Amphotericin stability

Hoeprich and Huston [117] assessed the stability of miconazole and three other antifungal agents under conditions encountered in bioassay and susceptibility testing in vitro. Although the amphotericins were labile as compared with other drugs, tests should be reliable with all four drugs in view of the rapid action of the polyenes and the relatively slow action of miconazole and 5-fluorocytosines. 

Patients may be initiated on amphotericin B and changed to oral itraconazole 200-400 mg orally daily once patient is clinically stabilized and a minimum dose of 500 mg of amphotericin B has been administered. 

Amphotericin B 0.7-1 Patients without CNS infection may be switched to itracon-mg/kg/day IV (total azole once clinically stabilized and a minimum dose of... 

The antimykotie amphotericine is eneapsulated in liposomes and marketed as Am-Bisome" against severe systemic mycosis. The liposomal encapsulation reduces the toxicity of amphotericine while increasing the half-life of the drug and plasma level peaks [31], For stability reasons, the parenteral formulation is a lyophilized powder whieh has to be reeonstituted by adding the solvent just before administration. 

Yu et al. (1998) were able to increase tha/itno antifungal efLciency of amphotericin B while at the same time decreasing its hemolytic activity by loading the drug into polymeric micelles. It was suggested that polymeric micelles could stabilize amphotericin B against autooxidation and/or enhance membrane perturbation of fungal cells. 

The defined range suitable for acceptable stability may approach the variability of the moisture determination method or may be as great as a few percent. For example, many lyophilized products with the USP have a finished product residual moisture specification of less than 2% of dry weight. Other products, such as amphotericin B, have a residual moisture limit of 8.0% [31]. Whether the allowable residual moisture specification is small or large, a range of acceptable residual moisture needs to be identified and correlated to suitable long-term stability. 

Renal damage is the most significant toxic reaction. Renal impairment occurs in nearly all patients treated with clinically significant doses of amphotericin. The degree of azotemia is variable and often stabilizes during therapy, but can be serious enough to necessitate dialysis. A reversible component is associated with decreased renal perfusion and represents a form of prerenal renal failure. An irreversible component results from renal tubular injury and subsequent dysfunction. 

Benzylpenicillin is incompatible with rubber products and metal ions. Stability is affected by alcohols, surfactants, oxidizing and reducing agents, macrogols and other hydroxy compounds, glycerol, glycols, some paraffins and ointment bases, preservatives such as chlorocresol or thiomersal, blood and blood products, and antibacterials such as amphotericin, cephalosporins, and vancomycin. Injections of benzylpenicillins and aminoglycosides should be administered separately. 

Stability of amphotericin in lipid emulsions was moderate,910 but some researchers have reported instability of amphotericin with lipid emulsion.1112 Vigorous mixing of amphotericin and a lipid emulsion mixture has a good effect on the stability of the formulation. 

Amsacrine Amsacrine is incompatible with sodium chloride mixtures and glucose-containing injections with acyclovir sodium, ganciclovir sodium, aztreonam, amphotericin, cimetidine hydrochloride, ceftazidime, frusemide, ceftriaxone sodium, heparin sodium, methylprednisolone sodium succinate, metoclopramide hydrochloride, and some antineoplastics.204 Asparaginase is incompatible with many drugs and rubber, and should be stored at 2° to 8 °C for stability. 

Other ophthalmic emulsions have been used to formulate prednisolone, piroxicam and amphotericin B emulsion. Although emulsions can produce sustained therapeutic effects and reduced irritancy of drag, their application in ophthalmology have been limited due to problems of stability. 

The photostability of some amphotericin B infusion solutions has also been demonstrated using high performance liquid chromatography (HPLC) assays. Kintzel et al. (16) studied the stability of amphotericin B solutions, packaged in polyolefin containers, at concentrations >0.1mg/mL, used for the administration via a central venous line. Amphotericin B infusion solutions (0.5,0.7, and 0.8mg/mL), without any protection from room irradiation, were found to be chemically stable when stored for up to 24 hours at 25°C. In addition, amphotericin B in 5% dextrose injection packaged in PVC containers at concentrations of 0.2, 0.5, and 1.0 mg/mL, was chemically stable when stored at 25°C for up to 120 hours, under 40 W fluorescent irradiation (17). 

Gallelli JF. Assay and stability of amphotericin B in aqueous solutions. Drug Intell 1967 1 103-105. 

Block ER, Bennett JE. Stability of amphotericin B in infusion bottles. Antimicrob Agents Chemother 1973 4 648-649. 

Lee MD, Hess MM, Boucher BA, Apple AM. Stability of amphotericin B in 5% dextrose injection stored at 4 or 25°C for 120 hours. Am J Hosp Pharm 1994 51 394-396. Kowaluk EA, Roberts MS, Polack AE. Interactions between drugs and intravenous delivery systems. Am J Hosp Pharm 1982 39 460 67. 

Amphotericin deoxycholate in glucose versus amphotericin in nutritional fat emulsion The safety of DAMB prepared in nutritional fat emulsion (a non-approved mode of amphotericin administration) has been reviewed (SEDA-21, 282) (SEDA-22, 285). It is not clear whether it has a better therapeutic index than other formulations, and methods of preparing it have not been standardized. The adverse effects of amphotericin prepared in nutritional fat emulsion have been compared with those of amphotericin prepared in 5% dextrose in two studies. While one of the studies showed a significantly lower frequency of infusion-related reactions and hypokalemia in patients receiving the fat emulsion (49), there were no differences in safety and tolerance between the two formulations in the other study (50). The safety of amphotericin prepared in nutritional fat emulsions has been reviewed (SEDA-21, 282) (SEDA-22, 285). Because of stability concerns and lack of systematic safety data, this form of amphotericin cannot be recommended. 

Miller CB, Waller EK, Klingemann HG, et al. Eipid formulations of amphotericin B preserve and stabilize renal function in EISCT... 

Other incompatibilities include the inactivation of certain types of insulin due to the chelation of zinc, and the chelation of trace metals in total parenteral nutrition (TPN) solutions following the addition of TPN additives stabilized with disodium edetate. Calcium disodium edetate has also been reported to be incompatible with amphotericin and with hydralazine hydrochloride in infusion fluids. 

The use of the polyenes for the treatment of systemic infections is limited by the toxicities of the drugs, their low water solubilities, and their poor chemical stabilities. Amphotericin B. the only polyene useful for the treatment of. serious systemic infections, must be solubilized with a detergent. The other polyenes are indicated only as topical agents for superficial fungal infections. 

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