Amphotericin B is available as a lyophilized powder or cake in vials containing amphotericin B 50 mg with sodium desoxycholate 41 mg and sodium phosphates 20.2 mg.2626 Reconstitute each vial with 10 mL of sterile water for injection without bacteriostatic agents, directing the stream directly on to the lyophilized powder or cake and shake until a clear colloidal dispersion is obtained.2626 The resultant concentration is 5 mg/mL of amphotericin B.2626 Use only sterile water for injection without bacteriostatic agents for reconstitution because other diluents, such as sodium chloride 0.9% or solutions containing a bacteriostatic agent such as benzyl alcohol, may result in precipitation of the antibiotic.2626
For intravenous infusion, the reconstituted colloidal dispersion should be further diluted to a recommended final concentration of 0.1 mg/mL in dextrose 5% with a pH above 4.2.2626 Commercially available dextrose 5% solutions usually have a pH above 4.2; however, the pH of each container of dextrose infusion solution should be determined before use.2626 Dextrose solutions with a pH below 4.2 should be adjusted by adding 1 or 2 mL of a buffer solution prior to dilution of amphotericin B.2626 The manufacturer recommends a buffer solution composed of dibasic sodium phosphate anhydrous 1.59 g and monobasic sodium phosphate anhydrous 0.96 g in water for injection qs to 100 mL.2626 The buffer solution should be sterilized either by filtration or by autoclaving for 30 minutes at 15 psi (121°C) prior to being added to the dextrose infusion solution.2626
Although various lipid complex and liposomal products of amphotericin B exist, they are sufficiently different from conventional amphotericin B formulations that extrapolating information to or from the other forms would be inappropriate.
pH
The pH of amphotericin B (Squibb) 100 mg/L in dextrose 5% has been reported as 5.7.149
Osmolality
The osmolality of amphotericin B (Squibb) 0.1 mg/mL in dextrose 5% was determined to be 256 mOsm/kg.1375
Trade Name(s)
Fungizone
Amphotericin B is administered by slow intravenous infusion over approximately 2 to 6 hours at a recommended concentration of 0.1 mg/mL.2626 The drug has also been given intra-articularly, intrathecally, intrapleurally, and by irrigation.4
Diluted solutions for infusion should be protected from light during administration.2626
CAUTION: Care should be taken to ensure that the correct drug product, dose, and administration procedure are used and that no confusion with other products occurs.
Amphotericin B is a yellow to orange lyophilized cake or powder.2626 Intact vials should be stored in the original carton at 2 to 8°C and protected from light.2626 The manufacturer has indicated that a 5 to 10% potency loss occurs in 1 month at room temperature.1433
Following reconstitution, the colloidal dispersion may be stored protected from light for up to 24 hours at room temperature or up to 1 week refrigerated.2626 One report indicates that aqueous solutions may be stable for over a week at both 5 and 28°C.352
Diluted solutions for infusion should be used promptly after preparation and should be protected from light during administration.2626
Amphotericin B was reported to precipitate when added to some evacuated containers due to a small residual amount of fluid that may have acetic acid and sodium acetate buffer or sodium chloride 0.9% solution. Only evacuated containers with residual sterile water should be used for preparing amphotericin B admixtures.1232
In an effort to reduce toxicity, amphotericin B has been admixed in Intralipid instead of the more usual dextrose 5%.1809; 1810; 1811; 2178 However, amphotericin B 0.75 mg/kg/day administered using this approach in 250 mL of Intralipid 20% has been associated with acute pulmonary toxicities, including sudden onset of coughing, tachypnea, cyanosis, and deterioration of oxygen saturation following administration. The temporal relationship between the drug administration and respiratory symptoms suggested a causal relationship. Furthermore, no reduction in renal toxicity or other side effects was observed. It was concluded amphotericin B should not be administered in Intralipid.2177
At a concentration of 0.6 mg/mL in Intralipid 10 or 20%, amphotericin B precipitates immediately or almost immediately. The precipitate is not visible to the unaided eye because of the emulsion’s dense opacity. Particle size evaluation found thousands of particles larger than 10 µm per mL. In dextrose 5%, very few particles were larger than 10 µm. Centrifuging the Intralipid admixtures resulted in rapid visualization of the precipitate as a mass at the bottom of the test tubes.1808
However, amphotericin B precipitation is observed in lipid emulsion within 2 to 4 hours without centrifuging. In concentrations ranging from 90 mg to 2 g/L in Intralipid 20%, amphotericin B precipitate is easily seen as yellow particulate matter on the bottom of the lipid emulsion containers.1872; 1988 Damage to the emulsion integrity with creaming has also been reported.1987
In other reports, the appearance of problems was observed in as little as 15 minutes, and actual amphotericin B precipitate formed within 20 minutes of mixing. Analysis of the precipitate confirmed its identity as amphotericin B. The authors hypothesized that amphotericin B precipitates as a consequence of the excipient desoxycholic acid, which is an anion, attracting oppositely charged choline groups from the egg yolk components of the lipid emulsion. As a consequence, desoxycholic acid and phosphatidylcholine form a precipitate and insufficient surfactant remains to keep the amphotericin B dispersed.2204; 2205
pH Effects
The pH range for optimum clarity and stability is 6 to 7.148 At a pH of less than approximately 6, the colloidal dispersion may become turbid.40; 148 Colloidal particles tend to coagulate rapidly at a pH of less than 5.4
Light Effects
Although the manufacturer recommends light protection for aqueous solutions of amphotericin B,2626 several reports indicate that for short-term exposure of 8 to 24 hours, little difference in potency is observed between light-protected and light-exposed solutions.150; 335; 353 Longer exposure periods150 or higher intensity light exposure2414 may result in unacceptable potency losses, however.
Elastomeric Reservoir Pumps
Amphotericin B (Lyphomed) 0.25 mg/mL in dextrose 5% was evaluated for binding potential to natural rubber elastomeric reservoirs (Baxter). No binding was found after storage for 2 weeks at 35°C with gentle agitation.2014
Filtration
Various studies have assessed the effects of filtration on the amphotericin B colloidal dispersion with differing results. The use of a 0.22-µm membrane filter was reported to be unacceptable with colloidal solutions adjusted to pH 4.7, 5.6, and 6.5. The concentration of amphotericin B in the filtrate decreased substantially after several hours. A 0.45-µm filter was satisfactory for infusions with a pH of 6.5, but the results at pH 5.6 were inconclusive. At pH 5.6 and 6.5, 1- and 5-µm filters both proved satisfactory in that they did not reduce the concentration of amphotericin B. For the turbid mixtures resulting at pH 4.7, however, all filters sharply reduced the concentration.148 A report tended to support this finding for the 0.22-µm filter. At pH 5.7, fine particles of amphotericin B formed and were retained by the 0.22-µm filter.149 No appreciable reduction in concentration with a 0.45-µm filter was found; but with a 0.22-µm filter, after 1 hour the concentration of amphotericin B delivered was about 30% of the initial concentration.152 When amphotericin B 50 mg/500 mL in dextrose 5% was filtered through a 0.22-µm circular cellulose ester membrane (Swinnex) or a 0.22-µm cylindrical cellulose ester filter (Ivex-2), the flow rate decreased dramatically after passage of as little as 30 mL. Flow ceased altogether after 100 to 200 mL. The last sample filtered contained no drug. With a 0.45-µm circular cellulose ester membrane (Swinnex), no loss of activity was determined after filtration of 200 mL. However, the flow rate had decreased.598 On the other hand, no significant difference in the amount or concentration of amphotericin B in dextrose 5% with phosphate buffer was found after filtration with 0.22-, 0.45-, and 5-µm filters.151
For amphotericin B infusions, only filters with a pore size not less than 1 µm should be used for filtration.2626; 148 This would allow a margin for error that would compensate for possible variations in particle size.148 Also, limiting the use of filtration to situations where it is believed to be necessary has been recommended.598; 599
For a list of references cited in the text of this monograph, search the monograph titled References.