Components:
Method of action:
Treatment option:
Medically reviewed by Fedorchenko Olga Valeryevna, PharmD. Last updated on 30.03.2022
Attention! Information on this page is intended only for medical professionals! Information is collected in open sources and may contain significant errors! Be careful and double-check all the information on this page!
AmBisome for Injection is available as single cartons (equivalent to 50mg amphotericin B) and in packs often individual vial cartons (NDC 0469-3051-30).
Each carton contains one pre-packaged, disposable sterile 5 micron filter.
References
1. Clinical and Laboratory Standards Institute (CLSI). Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard -3rd edition. CLSI document M27- A3. CLSI, 940 West Valley Rd. Suite 1400, Wayne, PA 19087-1898, 2008.
2. CLSI. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeast; 3rd Informational Supplement. CLSI document M27-S3, 2008.
3. CLSI. Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts; Approved Guideline- 2nd edition. CLSI document M44-A2, 2009.
4. CLSI Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi; Approved Standard - 2nd edition. CLSI document M38-A2, 2008.
5. CLSI. Method for Antifungal Disk Diffusion Susceptibility Testing of Nondermatophyte Filamentous Fungi; Approved Guideline. CLSI document M51-A, 2010.
Marketed by: Astellas Pharma US, Inc. Deerfield, IL 60015-2548. Manufactured by: Gilead Sciences, Inc. San Dimas, CA91773. AmBisome is a registered trademark of Gilead Sciences, Inc. Abelcet® is a registered trademark of The Liposome Company, Inc.
AmBisome is indicated for the following:
- Empirical therapy for presumed fungal infection in febrile, neutropenic patients.
- Treatment of Cryptococcal Meningitis in HIV infected patients (see Description Of Clinical Studies).
- Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections (see above for the treatment of Cryptococcal Meningitis) refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate.
- Treatment of visceral leishmaniasis. In immunocompromised patients with visceral leishmaniasis treated with AmBisome, relapse rates were high following initial clearance of parasites (see Description Of Clinical Studies).
See DOSAGE AND ADMINISTRATION for recommended doses by indication.
AmBisome should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes.
An in-line membrane filter may be used for the intravenous infusion of AmBisome; provided THE MEAN PORE DIAMETER OF THE FILTER IS NOT LESS THAN 1.0 MICRON.
NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of AmBisome. If this is not feasible, AmBisome must be administered through a separate line.
Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased.
The recommended initial dose of AmBisome for each indication for adult and pediatric patients is as follows:
| Indication | Dose (mg/kg/day) |
| Empirical therapy | 3 |
| Systemic fungal infections: Aspergillus Candida Cryptococcus |
3-5 |
| Cryptococcal meningitis in HIV infected patients (see Description Of Clinical Studies) | 6 |
Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events.
Doses recommended for visceral leishmaniasis are presented below:
| Visceral Leishmaniasis | Dose (mg/kg/day) |
| Immunocompetent patients | 3 (days 1-5) and 3 on days 14, 21 |
| Immunocompromised patients | 4 (days 1-5) and 4 on days 10, 17,24,31,38 |
For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, a repeat course of therapy may be useful.
For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information see Description Of Clinical Studies.
Directions for Reconstitution, Filtration and Dilution Read This Entire Section Carefully Before Beginning Reconstitution AmBisome must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of AmBisome containing 50 mg of amphotericin B are prepared as follows:
Reconstitution
- Aseptically add 12 mL of Sterile Water for Injection, USP to each AmBisome vial to yield a preparation containing 4 mg amphotericin B/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 in the solution, may cause precipitation of AmBisome.
- Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the AmBisome. AmBisome forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed.
Filtration and Dilution
3. Calculate the amount of reconstituted (4 mg/mL) AmBisome to be further diluted.
4. Withdraw this amount of reconstituted AmBisome 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 AmBisome.)
6. AmBisome must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL prior to administration. Lower concentrations (0.2 to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS.
Storage of AMBISOME
Unopened vials of lyophilized material are to be stored at temperatures up to 25° C (77° F).
Storage of Reconstituted Product Concentrate
The reconstituted product concentrate may be stored for up to 24 hours at 2°-8° C (36°-46° F) following reconstitution with Sterile Water for Injection, USP. Do not freeze.
Storage of Diluted Product
Injection of AmBisome should commence within 6 hours of dilution with 5% Dextrose Injection.
As with all parenteral drug products, the reconstituted AmBisome 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.
AmBisome is contraindicated in those patients who have demonstrated or have known hypersensitivity to amphotericin B deoxycholate or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk.
WARNINGS
Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including AmBisome. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of AmBisome.
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 underdose clinical observation. AmBisome has been shown to be significantly less toxic than amphotericin B deoxycholate; however, adverse events may still occur.
Laboratory Tests
Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, and serum electrolytes (particularly magnesium and potassium).
Drug-Laboratory Interactions: Serum phosphate false elevation
False elevations of serum phosphate may occur when samples from patients receiving AmBisome are analyzed using the PHOSm assay (e.g. used in Beckman Coulter analyzers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long term studies in animals have been performed to evaluate carcinogenic potential of AmBisome. AmBisome has not been tested to determine its mutagenic potential. A Segment I Reproductive Study in rats found an abnormal estrous cycle (prolonged diestrus) and decreased number of corpora lutea in the high dose groups (10 and 15 mg/kg, doses equivalent to human doses of 1.6 and 2.4 mg/kg based on body surface area considerations). AmBisome did not affect fertility or days to copulation. There were no effects on male reproductive function.
Pregnancy Category B
There have been no adequate and well-controlled studies of AmBisome in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B deoxycholate, but the number of cases reported has been small.
Segment II studies in both rats and rabbits have concluded that AmBisome had no teratogenic potential in these species. In rats, the maternal non-toxic dose of AmBisome was estimated to be 5 mg/kg (equivalent to 0.16 to 0.8 times the recommended human clinical dose range of 1 to 5 mg/kg) and in rabbits, 3 mg/kg (equivalent to 0.2 to 1 times the recommended human clinical dose range), based on body surface area correction. Rabbits receiving the higher doses, (equivalent to 0.5 to 2 times the recommended human dose) of AmBisome experienced a higher rate of spontaneous abortions than did the control groups. AmBisome should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks involved.
Nursing Mothers
Many drugs are excreted in human milk. However, it is not known whether AmBisome is excreted in human milk. Due to the potential for serious adverse reactions in breast-fed infants, a decision should be made whether to discontinue nursing or whether to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Pediatric patients, age 1 month to 16 years, with presumed fungal infection (empirical therapy), confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with AmBisome. In studies which included 302 pediatric patients administered AmBisome, there was no evidence of any differences in efficacy or safety of AmBisome compared to adults. Since pediatric patients have received AmBisome at doses comparable to those used in adults on a per kilogram body weight basis, no dosage adjustment is required in this population. Safety and effectiveness in pediatric patients below the age of one month have not been established. (See Description Of Clinical Studies - Empirical Therapy in Febrile Neutropenic Patients and DOSAGE AND ADMINISTRATION).
Elderly Patients
Experience with AmBisome in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of AmBisome for this population. As with most other drugs, elderly patients receiving AmBisome should be carefully monitored.
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:
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 |
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| 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%) | <|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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:
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 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.
Management
If overdosage should occur, cease administration immediately. Symptomatic supportive measures should be instituted. Particular attention should be given to monitoring renal function. Hemodialysis or peritoneal dialysis do not appear to significantly affect the elimination of AmBisome.
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
| Dose (mg/kg/day): |
1 | 2.5 | 5 | |||
| Day | 1 n = 8 |
Last n = 7 |
1 n = 7 |
Last n = 7 |
1 n = 12 |
Last n = 9 |
| Parameters | ||||||
| Cmax (mcg/mL) |
7.3 ± 3.8 | 12.2 ±4.9 | 17.2 ±7.1 | 31.4 ±17.8 | 57.6 ±21 | 83 ± 35.2 |
| AUC0-24 (mcg»hr/mL) |
27 ±14 | 60 ±20 | 65 ±33 | 197 ±183 | 269 ± 96 | 555 ± 31 1 |
| t1/2 (hr) |
10.7 ±6.4 | 7 ±2.1 | 8.1 ±2.3 | 6.3 ±2 | 6.4 ±2.1 | 6.8 ±2.1 |
| Vss (L/kg) | 0.44 ± 0.27 | 0.14 ±0.05 | 0.40 ± 0.37 | 0.16 ±0.09 | 0.16±0.10 | 0.10 ±0.07 |
| Cl (mL/hr/kg) | 39 ±22 | 17±6 | 51 ±44 | 22 ±15 | 21 ±14 | 11 ±6 |
Distribution
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.
Metabolism
The metabolic pathways of amphotericin B after administration of AmBisome are not known.
Excretion
The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of AmBisome has not been studied.
