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Intravenous Dilution Guidelines

(Amphotericin B) (Liposomal) - AMBISOME

Usual Diluents

D5W

Standard Dilution [Amount of drug] [Infusion volume] [Infusion rate]

[3 - 6 mg/kg/day]  [Final concentration: 1-2 mg/ml]  [120 minutes*]

*Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If  the patient experiences discomfort during infusion, the duration of infusion may be increased.  Final concentrations of 0.2 - 0.5 mg/ml  may be appropriate for infants and small children to provide sufficient volume for infusion.

Vial Reconstitution:
1. Aseptically add 12 mL of Sterile Water for Injection, USP to each AmBisome vial to yield a preparation containing 4 mg amphotericin B/mL.

CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation of AmBisome.

2. Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the AmBisome. AmBisome forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed.

Filtration and Dilution
3. Calculate the amount of reconstituted (4 mg/mL) AmBisome to be further diluted.

4. Withdraw this amount of reconstituted AmBisome into a sterile syringe.

5. Attach the 5-micron filter, provided, to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection. (Use only one filter per vial of AmBisome.)

6. AmBisome must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL prior to administration. Lower concentrations (0.2 to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS.

Stability / Miscellaneous

Stability (see below).

Stability data:

Drug Stability
Refrigerated
Stability
Room Temp.
Reconstituted
Vial/Powder
Notes P-Insert
Updated
Ambisome (Ampho B) The reconstituted product concentrate may be stored for up to 24 hours at 2º-8º C (36º-46º F) following reconstitution with Sterile Water for Injection, USP. Unopened vials of lyophilized material are to be stored at temperatures up to 25° C (77° F) Powder Discard partially used vials.
Do not freeze.
05 31 12


MICROBIOLOGY
Mechanism of Action
Amphotericin B, the active ingredient of AmBisome, acts by binding to the sterol component of a cell membrane leading to alterations in cell permeability and cell death. While amphotericin B has a higher affinity for the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell leading to cytotoxicity. AmBisome, the liposomal preparation of amphotericin B, has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.

Activity In Vitro and In Vivo
AmBisome has shown in vitro activity comparable to amphotericin B against the following organisms: Aspergillus species (A. fumigatus, A. flavus), Candida species (C. albicans, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis), Cryptococcus neoformans, and Blastomyces dermatitidis. However, standardized techniques for susceptibility testing of antifungal agents have not been established and results of such studies do not necessarily correlate with clinical outcome.

AmBisome is active in animal models against Aspergillus fumigatus , Candida albicans, Candida krusei, Candida lusitaniae, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Leishmania donovani, and Leishmania infantum. The administration of AmBisome in these animal models demonstrated prolonged survival of infected animals, reduction of microorganisms from target organs, or a decrease in lung weight.

Clinical Pharmacology
Pharmacokinetics
The assay used to measure amphotericin B in the serum after administration of AmBisome does not distinguish amphotericin B that is complexed with the phospholipids of AmBisome from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of AmBisome is based upon total serum concentrations of amphotericin B. The pharmacokinetic profile of amphotericin B was determined in febrile neutropenic cancer and bone marrow transplant patients who received 1-2 hour infusions of 1 to 5 mg/kg/day AmBisome for 3 to 20 days.

Distribution
Based on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of AmBisome, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of AmBisome, the mean half-life was 100-153 hours. The long terminal elimination half-life is probably a slow redistribution from tissues. Steady state concentrations were generally achieved within 4 days of dosing.

Although variable, mean trough concentrations of amphotericin B remained relatively constant with repeated administration of the same dose over the range of 1 to 5 mg/kg/day, indicating no significant drug accumulation in the serum.

Metabolism
The metabolic pathways of amphotericin B after administration of AmBisome are not known.

Excretion
The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of AmBisome has not been studied.

INDICATIONS AND USAGE
AmBisome is indicated for the following:
-Empirical therapy for presumed fungal infection in febrile, neutropenic patients.
-Treatment of Cryptococcal Meningitis in HIV infected patients.
-Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections (see above for the treatment of Cryptococcal Meningitis) refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate.
-Treatment of visceral leishmaniasis. In immunocompromised patients with visceral leishmaniasis treated with AmBisome, relapse rates were high following initial clearance of parasites.

CONTRAINDICATIONS
AmBisome is contraindicated in those patients who have demonstrated or have known hypersensitivity to amphotericin B deoxycholate or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk.

WARNINGS
Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including AmBisome. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of AmBisome.

DOSAGE AND ADMINISTRATION
AmBisome should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes.

An in-line membrane filter may be used for the intravenous infusion of AmBisome; provided THE MEAN PORE DIAMETER OF THE FILTER IS NOT LESS THAN 1.0 MICRON.

NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of AmBisome. If this is not feasible, AmBisome must be administered through a separate line.

Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased.

The recommended initial dose of AmBisome for each indication for adult and pediatric patients is as follows:
Indication Dose (mg/kg/day)
Empirical therapy 3
Systemic fungal infections:
Aspergillus
Candida 
Cryptococcus
3-5
Cryptococcal meningitis in HIV infected patients (see package insert for DESCRIPTION OF CLINICAL STUDIES) 6

Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events.

Doses recommended for visceral leishmaniasis are presented below:
Visceral Leishmaniasis Dose (mg/kg/day)
Immunocompetent patients 3 (days 1-5) and 3 on days 14, 21
Immunocompromised patients 4 (days 1-5) and  4 on days 10, 17, 24, 31, 38


For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, a repeat course of therapy may be useful.

For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information see package insert for DESCRIPTION OF CLINICAL STUDIES.

Directions for Reconstitution, Filtration and Dilution
Read This Entire Section Carefully Before Beginning Reconstitution

AmBisome must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of AmBisome containing 50 mg of amphotericin B are prepared as follows:

Reconstitution
1. Aseptically add 12 mL of Sterile Water for Injection, USP to each AmBisome vial to yield a preparation containing 4 mg amphotericin B/mL.

CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation of AmBisome.

2. Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the AmBisome. AmBisome forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed.


Filtration and Dilution
3. Calculate the amount of reconstituted (4 mg/mL) AmBisome to be further diluted.

4. Withdraw this amount of reconstituted AmBisome into a sterile syringe.

5. Attach the 5-micron filter, provided, to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection. (Use only one filter per vial of AmBisome.)

6. AmBisome must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL prior to administration. Lower concentrations (0.2 to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS.


STORAGE OF AMBISOME
Unopened vials of lyophilized material are to be stored at temperatures up to 25° C (77° F).

Storage of Reconstituted Product Concentrate
The reconstituted product concentrate may be stored for up to 24 hours at 2º-8º C (36º-46º F) following reconstitution with Sterile Water for Injection, USP. Do not freeze.


Storage of Diluted Product
Injection of AmBisome should commence within 6 hours of dilution with 5% Dextrose Injection.

As with all parenteral drug products, the reconstituted AmBisome should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in AmBisome or in the materials specified for reconstitution and dilution.


HOW SUPPLIED
AmBisome for Injection is available as single vial cartons (equivalent to 50mg amphotericin B) and in packs of ten individual vial cartons

(NDC 0469-3051-30).
Each carton contains one pre-packaged, disposable sterile 5 micron filter.
Rx only

Marketed by:
Astellas Pharma US, Inc.
Deerfield, IL 60015-2548

Manufactured by:
Gilead Sciences, Inc.
San Dimas, CA 91773
AmBisome is a registered trademark of Gilead Sciences, Inc.
Abelcet® is a registered trademark of The Liposome Company, Inc.
10062008AMB
Revised: 10/2008 Astellas Pharma US, Inc.

Reference(s)

Package Insert:  Astellas Pharma US, Inc. Deerfield, IL 60015-2548.  Revised: 10/2008

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