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Ambisome

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Ambisome

Side Effects
Interactions

SIDE 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

Adverse Event by Body System AmBisome
n=343
%
Amphotericin B
n=344
%
Body as a Whole
  Abdominal pain 19.8 21.8
  Asthenia 13.1 10.8
  Back pain 12 7.3
  Blood product transfusion react. 18.4 18.6
  Chills 47.5 75.9
  Infection 11.1 9.3
  Pain 14 12.8
  Sepsis 14 11.3
Cardiovascular System
  Chest pain 12 11.6
  Hypertension 7.9 16.3
  Hypotension 14.3 21.5
  Tachycardia 13.4 20.9
Digestive System
  Diarrhea 30.3 27.3
  Gastrointestinal hemorrhage 9.9 11.3
  Nausea 39.7 38.7
  Vomiting 31.8 43.9
Metabolic and Nutritional Disorders
  Alkaline phosphatase increased 22.2 19.2
  ALT (SGPT) increased 14.6 14
  AST (SCOT) increased 12.8 12.8
  Bilirubinemia 18.1 19.2
  BUN increased 21 31.1
  Creatinine increased 22.4 42.2
  Edema 14.3 14.8
  Hyperglycemia 23 27.9
  Hypematremia 4.1 11
  Hypervolemia 12.2 15.4
  Hypocalcemia 18.4 20.9
  Hypokalemia 42.9 50.6
  Hypomagnesemia 20.4 25.6
  Peripheral edema 14.6 17.2
Nervous System
  Anxiety 13.7 11
  Confusion 11.4 13.4
  Headache 19.8 20.9
  Insomnia 17.2 14.2
Respiratory System
  Cough increased 17.8 21.8
  Dyspnea 23 29.1
  Epistaxis 14.9 20.1
  Hypoxia 7.6 14.8
  Lung disorder 17.8 17.4
  Pleural effusion 12.5 9.6
  Rhinitis 11.1 11
Skin and Appendages
  Pruritus 10.8 10.2
  Rash 24.8 24.4
  Sweating 7 10.8
Urogenital System
  Hematuria 14 14

AmBisome was well tolerated. AmBisome had a lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin B deoxycholate.

In pediatric patients (16 years of age or less) in this double-blind study, AmBisome compared to amphotericin B deoxycholate had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Similar trends, although with a somewhat lower incidence, were observed in open-label, randomized Study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with AmBisome and 64 treated with amphotericin B deoxycholate). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin B deoxycholate.

The following adverse events are based on the experience of 244 patients (202 adult and 42 pediatric patients) of whom 85 patients were treated with AmBisome 3 mg/kg, 81 patients were treated with AmBisome 5 mg/kg and 78 patients treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized double-blind, multi-center study in febrile, neutropenic patients. AmBisome and amphotericin B lipid complex were infused over two hours. The incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table:

Empirical Therapy Study 97-0-034
Common Adverse Events

Adverse Event by Body System AmBisome
3 mg/kg/day
n=85
%
AmBisome
5 mg/kg/day
n=81
%
Amphotericin
B Lipid Complex
5 mg/kg/day
n=78
%
Body as a Whole
  Abdominal pain 12.9 9.9 11.5
  Asthenia 8.2 6.2 11.5
  Chills/rigors 40 48.1 89.7
  Sepsis 12.9 7.4 11.5
  Transfusion reaction 10.6 8.6 5.1
Cardiovascular System
  Chest pain 8.2 11.1 6.4
  Hypertension 10.6 19.8 23.1
  Hypotension 10.6 7.4 19.2
  Tachycardia 9.4 18.5 23.1
Digestive System
  Diarrhea 15.3 17.3 14.1
  Nausea 25.9 29.6 37.2
  Vomiting 22.4 25.9 30.8
Metabolic and Nutritional Disorders
  Alkaline phosphatase increased 7.1 8.6 12.8
  Bilirubinemia 16.5 11.1 11.5
  BUN increased 20 18.5 28.2
  Creatinine increased 20 18.5 48.7
  Edema 12.9 12.3 12.8
  Hyperglycemia 8.2 8.6 14.1
  Hypervolemia 8.2 11.1 14.1
  Hypocalcemia 10.6 4.9 5.1
  Hypokalemia 37.6 43.2 39.7
  Hypomagnesemia 15.3 25.9 15.4
  Liver function tests abnormal 10.6 7.4 11.5
Nervous System
  Anxiety 10.6 7.4 9
  Confusion 12.9 8.6 3.8
  Headache 9.4 17.3 10.3
Respiratory System
  Dyspnea 17.6 22.2 23.1
  Epistaxis 10.6 8.6 14.1
  Hypoxia 7.1 6.2 20.5
  Lung disorder 14.1 13.6 15.4
Skin and Appendages
  Rash 23.5 22.2 14.1

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

Adverse Event by Body System AmBisome
3 mg/kg/day
n=86
%
AmBisome
6 mg/kg/day
n=94
%
Amphotericin B
0.7 mg/kg/day
n=87
%
Body as a Whole
  Abdominal pain 7 7.4 10.3
  Infection 12.8 11.7 6.9
  Procedural Complication 8.1 9.6 10.3
Cardiovascular System
  Phlebitis 9.3 10.6 25.3
Digestive System
  Anorexia 14 9.6 11.5
  Constipation 15.1 14.9 20.7
  Diarrhea 10.5 16 10.3
  Nausea 16.3 21.3 25.3
  Vomiting 10.5 21.3 20.7
Hemic and Lymphatic System
  Anemia 26.7 47.9 43.7
  Leukopenia 15.1 17 17.2
  Thrombocytopenia 5.8 12.8 6.9
Metabolic and Nutritional Disorders
  Bilirubinemia 0 8.5 12.6
  BUN increased 9.3 7.4 10.3
  Creatinine increased 18.6 39.4 43.7
  Hyperglycemia 9.3 12.8 17.2
  Hypocalcemia 12.8 17 13.8
  Hypokalemia 31.4 51.1 48.3
  Hypomagnesemia 29.1 48.9 40.2
  Hyponatremia 11.6 8.5 9.2
  Liver Function Tests Abnormal 12.8 4.3 9.2
Nervous System
  Dizziness 7 8.5 10.3
  Insomnia 22.1 17 20.7
Respiratory System
  Cough Increased 8.1 2.1 10.3
Skin and Appendages
  Rash 4.7 11.7 4.6

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

  Pediatric Patients
( ≤ 16 years of age)
Adult Patients
( > 1 6 years of age)
AmBisome Amphotericin B AmBisome Amphotericin B
Total number of patients receiving at least one dose of study drug 48 47 295 297
Patients with fever
Increase ≥ 1.0°C
6(13%) 22 (47%) 52(18%) 128(43%)
Patients with chills/rigors 4 (8%) 22 (47%) 59 (20%) 165(56%)
Patients with nausea 4 (8%) 4 (9%) 38(13%) 31 (10%)
Patients with vomiting 2 (4%) 7(15%) 19(6%) 21 (7%)
Patients with other reactions 10(21%) 13(28%) 47(16%) 69 (23%)
Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded).

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

Event AmBisome
n=343
Amphotericin B
n=344
Hypotension 12 (3.5%) 28 (8.1%)
Tachycardia 8 (2.3%) 43 (12.5%)
Hypertension 8 (2.3%) 39 (11.3%)
Vasodilatation 18 (5.2%) 2 (0.6%)
Dyspnea 16 (4.7%) 25 (7.3%)
Hyperventilation 4(1.2%) 17 (4.9%)
Hypoxia 1 (0.3%) 22 (6.4%)

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

  AmBisome Amphotericin B
lipid complex
5 mg/kg/day
3 mg/kg/day 5 mg/kg/day BOTH
Total number of patients 85 81 166 78
Patients with Chills/Rigors (Day1) 16 (18.8%) 19 (23.5%) 35 (21.1%) 62 (79.5%)
Patients with other notable reactions: Fever ( > 1 .0°C increase in temperature)
  Nausea 20 (23.5%) 16(19.8%) 36 (21.7%) 45 (57.7%)
  Vomiting 9(10.6%) 7 (8.6%) 16 (9.6%) 9(11.5%)
  Hypertension 5 (5.9%) 5 (6.2%) 10 (6%) 11 (14.1%)
  Tachycardia 4 (4.7%) 7 (8.6%) 11 (6.6%) 12(15.4%)
  Dyspnea 2 (2.4%) 8 (9.9%) 10(6%) 14(17.9%)
  Hypoxia 4 (4.7%) 8 (9.9%) 12(7.2%) 8(10.3%)
  0 1 (1.2%) 1 ( < 1%) 9(11.5%)
Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded).

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

  AmBisome 3 mg/kg AmBisome 6 mg/kg Amphotericin B
Total number of patients receiving at least one dose of study drug 86 94 87
Patients with fever increase of > 1 °C 6 (7%) 8 (9%) 24 (28%)
Patients with chills/rigors 5 (6%) 8 (9%) 42 (48%)
Patients with nausea 11 (13%) 13(14%) 18(20%)
Patients with vomiting 14(16%) 13(14%) 16(18%)
Respiratory adverse events 0 1 (1%) 8 (9%)

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.

Toxicity and Discontinuation of Dosing

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.

Less Common Adverse Events

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:

Body as a Whole

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

Cardiovascular System

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

Digestive System

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.

Hemic & Lymphatic System

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

Metabolic & Nutritional Disorders

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

Musculoskeletal System

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

Nervous System

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

Respiratory System

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

Skin & Appendages

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

Special Senses

Conjunctivitis, dry eyes, and eye hemorrhage.

Urogenital System

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

Post-marketing Experience

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.

Clinical Laboratory Values

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

  AmBisome Amphotericin B
Total number of patients receiving at least one dose of study drug 343 344
Nephrotoxicity 64 (18.7%) 116 (33.7%)
Mean peak creatinine 1.24 mg/dL 1.52 mg/dL
Mean change from baseline in creatinine 0.48 mg/dL 0.77 mg/dL
Hypokalemia 23 (6.7%) 40 (11 .6%)

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:

The effect of AmBisome (3 mg/kg/day) vs. amphotericin B (0.6 mg/kg/day) on renal function - Illustration

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

  AmBisome Amphotericin B
lipid complex
5 mg/kg/day
3 mg/kg/day 5 mg/kg/day BOTH
Total number of patients 85 81 166 78
Number with nephrotoxicity        
1.5X baseline serum creatinine value 25 (29.4%) 21 (25.9%) 46 (27.7%) 49 (62.8%)
2X baseline serum creatinine value 12(14.1%) 12(14.8%) 24 (14.5%) 33 (42.3%)

The following graph shows the average serum creatinine concentrations in the compassionate use study and shows that there is a drop from pretreatment concentrations for all patients, especially those with elevated (greater than 1.7 mg/dL) pretreatment creatinine concentrations.

Average serum creatinine concentrations in the compassionate use study - Illustration

The incidence of nephrotoxicity in Study 94-0-013, comparative trial in cryptococcal meningitis was lower in the AmBisome groups as shown in the following table:

Laboratory Evidence of Nephrotoxicity Study 94-0-013

  AmBisome 3 mg/kg AmBisome 6 mg/kg Amphotericin B
Total number of patients receiving at least one dose of study drug 86 94 87
Number with Nephrotoxicity (%)
1 .5X baseline serum creatinine 30 (35%) 44 (47%) 52 (60%)
2 X baseline serum creatinine 12(14%) 20(21%) 29 (33%)

Read the Ambisome (amphotericin b) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No formal clinical studies of drug interactions have been conducted with AmBisome. However, the following drugs are known to interact with amphotericin B and may interact with AmBisome:

Antineoplastic 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.)

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 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.

Read the Ambisome Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 3/16/2012
This monograph has been modified to include the generic and brand name in many instances.

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