Ambisome

Overdose

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-related toxicity.

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 AmBisome.

Undesirable effects

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

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

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 AmBisome 3 mg/kg, 94 patients were treated with AmBisome 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:

Cryptococcal Meningitis Therapy Study 94-0-013
Common Adverse Events

Infusion Related Reactions In Study 94-0-002, the large, double-blind study of pediatric and adult febrile neutropenic patients, no premedication to prevent infusion related reaction was administered prior to the first dose of study drug (Day 1). AmBisome-treated patients had a lower incidence of infusion related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on Day 1 as compared to amphotericin B deoxycholate-treated patients.

The incidence of infusion related reactions on Day 1 in pediatric and adult patients is summarized in the following table:

Incidence of Day 1 Infusion Related Reactions (IRR) By Patient Age

Cardiorespiratory events, except for vasodilatation (flushing), during all study drug infusions were more frequent in amphotericin B-treated patients as summarized in the following table:

Incidence of Infusion Related Cardiorespiratory Events

The percentage of patients who received drugs either for the treatment or prevention of infusion related reactions (e.g., acetaminophen, diphenhydramine, meperidine and hydrocortisone) was lower in AmBisome-treated patients compared with amphotericin B deoxycholate-treated patients.

In the empirical therapy study 97-0-034, on Day 1, where no premedication was administered, the overall incidence of infusion related events of chills/rigors was significantly lower for patients administered AmBisome compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each AmBisome group compared with the amphotericin B lipid complex group. The infusion related event hypoxia was reported for 11.5% of amphotericin B lipid complex-treated patients compared with 0% of patients administered 3 mg/kg per day AmBisome and 1.2% of patients treated with 5 mg/kg per day AmBisome.

Incidence of Day 1 Infusion Related Reactions (IRR) Chills/Rigors
Empirical Therapy Study 97-0-034

Patients were not administered premedications to prevent infusion related reactions prior to the Day 1 study drug infusion.

In Study 94-0-013, a randomized double-blind multicenter trial comparing AmBisome and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion related reactions were permitted. AmBisome treated patients had a lower incidence of fever, chill/rigors and respiratory adverse events as summarized in the following table:

Incidence of Infusion-Related Reactions Study 94-0-013

There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with AmBisome administration; on occasion this has been severe. Where these symptoms were noted, the reaction developed within a few minutes after the start of 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.

In Study 94-0-002, a significantly lower incidence of grade 3 or 4 toxicity was observed in the AmBisome group compared with the amphotericin B group. In addition, nearly three times as many patients administered amphotericin B required a reduction in dose due to toxicity or discontinuation of study drug due to an infusion related reaction compared with those administered AmBisome.

In empirical therapy study 97-0-034, a greater proportion of patients in the amphotericin B lipid complex group discontinued the study drug due to an adverse event than in the AmBisome groups.

The following adverse events also have been reported in 2% to 10% of AmBisome-treated patients receiving chemotherapy or bone marrow transplantation, or had HIV disease in six comparative, clinical trials:

Abdomen enlarged, allergic reaction, cellulitis, cell mediated immunological reaction, face edema, graft versus host disease, malaise, neck pain, and procedural complication.

Arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing).

Anorexia, constipation, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, hepatocellular damage, hepatomegaly, liver function test abnormal, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis, and veno-occlusive liver disease.

Anemia, coagulation disorder, ecchymosis, fluid overload, petechia, prothrombin decreased, prothrombin increased, and thrombocytopenia.

Acidosis, amylase increased, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactate dehydrogenase increased, nonprotein nitrogen (NPN) increased, and respiratory alkalosis.

Arthralgia, bone pain, dystonia, myalgia, and rigors.

Agitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor.

Asthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis.

Alopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash.

Conjunctivitis, dry eyes, and eye hemorrhage.

Abnormal renal function, acute kidney failure, acute renal failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence, and vaginal hemorrhage.

The following infrequent adverse experiences have been reported in post-marketing surveillance, in addition to those mentioned above: angioedema, erythema, urticaria, bronchospasm, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis, and rhabdomyolysis.

The effect of AmBisome on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in Study 94-0-002. The frequency and magnitude of hepatic test abnormalities were similar in the AmBisome and amphotericin B groups. Nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels in pediatric patients, and creatinine values increasing 100% or more over pretreatment levels in adult patients provided the peak creatinine concentration was > 1.2 mg/dL. Hypokalemia was defined as potassium levels ≤ 2.5 mmol/L any time during treatment.

Incidence of nephrotoxicity, mean peak serum creatinine concentration, mean change from baseline in serum creatinine, and, incidence of hypokalemia in the double-blind randomized study were lower in the AmBisome group as summarized in the following table:

Study 94-0-002 Laboratory Evidence of Nephrotoxicity

The effect of AmBisome (3 mg/kg/day) vs. amphotericin B (0.6 mg/kg/day) on renal function in adult patients enrolled in this study is illustrated in the following figure:

In empirical therapy study 97-0-034, the incidence of nephrotoxicity as measured by increases of serum creatinine from baseline was significantly lower for patients administered AmBisome (individual dose groups and combined) compared with amphotericin B lipid complex.

Incidence of Nephrotoxicity
Empirical Therapy Study 97-0-034

Pharmacokinetic properties

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 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.

Pharmacokinetic Parameters of AmBisome

Based 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.

The metabolic pathways of amphotericin B after administration of AmBisome are not known.

The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of AmBisome has not been studied.

Interaction with other medicinal products and other forms of interaction

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

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

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 AmBisome 3 mg/kg, 94 patients were treated with AmBisome 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:

Cryptococcal Meningitis Therapy Study 94-0-013
Common Adverse Events

Infusion Related Reactions In Study 94-0-002, the large, double-blind study of pediatric and adult febrile neutropenic patients, no premedication to prevent infusion related reaction was administered prior to the first dose of study drug (Day 1). AmBisome-treated patients had a lower incidence of infusion related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on Day 1 as compared to amphotericin B deoxycholate-treated patients.

The incidence of infusion related reactions on Day 1 in pediatric and adult patients is summarized in the following table:

Incidence of Day 1 Infusion Related Reactions (IRR) By Patient Age

Cardiorespiratory events, except for vasodilatation (flushing), during all study drug infusions were more frequent in amphotericin B-treated patients as summarized in the following table:

Incidence of Infusion Related Cardiorespiratory Events

The percentage of patients who received drugs either for the treatment or prevention of infusion related reactions (e.g., acetaminophen, diphenhydramine, meperidine and hydrocortisone) was lower in AmBisome-treated patients compared with amphotericin B deoxycholate-treated patients.

In the empirical therapy study 97-0-034, on Day 1, where no premedication was administered, the overall incidence of infusion related events of chills/rigors was significantly lower for patients administered AmBisome compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each AmBisome group compared with the amphotericin B lipid complex group. The infusion related event hypoxia was reported for 11.5% of amphotericin B lipid complex-treated patients compared with 0% of patients administered 3 mg/kg per day AmBisome and 1.2% of patients treated with 5 mg/kg per day AmBisome.

Incidence of Day 1 Infusion Related Reactions (IRR) Chills/Rigors
Empirical Therapy Study 97-0-034

Patients were not administered premedications to prevent infusion related reactions prior to the Day 1 study drug infusion.

In Study 94-0-013, a randomized double-blind multicenter trial comparing AmBisome and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion related reactions were permitted. AmBisome treated patients had a lower incidence of fever, chill/rigors and respiratory adverse events as summarized in the following table:

Incidence of Infusion-Related Reactions Study 94-0-013

There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with AmBisome administration; on occasion this has been severe. Where these symptoms were noted, the reaction developed within a few minutes after the start of 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.

In Study 94-0-002, a significantly lower incidence of grade 3 or 4 toxicity was observed in the AmBisome group compared with the amphotericin B group. In addition, nearly three times as many patients administered amphotericin B required a reduction in dose due to toxicity or discontinuation of study drug due to an infusion related reaction compared with those administered AmBisome.

In empirical therapy study 97-0-034, a greater proportion of patients in the amphotericin B lipid complex group discontinued the study drug due to an adverse event than in the AmBisome groups.

The following adverse events also have been reported in 2% to 10% of AmBisome-treated patients receiving chemotherapy or bone marrow transplantation, or had HIV disease in six comparative, clinical trials:

Abdomen enlarged, allergic reaction, cellulitis, cell mediated immunological reaction, face edema, graft versus host disease, malaise, neck pain, and procedural complication.

Arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing).

Anorexia, constipation, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, hepatocellular damage, hepatomegaly, liver function test abnormal, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis, and veno-occlusive liver disease.

Anemia, coagulation disorder, ecchymosis, fluid overload, petechia, prothrombin decreased, prothrombin increased, and thrombocytopenia.

Acidosis, amylase increased, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactate dehydrogenase increased, nonprotein nitrogen (NPN) increased, and respiratory alkalosis.

Arthralgia, bone pain, dystonia, myalgia, and rigors.

Agitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor.

Asthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis.

Alopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash.

Conjunctivitis, dry eyes, and eye hemorrhage.

Abnormal renal function, acute kidney failure, acute renal failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence, and vaginal hemorrhage.

The following infrequent adverse experiences have been reported in post-marketing surveillance, in addition to those mentioned above: angioedema, erythema, urticaria, bronchospasm, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis, and rhabdomyolysis.

The effect of AmBisome on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in Study 94-0-002. The frequency and magnitude of hepatic test abnormalities were similar in the AmBisome and amphotericin B groups. Nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels in pediatric patients, and creatinine values increasing 100% or more over pretreatment levels in adult patients provided the peak creatinine concentration was > 1.2 mg/dL. Hypokalemia was defined as potassium levels ≤ 2.5 mmol/L any time during treatment.

Incidence of nephrotoxicity, mean peak serum creatinine concentration, mean change from baseline in serum creatinine, and, incidence of hypokalemia in the double-blind randomized study were lower in the AmBisome group as summarized in the following table:

Study 94-0-002 Laboratory Evidence of Nephrotoxicity

The effect of AmBisome (3 mg/kg/day) vs. amphotericin B (0.6 mg/kg/day) on renal function in adult patients enrolled in this study is illustrated in the following figure:

In empirical therapy study 97-0-034, the incidence of nephrotoxicity as measured by increases of serum creatinine from baseline was significantly lower for patients administered AmBisome (individual dose groups and combined) compared with amphotericin B lipid complex.

Incidence of Nephrotoxicity
Empirical Therapy Study 97-0-034