Amphotericin B cholesteryl sulfate indications and usage

# Indications And Usage
AMPHOTEC is indicated for the treatment of invasive aspergillosis in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate in effective doses, and in patients with invasive aspergillosis where prior amphotericin B deoxycholate therapy has failed.

# Description Of Clinical Studies

## Clinical Studies in Aspergillosis
Data from 161 patients with proven or probable aspergillus infection were pooled from 5 non-comparative open label studies, one of which included emergency use patients. The patients were treated with AMPHOTEC because of failure to respond to amphotericin B deoxycholate (n=49), development of nephrotoxicity while receiving amphotericin B deoxycholate (n=62), preexisting renal impairment (n=25), or other reasons (n=25).
The median age of these 161 patients (92 males and 69 females) was 41 years (range 2 months to 85 years). For the 155 patients with baseline neutrophil data, 33 patients (21%) had neutrophil counts of  14 days (22 patients).
Patients were defined by their physicians as being refractory to amphotericin B deoxycholate therapy based on overall clinical judgment after receiving either a minimum of 7 days of amphotericin B deoxycholate or a minimum total dose of 15 mg/kg of amphotericin B deoxycholate. Nephrotoxicity was defined as a serum creatinine that had doubled from baseline, increased by  1.5 mg/dL or increased to  2.0 mg/dL. Preexisting renal impairment was defined as a serum creatinine that had increased to  2.0 mg/dL due to reasons other than amphotericin B deoxycholate administration.
Classifications of diagnosis and response were based on the definitions previously developed by the Mycoses Study Group.1 A retrospective response analysis was conducted in which a complete response was defined as resolution of all attributable symptoms, signs, and radiographic abnormalities present at enrollment, and a partial response was defined as major improvement of the abovementioned parameters. The total number of responders was the sum of the number of complete and partial responses.
Of the 161 patients, 80 were considered evaluable for response. Eighty-one (81) were excluded on the basis of inadequate diagnosis, confounding factors, or receiving  4 doses of AMPHOTEC. In the evaluable patients, the median daily dose was 4 mg/kg/day (range 0.73 - 7.5 mg/kg/day) and the cumulative median dose was 6.3 g (range 0.36 - 34.4 grams). Median duration of treatment was 24 days (range 5 - 129 days).

## Renal Function
Patients with Renal Dysfunction at Baseline
The subset of patients with aspergillosis from the above five noncomparative open label studies, who initiated treatment with AMPHOTEC when their serum creatinine was  2.0 mg/dL (n = 47) experienced a mean decline in serum creatinine during treatment. In part, this decline may be attributed to patient dropout over time from this group. A historical control group was selected by reviewing medical charts of patients from January 1990 to June 1994 at 6 medical centers ( M.D. Anderson Cancer Center, Fred Hutchinson Cancer Research Center, H. Lee Moffitt Cancer Center, University of Pittsburgh, Memorial Sloan-Kettering Cancer Center, and Bone Marrow Transplant Program at Emory  University). The mean change in serum creatinine was evaluated for similar cohorts of patients from this historical control group, with the baseline for assessing change being the day each patients serum creatinine reached  2.0 mg/dL. As shown in the figure, serum creatinine levels were lower during treatment with AMPHOTEC when compared to the serum creatinine levels of amphotericin B deoxycholate patients in the historical control group. There is no directly comparable group to be certain whether this decline is significantly better than the results of serum creatinine levels in patients who had continued on amphotericin B deoxycholate. Since these data were obtained from two separate studies, no statistical testing of the differences between these two groups was performed.
In a randomized, double-blind, multicenter study, 213 febrile neutropenic patients were given empirically either 4 mg/kg/day of AMPHOTEC or 0.8 mg/kg/day of amphotericin B deoxycholate for a maximum of 14 days. This study was primarily designed to compare the safety profiles of these two treatments. NOTE: AMPHOTEC is NOT approved for empirical treatment in febrile neutropenic patients.
In the above study, patients had largely normal renal function at baseline; median serum creatinine levels were 0.8 mg/dL for both treatment groups. The mean change in serum creatinine was evaluated for patients with baseline creatinine  1.5 mg/dL. As shown in the graph, patients in both treatment groups showed an increase in serum creatinine while on study, however AMPHOTEC patients experienced significantly less creatinine increase at each time point.
Hypokalemia
In the same empiric study, significantly more amphotericin B deoxycholate patients had at least one laboratory result of serum potassium < 3.0 mEq/L at least one time in the study compared with AMPHOTEC patients (23% vs. 7%), although concomitant supplemental potassium was allowed in the study design. Both groups received approximately equal amounts of potassium supplementation.
Hypomagnesemia
In the same empiric study, there was no overall trend for decreasing serum magnesium in either group.