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AmBisome (Liposomal Amphotericin B)
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Pharmacology
The active component of AmBisome is amphotericinB which acts by binding to the ergosterol component in the cell membrane of susceptible fungi. This results in a change in membrane permeability allowing leakage of cell components. 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 membrane and the damage to human cells and fungal cells may share a common mechanism.
AmBisome is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphiphilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. AmBisome consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane, forming a charge transfer complex with the distearoylphosphatidylglycerol. Due to the nature and quantity of amphiphilic 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. The unique size of the liposomes results in therapeutic levels at diverse sites of fungal infections within the body.
Studies have shown that AmBisome can remain as an intact liposome and stay in circulation for prolonged periods of time. It is taken up and retained in tissues rich in reticuloendothelial cells where fungal infection may occur. Preclinical studies have shown that liposomes with and without amphotericin B bind to the fungal cell wall. Liposomal amphotericin B acts by liposomal binding to the outer cell wall of fungi followed by drug release. On release the drug is thought to transfer to the ergosterol-rich fungal cell wall for which it has high affinity. Interaction with fungi occurs both within and outside macrophages. Liposomal and various lipid-complexed amphotericin B preparations differ significantly in their pharmacokinetic profile and tissue distribution.
Pharmacokinetics : The pharmacokinetic profile of amphotericin B after administration of liposomal amphotericin B is different from that of conventional amphotericin B (amphotericin B desoxycholate). In Phase I pharmacokinetic studies, liposomal amphotericin B produced higher peak serum concentrations between daily doses of 1.0 to 5.0 mg/kg/day (6- to 10-fold greater) and area under the serum concentration curve (AUC, approximately 13-fold higher) than those reported for conventional amphotericin B. The apparent volume of distribution ranged from 18.9 to 49.1L. The total body clearance of liposomal amphotericin B ranged from 0.5 to 1.3L/h. Data are shown in Table I. Detailed comparative studies with conventional amphotericin B are lacking. Some variability of the data in patients has been observed.
Amphotericin B concentrations were measured in autopsy material from 3 patients who died within 24 hours of receiving their last dose of liposomal amphotericin B. Drug concentrations were highest in the liver and spleen (tissues rich in reticuloendothelial cells) confirming data obtained from animal studies. Concentrations in lungs, kidneys, brain and heart were comparatively low. Detailed human tissue distribution have not been established for liposomal amphotericin B.
The active component of AmBisome is amphotericinB which acts by binding to the ergosterol component in the cell membrane of susceptible fungi. This results in a change in membrane permeability allowing leakage of cell components. 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 membrane and the damage to human cells and fungal cells may share a common mechanism.
AmBisome is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphiphilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. AmBisome consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane, forming a charge transfer complex with the distearoylphosphatidylglycerol. Due to the nature and quantity of amphiphilic 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. The unique size of the liposomes results in therapeutic levels at diverse sites of fungal infections within the body.
Studies have shown that AmBisome can remain as an intact liposome and stay in circulation for prolonged periods of time. It is taken up and retained in tissues rich in reticuloendothelial cells where fungal infection may occur. Preclinical studies have shown that liposomes with and without amphotericin B bind to the fungal cell wall. Liposomal amphotericin B acts by liposomal binding to the outer cell wall of fungi followed by drug release. On release the drug is thought to transfer to the ergosterol-rich fungal cell wall for which it has high affinity. Interaction with fungi occurs both within and outside macrophages. Liposomal and various lipid-complexed amphotericin B preparations differ significantly in their pharmacokinetic profile and tissue distribution.
Pharmacokinetics : The pharmacokinetic profile of amphotericin B after administration of liposomal amphotericin B is different from that of conventional amphotericin B (amphotericin B desoxycholate). In Phase I pharmacokinetic studies, liposomal amphotericin B produced higher peak serum concentrations between daily doses of 1.0 to 5.0 mg/kg/day (6- to 10-fold greater) and area under the serum concentration curve (AUC, approximately 13-fold higher) than those reported for conventional amphotericin B. The apparent volume of distribution ranged from 18.9 to 49.1L. The total body clearance of liposomal amphotericin B ranged from 0.5 to 1.3L/h. Data are shown in Table I. Detailed comparative studies with conventional amphotericin B are lacking. Some variability of the data in patients has been observed.
Amphotericin B concentrations were measured in autopsy material from 3 patients who died within 24 hours of receiving their last dose of liposomal amphotericin B. Drug concentrations were highest in the liver and spleen (tissues rich in reticuloendothelial cells) confirming data obtained from animal studies. Concentrations in lungs, kidneys, brain and heart were comparatively low. Detailed human tissue distribution have not been established for liposomal amphotericin B.
Indications
The Active Component Of AmBisome Is AmphotericinB Which Acts By Binding To The Ergosterol Component In The Cell Membrane Of Susceptible Fungi. This Results In A Change In Membrane Permeability Allowing Leakage Of Cell Components. 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 Membrane And The Damage To Human Cells And Fungal Cells May Share A Common Mechanism.
AmBisome Is A True Single Bilayer Liposomal Drug Delivery System. Liposomes Are Closed, Spherical Vesicles Created By Mixing Specific Proportions Of Amphiphilic Substances Such As Phospholipids And Cholesterol So That They Arrange Themselves Into Multiple Concentric Bilayer Membranes When Hydrated In Aqueous Solutions. AmBisome Consists Of These Unilamellar Bilayer Liposomes With Amphotericin B Intercalated Within The Membrane, Forming A Charge Transfer Complex With The Distearoylphosphatidylglycerol. Due To The Nature And Quantity Of Amphiphilic 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. The Unique Size Of The Liposomes Results In Therapeutic Levels At Diverse Sites Of Fungal Infections Within The Body.
Studies Have Shown That AmBisome Can Remain As An Intact Liposome And Stay In Circulation For Prolonged Periods Of Time. It Is Taken Up And Retained In Tissues Rich In Reticuloendothelial Cells Where Fungal Infection May Occur. Preclinical Studies Have Shown That Liposomes With And Without Amphotericin B Bind To The Fungal Cell Wall. Liposomal Amphotericin B Acts By Liposomal Binding To The Outer Cell Wall Of Fungi Followed By Drug Release. On Release The Drug Is Thought To Transfer To The Ergosterol-rich Fungal Cell Wall For Which It Has High Affinity. Interaction With Fungi Occurs Both Within And Outside Macrophages. Liposomal And Various Lipid-complexed Amphotericin B Preparations Differ Significantly In Their Pharmacokinetic Profile And Tissue Distribution.
Pharmacokinetics : The Pharmacokinetic Profile Of Amphotericin B After Administration Of Liposomal Amphotericin B Is Different From That Of Conventional Amphotericin B (amphotericin B Desoxycholate). In Phase I Pharmacokinetic Studies, Liposomal Amphotericin B Produced Higher Peak Serum Concentrations Between Daily Doses Of 1.0 To 5.0 Mg/kg/day (6- To 10-fold Greater) And Area Under The Serum Concentration Curve (AUC, Approximately 13-fold Higher) Than Those Reported For Conventional Amphotericin B. The Apparent Volume Of Distribution Ranged From 18.9 To 49.1L. The Total Body Clearance Of Liposomal Amphotericin B Ranged From 0.5 To 1.3L/h. Data Are Shown In Table I. Detailed Comparative Studies With Conventional Amphotericin B Are Lacking. Some Variability Of The Data In Patients Has Been Observed.
Amphotericin B Concentrations Were Measured In Autopsy Material From 3 Patients Who Died Within 24 Hours Of Receiving Their Last Dose Of Liposomal Amphotericin B. Drug Concentrations Were Highest In The Liver And Spleen (tissues Rich In Reticuloendothelial Cells) Confirming Data Obtained From Animal Studies. Concentrations In Lungs, Kidneys, Brain And Heart Were Comparatively Low. Detailed Human Tissue Distribution Have Not Been Established For Liposomal Amphotericin B.
The Active Component Of AmBisome Is AmphotericinB Which Acts By Binding To The Ergosterol Component In The Cell Membrane Of Susceptible Fungi. This Results In A Change In Membrane Permeability Allowing Leakage Of Cell Components. 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 Membrane And The Damage To Human Cells And Fungal Cells May Share A Common Mechanism.
AmBisome Is A True Single Bilayer Liposomal Drug Delivery System. Liposomes Are Closed, Spherical Vesicles Created By Mixing Specific Proportions Of Amphiphilic Substances Such As Phospholipids And Cholesterol So That They Arrange Themselves Into Multiple Concentric Bilayer Membranes When Hydrated In Aqueous Solutions. AmBisome Consists Of These Unilamellar Bilayer Liposomes With Amphotericin B Intercalated Within The Membrane, Forming A Charge Transfer Complex With The Distearoylphosphatidylglycerol. Due To The Nature And Quantity Of Amphiphilic 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. The Unique Size Of The Liposomes Results In Therapeutic Levels At Diverse Sites Of Fungal Infections Within The Body.
Studies Have Shown That AmBisome Can Remain As An Intact Liposome And Stay In Circulation For Prolonged Periods Of Time. It Is Taken Up And Retained In Tissues Rich In Reticuloendothelial Cells Where Fungal Infection May Occur. Preclinical Studies Have Shown That Liposomes With And Without Amphotericin B Bind To The Fungal Cell Wall. Liposomal Amphotericin B Acts By Liposomal Binding To The Outer Cell Wall Of Fungi Followed By Drug Release. On Release The Drug Is Thought To Transfer To The Ergosterol-rich Fungal Cell Wall For Which It Has High Affinity. Interaction With Fungi Occurs Both Within And Outside Macrophages. Liposomal And Various Lipid-complexed Amphotericin B Preparations Differ Significantly In Their Pharmacokinetic Profile And Tissue Distribution.
Pharmacokinetics : The Pharmacokinetic Profile Of Amphotericin B After Administration Of Liposomal Amphotericin B Is Different From That Of Conventional Amphotericin B (amphotericin B Desoxycholate). In Phase I Pharmacokinetic Studies, Liposomal Amphotericin B Produced Higher Peak Serum Concentrations Between Daily Doses Of 1.0 To 5.0 Mg/kg/day (6- To 10-fold Greater) And Area Under The Serum Concentration Curve (AUC, Approximately 13-fold Higher) Than Those Reported For Conventional Amphotericin B. The Apparent Volume Of Distribution Ranged From 18.9 To 49.1L. The Total Body Clearance Of Liposomal Amphotericin B Ranged From 0.5 To 1.3L/h. Data Are Shown In Table I. Detailed Comparative Studies With Conventional Amphotericin B Are Lacking. Some Variability Of The Data In Patients Has Been Observed.
Amphotericin B Concentrations Were Measured In Autopsy Material From 3 Patients Who Died Within 24 Hours Of Receiving Their Last Dose Of Liposomal Amphotericin B. Drug Concentrations Were Highest In The Liver And Spleen (tissues Rich In Reticuloendothelial Cells) Confirming Data Obtained From Animal Studies. Concentrations In Lungs, Kidneys, Brain And Heart Were Comparatively Low. Detailed Human Tissue Distribution Have Not Been Established For Liposomal Amphotericin B.
Contraindications
In patients who have demonstrated or have known hypersensitivity to conventional amphotericin B or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk.
In patients who have demonstrated or have known hypersensitivity to conventional amphotericin B or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk.
Safety Information / Warning
Anaphylaxis has been reported with conventional amphotericin B and other amphotericin-containing drugs. Anaphylactoid type reactions have been reported with liposomal amphotericin B. If a severe reaction occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of liposomal amphotericin B.
Liposomal amphotericin B should be administered primarily to patients with progressive, potentially fatal infections. This drug should not be used to treat the common apparent forms of fungal diseases which show only positive skin or serologic tests.
Anaphylaxis has been reported with conventional amphotericin B and other amphotericin-containing drugs. Anaphylactoid type reactions have been reported with liposomal amphotericin B. If a severe reaction occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of liposomal amphotericin B.
Liposomal amphotericin B should be administered primarily to patients with progressive, potentially fatal infections. This drug should not be used to treat the common apparent forms of fungal diseases which show only positive skin or serologic tests.
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. Liposomal amphotericin B has been shown to be significantly less toxic than traditional amphotericin B; however, adverse events may still occur. In general, patients should be monitored for any of the adverse events associated with the use of amphotericin B. In particular, caution should be exercised when prolonged therapy is required.
Geriatrics: Experience with liposomal amphotericin B in the elderly (³65 years) is limited to 23 patients. As is necessary with most other drugs, elderly patients receiving liposomal amphotericin B should be carefully monitored.
Children: Pediatric patients £16 years with confirmed systemic fungal infections or with visceral leishmaniasis have been treated with liposomal amphotericin B. In addition, pediatric patients with presumed fungal infection (empiric therapy) have been treated with liposomal amphotericin B. In studies which included 217 pediatric patients there was no evidence of any differences in safety compared to adults. Since pediatric patients have received liposomal amphotericin B at doses comparable to those used in adults on a per kg body weight basis, no dosage adjustment is required in this population.
Pregnancy : Reproduction studies in animals have revealed no evidence of teratogenicity at human therapeutic doses. Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin B without obvious effects to the fetus, but the number of case reports has been small. Because animal reproduction studies are not always predictive of human response, and adequate and well controlled studies have not been conducted in pregnant women, this drug should be administered during pregnancy with caution and only if the potential benefit to the mother outweighs the potential risk to the fetus.
Lactation : Many drugs are excreted in human milk. However, it is not known whether liposomal amphotericin B 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.
Carcinogenicity/Mutagenicity: Liposomal amphotericin B has not undergone testing for mutagenic or carcinogenic potential.
Special Diseases or Conditions: Hepatic Impairment: The effect of hepatic impairment on the disposition of liposomal amphotericin B is not known.
Renal Impairment: The effect of renal impairment on the disposition of liposomal amphotericin B has not been studied. However, liposomal amphotericin B has been successfully administered to patients with pre-existing renal impairment.
Diabetic Patients: It should be noted that liposomal amphotericin B contains approximately 900 mg of sucrose in each vial.
Renal Dialysis Patients: The administration of liposomal amphotericin B should be initiated after dialysis is completed.
Laboratory Tests: Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, complete blood counts and serum electrolytes (particularly magnesium and potassium).
Drug Interactions : No formal clinical studies of drug interactions have been conducted with liposomal amphotericin B. However, the following drugs are known to interact with amphotericin B and may interact with liposomal amphotericin B:
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 Corticotrophin (ACTH): Concurrent use of corticosteroids and corticotropin (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 with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with liposomal amphotericin B with caution.
Imidazoles (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 Transfusions: Acute pulmonary toxicity has been reported in patients simultaneously receiving i.v. amphotericin B and leukocyte transfusions. Leukocyte transfusions should not be given concurrently.
Other Nephrotoxic Agents: Concurrent use of amphotericin B and agents such as aminoglycosides and pentamidine may enhance the potential for drug-induced renal toxicity and should be used only with caution. 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., tubocurine) due to hypokalemia. When administered concomitantly, serum potassium levels should be closely monitored.
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. Liposomal amphotericin B has been shown to be significantly less toxic than traditional amphotericin B; however, adverse events may still occur. In general, patients should be monitored for any of the adverse events associated with the use of amphotericin B. In particular, caution should be exercised when prolonged therapy is required.
Geriatrics: Experience with liposomal amphotericin B in the elderly (³65 years) is limited to 23 patients. As is necessary with most other drugs, elderly patients receiving liposomal amphotericin B should be carefully monitored.
Children: Pediatric patients £16 years with confirmed systemic fungal infections or with visceral leishmaniasis have been treated with liposomal amphotericin B. In addition, pediatric patients with presumed fungal infection (empiric therapy) have been treated with liposomal amphotericin B. In studies which included 217 pediatric patients there was no evidence of any differences in safety compared to adults. Since pediatric patients have received liposomal amphotericin B at doses comparable to those used in adults on a per kg body weight basis, no dosage adjustment is required in this population.
Pregnancy : Reproduction studies in animals have revealed no evidence of teratogenicity at human therapeutic doses. Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin B without obvious effects to the fetus, but the number of case reports has been small. Because animal reproduction studies are not always predictive of human response, and adequate and well controlled studies have not been conducted in pregnant women, this drug should be administered during pregnancy with caution and only if the potential benefit to the mother outweighs the potential risk to the fetus.
Lactation : Many drugs are excreted in human milk. However, it is not known whether liposomal amphotericin B 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.
Carcinogenicity/Mutagenicity: Liposomal amphotericin B has not undergone testing for mutagenic or carcinogenic potential.
Special Diseases or Conditions: Hepatic Impairment: The effect of hepatic impairment on the disposition of liposomal amphotericin B is not known.
Renal Impairment: The effect of renal impairment on the disposition of liposomal amphotericin B has not been studied. However, liposomal amphotericin B has been successfully administered to patients with pre-existing renal impairment.
Diabetic Patients: It should be noted that liposomal amphotericin B contains approximately 900 mg of sucrose in each vial.
Renal Dialysis Patients: The administration of liposomal amphotericin B should be initiated after dialysis is completed.
Laboratory Tests: Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, complete blood counts and serum electrolytes (particularly magnesium and potassium).
Drug Interactions : No formal clinical studies of drug interactions have been conducted with liposomal amphotericin B. However, the following drugs are known to interact with amphotericin B and may interact with liposomal amphotericin B:
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 Corticotrophin (ACTH): Concurrent use of corticosteroids and corticotropin (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 with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with liposomal amphotericin B with caution.
Imidazoles (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 Transfusions: Acute pulmonary toxicity has been reported in patients simultaneously receiving i.v. amphotericin B and leukocyte transfusions. Leukocyte transfusions should not be given concurrently.
Other Nephrotoxic Agents: Concurrent use of amphotericin B and agents such as aminoglycosides and pentamidine may enhance the potential for drug-induced renal toxicity and should be used only with caution. 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., tubocurine) due to hypokalemia. When administered concomitantly, serum potassium levels should be closely monitored.
Side Effects / Adverse Effects
Liposomal amphotericin B is generally well tolerated. Chills and rigors associated with traditional amphotericin B are infrequent with liposomal amphotericin B. In addition, elevated serum creatinine levels and hypokalemia reported with traditional amphotericinB are much less frequent with liposomal amphotericinB therapy.
In both adult and pediatric patients treated with liposomal amphotericin B, the incidence of fever, rigors, and events associated with reduced renal function was reduced compared with the incidence seen in patients treated with conventional amphotericinB. There was a higher incidence of diarrhea in adult patients (17% for liposomal amphotericin B vs 7% for conventional amphotericin B) and a higher incidence of diarrhea and vomiting in pediatric patients (7% vs 3% for both events). In pediatric patients, there was a much lower incidence of hypokalemia in the liposomal amphotericinB group (9% with liposomal amphotericin B vs 23% with amphotericin B).
In a double-blind, placebo-controlled study of patients undergoing bone marrow transplantation or chemotherapy, there were no significant differences between liposomal amphotericin B and placebo in the incidence of adverse events.
There have been a few reports of back pain with or without chest tightness and chest pain associated with liposomal amphotericin B administration; on rare occasions this has been severe. In the few patients where these symptoms were noted, the reaction developed within a few minutes after the start of the infusion and disappeared rapidly when the infusion was stopped. The symptoms do not occur with every dose and usually do not recur on subsequent administrations when the infusion rate is slowed.
Postmarketing Experience: The following adverse events have also been reported in postmarketing surveillance in patients treated with liposomal amphotericin B. The causal relationship between these adverse events and liposomal amphotericin B is uncertain. All events occurred at a rate of less than 0.1%. It is estimated that more than 35300 patients have been treated with liposomal amphotericin B.
Body as a Whole: allergic reaction, anaphylactic reaction, fever, generalized edema, injection site reactions involving pain and inflammation, multi-organ failure, retrosternal pain and swelling (face, lips, eyes).
Cardiovascular: bradycardia, cardiac arrest, vasodilation (flushing), myocardial infarction and tachycardia.
Digestive: cholestasis, hyperbilirubinemia, jaundice, increased liver enzymes and stomach pain.
Hemic and Lymphatic: agranulocytosis, hemorrhagic cystitis, leukopenia, pelvic bleeding, fluid overload and thrombocytopenia.
Metabolic and Nutritional: hypocalcemia and urea increase.
Musculoskeletal: arthralgia.
Nervous System: dizziness, epilepsy and headache.
Respiratory: cough, cyanosis/hypoventilation, bronchospasm/wheezing and pulmonary edema.
Skin and Appendages: angioedema, erythema, sweating and urticaria.
Urogenital: nephrotoxicity/ renal impairment.
Clinical Laboratory Values: The effect of liposomal amphotericin B on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in randomized clinical trials. The laboratory data from the controlled clinical trials previously discussed were used in this analysis. Nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels. Hypokalemia was defined as potassium levels £2.5mmol/L any time during treatment.
For liposomal amphotericin B, 13% of patients had nephrotoxicity compared with 33% for patients treated with conventional amphotericin B. For hypokalemia, 10% of liposomal amphotericin B-treated patients had decreased serum potassium levels compared with 32% of patients who received the traditional amphotericin B formulation.
Liposomal amphotericin B is generally well tolerated. Chills and rigors associated with traditional amphotericin B are infrequent with liposomal amphotericin B. In addition, elevated serum creatinine levels and hypokalemia reported with traditional amphotericinB are much less frequent with liposomal amphotericinB therapy.
In both adult and pediatric patients treated with liposomal amphotericin B, the incidence of fever, rigors, and events associated with reduced renal function was reduced compared with the incidence seen in patients treated with conventional amphotericinB. There was a higher incidence of diarrhea in adult patients (17% for liposomal amphotericin B vs 7% for conventional amphotericin B) and a higher incidence of diarrhea and vomiting in pediatric patients (7% vs 3% for both events). In pediatric patients, there was a much lower incidence of hypokalemia in the liposomal amphotericinB group (9% with liposomal amphotericin B vs 23% with amphotericin B).
In a double-blind, placebo-controlled study of patients undergoing bone marrow transplantation or chemotherapy, there were no significant differences between liposomal amphotericin B and placebo in the incidence of adverse events.
There have been a few reports of back pain with or without chest tightness and chest pain associated with liposomal amphotericin B administration; on rare occasions this has been severe. In the few patients where these symptoms were noted, the reaction developed within a few minutes after the start of the infusion and disappeared rapidly when the infusion was stopped. The symptoms do not occur with every dose and usually do not recur on subsequent administrations when the infusion rate is slowed.
Postmarketing Experience: The following adverse events have also been reported in postmarketing surveillance in patients treated with liposomal amphotericin B. The causal relationship between these adverse events and liposomal amphotericin B is uncertain. All events occurred at a rate of less than 0.1%. It is estimated that more than 35300 patients have been treated with liposomal amphotericin B.
Body as a Whole: allergic reaction, anaphylactic reaction, fever, generalized edema, injection site reactions involving pain and inflammation, multi-organ failure, retrosternal pain and swelling (face, lips, eyes).
Cardiovascular: bradycardia, cardiac arrest, vasodilation (flushing), myocardial infarction and tachycardia.
Digestive: cholestasis, hyperbilirubinemia, jaundice, increased liver enzymes and stomach pain.
Hemic and Lymphatic: agranulocytosis, hemorrhagic cystitis, leukopenia, pelvic bleeding, fluid overload and thrombocytopenia.
Metabolic and Nutritional: hypocalcemia and urea increase.
Musculoskeletal: arthralgia.
Nervous System: dizziness, epilepsy and headache.
Respiratory: cough, cyanosis/hypoventilation, bronchospasm/wheezing and pulmonary edema.
Skin and Appendages: angioedema, erythema, sweating and urticaria.
Urogenital: nephrotoxicity/ renal impairment.
Clinical Laboratory Values: The effect of liposomal amphotericin B on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in randomized clinical trials. The laboratory data from the controlled clinical trials previously discussed were used in this analysis. Nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels. Hypokalemia was defined as potassium levels £2.5mmol/L any time during treatment.
For liposomal amphotericin B, 13% of patients had nephrotoxicity compared with 33% for patients treated with conventional amphotericin B. For hypokalemia, 10% of liposomal amphotericin B-treated patients had decreased serum potassium levels compared with 32% of patients who received the traditional amphotericin B formulation.
Overdose
Symptoms and Treatment: Repeated daily doses up to 7.5 mg/kg have been administered in clinical trials with no significant toxicity. If an overdose is suspected, discontinue therapy, monitor the patient's clinical status and administer supportive therapy as required.
Symptoms and Treatment: Repeated daily doses up to 7.5 mg/kg have been administered in clinical trials with no significant toxicity. If an overdose is suspected, discontinue therapy, monitor the patient's clinical status and administer supportive therapy as required.
Recommended Dosage
Should be administered by i.v. infusion over a 30- to 60-minute period. If the patient experiences discomfort during infusion, the duration of infusion may be increased. The recommended concentration for i.v. infusion is 0.2 to 2.0 mg/mL.
Data are presently insufficient to define total dose requirements and duration of treatment necessary for resolution of mycoses. The daily dose and duration of therapy should be based on the infecting organism, the patient's condition and the response to therapy. Treatment should be continued until clinical parameters and laboratory tests indicate that an active fungal infection has been cured or subsided. An inadequate period of treatment may lead to recurrence of active infection. Dose and duration of treatment may have to be individualized for the needs of specific patients.
Systemic Mycoses: Therapy is usually instituted at a daily dose of 1 mg/kg/day and increased stepwise up to 5 mg/kg/day, as required. A cumulative dose of 1.0 to 3.0 g of amphotericin B as liposomal amphotericin B over 3 to 4 weeks has been typical. Liposomal amphotericin B therapy has been administered for as long as 3months with a cumulative dose of 16.8 g of amphotericin B as liposomal amphotericin B without significant toxicity.
HIV-infected patients with disseminated cryptococcosis and including cryptococcal meningitis have been treated with a dose of 3 mg/kg/day for up to 42 days. Because of the high frequency of relapses, chronic suppressive therapy with another agent may be necessary after completion of a treatment course with liposomal amphotericin B.
Renal Impairment: The effect of renal impairment on the disposition of liposomal amphotericin B has not been studied. Liposomal amphotericin B has been successfully administered to patients with pre-existing renal impairment. For renal dialysis patients, administration should be initiated after dialysis is completed.
Hepatic Impairment: The effect of hepatic impairment on the disposition of liposomal amphotericin B is unknown.
Stability and Storage: Unopened Vials: Unopened vials of lyophilized material must be stored under refrigerated conditions of 2 to 8°C. Refrigerate. Do not freeze. Protect from light.
Reconstituted Product Concentrate: The reconstituted product concentrate may be stored for up to 24 hours at 2 to 8°C following reconstitution with Sterile Water for Injection USP. Do not freeze.
Reconstituted Product Diluted With 5% Dextrose: Do not freeze. Injection of liposomal amphotericin B should commence within 6 hours of dilution with 5% Dextrose.
Caution: Discard partially used vials.
Directions for Reconstitution and Dilution: Read this entire section carefully before beginning reconstitution.
Liposomal amphotericin B must be reconstituted using Sterile Water for Injection USP (without a bacteriostatic agent). Vials of liposomal amphotericin B containing 50 mg of amphotericin B are prepared as follows:
Reconstitution: 1)Aseptically add 12 mL of Sterile Water for Injection USP to each vial to yield a preparation containing 4 mg of amphotericin B/mL (50 mg/12.9 mL).
Caution: Do not reconstitute with saline or add saline to the reconstituted concentration, or mix with other drugs.
The use of any solution other than those recommended, or the presence of a bacteriostatic agent (e.g., benzyl alcohol) in the solution, may cause precipitation of liposomal amphotericin B.
2) Shake the vials vigorously for 15 seconds to completely disperse the liposomal amphotericin B. Liposomal amphotericin B forms a yellow, translucent suspension.
3) Calculate the amount of reconstituted (4 mg/mL) liposomal amphotericin B to be further diluted. Liposomal amphotericin B must be diluted with 5% dextrose injection to a final concentration between 0.2 and 2.0 mg/mL prior to administration.
4) Withdraw this amount of reconstituted liposomal amphotericin B into a sterile syringe.
5) Attach the 5-micron filter, provided, to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% dextrose injection. (Use only one filter per vial of liposomal amphotericin B).
As with all parenteral drug products, the reconstituted liposomal amphotericin B should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 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.
An in-line membrane filter may be used for i.v. infusion of liposomal amphotericin B. However, the mean pore diameter of the filter should not be less than 1.0 micron.
Note: An existing i.v. line must be flushed with 5% Dextrose Injection prior to infusion of liposomal amphotericin B. If this is not feasible, liposomal amphotericin B should be administered through a separate line.
Should be administered by i.v. infusion over a 30- to 60-minute period. If the patient experiences discomfort during infusion, the duration of infusion may be increased. The recommended concentration for i.v. infusion is 0.2 to 2.0 mg/mL.
Data are presently insufficient to define total dose requirements and duration of treatment necessary for resolution of mycoses. The daily dose and duration of therapy should be based on the infecting organism, the patient's condition and the response to therapy. Treatment should be continued until clinical parameters and laboratory tests indicate that an active fungal infection has been cured or subsided. An inadequate period of treatment may lead to recurrence of active infection. Dose and duration of treatment may have to be individualized for the needs of specific patients.
Systemic Mycoses: Therapy is usually instituted at a daily dose of 1 mg/kg/day and increased stepwise up to 5 mg/kg/day, as required. A cumulative dose of 1.0 to 3.0 g of amphotericin B as liposomal amphotericin B over 3 to 4 weeks has been typical. Liposomal amphotericin B therapy has been administered for as long as 3months with a cumulative dose of 16.8 g of amphotericin B as liposomal amphotericin B without significant toxicity.
HIV-infected patients with disseminated cryptococcosis and including cryptococcal meningitis have been treated with a dose of 3 mg/kg/day for up to 42 days. Because of the high frequency of relapses, chronic suppressive therapy with another agent may be necessary after completion of a treatment course with liposomal amphotericin B.
Renal Impairment: The effect of renal impairment on the disposition of liposomal amphotericin B has not been studied. Liposomal amphotericin B has been successfully administered to patients with pre-existing renal impairment. For renal dialysis patients, administration should be initiated after dialysis is completed.
Hepatic Impairment: The effect of hepatic impairment on the disposition of liposomal amphotericin B is unknown.
Stability and Storage: Unopened Vials: Unopened vials of lyophilized material must be stored under refrigerated conditions of 2 to 8°C. Refrigerate. Do not freeze. Protect from light.
Reconstituted Product Concentrate: The reconstituted product concentrate may be stored for up to 24 hours at 2 to 8°C following reconstitution with Sterile Water for Injection USP. Do not freeze.
Reconstituted Product Diluted With 5% Dextrose: Do not freeze. Injection of liposomal amphotericin B should commence within 6 hours of dilution with 5% Dextrose.
Caution: Discard partially used vials.
Directions for Reconstitution and Dilution: Read this entire section carefully before beginning reconstitution.
Liposomal amphotericin B must be reconstituted using Sterile Water for Injection USP (without a bacteriostatic agent). Vials of liposomal amphotericin B containing 50 mg of amphotericin B are prepared as follows:
Reconstitution: 1)Aseptically add 12 mL of Sterile Water for Injection USP to each vial to yield a preparation containing 4 mg of amphotericin B/mL (50 mg/12.9 mL).
Caution: Do not reconstitute with saline or add saline to the reconstituted concentration, or mix with other drugs.
The use of any solution other than those recommended, or the presence of a bacteriostatic agent (e.g., benzyl alcohol) in the solution, may cause precipitation of liposomal amphotericin B.
2) Shake the vials vigorously for 15 seconds to completely disperse the liposomal amphotericin B. Liposomal amphotericin B forms a yellow, translucent suspension.
3) Calculate the amount of reconstituted (4 mg/mL) liposomal amphotericin B to be further diluted. Liposomal amphotericin B must be diluted with 5% dextrose injection to a final concentration between 0.2 and 2.0 mg/mL prior to administration.
4) Withdraw this amount of reconstituted liposomal amphotericin B into a sterile syringe.
5) Attach the 5-micron filter, provided, to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% dextrose injection. (Use only one filter per vial of liposomal amphotericin B).
As with all parenteral drug products, the reconstituted liposomal amphotericin B should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 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.
An in-line membrane filter may be used for i.v. infusion of liposomal amphotericin B. However, the mean pore diameter of the filter should not be less than 1.0 micron.
Note: An existing i.v. line must be flushed with 5% Dextrose Injection prior to infusion of liposomal amphotericin B. If this is not feasible, liposomal amphotericin B should be administered through a separate line.
Supplied / Packaging
Each vial of sterile, nonpyrogenic lyophilized powder for i.v. infusion contains amphotericin B, USP 50 mg, intercalated into a liposomal membrane consisting of hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphtidylglycerol, a-tocopherol, together with sucrose, and disodium succinate hexahydrate (as buffer). Following reconstitution with Sterile Water for Injection, the resulting pH of the suspension is 5.0 to 6.0. Single unit vials, packs of 4 and 10 in individual cartons. Each carton contains 1prepackaged, disposable sterile 5 micron filter. Store under refrigerated conditions of 2 to 8°C. Do not freeze. Protect from light.
Each vial of sterile, nonpyrogenic lyophilized powder for i.v. infusion contains amphotericin B, USP 50 mg, intercalated into a liposomal membrane consisting of hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphtidylglycerol, a-tocopherol, together with sucrose, and disodium succinate hexahydrate (as buffer). Following reconstitution with Sterile Water for Injection, the resulting pH of the suspension is 5.0 to 6.0. Single unit vials, packs of 4 and 10 in individual cartons. Each carton contains 1prepackaged, disposable sterile 5 micron filter. Store under refrigerated conditions of 2 to 8°C. Do not freeze. Protect from light.
