AmBisome for Injection is a sterile, non-pyrogenic lyophilized product for intravenous infusion. Each vial contains 50 mg of amphotericin B, USP, intercalated into a liposomal membrane consisting of approximately 213 mg hydrogenated soy phosphatidylcholine; 52 mg cholesterol, NF; 84 mg distearoylphosphatidylglycerol; 0.64 mg alpha tocopherol, USP; together with 900 mg sucrose, NF; and 27 mg disodium succinate hexahydrate as buffer. Following reconstitution with Sterile Water for Injection, USP, the resulting pH of the suspension is between 5-6.
AmBisome is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. AmBisome consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the AmBisome liposomes. AmBisome contains true liposomes that are less than 100 nm in diameter. A schematic depiction of the liposome is presented below.
Note: Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated drug or non-lipid associated drug. In addition, different liposomal or lipid-complex products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect the functional properties of these drug products.
Amphotericin B is a macrocyclic, polyene, antifungal antibiotic produced from a strain of Streptomyces nodosus. Amphotericin B is designated chemically as:
[1R-(1R*,3S*,5R*,6R*,9R*,11R*,15S*,16R*,17R*,18S*,
19E,21E,23E,25E,27E,29E,31E,33R*,35S*,36R*,37S*)] - 33 - [(3 - Amino - 3,6 - dideoxy - β - D - mannopyranosyl)oxy] - 1,3,5,6,9,11,17,37 - octahydroxy - 15,16,18 - trimethyl - 13 - oxo - 14,39 - dioxabicyclo[33.3.1]nonatriaconta - 19,21,23,25,27,29,31 - heptaene - 36 - carboxylic acid (CAS No. 1397-89-3).
Amphotericin B has a molecular formula of C47H73NO17 and a molecular weight of 924.09.
The structure of amphotericin B is shown below:
MICROBIOLOGY
Mechanism of Action
Amphotericin B, the active ingredient of AmBisome, acts by binding to the sterol component of a cell membrane leading to alterations in cell permeability and cell death. While amphotericin B has a higher affinity for the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell leading to cytotoxicity. AmBisome, the liposomal preparation of amphotericin B, has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.
Activity In Vitro and In Vivo
AmBisome has shown in vitro activity comparable to amphotericin B against the following organisms: Aspergillus species (A. fumigatus, A. flavus), Candida species (C. albicans, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis), Cryptococcus neoformans, and Blastomyces dermatitidis. However, standardized techniques for susceptibility testing of antifungal agents have not been established and results of such studies do not necessarily correlate with clinical outcome.
AmBisome is active in animal models against Aspergillus fumigatus , Candida albicans, Candida krusei, Candida lusitaniae, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Leishmania donovani, and Leishmania infantum. The administration of AmBisome in these animal models demonstrated prolonged survival of infected animals, reduction of microorganisms from target organs, or a decrease in lung weight.
Drug Resistance
Mutants with decreased susceptibility to amphotericin B have been isolated from several fungal species after serial passage in culture media containing the drug, and from some patients receiving prolonged therapy. Drug combination studies in vitro and in vivo suggest that imidazoles may induce resistance to amphotericin B. However, the clinical relevance of drug resistance has not been established.
AmBisome - Clinical Pharmacology
Pharmacokinetics
The assay used to measure amphotericin B in the serum after administration of AmBisome does not distinguish amphotericin B that is complexed with the phospholipids of AmBisome from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of AmBisome is based upon total serum concentrations of amphotericin B. The pharmacokinetic profile of amphotericin B was determined in febrile neutropenic cancer and bone marrow transplant patients who received 1-2 hour infusions of 1 to 5 mg/kg/day AmBisome for 3 to 20 days.
The pharmacokinetics of amphotericin B after administration of AmBisome are nonlinear such that there is a greater than proportional increase in serum concentrations with an increase in dose from 1 to 5 mg/kg/day. The pharmacokinetic parameters of total amphotericin B (mean ± SD) after the first dose and at steady state are shown in the table below.
Pharmacokinetic Parameters of AmBisome
Dose
(mg/kg/day): |
1 |
2.5 |
5 |
| Day |
1
n = 8 |
Last
n = 7 |
1
n = 7 |
Last
n = 7 |
1
n = 12 |
Last
n = 9 |
| Parameters |
| Cmax (mcg/mL) |
7.3 ± 3.8 |
12.2 ± 4.9 |
17.2 ± 7.1 |
31.4 ± 17.8 |
57.6 ± 21 |
83 ± 35.2 |
| AUC0-24 (mcg•hr/mL) |
27 ± 14 |
60 ± 20 |
65 ± 33 |
197 ± 183 |
269 ± 96 |
555 ± 311 |
| t½(hr) |
10.7 ± 6.4 |
7 ± 2.1 |
8.1 ± 2.3 |
6.3 ± 2 |
6.4 ± 2.1 |
6.8 ± 2.1 |
| Vss(L/kg) |
0.44 ± 0.27 |
0.14 ± 0.05 |
0.40 ± 0.37 |
0.16 ± 0.09 |
0.16 ± 0.10 |
0.10 ± 0.07 |
| Cl (mL/hr/kg) |
39 ± 22 |
17 ± 6 |
51 ± 44 |
22 ± 15 |
21 ± 14 |
11 ± 6 |
DistributionBased on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of AmBisome, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of AmBisome, the mean half-life was 100-153 hours. The long terminal elimination half-life is probably a slow redistribution from tissues. Steady state concentrations were generally achieved within 4 days of dosing.
Although variable, mean trough concentrations of amphotericin B remained relatively constant with repeated administration of the same dose over the range of 1 to 5 mg/kg/day, indicating no significant drug accumulation in the serum.
MetabolismThe metabolic pathways of amphotericin B after administration of AmBisome are not known.
ExcretionThe mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of AmBisome has not been studied.
Pharmacokinetics in Special Populations
Renal ImpairmentThe effect of renal impairment on the disposition of amphotericin B after administration of AmBisome has not been studied. However, AmBisome has been successfully administered to patients with pre-existing renal impairment (see DESCRIPTION OF CLINICAL STUDIES).
Hepatic ImpairmentThe effect of hepatic impairment on the disposition of amphotericin B after administration of AmBisome is not known.
Pediatric and Elderly PatientsThe pharmacokinetics of amphotericin B after administration of AmBisome in pediatric and elderly patients have not been studied; however, AmBisome has been used in pediatric and elderly patients (see DESCRIPTION OF CLINICAL STUDIES).
Gender and EthnicityThe effect of gender or ethnicity on the pharmacokinetics of amphotericin B after administration of AmBisome is not known.
Indications and Usage for AmBisome
AmBisome 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 AmBisome, 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 AmBisome were conducted. This clinical program included both controlled and uncontrolled studies. These studies, which involved 2171 patients, included patients with confirmed systemic mycoses, empirical therapy, and visceral leishmaniasis.
Nineteen hundred and forty-six episodes were evaluable for efficacy, of which 1280 (302 pediatric and 978 adults) were treated with AmBisome.
Three controlled empirical therapy trials compared the efficacy and safety of AmBisome 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 AmBisome to Abelcet® (amphotericin B lipid complex) was conducted in patients aged 2 years or more.
One controlled trial compared the efficacy and safety of AmBisome 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 AmBisome (1.5-6 mg/kg/day) compared with amphotericin B deoxycholate (0.3-1.2 mg/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 7 days 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 AmBisome 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
|
AmBisome |
Amphotericin B |
|
| 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. AmBisome 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
|
AmBisome |
Amphotericin B |
| 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 AmBisome 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 AmBisome (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 patients received AmBisome (85 patients received 3 mg/kg/day and 81 received 5 mg/kg/day) and 78 patients received amphotericin B lipid complex. The study patients were febrile despite having received at least 72 hours 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 AmBisome (1 and 3 mg/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 AmBisome 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 AmBisome 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 AmBisome 3 mg/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 76 patients, 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 AmBisome and amphotericin B deoxycholate are summarized in the following table:
Success Rates at 2 weeks (CSF Culture Conversion) Study 94-0-013
|
AmBisome
3 mg/kg |
AmBisome
6 mg/kg |
Amphotericin B
0.7 mg/kg |
|
Success at Week 2
|
35/60 (58.3%)
97.5% CI=
-9.4%, +31% |
36/75 (48%)
97.5% C*=
-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 AmBisome 6 mg/kg/day approximates the efficacy of the amphotericin B deoxycholate regimen. These data do not support the conclusion that AmBisome 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)
|
AmBisome
3 mg/kg |
AmBisome
6 mg/kg |
Amphotericin B
0.7 mg/kg |
|
| 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 AmBisome 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
AmBisome 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
AmBisome 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.
AmBisome achieved high rates of acute parasite clearance in immunocompetent patients when total doses of 12-30 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 30-40 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:
AmBisome 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 |
29-38.9 mg/kg
|
10/10 (100) |
2/10 (20) |
4 mg/kg/day, days 1-5, 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 AmBisome or of maintenance therapy with this drug among immunocompromised patients.
Contraindications
AmBisome is contraindicated in those patients who have demonstrated or have known hypersensitivity to amphotericin B deoxycholate or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk.
Warnings
Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including AmBisome. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of AmBisome.
Precautions
General
As with any amphotericin B-containing product the drug should be administered by medically trained personnel. During the initial dosing period, patients should be under close clinical observation. AmBisome has been shown to be significantly less toxic than amphotericin B deoxycholate; however, adverse events may still occur.
Laboratory Tests
Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, and serum electrolytes (particularly magnesium and potassium).
Drug Interactions
No formal clinical studies of drug interactions have been conducted with AmBisome. However, the following drugs are known to interact with amphotericin B and may interact with AmBisome:
Antineoplastic AgentsConcurrent use of antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with caution.
Corticosteroids and Corticotropin (ACTH)Concurrent use of corticosteroids and ACTH may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly, serum electrolytes and cardiac function should be closely monitored.
Digitalis GlycosidesConcurrent use may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly, serum potassium levels should be closely monitored.
FlucytosineConcurrent use of flucytosine may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion.
Azoles (e.g. ketoconazole, miconazole, clotrimazole, fluconazole, etc.)In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazoles may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
Leukocyte TransfusionsAcute pulmonary toxicity has been reported in patients simultaneously receiving intravenous amphotericin B and leukocyte transfusions.
Other Nephrotoxic MedicationsConcurrent use of amphotericin B and other nephrotoxic medications may enhance the potential for drug-induced renal toxicity. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications.
Skeletal Muscle RelaxantsAmphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g. tubocurarine) due to hypokalemia. When administered concomitantly, serum potassium levels should be closely monitored.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long term studies in animals have been performed to evaluate carcinogenic potential of AmBisome. AmBisome has not been tested to determine its mutagenic potential. A Segment I Reproductive Study in rats found an abnormal estrous cycle (prolonged diestrus) and decreased number of corpora lutea in the high dose groups (10 and 15 mg/kg, doses equivalent to human doses of 1.6 and 2.4 mg/kg based on body surface area considerations). AmBisome did not affect fertility or days to copulation. There were no effects on male reproductive function.
Pregnancy Category B
There have been no adequate and well-controlled studies of AmBisome in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B deoxycholate, but the number of cases reported has been small.
Segment II studies in both rats and rabbits have concluded that AmBisome had no teratogenic potential in these species. In rats, the maternal non-toxic dose of AmBisome was estimated to be 5 mg/kg (equivalent to 0.16 to 0.8 times the recommended human clinical dose range of 1 to 5 mg/kg) and in rabbits, 3 mg/kg (equivalent to 0.2 to 1 times the recommended human clinical dose range), based on body surface area correction. Rabbits receiving the higher doses, (equivalent to 0.5 to 2 times the recommended human dose) of AmBisome experienced a higher rate of spontaneous abortions than did the control groups. AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks involved.
Nursing Mothers
Many drugs are excreted in human milk. However, it is not known whether AmBisome is excreted in human milk. Due to the potential for serious adverse reactions in breast-fed infants, a decision should be made whether to discontinue nursing or whether to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Pediatric patients, age 1 month to 16 years, with presumed fungal infection (empirical therapy), confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with AmBisome. In studies which included 302 pediatric patients administered AmBisome, there was no evidence of any differences in efficacy or safety of AmBisome compared to adults. Since pediatric patients have received AmBisome at doses comparable to those used in adults on a per kilogram body weight basis, no dosage adjustment is required in this population. Safety and effectiveness in pediatric patients below the age of one month have not been established. (See DESCRIPTION OF CLINICAL STUDIES - Empirical Therapy in Febrile Neutropenic Patients and DOSAGE AND ADMINISTRATION).
Elderly Patients
Experience with AmBisome in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of AmBisome for this population. As with most other drugs, elderly patients receiving AmBisome should be carefully monitored.
Adverse Reactions
The following adverse events are based on the experience of 592 adult patients (295 treated with AmBisome and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with AmBisome and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multi-center study in febrile, neutropenic patients. AmBisome and amphotericin B were infused over two hours.
The incidence of common adverse events (incidence of 10% or greater) occurring with AmBisome compared to amphotericin B deoxycholate, regardless of relationship to study drug, is shown in the following table:
Empirical Therapy Study 94-0-002 Common Adverse Events
| Adverse Event by Body System |
AmBisome
n=343
% |
Amphotericin B
n=344
% |
| Body as a Whole |
Abdominal pain
Asthenia
Back pain
Blood product transfusion react.
Chills
Infection
Pain
Sepsis |
19.8
13.1
12
18.4
47.5
11.1
14
14 |
21.8
10.8
7.3
18.6
75.9
9.3
12.8
11.3 |
| Cardiovascular System |
Chest pain
Hypertension
Hypotension
Tachycardia |
12
7.9
14.3
13.4 |
11.6
16.3
21.5
20.9 |
| Digestive System |
Diarrhea
Gastrointestinal hemorrhage
Nausea
Vomiting |
30.3
9.9
39.7
31.8 |
27.3
11.3
38.7
43.9 |
| Metabolic and Nutritional Disorders |
Alkaline phosphatase increased
ALT (SGPT) increased
AST (SGOT) increased
Bilirubinemia
BUN increased
Creatinine increased
Edema
Hyperglycemia
Hypernatremia
Hypervolemia
Hypocalcemia
Hypokalemia
Hypomagnesemia
Peripheral edema |
22.2
14.6
12.8
18.1
21
22.4
14.3
23
4.1
12.2
18.4
42.9
20.4
14.6 |
19.2
14
12.8
19.2
31.1
42.2
14.8
27.9
11
15.4
20.9
50.6
25.6
17.2 |
| Nervous System |
Anxiety
Confusion
Headache
Insomnia |
13.7
11.4
19.8
17.2 |
11
13.4
20.9
14.2 |
| Respiratory System |
Cough increased
Dyspnea
Epistaxis
Hypoxia
Lung disorder
Pleural effusion
Rhinitis |
17.8
23
14.9
7.6
17.8
12.5
11.1 |
21.8
29.1
20.1
14.8
17.4
9.6
11 |
|
|
|
| Skin and Appendages |
Pruritus
Rash
Sweating |
10.8
24.8
7 |
10.2
24.4
10.8 |
| Urogenital System |
| Hematuria |
14 |
14 |
AmBisome was well tolerated. AmBisome had a lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin B deoxycholate.
In pediatric patients (16 years of age or less) in this double-blind study, AmBisome compared to amphotericin B deoxycholate had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Similar trends, although with a somewhat lower incidence, were observed in open-label, randomized Study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with AmBisome and 64 treated with amphotericin B deoxycholate). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin B deoxycholate.
The following adverse events are based on the experience of 244 patients (202 adult and 42 pediatric patients) of whom 85 patients were treated with AmBisome 3 mg/kg, 81 patients were treated with AmBisome 5 mg/kg and 78 patients treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized double-blind, multi-center study in febrile, neutropenic patients. AmBisome and amphotericin B lipid complex were infused over two hours. The incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table:
Empirical Therapy Study 97-0-034 Common Adverse Events
| Adverse Event by Body System |
AmBisome
3 mg/kg/day
n=85
% |
AmBisome
5 mg/kg/day
n=81
% |
Amphotericin B Lipid Complex
5 mg/kg/day
n=78
% |
| Body as a Whole |
Abdominal pain
Asthenia
Chills/rigors
Sepsis
Transfusion reaction |
12.9
8.2
40
12.9
10.6 |
9.9
6.2
4 |
