AmBisome

AmBisome

Manufacturer:

Gilead

Distributor:

DCH Auriga
Full Prescribing Info
Contents
Liposomal amphotericin B.
Description
Each vial contains amphotericin B 50 mg (50,000 units) encapsulated in liposomes.
Action
Pharmacology: Amphotericin is macrocyclic, polyene antifungal antibiotic produced by Streptomyces nodosus. Liposomes are closed, spherical vesicles formed from a variety of amphiphilic substances eg, phospholipids. Phospholipids arrange themselves into membrane bilayers when exposed to aqueous solutions. The lipophilic moiety of amphotericin allows the drug to be integrated into the lipid bilayer of the liposomes.
Amphotericin is fungistatic or fungicidal depending on the concentration attained in body fluids and the susceptibility of the fungus. AmBisome probably acts by binding to sterols in the fungal cell membrane, with a resulting change in membrane permeability, allowing leakage of a variety of small molecules. Mammalian cell membranes also contain sterols, and it has been suggested that the damage to human cells and fungal cells caused by amphotericin B may share common mechanisms.
Pharmacokinetics: The pharmacokinetic profile of AmBisome, based upon total plasma concentrations of amphotericin B, was determined in cancer patients with febrile neutropenia and bone marrow transplant patients who received 1-hr infusions of 1-7.5 mg/kg/day AmBisome for 3-20 days. AmBisome has a significantly different pharmacokinetic profile from that reported in the literature for conventional presentations of amphotericin B, with higher amphotericin B plasma concentrations (Cmax) and increased exposure (AUC0-24) following administration of AmBisome than conventional amphotericin B. After the 1st and last dose, the pharmacokinetic parameters of AmBisome (mean±standard deviation) ranged from: Cmax: 7.3 (±3.8) to 83.7 (±43) mcg/mL. T½: 6.3 (±2) to 10.7 (±6.4) hrs. AUC0-24: 27 (±14) to 555 (±311) mg·hr/mL. Clearance (Cl): 11 (±6) to 51 (±44) mL/hr/kg. Volume of Distribution (Vss): 0.1 (±0.07) to 0.44 (±0.27) L/kg.
Minimum and maximum pharmacokinetic values do not necessarily come from the lowest and highest doses, respectively. Following administration of AmBisome, steady state was reached quickly (generally within 4 days of dosing). AmBisome pharmacokinetics following the 1st dose appears nonlinear such that serum AmBisome concentrations are greater than proportional with increasing dose. This nonproportional dose response is believed to be due to saturation of reticuloendothelial AmBisome clearance. There was no significant drug accumulation in the plasma following repeated administration of 1-7.5 mg/kg/day. Volume of distribution on day 1 and at steady state suggests that there is extensive tissue distribution of AmBisome. After repeated administration of AmBisome the terminal elimination half-life (t½β) for AmBisome was approximately 7 hrs. The excretion of AmBisome has not been studied. The metabolic pathways of amphotericin B and AmBisome are not known. Due to the size of the liposomes there is no glomerular filtration and renal elimination of AmBisome, thus avoiding interaction of amphotericin B with the cells of the distal tubuli and reducing the potential for nephrotoxicity seen with conventional amphotericin B presentations.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of AmBisome has not been formally studied.
Microbiology: Amphotericin, the antifungal component of AmBisome, shows a high order of in vitro activity against many species of fungi. Most strains of Histoplasma capsulatum, Coccidioides immitis, Candida sp, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenkii, Mucor mucedo and Aspergillus fumigatus, are inhibited by concentrations of amphotericin ranging from 0.03-1 mcg/mL in vitro. Amphotericin has minimal or no effect on bacteria and viruses.
Indications/Uses
Treatment of systemic mycotic infections due to organisms susceptible to AmBisome eg, cryptococcosis, North American blastomycosis, disseminated candidiasis, coccidioidomycosis, aspergillosis, histoplasmosis, mucormycosis and in the treatment of some cases of American mucocutaneous leishmaniasis.
Treatment of fever of unknown origin (FUO) in neutropenic patients. In this context, FUO is defined as persisting fever, unresponsive to at least 96 hrs of antibiotic treatment; it is highly indicative of a systemic fungal infection in this patient population. Before initiating AmBisome treatment, common viral, parasitic or mycobacterial infections should also be excluded as far as possible as causes for the observed FUO.
Primary therapy of visceral leishmaniasis in immunocompetent patients including both adults and children and in immunocompromised patients (eg, HIV-positive).
AmBisome should not be used to treat the common clinically inapparent forms of fungal disease which show only positive skin or serologic tests.
Dosage/Direction for Use
A test dose (1 mg) should be infused slowly for up to 10 min and the patient carefully observed for 30 min afterwards.
Adults and Children: AmBisome should be administered by IV infusion over a 30- to 60-min period. The recommended concentration for IV infusion is 0.2-2 mg/mL amphotericin (see Administration).
Dosage of amphotericin must be adjusted to the specific requirements of each patient.
AmBisome therapy has been administered for as long as 5 months with a cumulative dose of 30 g of amphotericin without significant toxicity.
Treatment of Systemic Mycotic Infections: Therapy is usually instituted at a daily dose of 1 mg/kg body weight and increased stepwise to 3 mg/kg, as required. A cumulative dose of 1-3 g of amphotericin over 3-4 weeks has been typical.
For fever of unknown origin in neutropenic patients, therapy should be initiated at 1 mg/kg/day; the dose may be raised to 3 mg/kg/day if indicated.
Visceral Leishmaniasis: A dose of 1-1.5 mg/kg/day for 21 days or alternatively, a dose of 3 mg/kg/day for 10 days. In immunocompromised patients (eg, HIV-positive), a dose of 1-1.5 mg/kg/day for 21 days may be used. Because of the risk of relapse, maintenance therapy or re-induction therapy may be necessary.
Pediatric Patients: Systemic fungal infections and fever of unknown origin have been successfully treated with AmBisome in pediatric patients, without reports of unusual adverse events. Pediatric patients have received AmBisome at doses comparable to those used in adults on a per kilogram body weight basis.
Elderly: No specific dosage recommendations or precautions.
Renal Impairment: AmBisome has been successfully administered to a large number of patients with preexisting renal impairment at starting doses ranging from 1-3 mg/kg/day in clinical trials and no adjustment in dose or frequency of administration was required.
Administration: Reconstitution: Add 12 mL of water for injection to each vial to yield a preparation containing 4 mg/mL of amphotericin. AmBisome must be reconstituted using water for injection (without bacteriostatic agent).
After the addition of water, immediately shake vials vigorously for 30 sec to completely disperse the AmBisome. Visually inspect the vial for particulate matter and continue shaking until complete dispersion is obtained.
Calculate the amount of reconstituted (4 mg/mL) AmBisome to be further diluted.
The infusion, providing from 2-0.2 mg amphotericin/mL, is obtained by dilution with 1-19 parts, respectively, by volume of 5% dextrose injection. Withdraw the calculated volume of reconstituted AmBisome into a sterile syringe. Using the 5-micron filter provided, instill the AmBisome preparation into a sterile container with the correct amount of 5% dextrose injection.
Overdosage
The toxicity of AmBisome 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-dependent toxicity. If overdose should occur, cease administration immediately. Carefully monitor clinical status including renal and hepatic function, serum electrolytes and hematological status. Hemodialysis or peritoneal dialysis does not appear to affect the elimination of AmBisome.
Contraindications
Patients who have shown hypersensitivity to any of the constituents of AmBisome unless, in the opinion of the physician, the condition requiring treatment is life threatening and amenable only to AmBisome therapy.
Special Precautions
Anaphylaxis has been reported rarely in association with AmBisome infusion. To detect idiosyncratic anaphylactic reactions and minimize the dose administered if a reaction occurs, a test dose should be administered initially. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of AmBisome. Severe infusion-related reactions can occur during administration of amphotericin B-containing products, including AmBisome. Although infusion-related reactions are not usually serious, consideration of precautionary measures for the prevention or treatment of these reactions should be given to patients who receive AmBisome therapy. Slower infusion rates or routine doses of diphenhydramine, paracetamol, pethidine, and/or hydrocortisone have been reported as successful in their prevention or treatment.
AmBisome has shown to be substantially less toxic than conventional amphotericin; however, adverse events may still occur. In particular, caution should be exercised when prolonged therapy is required.
Laboratory evaluation of renal, hepatic and hematopoietic function should be performed regularly. In addition, serum electrolytes, particularly potassium and magnesium should also be evaluated. If clinically significant reduction in renal function or worsening of other parameters occurs, subsequent dosage should be reduced or interrupted on the basis of laboratory measures.
Amphotericin is nephrotoxic. If renal function deteriorates significantly during AmBisome therapy, consideration should be given to dose reduction or discontinuation until renal function improves, however, this decision should take into account any concomitant therapy with known nephrotoxic drugs.
Treatment of Diabetic Patients: It should be noted that AmBisome contains approximately 900 mg of sucrose in each vial.
Treatment of Renal Dialysis Patients: Data suggest that no dose adjustment is required in patients undergoing hemodialysis or filtration procedures, however AmBisome administration should be avoided during the procedure.
Use in Pregnancy & Lactation: Teratogenicity studies in both rats and rabbits have concluded that AmBisome had no teratogenic potential in these species.
No reproductive toxicity studies have been conducted with AmBisome in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin without obvious effect on the fetus, but the number of cases reported has been small. Safety for use in pregnant women has not been established with AmBisome. It is not known if AmBisome is excreted in human milk. AmBisome should only be used during pregnancy and breastfeeding if the possible benefits to be derived outweigh the potential risks involved.
Use In Pregnancy & Lactation
Use in Pregnancy & Lactation: Teratogenicity studies in both rats and rabbits have concluded that AmBisome had no teratogenic potential in these species.
No reproductive toxicity studies have been conducted with AmBisome in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin without obvious effect on the fetus, but the number of cases reported has been small. Safety for use in pregnant women has not been established with AmBisome. It is not known if AmBisome is excreted in human milk. AmBisome should only be used during pregnancy and breastfeeding if the possible benefits to be derived outweigh the potential risks involved.
Side Effects
In pooled study data from randomized, controlled clinical trials comparing AmBisome with conventional amphotericin B therapy in >1000 patients, reported adverse effects were considerably less severe and less frequent in AmBisome-treated patients, as compared with conventional amphotericin B-treated patients. Fever and chills/rigors are the most frequent infusion-related reactions expected to occur during the first AmBisome dose administration when no premedication to prevent these reactions is provided. In 2 double-blind, comparative studies, AmBisome-treated patients experienced a significantly lower incidence of infusion-related reactions, as compared to patients treated with conventional amphotericin B or amphotericin B lipid complex. Less frequent infusion-related reactions may consist of one or more of the following symptoms including back pain and/or chest tightness or pain, dyspnoea, bronchospasm, flushing, tachycardia and hypotension, and these resolved rapidly when the infusion was stopped. These reactions may not occur with every subsequent dose or when slower infusion rates (>2 hrs) are used (see Precautions).
The following adverse effects have been attributed to AmBisome. The incidence is based on analysis from pooled clinical trials of 688 AmBisome-treated patients. ≥10%: Fever, chills/rigors, hypokalaemia, nausea, vomiting.
10% to ≥1%: Creatinine increase, BUN increase, hypomagnesaemia, hypocalcaemia, hyperglycaemia, hyponatraemia, increased alkaline phosphatase, bilirubinaemia, abnormal liver function tests, diarrhoea, abdominal pain, dyspnoea, flushing/vasodilatation, headache, back pain, chest pain, tachycardia, hypotension, rash.
1% to ≥0.1%: Convulsion, bronchospasm, thrombocytopenia, anaphylactoid reaction, anaemia, phlebitis.
In 2 double-blind studies, the incidence of nephrotoxicity with AmBisome (as measured by serum creatinine increase >2 times the baseline measurement), is approximately ½ of that reported for conventional amphotericin B or amphotericin B lipid complex.
In addition to rare post-marketing reports of anaphylactoid reactions, occasional reports of less severe allergic-type reactions have been received in association with AmBisome infusion including very rare reports of angioedema.
Drug Interactions
No specific interaction studies have been performed with AmBisome. Although no clinically significant interactions of AmBisome with other drugs have been reported in clinical trials, patients requiring concomitant drug therapy should be monitored closely.
Conventional amphotericin has been reported to interact with antineoplastic agents and nephrotoxic drugs. In view of the potential of amphotericin B to cause reduction in serum potassium, AmBisome, like amphotericin B, may increase the effects of digitalis glycosides or muscle relaxants or may increase the potassium loss in the case of concurrent administration of AmBisome and corticosteroids or corticotropin (ACTH).
Concurrent administration of AmBisome with other nephrotoxic agents eg, cyclosporin and aminoglycosides, may increase the risk of nephrotoxicity in some patients. However, in patients receiving concomitant cyclosporin and/or aminoglycosides, AmBisome was associated with significantly less nephrotoxicity as compared to amphotericin B.
Caution For Usage
Do not reconstitute the lyophilised powder/cake with saline or add saline to the reconstituted concentrate, or mix with other drugs.
The use of any solution other than those recommended, or the presence of a bacteriostatic agent (eg, benzyl alcohol) in the solution, may cause precipitation of AmBisome.
Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in AmBisome, or in the materials specified for reconstitution and dilution.
Use only water for injection to reconstitute the powder/cake. Use only 5% dextrose injection to dilute the reconstituted product to the appropriate concentration for infusion. An in-line membrane filter may be used for IV infusion of AmBisome. However, the mean pore diameter of the filter should not be <1 micron.
Incompatibilities: AmBisome is not physically compatible with saline solutions and should not be mixed with other drugs or electrolytes. An existing IV line must be flushed with 5% dextrose injection prior to infusion of AmBisome. If this is not feasible, AmBisome should be administered through a separate line.
Storage
Unopened Vials: Store under refrigeration at 2-8°C (36-46°F). Protect against exposure to light. Do not freeze.
Reconstituted AmBisome Concentrate: May be stored for up to 24 hrs at 2-8°C (36-46°F) if AmBisome has been reconstituted aseptically with water. Do not freeze.
Reconstituted AmBisome, Diluted with 5% Dextrose: Do not freeze. As the product contains no bacteriostatic agent, infusion of AmBisome should commence as soon as possible after dilution with 5% dextrose.
Do not store partially used vials for future patient use.
MIMS Class
ATC Classification
J02AA01 - amphotericin B ; Belongs to the class of antibiotics. Used in the systemic treatment of mycotic infections.
Presentation/Packing
Infusion (vial) 50 mg (sterile, lyophilized, with filters) x 1's.
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