INDICATIONS AND USAGE
Amphotericin B liposome for injection is indicated for the following:
Empirical therapy for presumed fungal infection in febrile, neutropenic patients.
Treatment of Cryptococcal Meningitis in HIV-infected patients (see
DESCRIPTION OF CLINICAL STUDIES
).
Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections (see above for the treatment of Cryptococcal Meningitis) refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate.
Treatment of visceral leishmaniasis. In immunocompromised patients with visceral leishmaniasis treated with amphotericin B liposome for injection, relapse rates were high following initial clearance of parasites (see
DESCRIPTION OF CLINICAL STUDIES
).
See
DOSAGE AND ADMINISTRATION
for recommended doses by indication.
DESCRIPTION OF CLINICAL STUDIES
Eleven clinical studies supporting the efficacy and safety of amphotericin B were conducted. This clinical program included both controlled and uncontrolled studies. These studies, which involved 2,171 patients, included patients with confirmed systemic mycoses, empirical therapy, and visceral leishmaniasis.
Nineteen hundred and forty-six (1,946) episodes were evaluable for efficacy, of which 1,280 (302 pediatric and 978 adults) were treated with amphotericin B.
Three controlled empirical therapy trials compared the efficacy and safety of amphotericin B liposome for injection to amphotericin B. One of these studies was conducted in a pediatric population, one in adults, and a third in patients aged 2 years or more. In addition, a controlled empirical therapy trial comparing the safety of amphotericin B liposome for injection to Abelcet (amphotericin B lipid complex) was conducted in patients aged 2 years or more.
One controlled trial compared the efficacy and safety of amphotericin B liposome for injection to amphotericin B in HIV patients with cryptococcal meningitis.
One compassionate use study enrolled patients who had failed amphotericin B deoxycholate therapy or who were unable to receive amphotericin B deoxycholate because of renal insufficiency.
Empirical Therapy in Febrile Neutropenic Patients
Study 94-0-002, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of amphotericin B liposome for injection (1.5 to 6 mg/kg/day) compared with amphotericin B deoxycholate (0.3 to 1.2mg/kg/day) in the empirical treatment of 687 adult and pediatric neutropenic patients who were febrile despite having received at least 96 hours of broad spectrum antibacterial therapy. Therapeutic success required (a) resolution of fever during the neutropenic period, (b) absence of an emergent fungal infection, (c) patient survival for at least 7days post therapy, (d) no discontinuation of therapy due to toxicity or lack of efficacy, and (e) resolution of any study-entry fungal infection.
The overall therapeutic success rates for amphotericin B liposome for injection and the amphotericin B deoxycholate were equivalent. Results are summarized in the following table. Note: The categories presented below are not mutually exclusive.
Empirical Therapy in Febrile Neutropenic Patients: Randomized, Double-Blind Study in 687 Patients
* 8 and 10 patients, respectively, were treated as failures due to premature discontinuation alone.
Amphotericin B
Liposome for Injection
3 mg/kg/day
Amphotericin B
0.6 mg/kg/day
Number of patients receiving at least one dose of study drug
343
344
Overall Success
171 (49.9%)
169 (49.1%)
Fever resolution during neutropenic period
199 (58%)
200 (58.1%)
No treatment-emergent fungal infection
300 (87.5%)
301 (87.7%)
Survival through 7 days post study drug
318 (92.7%)
308 (89.5%)
Study drug not prematurely discontinued due to toxicity or lack of efficacy*
294 (85.7%)
280 (81.4%)
This therapeutic equivalence had no apparent relationship to the use of prestudy antifungal prophylaxis or concomitant granulocytic colony-stimulating factors.
The incidence of mycologically-confirmed, and clinically-diagnosed, emergent fungal infections are presented in the following table. Amphotericin B liposome for injection and amphotericin B were found to be equivalent with respect to the total number of emergent fungal infections.
Empirical Therapy in Febrile Neutropenic Patients: Emergent Fungal Infections
Amphotericin B
Liposome for Injection
3 mg/kg/day
Amphotericin B
0.6 mg/kg/day
Number of patients receiving at least one dose of study drug
343
344
Mycologically-confirmed fungal infection
11 (3.2%)
27 (7.8%)
Clinically-diagnosed fungal infection
32 (9.3%)
16 (4.7%)
Total emergent fungal infections
43 (12.5%)
43 (12.5%)
Mycologically-confirmed fungal infections at study entry were cured in 8 of 11 patients in the amphotericin B liposome for injection group and 7 of 10 in the amphotericin B group.
Study 97-0-034, a randomized, double-blind, comparative multi-center trial, evaluated the safety of amphotericin B liposome for injection (3 and 5 mg/kg/day) compared with amphotericin B lipid complex (5 mg/kg/day) in the empirical treatment of 202 adult and 42 pediatric neutropenic patients. One hundred and sixty-six (166) patients received amphotericin B liposome for injection (85 patients received 3 mg/kg/day and 81 received 5mg/kg/day) and 78 patients received amphotericin B lipid complex. The study patients were febrile despite having received at least 72hours of broad spectrum antibacterial therapy. The primary endpoint of this study was safety. The study was not designed to draw statistically meaningful conclusions related to comparative efficacy and, in fact, Abelcet is not labeled for this indication.
Two supportive, prospective, randomized, open-label, comparative multi-center studies examined the efficacy of two dosages of amphotericin B liposome for injection (1 and 3mg/kg/day) compared to amphotericin B deoxycholate (1 mg/kg/day) in the treatment of neutropenic patients with presumed fungal infections. These patients were undergoing chemotherapy as part of a bone marrow transplant or had hematological disease. Study 104-10 enrolled adult patients (n=134). Study 104-14 enrolled pediatric patients (n=214). Both studies support the efficacy equivalence of amphotericin B liposome for injection and amphotericin B as empirical therapy in febrile neutropenic patients.
Treatment of Cryptococcal Meningitis in HIV-Infected Patients
Study 94-0-013, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of amphotericin B liposome for injection at doses (3 and 6 mg/kg/day) compared with amphotericin B deoxycholate (0.7 mg/kg/day) for the treatment of cryptococcal meningitis in 266 adult and one pediatric HIV-positive patients (the pediatric patient received amphotericin B deoxycholate). Of the 267 treated patients, 86 received amphotericin B liposome for injection 3mg/kg/day, 94 received 6 mg/kg/day and 87 received amphotericin B deoxycholate; cryptococcal meningitis was documented by a positive CSF culture at baseline in 73, 85 and 76patients, respectively. Patients received study drug once daily for an induction period of 11 to 21 days. Following induction, all patients were switched to oral fluconazole at 400 mg/day for adults and 200 mg/day for patients less than 13 years of age to complete 10 weeks of protocol-directed therapy. For mycologically evaluable patients, defined as all randomized patients who received at least one dose of study drug, had a positive baseline CSF culture, and had at least one follow-up culture, success was evaluated at week 2 (i.e., 14
4 days), and was defined as CSF culture conversion. Success rates at 2 weeks for amphotericin B liposome for injection and amphotericin B deoxycholate are summarized in the following table:
Success Rates at 2 Weeks (CSF Culture Conversion) Study 94-0-013
* 97.5% Confidence Interval for the difference between amphotericin B liposome for injection and amphotericin B success rates. A negative value is in favor of amphotericin B. A positive value is in favor of amphotericin B liposome for injection.
Amphotericin B Liposome
for Injection
3 mg/kg/day
Amphotericin B Liposome for
Injection
6 mg/kg/day
Amphotericin B
0.7 mg/kg/day
Success at Week 2
35/60 (58.3%)97.5% CI*= -9.4%, +31%
36/75 (48%) 97.5% CI*= -18.8%, +19.8%
29/61 (47.5 %)
Success at 10 weeks was defined as clinical success at week 10 plus CSF culture conversion at or prior to week 10. Success rates at 10 weeks in patients with positive baseline culture for cryptococcus species are summarized in the following table and show that the efficacy of amphotericin B liposome for injection 6 mg/kg/day approximates the efficacy of the amphotericin B deoxycholate regimen. These data do not support the conclusion that amphotericin B liposome for injection 3 mg/kg/day is comparable in efficacy to amphotericin B deoxycholate. The table also presents 10-week survival rates for patients treated in this study.
Success Rates and Survival Rates at Week 10, Study 94-0-013 (see text for definitions)
Amphotericin B Liposome for Injection
3 mg/kg/day
Amphotericin B Liposome for Injection
6 mg/kg/day
Amphotericin B
0.7 mg/kg/day
* 97.5% Confidence Interval for the difference between amphotericin B liposome for injection and amphotericin B rates. A negative value is in favor of amphotericin B. A positive value is in favor of amphotericin B liposome for injection.
Success in patients with documented cryptococcal meningitis
27/73 (37%)97.5% CI* =-33.7%, +2.4%
42/85 (49%)97.5% CI* =-20.9%, +14.5%
40/76 (53%)
Survival rates
74/86 (86%)97.5% CI* =-13.8%, +8.9%
85/94 (90%)97.5% CI* =-8.3%, +12.2%
77/87 (89%)
The incidence of infusion-related, cardiovascular and renal adverse events was lower in patients receiving amphotericin B liposome for injection compared to amphotericin B deoxycholate (see
ADVERSE REACTIONS
section for details); therefore, the risks and benefits (advantages and disadvantages) of the different amphotericin B formulations should be taken into consideration when selecting a patient treatment regimen.
Treatment of Patients with Aspergillus Species, Candida Species and/or Cryptococcus Species Infections Refractory to Amphotericin B Deoxycholate, or in Patients Where Renal Impairment or Unacceptable Toxicity Precludes the Use of Amphotericin B Deoxycholate
Amphotericin B liposome for injection was evaluated in a compassionate use study in hospitalized patients with systemic fungal infections. These patients either had fungal infections refractory to amphotericin B deoxycholate, were intolerant to the use of amphotericin B deoxycholate, or had pre-existing renal insufficiency. Patient recruitment involved 140 infectious episodes in 133 patients, with 53 episodes evaluable for mycological response and 91 episodes evaluable for clinical outcome. Clinical success and mycological eradication occurred in some patients with documented aspergillosis, candidiasis, and cryptococcosis.
Treatment of Visceral Leishmaniasis
Amphotericin B was studied in patients with visceral leishmaniasis who were infected in the Mediterranean basin with documented or presumed Leishmania infantum. Clinical studies have not provided conclusive data regarding efficacy against L. donovani or L. chagasi.
Amphotericin B achieved high rates of acute parasite clearance in immunocompetent patients when total doses of 12 to 30 mg/kg were administered. Most of these immunocompetent patients remained relapse-free during follow-up periods of 6 months or longer. While acute parasite clearance was achieved in most of the immunocompromised patients who received total doses of 30 to 40 mg/kg, the majority of these patients were observed to relapse in the 6 months following the completion of therapy. Of the 21 immunocompromised patients studied, 17 were coinfected with HIV; approximately half of the HIV-infected patients had AIDS. The following table presents a comparison of efficacy rates among immunocompetent and immunocompromised patients infected in the Mediterranean basin who had no prior treatment or remote prior treatment for visceral leishmaniasis. Efficacy is expressed as both acute parasite clearance at the end of therapy (EOT) and as overall success (clearance with no relapse) during the follow-up period (F/U) of greater than 6 months for immunocompetent and immunocompromised patients:
Amphotericin B Liposome for Injection Efficacy in Visceral Leishmaniasis
Immunocompetent Patients
No. of Patients
Parasite (%) Clearance at EOT
Overall Success (%) at F/U
87
86/87 (98.9)
83/86 (96.5)
Immunocompromised Patients
Regimen
Total Dose
Parasite (%) Clearance at EOT
Overall Success (%) at F/U
100 mg/day X 21 days
29 to 38.9 mg/kg
10/10 (100)
2/10 (20)
4 mg/kg/day, days 1 to 5, and 10, 17, 24, 31, 38
40 mg/kg
8/9 (88.9)
0/7 (0)
TOTAL
18/19 (94.7)
2/17 (11.8)
When followed for 6 months or more after treatment, the overall success rate among immunocompetent patients was 96.5% and the overall success rate among immunocompromised patients was 11.8% due to relapse in the majority of patients. While case reports have suggested there may be a role for long-term therapy to prevent relapses in HIV coinfected patients (Lopez-Dupla, et al. J Antimicrob Chemother 1993; 32: 657-659), there are no data to date documenting the efficacy or safety of repeat courses of amphotericin B or of maintenance therapy with this drug among immunocompromised patients.