Amphotericin B, an amphoteric polyene macrolide, is an antifungal antibiotic.
Drug Interactions
Systematic drug interaction studies have not been performed to date using amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal. The fact that drug interactions reported with conventional IV amphotericin B could also occur with these lipid-based or liposomal formulations of the drug should be considered.
Nephrotoxic Drugs
Since nephrotoxic effects may be additive, the concurrent or sequential use of IV amphotericin B and other drugs with similar toxic potentials (e.g., aminoglycosides, capreomycin, colistin, cisplatin, cyclosporine, methoxyflurane, pentamidine, polymyxin B, vancomycin) should be avoided, if possible. Intensive monitoring of renal function is recommended if any amphotericin B formulation is used concomitantly with a nephrotoxic agent.
Cyclosporine
In a randomized, double-blind study that evaluated use of conventional IV amphotericin B and amphotericin B cholesteryl sulfate complex in febrile neutropenic patients with normal baseline serum creatinine concentrations, the incidence of renal toxicity (defined as a doubling or an increase of 1 mg/dL or more from baseline serum creatinine or a 50% or greater decrease from baseline in calculated creatinine clearance) was 31% in adults and pediatric patients who received amphotericin B cholesteryl sulfate complex concomitantly with cyclosporine or tacrolimus compared with 68% in those who received conventional amphotericin B concomitantly with these agents. In adults and pediatric patients who did not receive cyclosporine or tacrolimus therapy, the incidence of renal toxicity was 8% in those who received amphotericin B cholesteryl sulfate complex and 35% in those who received conventional amphotericin B.
In a renal transplant recipient who was receiving cyclosporine and had stable whole blood cyclosporine concentrations, blood cyclosporine concentrations in the days after initiation of amphotericin B lipid complex therapy were more than twice those reported prior to initiation of antifungal therapy; however, this increase was transient and did not necessitate adjustment of cyclosporine dosage.
Pentamidine
Acute, reversible renal failure occurred in at least 4 patients with human immunodeficiency virus (HIV) infection who received IV amphotericin B concomitantly with IV or IM pentamidine; there was no evidence of adverse renal effects in patients who received IV amphotericin B concomitantly with pentamidine administered by oral inhalation.
Drugs Affected by Potassium Depletion
Because conventional IV amphotericin B may induce hypokalemia, the drug may predispose patients receiving cardiac glycosides to glycoside-induced cardiotoxicity and may enhance the effects of skeletal muscle relaxants (e.g., tubocurarine). Serum potassium concentrations should be monitored closely in patients receiving any amphotericin B formulation concomitantly with a cardiac glycoside or skeletal muscle relaxant.
Anti-infective Agents
Flucytosine
In some in vitro studies, the combination of flucytosine and amphotericin B resulted in synergistic inhibition of strains of Cryptococcus neoformans, Candida albicans, and C. tropicalis. The suggested mechanism of the synergism is that the binding of amphotericin B to sterols in cell membranes increases the permeability of the cytoplasmic membrane, thus allowing greater penetration of flucytosine into the fungal cell.
However, in a study evaluating the antifungal effects of the drugs in the presence of serum, the combination of amphotericin B and flucytosine was not additive or synergistic against C. albicans.
There is some evidence that concomitant use of conventional IV amphotericin B and flucytosine may increase the toxicity of flucytosine, possibly by increasing cellular uptake and/or by decreasing renal excretion of the drug. If flucytosine is used in conjunction with amphotericin B, especially in HIV-infected patients, serum flucytosine concentrations and blood cell counts should be monitored carefully. In addition, it has been suggested that flucytosine be initiated at a low dosage (i.e., 75-100 mg/kg daily) and subsequent dosage adjusted based on serum flucytosine concentrations.
Imidazole and Triazole Antifungal Agents
Although the clinical importance is unclear, results of in vitro studies evaluating the antifungal effects of amphotericin B used concomitantly with imidazole- or triazole-derivative antifungal agents (e.g., clotrimazole, fluconazole, itraconazole, ketoconazole) against C. albicans, C. pseudotropicalis, C. glabrata, or Aspergillus fumigatus indicate that antagonism can occur with these combinations.
Since amphotericin B exerts its antifungal activity by binding to sterols in the fungal cell membrane and imidazoles and triazoles act by altering the cell membrane, antagonism is theoretically possible; however, it is unclear whether such antagonism actually would occur in vivo.
Results of studies evaluating combined use of amphotericin B and fluconazole, ketoconazole, or itraconazole in animal models of aspergillosis, candidiasis, or cryptococcosis have been conflicting. While antagonism occurred in some models (A. fumigatus infection in mice, rabbits, or rats treated with amphotericin B and fluconazole or itraconazole), these combinations resulted in additive or indifferent effects in other models (e.g., C. albicans or C. neoformans infection in mice or rabbits treated with amphotericin B and fluconazole).
In a few studies evaluating the drugs in murine cryptococcosis or candidiasis, sequential use of an initial large dose of amphotericin B followed by an azole antifungal agent (e.g., fluconazole) was uniformly effective in prolonging survival and decreasing fungal burden.
Because further study is needed regarding the interaction between amphotericin B and imidazole- or triazole-derivative antifungal agents (e.g., fluconazole, itraconazole, or ketoconazole), such combination therapy should be used with caution, particularly in immunocompromised patients.
Results of an in vitro study indicate that the combination of amphotericin B and fluconazole or itraconazole may be synergistic, additive, or indifferent against Pseudallescheria boydii; there was no evidence of antagonism.
Quinolones
Norfloxacin may enhance the antifungal activity of antifungal agents (e.g., amphotericin B, flucytosine, ketoconazole, nystatin). There are conflicting reports on this interaction, however, and in at least one in vitro study norfloxacin had no effect on the antifungal activity of amphotericin B. Further study is needed to evaluate the antifungal effect when norfloxacin is used in conjunction with an antifungal agent.
Rifabutin
Results of an in vitro study indicate that the combination of rifabutin and amphotericin B may be additive or synergistic against Aspergillus fumigatus, A. flavus, Fusarium solani, F. moniliforme, F. pallidoroseum (formerly F. semitectum), and F. proliferatum; there was no evidence of antagonism with this combination. While rifabutin has no in vitro antifungal activity against Aspergillus or Fusarium when used alone, an antifungal effect was evident when the drug was used in combination with amphotericin B.
Zidovudine
Results of a study in dogs indicate that concomitant administration of zidovudine and conventional amphotericin B (at 0.5 times the recommended human dosage) or amphotericin B lipid complex (at 0.16 or 0.5 times the recommended human dosage) for 30 days was associated with increased myelotoxicity and nephrotoxicity. Although the clinical importance of this animal study is unclear, renal and hematologic function should be closely monitored in patients receiving zidovudine concomitantly with amphotericin B.
Antineoplastic Agents
The manufacturers state that antineoplastic agents (e.g., mechlorethamine) may enhance the potential for renal toxicity, bronchospasm, and hypotension in patients receiving amphotericin B and such concomitant therapy should be used only with great caution.
Corticosteroids
Corticosteroids reportedly may enhance the potassium depletion caused by conventional amphotericin B and should not be used concomitantly unless necessary to control adverse reactions to amphotericin B. If corticosteroids are used concomitantly with any amphotericin B formulation, serum electrolytes and cardiac function should be monitored closely.
Leukocyte Transfusions
IV infusion of conventional amphotericin B during or shortly after leukocyte transfusions has rarely been associated with acute pulmonary reactions characterized by acute dyspnea, tachypnea, hypoxemia, hemoptysis, and diffuse interstitial infiltrates.
The most severe pulmonary reactions have been reported when amphotericin B was administered within the first 4 hours after a leukocyte transfusion; respiratory deterioration appeared to contribute to death in at least 5 patients with such reactions. It has been recommended that amphotericin B be used with caution in patients receiving leukocyte transfusions, especially in those with gram-negative septicemia.
The manufacturer of conventional amphotericin B recommends that doses of the drug be separated in time as much as possible from leukocyte transfusions and that pulmonary function be monitored in patients receiving both therapies.
Acute Toxcicity
Manifestations
Acute overdosage of conventional amphotericin B may result in cardiorespiratory arrest. Adverse cardiovascular effects, including hypotension, bradycardia, and cardiac arrest, have been reported in several pediatric patients who inadvertently received overdosage of conventional amphotericin B. One child who received conventional amphotericin B in a dosage of 4.6 mg/kg given by IV infusion over 2 hours experienced vomiting, followed by seizures, and cardiac arrest immediately after the infusion. Information on acute toxicity of amphotericin B liposomal is not available. There was no reported dose-related toxicity following repeated daily doses up to 15 mg/kg in adult patients or up to 10 mg/kg in pediatric patients.
Treatment
In the event of overdosage with any amphotericin B formulation, therapy with the drug should be discontinued and the patient’s clinical status (e.g., cardiorespiratory, renal, and liver function, hematologic status, serum electrolytes) monitored. Supportive therapy should be administered as required. Amphotericin B is not removed by hemodialysis. The patient’s condition should be stabilized, including correction of electrolyte abnormalities, prior to reinstituting amphotericin B therapy.
Mechanism of Action
Amphotericin B usually is fungistatic in action at concentrations obtained clinically, but may be fungicidal in high concentrations or against very susceptible organisms. Amphotericin B exerts its antifungal activity principally by binding to sterols (e.g., ergosterol) in the fungal cell membrane.
As a result of this binding, the cell membrane is no longer able to function as a selective barrier and leakage of intracellular contents occurs. Cell death occurs in part as a result of permeability changes, but other mechanisms also may contribute to the in vivo antifungal effects of amphotericin B against some fungi.
Amphotericin B is not active in vitro against organisms that do not contain sterols in their cell membranes (e.g., bacteria). Binding to sterols in mammalian cells (such as certain kidney cells and erythrocytes) may account for some of the toxicities reported with conventional amphotericin B therapy. At usual therapeutic concentrations of amphotericin B, the drug does not appear to hemolyze mature erythrocytes, and the anemia seen with conventional IV amphotericin B therapy may result from the action of the drug on actively metabolizing and dividing erythropoietic cells.
Spectrum
Amphotericin B is active against most pathogenic fungi, including yeasts, and also is active against some protozoa. Amphotericin B is inactive against bacteria, rickettsiae, or most viruses.
In Vitro Susceptibility Testing
Optimal methods for antifungal agent in vitro susceptibility testing have been difficult to identify and are still being investigated. Until further data becomes available regarding the reliability and predictability of antifungal in vitro susceptibility testing, routine in vitro susceptibility testing with amphotericin B is not recommended.
The National Committee for Clinical Laboratory Standards (NCCLS) has recommended standardized procedures for reference broth dilution antifungal susceptibility testing that can be used to test in vitro susceptibility of yeasts (e.g., Candida, Cryptococcus neoformans); however, additional study is needed before these procedures can be adapted for routine testing of clinical isolates of yeast or for testing the in vitro susceptibility of the yeast forms of dimorphic fungi (e.g., Blastomyces dermatitidis, Histoplasma capsulatum, Sporothrix schenckii) or filamentous fungi (e.g., Aspergillus, Pseudallescheria boydii, Rhizopus).
In contrast to results obtained with azole antifungal agents (imidazole or triazole derivatives) or flucytosine, endpoints obtained for amphotericin B using the standardized reference NCCLS broth dilution procedures typically are easily defined and MICs are reported as the lowest drug concentration that prevents any discernible growth. Since trailing endpoints rarely occur, such a pattern may reflect clinically relevant drug resistance.
Criteria regarding specific minimum inhibitory concentrations (MICs) that would indicate in vitro susceptibility or resistance to amphotericin B are still being established.
Experience to date indicates that, when the NCCLS reference broth dilution procedure is used to evaluate susceptibility of Candida to amphotericin B, MICs for most strains tested generally range from 0.25-1 mcg/mL and MICs for apparently resistant strains generally are greater than 1 mcg/mL. However, current methods do not consistently detect resistant isolates and modifications are being evaluated to permit more reliable detection of amphotericin B-resistant strains.
Fungi
In vitro, amphotericin B concentrations of 0.03-1.0 mcg/mL usually inhibit Aspergillus fumigatus, A. flavus, Coccidioides immitis, Cryptococcus neoformans, Exophiala castellanii, E. spinifera, Histoplasma capsulatum, Mucor, Paracoccidioides brasiliensis, Rhodotorula spp., and Sporothrix schenckii. Blastomyces dermatitidis may require slightly higher drug concentrations for inhibition. Clinical isolates of Apophysomyces elegans have been susceptible in vitro to amphotericin B concentrations of 0.125 mcg/mL.While some strains of Scopulariopsis, including some strains of S. acremonium and S. brevicaulis, are inhibited in vitro by amphotericin B concentrations of 1-4 mcg/mL, other strains are resistant to the drug. Amphotericin B is active in vitro against most strains of Candida. In vitro, C. albicans, C. dubliniensis, C. glabrata (formerly Torulopsis glabrata), C. krusei, C. parapsilosis, and C. tropicalis usually are inhibited by amphotericin B concentrations of 0.03-1 mcg/mL. When the NCCLS standardized procedure was used to test in vitro susceptibility of clinical isolates of C. dubliniensis obtained from patients with or without human immunodeficiency virus (HIV) infection, these strains were inhibited by amphotericin B concentrations of 0.03-0. mcg/mL.
While some strains of C. lusitaniae are inhibited in vitro by amphotericin B concentrations of 0.06-0.5 mcg/mL, other strains appear to be resistant to the drug. Only limited data are available comparing the in vitro antifungal activity of conventional amphotericin B with that of the lipid-based formulations of the drug. In one in vitro study, MICs of conventional amphotericin B or amphotericin B cholesteryl sulfate complex reported for B. dermatitidis, C. immitis, H. capsulatum, P. brasiliensis, C. albicans, C. tropicalis, C. parapsilosis, and C. neoformans were similar and ranged from 0.125-2 mcg/mL.
However, higher concentrations of amphotericin B cholesteryl sulfate complex were required for in vitro inhibition of C. glabrata and Aspergillus. While C. glabrata or A. fumigatus were inhibited in vitro by conventional amphotericin B concentrations of 1-2 mcg/mL, these strains required amphotericin B cholesteryl sulfate complex concentrations of 4-8 mcg/mL for in vitro inhibition; A. flavus was inhibited in vitro by conventional amphotericin B concentrations of 4 mcg/mL but required amphotericin B cholesteryl sulfate complex concentrations of 4 to greater than 16 mcg/mL for in vitro inhibition. In a study that evaluated the in vitro susceptibility of C. albicans, C. parapsilosis, C. tropicalis, and C. glabrata to several different amphotericin B formulations, MICs reported for conventional amphotericin B, amphotericin B lipid complex, or amphotericin B liposomal were 0.1-0.78, 0.2-0.78, or 0.2-6.25 mcg/mL, respectively.
When C. krusei was tested, the MICs of conventional amphotericin B or amphotericin B lipid complex were 0.78-1. or 3.13-6. mcg/mL, respectively; however, MICs of amphotericin B liposomal reported for this organism were greater than 50 mcg/mL. MICs of amphotericin B cholesteryl sulfate complex reported for most Aspergillus and Candida tested to date generally have been less than 1 mcg/mL. While some strains of Pseudallescheria boydii are inhibited in vitro by amphotericin B concentrations of 0.5 mcg/mL or less, most strains are resistant to the drug. Amphotericin B concentrations of 1-16 mcg/mL were necessary for in vitro inhibition of clinical isolates of Scedosporium apiospermum or S. prolificans, and these filamentous fungi probably are resistant to the drug. Fusarium generally are resistant to amphotericin B. Several clinical isolates of Basidiobolus ranarum had amphotericin B MICs of 2-4 mcg/mL when the NCCLS reference broth dilution procedure was used; however, other isolates were resistant to the drug.
Protozoa
Amphotericin B is active in vitro and in vivo against Leishmania braziliensis. The drug also is active in vitro and in vivo against L. mexicana and L. donovani, including antimony-resistant strains of the organisms.n vitro, amphotericin B concentrations of 1 mcg/mL result in complete elimination of L. donovani amastigotes in human monocyte-derived macrophages and L. donovani promastigotes in cell-free media.
The drug also is active in vitro against L. tropica. Amphotericin B is active in vitro and apparently in vivo against Naegleria spp., particularly N. fowleri. The drug has variable and limited activity in vitro against Acanthamoeba castellanii and A. polyphaga. Resistance Resistance to amphotericin B has been produced in vitro by serial passage of fungi in the presence of increasing concentrations of the drug, and resistant strains of some fungi (e.g., Candida) have been isolated from patients who received long-term therapy with conventional amphotericin B.
Amphotericin B-resistant Candida are reported relatively infrequently; however, primary resistance to the drug occurs in some strains of C. lusitaniae and also occurs inC. guilliermondii. While the clinical importance is unclear, fluconazole-resistant strains of C. albicans that were cross-resistant to amphotericin B have been isolated from a few immunocompromised individuals, including leukemia patients and patients with human immunodeficiency virus (HIV) infection. In addition, a few isolates of Cryptococcus neoformans resistant to fluconazole also have been resistant to amphotericin B. Fungi resistant to conventional amphotericin B also may be resistant to amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal.
Pharmacokinetics
The pharmacokinetics of amphotericin B vary substantially depending on whether the drug is administered as conventional amphotericin B (formulated with sodium desoxycholate), amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal, and pharmacokinetic parameters reported for one amphotericin B formulation should not be used to predict the pharmacokinetics of any other amphotericin B formulation. In general, usual dosages of amphotericin B cholesteryl sulfate complex or amphotericin B lipid complex result in lower serum concentrations of amphotericin B and greater volumes of distribution than those reported for the conventional formulation of the drug.
Plasma drug concentrations attained after administration of amphotericin B liposomal generally are higher and the volume of distribution is lower than those reported for similar doses of conventional amphotericin B.
The clinical importance of differences in pharmacokinetics of the various amphotericin B formulations has not been elucidated, and interpretation of serum or tissue concentrations of amphotericin B reported in published studies is complicated by the fact that many assays used to measure the drug do not differentiate between free amphotericin B and amphotericin B that is lipid-complexed, liposome-encapsulated, or protein-bound.
It has been suggested that differences in the distribution and clearance of amphotericin B following administration of lipid-complexed or liposomal-encapsulated formulations relative to those reported following administration of conventional amphotericin B (i.e., increased uptake by the liver and spleen and decreased kidney concentrations) are one of several factors that may contribute to the improved toxicity profiles reported for these formulations; however, how these pharmacokinetic differences affect the therapeutic efficacy of the various formulations is unclear.
The manufacturers’ literature and specialized references should be consulted for information regarding the absorption, distribution, or elimination of amphotericin B administered as amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal.
Absorption
Amphotericin B is poorly absorbed from the GI tract and must be given parenterally to treat systemic fungal infections. In one study, immediately after completion of IV infusion of 30 mg of amphotericin B (administered as conventional amphotericin B over a period of several hours), average peak serum concentrations were about 1 mcg/mL; when the dose was 50 mg, average peak serum concentrations were approximately 2 mcg/mL. Immediately after infusion, no more than 10% of the amphotericin B dose can be accounted for in serum. Average minimum serum concentrations (recorded just prior to the next drug infusion) of approximately 0.4 mcg/mL have been reported when 30-mg doses of conventional amphotericin B were given once daily or 60-mg doses were given every other day.
Distribution
Information on the distribution of amphotericin B is limited, although distribution is apparently multicompartmental.
The volume of distribution of the drug following administration of conventional amphotericin B has been reported to be 4 L/kg; the volume of distribution at steady state after administration of amphotericin B cholesteryl sulfate is reported to be 3.8-4.1 L/kg. Amphotericin B concentrations attained in inflamed pleura, peritoneum, synovium, and aqueous humor following IV administration of conventional amphotericin B reportedly are about 60% of concurrent plasma concentrations; the drug also is distributed into vitreous humor, pleural, pericardial, peritoneal, and synovial fluid. Amphotericin B reportedly crosses the placenta and low concentrations are attained in amniotic fluid.
Following IV administration of conventional amphotericin B, CSF concentrations of the drug are approximately 3% of concurrent serum concentrations. To achieve fungistatic CSF concentrations, the drug must usually be administered intrathecally. In patients with meningitis, intrathecal administration of 0.2-0.3 mg of conventional amphotericin B via a subcutaneous reservoir has produced peak CSF concentrations of 0.5-0.8 mcg/mL; 24 hours after the dose, CSF concentrations were 0.11-0.29 mcg/mL. Amphotericin B is removed from the CSF by arachnoid villi and appears to be stored in the extracellular compartment of the brain, which may act as a reservoir for the drug. Amphotericin B is more than 90% bound to plasma proteins, mainly lipoproteins.
Elimination
The metabolic fate of amphotericin B in humans has not been fully elucidated. Following IV administration of conventional amphotericin B in patients whose renal function is normal prior to therapy, the initial plasma half-life is approximately 24 hours. After the first 24 hours, the rate at which amphotericin B is eliminated decreases and an elimination half-life of approximately 15 days has been reported.
Conventional amphotericin B is eliminated very slowly (over weeks to months) by the kidneys; slow release of the drug from the peripheral compartment may account for the long elimination half-life.
Over a 7-day period, the cumulative urinary excretion of a single dose of conventional amphotericin B is about 40% of the administered drug. It has been estimated that only about 3% of a total dose of amphotericin B is excreted in urine unchanged.
When conventional IV amphotericin B therapy is discontinued, the drug can be detected in blood for up to 4 weeks and in urine for up to 4-8 weeks. Amphotericin B is not hemodialyzable. Amphotericin B cholesteryl sulfate complex has a distribution half-life of 3.5 minutes and an elimination half-life of 27.5-28.2 hours.
Chemistry and Stability
Chemistry
Amphotericin B is an antifungal antibiotic produced by Streptomyces nodosus. The drug is an amphoteric polyene macrolide which occurs as a yellow to orange, odorless or practically odorless powder and is insoluble in water and in anhydrous alcohol. Each mg of amphotericin B contains not less than 750 mcg of anhydrous drug, and amphotericin A (a contaminant of amphotericin B) may be present in a concentration of not more than 5%.
Because amphotericin B is amphoteric, it can form salts in acidic or basic media. Although the salts are more water soluble, they have less antifungal activity. A variety of amphotericin B preparations are commercially available for parenteral administration. Amphotericin B formulated with sodium desoxycholate (conventional amphotericin B) was the first parenteral amphotericin B preparation to become commercially available.
Because conventional amphotericin B is associated with certain dose-limiting toxicities (principally nephrotoxicity), various other formulations have been investigated with the goal of increasing the tolerability of amphotericin B without compromising the antifungal effects of the drug. As a result, amphotericin B now also is commercially available as amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal. These formulations contain novel lipid-based drug delivery systems that may affect the pharmacokinetics and functional properties of amphotericin B and improve the toxicity profile of the drug.
Conventional Amphotericin B
Conventional amphotericin B for injection contains amphotericin B and sodium desoxycholate. Amphotericin B is insoluble in water; presence of sodium desoxycholate in the formulation solubilizes amphotericin B during reconstitution with sterile water providing a colloidal dispersion of the drug. Commercially available conventional amphotericin B occurs as a sterile, yellow to orange lyophilized cake which may partially reduce to powder following manufacture.
Each vial labeled as containing 50 mg of amphotericin B contains 41 mg of sodium desoxycholate and is buffered with 20. mg of sodium phosphates; at the time of manufacture, air in the vial is replaced with nitrogen. Extemporaneous lipid emulsions of conventional IV amphotericin B have been prepared by diluting the drug in 20% fat emulsion (Intralipid®) in an attempt to provide a vehicle for amphotericin B that would decrease the nephrotoxicity of the drug; however, because of limited information on the safety and efficacy of these admixtures, lack of standardization, and the commercial availability of lipid-based and liposomal formulations of amphotericin B, these extemporaneous lipid emulsions are not recommended.
Amphotericin B Cholesteryl Sulfate Complex
Amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion; ABCD; Amphotec®) consists of a 1:1 molar ratio of amphotericin B to cholesteryl sulfate. Amphotericin B cholesteryl sulfate complex is commercially available as a lyophilized powder and each vial labeled as containing 50 mg of amphotericin B contains 26. mg of sodium cholesteryl sulfate, 5.64 mg of tromethamine, 0.372 mg of disodium edetate dihydrate, and 950 mg of lactose monohydrate; hydrochloric acid is added to adjust pH. Following reconstitution with sterile water for injection, amphotericin B cholesteryl sulfate complex occurs as an opalescent or clear colloidal dispersion. The colloidal dispersion contains amphotericin B complexed to cholesteryl sulfate. These components form a bilayer in microscopic, disk-shaped particles which have a diameter of about 115 nm and a thickness of 4 nm.
Amphotericin B Lipid Complex
Amphotericin B lipid complex (ABLC; Abelcet®) consists of a 1:1 molar ratio of amphotericin B complexed to a phospholipid vehicle composed of a 7:3 molar ratio of L-a-dimyristoylphosphatidylcholine (DMPC) to L-a-dimyristoylphosphatidylglycerol (DMPG). The amphotericin B-phospholipid complex has a microscopic, ribbon-like structure with a diameter of about 2-11 µm. Each mL of commercially available amphotericin B lipid complex suspension contains 5 mg of amphotericin B, 3.4 mg of DMPC, 1.5 mg of DMPG, and 9 mg of sodium chloride. The suspension occurs as a yellow, opaque liquid with a pH of 5-7.
Amphotericin B Liposomal
Commercially available amphotericin B liposomal (L-AmB; AmBisome®) is a lyophilized powder containing amphotericin B intercalated into a unilamellar bilayer liposomal membrane. Liposomes are microscopic vesicles composed of a phospholipid bilayer capable of encapsulating drugs; the lipid bilayer separates the internal aqueous core from the external environment. The liposomal membranes used in commercially available amphotericin B liposomal have a diameter of less than 100 nm and consist of hydrogenated soy phosphatidylcholine (HSPC), cholesterol, distearoylphosphatidylglycerol, and alpha tocopherol.
Commercially available amphotericin B liposomal also contains sucrose for isotonicity and disodium succinate hexahydrate as a buffer.
Because of the amphophilic substances used in the membrane and the lipophilic nature of amphotericin B, the drug is an integral part of the overall structure of the liposomes. Reconstitution of commercially available amphotericin B liposomal with sterile water for injection results in a yellow, translucent suspension with a pH of 5-6.
Stability
Conventional Amphotericin B
Conventional amphotericin B powder for injection should be stored at 2-8°C. Reconstituted colloidal dispersions of conventional amphotericin B should be protected from light and are stable for 24 hours at room temperature or 1 week when refrigerated at 2-8°C. Although the manufacturers state that reconstituted dispersions or IV infusions of amphotericin B should be protected from light during administration, potency is unaffected if the infusion is exposed to light for less than 8-24 hours.
Reconstituted conventional amphotericin B must be diluted only with 5% dextrose in water having a pH greater than 4.2 since the colloidal particles of the drug tend to coagulate quickly at pH less than 5. Dilutions of amphotericin B apparently are compatible with limited amounts of heparin sodium and hydrocortisone sodium succinate or methylprednisolone sodium succinate. Specialized references should be consulted for specific compatibility information.
Amphotericin B Cholesteryl Sulfate Complex
Commercially available lyophilized amphotericin B cholesteryl sulfate complex should be stored at 15-30°C. Following reconstitution with sterile water for injection, the colloidal dispersion should be refrigerated at 2-8°C and used within 24 hours; reconstituted amphotericin B cholesteryl sulfate complex should not be frozen. Reconstituted amphotericin B cholesteryl sulfate complex that has been further diluted in 5% dextrose injection should be stored at 2-8°C and used within 24 hours; any partially used vials of the drug should be discarded.
Amphotericin B Lipid Complex
Commercially available amphotericin B lipid complex suspension for IV infusion should be refrigerated at 2-8°C and protected from light. Following dilution in 5% dextrose injection, amphotericin B lipid complex is stable for up to 48 hours at 2-8°C and for an additional 6 hours at room temperature. Amphotericin B lipid complex should not be frozen; any unused solutions of the drug should be discarded.
Amphotericin B Liposomal
Commercially available lyophilized amphotericin B liposomal should be refrigerated at 2-8°C. Following reconstitution with sterile water for injection, liposomal amphotericin B solutions containing 4 mg/mL may be stored for up to 24 hours at 2-8°C and should not be frozen. IV infusions of amphotericin B liposomal should be initiated within 6 hours after dilution in 5% dextrose injection. Any partially used vials of the drug should be discarded.
Preparations
Amphotericin B Parenteral For injection, for 50 mg Amphocin®, (with sodium IV infusion deoxycholate and sodium phosphates) Pfizer Amphotericin B for Injection, (with sodium deoxycholate and sodium phosphates) GensiaSicor Pharma-Tek Fungizone® Intravenous, (with sodium deoxycholate 41 mg and sodium phosphates 20.5 mg) Sandoz Amphotericin B Cholesteryl Sulfate Complex Parenteral For injection, for 50 mg (of amphotericin B) Amphotec®, (formulated as a IV infusion 1:1 molar ratio of amphotericin B complexed to cholesteryl sulfate) InterMune 100 mg (of amphotericin B) Amphotec®, (formulate as a 1:1 molar ratio or amphotericin B complexed to cholesteryl sulfate) InterMune Amphotericin B Lipid Complex Parenteral Injectable 5 mg (of amphotericin B) per Abelcet®, (formulated as a 1:1 suspension mL (100 mg) molar ratio of amphotericin B concentrate, for to lipid complex; lipid IV infusion complex composed of L-a-dimyristoylphosphatidylcholine [DMPC] 3.4 mg and L-a- dimyristoylphosphatidylglycero-l [DMPG] 1.5 mg; with 5-µm filter needle) Enzon Amphotericin B Liposomal Parenteral For injection, for 50 mg (of amphotericin B) AmBisome®, (formulated in IV infusion liposomes composed of hydrogenated soy, phosphatidylcholine [HSPC] 213 mg, cholesterol 52 mg, distearoylphosphatidylglycerol 84 mg, and a tocopherol 0.64 mg; with 5-µm filter) Fujisawa (also promoted by Gilead Sciences)