted in pregnant women.

While reproduction studies in rats and rabbits using conventional amphotericin, amphotericin lipid complex and liposomal amphotericin have not revealed any evidence of harm to the foetus, rabbits receiving amphotericin B liposomal doses equivalent to 0.5-2 times the usual human dose experienced a higher rate of spontaneous abortions than the control group.

Amphotericin crosses the placenta and exposure to the foetus and neonate may be prolonged by its retention in the placenta and other tissue. To date there is only one report of amphotericin liposome exposure during the second trimester of pregnancy and this was without adverse effects.

Schaefer advises that parenteral use during pregnancy should be restricted to dangerous disseminated mycoses.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Crosses placenta? - Yes. May be retained in the placenta and other foetal tissue.

Lactation

Should only be used during breastfeeding if the possible benefits to be derived outweigh the potential risks.

It is not known whether amphotericin is excreted in human milk. Amphotericin is highly protein bound with a large molecular weight and virtually unabsorbed orally (less than 9%) and is unlikely to be clinically significant to a breastfeeding infant. However, because amphotericin has a potential for serious adverse reactions in nursing infants if it were distributed in human milk, it is recommended that a decision should be made whether to discontinue the drug or breastfeeding, taking into account the benefit to the nursing mother.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Fever
Chills
Rigors
Back pain
Chest tightness
Chest pain
Dyspnoea
Bronchospasm
Flushing
Vasodilation
Tachycardia
Hypokalaemia
Nausea
Vomiting
Diarrhoea
Serum creatinine increased
Hypomagnesaemia
Hyperglycaemia
Hyponatraemia
Blood urea increased
Increase in alkaline phosphatase
Hyperbilirubinaemia
Abnormal liver function tests
Abdominal pain
Headache
Rash
Convulsions
Thrombocytopenia
Anaphylactoid reaction
Nephrotoxicity
Angioneurotic oedema
Anorexia
Arthralgia
Myalgia
Anaemia
Arrhythmias
Blood disorders
Hearing loss
Diplopia
Peripheral neuropathy
Thrombophlebitis (injection site)
Local pain (injection site)
Hypersensitivity reactions
Renal failure
Renal impairment
Cardiovascular toxicity
Neurological effects
Anaphylaxis
Cardiac arrest
Encephalopathy
Blood pressure changes
Epigastric pain
Hypotension
Rhabdomyolysis
Pyrexia
Bone pain
Hypocalcaemia

Presentation

Lyophilised powder for solution for infusion containing amphotericin B (encapsulated in liposomes) 50mg (50,000 units) per vial.

Drugs List

Therapeutic Indications

Uses

Treatment of severe systemic and/or deep mycoses where toxicity (particularly nephrotoxicity) precludes the use of conventional systemic amphotericin in effective doses.

Treatment of visceral leishmaniasis in immunocompetent patients (adults and children)

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 identify a bacterial or viral cause.

Types of infections treated successfully with amphotericin liposomal powder for solution for infusion include:
Disseminated candidiasis
Aspergillosis
Mucormycosis
Chronic mycetoma
Cryptococcal meningitis
Visceral leishmaniasis

Amphotericin liposomal powder for solution for infusion should not be used to treat the common clinically inapparent forms of fungal infection which show only positive skin or serologic tests.

Consideration should be given to official local guidance on the appropriate use of antifungal agents.

Dosage

Different formulations of intravenous amphotericin are not interchangeable.
There is a risk of confusion between non-lipid formulations and lipid formulations of injectable amphotericin. Care should be taken in the selection and administration of intravenous amphotericin preparations especially with regard to dose calculations.

Severe infusion-related reactions can occur during administration, therefore it is advisable to give a test dose before a new course of treatment.
For this purpose, give a small amount of the infusion (e.g. 1 mg in adults or 100micrograms/kg (maximum 1mg) in children) over about 10 minutes, stop the infusion and observe the patient for the next 30 minutes. If there have been no severe allergic or anaphylactic reactions, the infusion can be continued. If a severe allergic or anaphylactic reaction occurs, the patient should not receive further infusions of amphotericin liposomal powder for solution for infusion.

Adults

Elderly

Children

Neonates

Patients with Renal Impairment

Administration

For intravenous infusion.

Following reconstitution, the solution should be administered by intravenous infusion over 30 - 60 minutes. Rapid infusion should be avoided as this increases the risk of arrhythmias. For doses greater than 5mg/kg/day, intravenous infusion over a 2 hour period is recommended.

An existing intravenous line must be flushed with glucose injection (5%, 10% or 20%) before infusion of amphotericin. If this is not feasible, amphotericin should be administered through a separate line.

Recommended concentration for intravenous infusion is 0.2 to 2 mg/ml amphotericin.

Handling

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 degrees C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Shelf life after reconstitution
Glass vials for 24 hours at 25 +/- 2 degrees C exposed to ambient light
Glass vials and polypropylene syringes up to 7 days at 2-8 degrees C

Shelf life after dilution with glucose (in PVC or Polyolefin infusion bags)
5% Glucose
A 1:2 dilution with concentration of amphotericin 2mg/ml may be stored for 7 days at 2-8 degrees C or for 48 hours at 25 +/- 2 degrees C
A 1:8 dilution with concentration of amphotericin 0.5mg/ml may be stored for 7 days at 2-8 degrees C or for 48 hours at 25 +/- 2 degrees C
A 1:20 dilution with concentration of amphotericin 0.2mg/ml may be stored for 4 days at 2-8 degrees C or for 24 hours at 25 +/- 2 degrees C
10% Glucose
A 1:2 dilution with concentration of amphotericin 2mg/ml may be stored for 48 hours at 2-8 degrees C or for 72 hours at 25 +/- 2 degrees C
20% Glucose
A 1:2 dilution with concentration of amphotericin 2mg/ml may be stored for 48 hours at 2-8 degrees C or for 72 hours at 25 +/- 2 degrees C

Reconstitution

Reconstitution
Reconstitution must only be carried out by suitably trained staff.
Amphotericin liposomal powder for solution for infusion must be reconstituted with Water for Injections (without a bacteriostatic agent).

Add 12ml of Water for injection to the vial. Immediately after addition of water, shake the vial vigorously for 30 seconds until dispersion is complete. After reconstitution the concentrate is a translucent, yellow dispersion.
Inspect the vial visually for particulate matter and continue shaking until complete dispersion is obtained. The concentration of this solution is 4mg/ml.

Further dilution
Calculate the amount of reconstituted amphotericin 4mg/ml to be further diluted. The infusion is obtained by dilution of the reconstituted solution with between 1 and 19 parts glucose injection (5%, 10% or 20%) to give a final concentration in the range of 0.2 to 2mg/ml amphotericin.
Withdraw the calculated volume of reconstituted amphotericin into a sterile syringe. Using the 5 micron filter provided, instil the amphotericin preparation into a sterile container with the correct amount of glucose solution (5%, 10% or 20%) for infusion.

Incompatibilities

Amphotericin liposomal powder for solution for infusion is not physically compatible with saline solutions and should not be mixed with other drugs or electrolytes.

Contraindications

None known

Precautions and Warnings

Different formulations of intravenous amphotericin are not interchangeable.
There is a risk of confusion between non-lipid formulations and lipid formulations of injectable amphotericin. Care should be taken in the selection and administration of intravenous amphotericin preparations especially with regard to dose calculations.

Consideration should be given to official local guidance on the appropriate use of antifungal agents.

May be used in hypersensitive patients only in life-threatening situations.

Allergic type reactions, including severe infusion-related reactions, can occur during administration of amphotericin containing products. Administration of a test dose before a new course of treatment is advisable (see Dosage for details ).
If there have been no severe allergic or anaphylactic reactions to the test dose, the infusion can be continued. If a severe allergic or anaphylactic reaction occurs, the patient should not receive further infusions of amphotericin liposomal powder for solution for infusion.

Consider precautionary measures to prevent or treat infusion-related reactions, such as slower infusion rates (over 2 hours) or routine doses of diphenhydramine, paracetamol, pethidine and/or hydrocortisone.

When treating diabetic patients, note that this formulation contains approximately 900mg sucrose per vial.

Caution should be exercised when prolonged therapy is required.

Laboratory evaluation of renal, hepatic and haematopoietic function should be performed at least once weekly.

Monitor serum electrolytes, particularly potassium and magnesium at least once a week. Due to the risk of hypokalaemia, appropriate potassium supplementation may be required during the course of amphotericin administration.

Monitor renal function closely. Although amphotericin (encapsulated in liposomes) is less nephrotoxic than conventional amphotericin preparations, renal adverse reactions may still occur. If clinically significant reduction in renal function or worsening of other parameters occur, consideration should be given to dose reduction, treatment interruption or discontinuation. Concurrent administration of amphotericin with other nephrotic drugs may enhance the potential for drug induced renal toxicity in some patients therefore regular monitoring of renal function is required in these patients. Use with caution in patients with renal impairment.

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.

May interfere with certain phosphorus chemistry assays. See Effects on Laboratory Tests section.

Pregnancy - see Pregnancy section

Breastfeeding - see Lactation section

Children under 1 month - see Dosage - Neonates

CSM Warnings

The CSM has advised that anaphylaxis occurs rarely with any intravenous amphotericin product and a test dose is advisable before the first infusion; the patient should be carefully observed for at least 30 minutes after the test dose. Prophylactic antipyretics or hydrocortisone should only be used in patients who have previously experienced acute adverse reactions (in whom continued treatment with amphotericin is essential).

Pregnancy and Lactation

Pregnancy

Should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks.

Safety of amphotericin B during human pregnancy has not been established. Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin without obvious effects on the foetus, but the number of cases reported has been small.

No reproductive toxicity studies have been conducted in pregnant women.

While reproduction studies in rats and rabbits using conventional amphotericin, amphotericin lipid complex and liposomal amphotericin have not revealed any evidence of harm to the foetus, rabbits receiving amphotericin B liposomal doses equivalent to 0.5-2 times the usual human dose experienced a higher rate of spontaneous abortions than the control group.

Amphotericin crosses the placenta and exposure to the foetus and neonate may be prolonged by its retention in the placenta and other tissue. To date there is only one report of amphotericin liposome exposure during the second trimester of pregnancy and this was without adverse effects.

Schaefer advises that parenteral use during pregnancy should be restricted to dangerous disseminated mycoses.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Crosses placenta? - Yes. May be retained in the placenta and other foetal tissue.

Lactation

Should only be used during breastfeeding if the possible benefits to be derived outweigh the potential risks.

It is not known whether amphotericin is excreted in human milk. Amphotericin is highly protein bound with a large molecular weight and virtually unabsorbed orally (less than 9%) and is unlikely to be clinically significant to a breastfeeding infant. However, because amphotericin has a potential for serious adverse reactions in nursing infants if it were distributed in human milk, it is recommended that a decision should be made whether to discontinue the drug or breastfeeding, taking into account the benefit to the nursing mother.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Effects on Ability to Drive and Operate Machinery

The effects of amphotericin on the ability to drive or operate machinery have not been investigated.

The clinical condition of most patients treated with amphotericin liposomal powder for solution for infusion precludes driving vehicles or operating machinery.

Side Effects

Fever
Chills
Rigors
Back pain
Chest tightness
Chest pain
Dyspnoea
Bronchospasm
Flushing
Vasodilation
Tachycardia
Hypokalaemia
Nausea
Vomiting
Diarrhoea
Serum creatinine increased
Hypomagnesaemia
Hyperglycaemia
Hyponatraemia
Blood urea increased
Increase in alkaline phosphatase
Hyperbilirubinaemia
Abnormal liver function tests
Abdominal pain
Headache
Rash
Convulsions
Thrombocytopenia
Anaphylactoid reaction
Nephrotoxicity
Angioneurotic oedema
Anorexia
Arthralgia
Myalgia
Anaemia
Arrhythmias
Blood disorders
Hearing loss
Diplopia
Peripheral neuropathy
Thrombophlebitis (injection site)
Local pain (injection site)
Hypersensitivity reactions
Renal failure
Renal impairment
Cardiovascular toxicity
Neurological effects
Anaphylaxis
Cardiac arrest
Encephalopathy
Blood pressure changes
Epigastric pain
Hypotension
Rhabdomyolysis
Pyrexia
Bone pain
Hypocalcaemia

Effects on Laboratory Tests

Interference with phosphorus chemistry assay: False elevations of serum phosphate may occur when samples from patients receiving amphotericin (encapsulated in liposomes) are analysed using the PHOSm assay (e.g. used in Beckman Coulter analysers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples.

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Shelf Life and Storage

Unopened vials
Do not store above 25 degrees C
Keep container in the outer carton
Do not freeze

Further Information

Last Full Review Date: November 2012

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

Summary of Product Characteristics: AmBisome. Gilead Sciences Ltd. Revised March 2017.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 04 September 2017

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Amphotericin. Last revised: February 12, 2010
Last accessed: September 09, 2012