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amphotericin B
Overview
What is AmBisome?
Amisome 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.
Amisome 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. Amisome 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 Amisome liposomes. Amisome 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 . 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 CHNO and a molecular weight of 924.09.
The structure of amphotericin B is shown below:
What does AmBisome look like?
What are the available doses of AmBisome?
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What should I talk to my health care provider before I take AmBisome?
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How should I use AmBisome?
Amisome is indicated for the following:
See for recommended doses by indication.
Amisome should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes.
An in-line membrane filter may be used for the intravenous infusion of Amisome; provided .
NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of AmBisome. If this is not feasible, AmBisome must be administered through a separate line.
Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased.
The recommended initial dose of Amisome for each indication for adult and pediatric patients is as follows:
Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events.
Doses recommended for visceral leishmaniasis are presented below:
For immunocompetent patients
For immunocompromised patients
What interacts with AmBisome?
Amisome 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.
What are the warnings of AmBisome?
Because Amantadine Hydrochloride Capsules has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma.
What are the precautions of AmBisome?
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. Amisome 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-Laboratory Interactions: Serum phosphate false elevation
False elevations of serum phosphate may occur when samples from patients receiving Amisome are analyzed using the PHOSm assay (e.g. used in Beckman Coulter analyzers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples.
Drug Interactions
No formal clinical studies of drug interactions have been conducted with Amisome. However, the following drugs are known to interact with amphotericin B and may interact with Amisome:
Antineoplastic Agents
Concurrent 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 Glycosides
Concurrent use may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly, serum potassium levels should be closely monitored.
Flucytosine
Concurrent 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.)
Array
Leukocyte Transfusions
Acute pulmonary toxicity has been reported in patients simultaneously receiving intravenous amphotericin B and leukocyte transfusions.
Other Nephrotoxic Medications
Concurrent 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 Relaxants
Amphotericin 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 Amisome. Amisome 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). Amisome 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 Amisome 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 Amisome had no teratogenic potential in these species. In rats, the maternal non-toxic dose of Amisome 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 Amisome experienced a higher rate of spontaneous abortions than did the control groups. Amisome 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 Amisome 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 Amisome. In studies which included 302 pediatric patients administered Amisome, there was no evidence of any differences in efficacy or safety of Amisome compared to adults. Since pediatric patients have received Amisome 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 and ).
Elderly Patients
Experience with Amisome in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of Amisome for this population. As with most other drugs, elderly patients receiving Amisome should be carefully monitored.
What are the side effects of AmBisome?
Sorry No records found
What should I look out for while using AmBisome?
Amisome 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.
Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including Amisome. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of Amisome.
What might happen if I take too much AmBisome?
The toxicity of Amisome due to overdose has not been defined. Repeated daily doses up to 10 mg/kg in pediatric patients and 15 mg/kg in adult patients have been administered in clinical trials with no reported dose-related toxicity.
Management
If overdosage should occur, cease administration immediately. Symptomatic supportive measures should be instituted. Particular attention should be given to monitoring renal function. Hemodialysis or peritoneal dialysis do not appear to significantly affect the elimination of Amisome.
How should I store and handle AmBisome?
Topiramate tablets should be stored in tightly-closed containers at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Amisome for Injection is available as single vial cartons (equivalent to 50mg amphotericin B) and in packs of ten individual vial cartons(NDC 0469-3051-30).Each carton contains one pre-packaged, disposable sterile 5 micron filter.Amisome for Injection is available as single vial cartons (equivalent to 50mg amphotericin B) and in packs of ten individual vial cartons(NDC 0469-3051-30).Each carton contains one pre-packaged, disposable sterile 5 micron filter.Amisome for Injection is available as single vial cartons (equivalent to 50mg amphotericin B) and in packs of ten individual vial cartons(NDC 0469-3051-30).Each carton contains one pre-packaged, disposable sterile 5 micron filter.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The assay used to measure amphotericin B in the serum after administration of Amisome does not distinguish amphotericin B that is complexed with the phospholipids of Amisome from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of Amisome 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 Amisome for 3 to 20 days.
The pharmacokinetics of amphotericin B after administration of Amisome is 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.
Distribution
Based on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of Amisome, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of Amisome, 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.
Metabolism
The metabolic pathways of amphotericin B after administration of Amisome are not known.
Excretion
The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of Amisome has not been studied.
Non-Clinical Toxicology
Amisome 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.Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including Amisome. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of Amisome.
No formal clinical studies of drug interactions have been conducted with Amisome. However, the following drugs are known to interact with amphotericin B and may interact with Amisome:
Antineoplastic Agents
Concurrent 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 Glycosides
Concurrent use may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly, serum potassium levels should be closely monitored.
Flucytosine
Concurrent 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.)
Leukocyte Transfusions
Acute pulmonary toxicity has been reported in patients simultaneously receiving intravenous amphotericin B and leukocyte transfusions.
Other Nephrotoxic Medications
Concurrent 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 Relaxants
Amphotericin 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.
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. Amisome has been shown to be significantly less toxic than amphotericin B deoxycholate; however, adverse events may still occur.
The following adverse events are based on the experience of 592 adult patients (295 treated with Amisome and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with Amisome and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multi-center study in febrile, neutropenic patients. Amisome and amphotericin B were infused over two hours.
The incidence of common adverse events (incidence of 10% or greater) occurring with Amisome compared to amphotericin B deoxycholate, regardless of relationship to study drug, is shown in the following table:
Amisome was well tolerated. Amisome 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, Amisome 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 Amisome 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 Amisome 3 mg/kg, 81 patients were treated with Amisome 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. Amisome 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:
The following adverse events are based on the experience of 267 patients (266 adult patients and 1 pediatric patient) of whom 86 patients were treated with Amisome 3 mg/kg, 94 patients were treated with Amisome 6 mg/kg and 87 patients treated with amphotericin B deoxycholate 0.7 mg/kg in Study 94-0-013 a randomized, double-blind, comparative multi-center trial, in the treatment of cryptococcal meningitis in HIV positive patients. 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:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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