Amphotericin B

AMPHOTERICIN-B

Usual Diluents

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

Central line: 0.25 mg/ml (higher
concentrations possible)

Stability / Miscellaneous

Storage / Stability:
Prior to reconstitution FUNGIZONE Intravenous should be stored in the refrigerator, protected against exposure to light. The concentrate (5 mg amphotericin B per mL after reconstitution with 10 mL Sterile Water for Injection, USP) may be stored in the dark, at room temperature for 24 hours, or at refrigerator temperatures for 1 week with minimal loss of potency and clarity. Any unused material should then be discarded. Solutions prepared for intravenous infusion (0.1 mg or less amphotericin B per mL) should be used promptly after preparation and should be protected from light during administration.

Reconstitute only with sterile water without preservatives, not bacteriostatic water. Benzyl alcohol, sodium chloride, or other electrolyte solutions may cause precipitation.
Label: REFRIGERATE.

ALT:
Short-term exposure (<24 hours) to light during I.V. infusion does not appreciably affect potency

Reconstituted solutions with sterile water for injection and kept in the dark remain stable for 24 hours at room temperature and 1 week when refrigerated

Stability of parenteral admixture at room temperature (25°C): 24 hours; at refrigeration (4°C): 2 days

Test dose: 1 mg/20 ml D5W over 10-30 min. Monitor Temp, pulse, RR and BP q30min x 4 hours.

Dosing: initially 0.25 to 0.3 mg/kg (possibly up to 0.5 mg/kg for life threatening infections). Increase as tolerated on the following days to 0.5 to 1.0 mg/kg/day or 1.5 mg/kg qod. If central line is used, may increase concentration up to 0.25 mg/ml.

Bladder irrigation: add 10-50mg to 1000ml sterile water. Instill 200-300ml into bladder then clamp off for 60-90min, then allow bladder to drain-then repeat. Continue treatment for 2-5 days.

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DOSAGE AND ADMINISTRATION
**VERIFY PRODUCT NAME AND DOSAGE.**

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

FUNGIZONE Intravenous (Amphotericin B for Injection) should be administered by slow intravenous infusion. Intravenous infusion should be given over a period of approximately 2 to 6 hours (depending on the dose) observing the usual precautions for intravenous therapy (see package insert: PRECAUTIONS: General). The recommended concentration for intravenous infusion is 0.1 mg/mL (1 mg/10 mL).

Since patient tolerance varies greatly, the dosage of amphotericin B must be individualized and adjusted according to the patient’s clinical status (e.g., site and severity of infection, etiologic agent, cardio-renal function, etc.).

A single intravenous test dose (1 mg in 20 mL of 5% dextrose solution) administered over 20 to 30 minutes may be preferred. The patient’s temperature, pulse, respiration, and blood pressure should be recorded every 30 minutes for 2 to 4 hours.

In patients with good cardio-renal function and a well tolerated test dose, therapy is usually initiated with a daily dose of 0.25 mg/kg of body weight. However, in those patients having severe and rapidly progressive fungal infection, therapy may be initiated with a daily dose of 0.3 mg/kg of body weight. In patients with impaired cardio-renal function or a severe reaction to the test dose, therapy should be initiated with smaller daily doses (i.e., 5 to 10 mg).

Depending on the patient’s cardio-renal status (see package insert PRECAUTIONS: Laboratory Tests), doses may gradually be increased by 5 to 10 mg per day to final daily dosage of 0.5 to 0.7 mg/kg.

There are insufficient data presently available to define total dosage requirements and duration of treatment necessary for eradication of specific mycoses. The optimal dose is unknown. Total daily dosage may range up to 1.0 mg/kg per day or up to 1.5 mg/kg when given on alternate days.

Sporotrichosis: Therapy with intravenous amphotericin B for sporotrichosis has ranged up to 9 months with a total dose up to 2.5 g.

Aspergillosis: Aspergillosis has been treated with amphotericin B intravenously for a period up to 11 months with a total dose up to 3.6 g.

Rhinocerebral phycomycosis: This fulminating disease generally occurs in association with diabetic ketoacidosis. It is, therefore, imperative that diabetic control be restored in order for treatment with FUNGIZONE Intravenous to be successful. In contradistinction, pulmonary phycomycosis, which is more common in association with hematologic malignancies, is often an incidental finding at autopsy. A cumulative dose of at least 3 g of amphotericin B is recommended to treat rhinocerebral phycomycosis. Although a total dose of 3 to 4 g will infrequently cause lasting renal impairment, this would seem a reasonable minimum where there is clinical evidence of invasion of deep tissue. Since rhinocerebral phycomycosis usually follows a rapidly fatal course, the therapeutic approach must necessarily be more aggressive than that used in more indolent mycoses.

Preparation of Solutions
Reconstitute as follows: An initial concentrate of 5 mg amphotericin B per mL is first prepared by rapidly expressing 10 mL Sterile Water for Injection, USP without a bacteriostatic agent directly into the lyophilized cake, using a sterile needle (minimum diameter: 20 gauge) and syringe. Shake the vial immediately until the colloidal solution is clear. The infusion solution, providing 0.1 mg amphotericin B per mL, is then obtained by further dilution (1:50) with 5% Dextrose Injection, USP of pH above 4.2. The pH of each container of Dextrose Injection should be ascertained before use. Commercial Dextrose Injection usually has a pH above 4.2; however, if it is below 4.2, then 1 or 2 mL of buffer should be added to the Dextrose Injection before it is used to dilute the concentrated solution of amphotericin B. The recommended buffer has the following composition:

Dibasic sodium phosphate (anhydrous) 1.59 g
Monobasic sodium phosphate (anhydrous) 0.96 g
Water for Injection, USP qs 100.0 mL

The buffer should be sterilized before it is added to the Dextrose Injection, either by filtration through a bacterial retentive stone, mat, or membrane, or by autoclaving for 30 minutes at 15 lb pressure (121° C).

CAUTION: Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in the antibiotic or in the materials used to prepare it for administration. All entries into the vial or into the diluents must be made with a sterile needle. Do not reconstitute with saline solutions. The use of any diluent other than the ones recommended or the presence of a bacteriostatic agent (e.g., benzyl alcohol) in the diluent may cause precipitation of the antibiotic. Do not use the initial concentrate or the infusion solution if there is any evidence of precipitation or foreign matter in either one.

An in-line membrane filter may be used for intravenous infusion of amphotericin B; however, the mean pore diameter of the filter should not be less than 1.0 micron in order to assure passage of the antibiotic dispersion.

HOW SUPPLIED
FUNGIZONE Intravenous (Amphotericin B for Injection, USP)

Available as single vials providing 50 mg amphotericin B as a yellow to orange lyophilized cake (which may partially reduce to powder following manufacture). NDC 0003-0437-30.

Source:
APOTHECON®
Manufactured by: Ben Venue Laboratories, Inc.
Bedford, OH 44146 USA

Manufactured for: Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

Distributed by: Geneva Pharmaceuticals, Inc.
Dayton, NJ 08810 USA
Rev January 2008