1. How is AmBisome^® supplied?
2. How rapidly can AmBisome be infused?
3. Does the dose of AmBisome need to be adjusted in pediatric patients?
4. Does the dose of AmBisome need to be adjusted in elderly patients?
5. Is AmBisome excreted in the milk of nursing mothers?
6. Should AmBisome be administered in pregnant women?
7. What is the recommended initial dose of AmBisome?
8. What are the directions for reconstitution, filtration, and dilution of AmBisome?
9. What are the most frequent adverse reactions associated with AmBisome therapy and how do they compare with those of amphotericin B deoxycholate?
10. Is AmBisome associated with infusion-related reactions and how do they compare with those of amphotericin B deoxycholate?
11. What are the approved indications of AmBisome?
12. What drug interactions are associated with AmBisome?
13. What organisms is AmBisome active against in vitro?
14. Does AmBisome need to be filtered?
15. How is an AmBisome overdose managed?
16. What laboratory tests should be monitored for patients receiving AmBisome?
17. How does AmBisome compare with Abelcet^® in terms of infusion-related reactions (IRR)?
18. How does AmBisome compare with Abelcet in terms of nephrotoxicity?
19. How does AmBisome compare to other lipid-complex Amphotericin B containing products ?
20. How is AmBisome stored?
21. Are there any warnings regarding the use of AmBisome?

1. How is AmBisome^® supplied?

AmBisome (amphotericin B) liposome for injection is available as single 50 mg vial cartons and in packs of ten individual vial cartons. Each vial contains 50 mg of amphotericin B, USP, intercalated into a liposomal membrane consisting of approximately 213 mg hydrogenated soy phosphatidylcholine; 52 mg cholesterol, NF; 84 mg distearoylphosphatidylglycerol; 0.64 mg alpha tocopherol, USP; together with 900 mg sucrose, NF; and 27 mg disodium succinate hexahydrate as buffer. Following reconstitution with Sterile Water for Injection, USP, the resulting pH of the suspension is between 5.0-6.0.

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2. How rapidly can AmBisome be infused?

AmBisome should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes. 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.

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3. Does the dose of AmBisome need to be adjusted in pediatric patients?

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.

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4. Does the dose of AmBisome need to be adjusted in 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.

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5. Is AmBisome excreted in the milk of 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 discontinue the drug, taking into account the importance of the drug to the mother.

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6. Should AmBisome be administered in pregnant women?

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.

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7. What is the recommended initial dose of AmBisome?

The recommended initial dose of AmBisome for each indication for adult and pediatric patients is as follows:

Indication	Dose (mg/kg/day)
Empirical Therapy	3.0
Systemic fungal infections: Aspergillus Candida Cryptococcus Cryptococcal meningitis in HIV-infected patients	3.0 - 5.0 6.0

*AmBisome is indicated for the following:

• Empirical therapy for presumed fungal infection in febrile, neutropenic patients.
• Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections 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.
• Treatment of cryptococcal meningitis in HIV-infected patients.

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	3.0 (days 1-5) and 3.0 on days 14, 21
Immunocompromised patients	4.0 (days 1-5) and 4.0 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 in package insert).

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8. What are the directions for reconstitution, filtration, and dilution of AmBisome?

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

1. 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.
2. 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 1.0 to 2.0 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.

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.

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9. What are the most frequent adverse reactions associated with AmBisome therapy and how do they compare with those of amphotericin B deoxycholate?

The following adverse events are based on the results of a randomized double-blind, multi-center study (Study 94-0-002) in febrile, neutropenic patients. The study involved 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). AmBisome and amphotericin B were infused over two hours. The incidence of the most common adverse events (incidence of 10% or greater) occurring with AmBisome in comparison to amphotericin B deoxycholate, regardless of relationship to study drug, is shown in the following table:

Common Adverse Events

Adverse Event by Body System	AmBisome n=343 %	amphotericin B n=344 %
Body as a Whole
Abdominal pain Asthenia Back pain Blood product transfusion react. Chills Infection Pain Sepsis	19.8 13.1 12.0 18.4 47.5 11.1 14.0 14.0	21.8 10.8 7.3 18.6 75.9 9.3 12.8 11.3
Cardiovascular System
Chest pain Hypertension Hypotension Tachycardia	12.0 7.9 14.3 13.4	11.6 16.3 21.5 20.9
Digestive System
Diarrhea Gastrointestinal hemorrhage Nausea Vomiting	30.3 9.9 39.7 31.8	27.3 11.3 38.7 43.9
Metabolic and Nutritional Disorders
Alkaline phosphatase increased ALT (SGPT) increased AST (SGOT) increased Bilirubinemia BUN increased Creatinine increased Edema Hyperglycemia Hypernatremia Hypervolemia Hypocalcemia Hypokalemia Hypomagnesemia Peripheral edema	22.2 14.6 12.8 18.1 21.0 22.4 14.3 23.0 4.1 12.2 18.4 42.9 20.4 14.6	19.2 14.0 12.8 19.2 31.1 42.2 14.8 27.9 11.0 15.4 20.9 50.6 25.6 17.2
Nervous System
Anxiety Confusion Headache Insomnia	13.7 11.4 19.8 17.2	11.0 13.4 20.9 14.2
Respiratory System
Cough increased Dyspnea Epistaxis Hypoxia Lung disorder Pleural effusion Rhinitis	17.8 23.0 14.9 7.6 17.8 12.5 11.1	21.8 29.1 20.1 14.8 17.4 9.6 11.0
Skin and Appendages
Pruritus Rash Sweating	10.8 24.8 7.0	10.2 24.4 10.8
Urogenital System
Hematuria	14.0	14.0

AmBisome was well tolerated and 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 a double-blind study comparing AmBisome to amphotericin B (study 94-0-002), pediatric patients (16 years of age or less), had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin B deoxycholate.

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10. Is AmBisome associated with infusion-related reactions and how do they compare with those of amphotericin B deoxycholate?

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 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.

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.

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11. What are the approved indications of AmBisome?

AmBisome is indicated for the following:

• Empirical therapy for presumed fungal infection in febrile, neutropenic patients (see Pivotal Trials).
• Treatment of cryptococcal meningitis in HIV-infected patients (see Pivotal Trials).
• 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 Pivotal Trials).

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12. What drug interactions are associated with AmBisome?

There have been no formal clinical studies of drug interactions conducted with AmBisome, however, the following drugs are known to interact with amphotericin B and may interact with AmBisome as well:

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.

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13. What organisms is AmBisome active against in vitro?

AmBisome has shown in vitro activity comparable to amphotericin B against the following organisms:

Aspergillus species (A. fumigatus, A. flavus), Candida species (C. albicans, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis), Cryptococcus neoformans, and Blastomyces dermatitidis.

AmBisome is active in animal models against Aspergillus fumigatus, Candida albicans, Candida krusei, Candida lusitaniae, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Leishmania donovani, and Leishmania infantum. The administration of AmBisome in these animal models demonstrated prolonged survival of infected animals, reduction of microorganisms from target organs, or a decrease in lung weight.

However, standardized techniques for susceptibility testing of antifungal agents have not been established and results of such studies do not necessarily correlate with clinical outcome.

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14. Does AmBisome need to be filtered?

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.

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15. How is an AmBisome overdose managed?

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.

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16. What laboratory tests should be monitored for patients receiving AmBisome?

Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, and serum electrolytes (particularly magnesium and potassium).

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17. How does AmBisome compare with Abelcet^® in terms of infusion-related reactions (IRR)?

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
				Amphotericin B Lipid Complex 5 mg/kg/day
		AmBisome
	3 mg/kg/day	5 mg/kg/day	BOTH
Total number of patients	85	81	166	78
Patients with Chills/Rigors (Day 1)	16 (18.8%)	19 (23.5%)	35 (21.1%)	62 (79.5%)
Patients with other notable reactions:
Fever (.1o C increase in temperature).†	20 (23.5%)	16 (19.8%)	36 (21.7%)	45 (57.7%)
Nausea	9 (10.6%)	7 (8.6%)	16 (9.6%)	9 (11.5%)
Vomiting	5 (5.9%)	5 (6.2%)	10 (6%)	11 (14.1%)
Hypertension	4 (4.7%)	7 (8.6%)	11 (6.6%)	12 (15.4%)
Tachycardia	2 (2.4%)	8 (9.9%)	10 (6%)	14 (17.9%)
Dyspnea	4 (4.7%)	8 (9.9%)	12 (7.2%)	8 (10.3%)
Hypoxia	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.

Despite significantly fewer infusion-related reactions, chills, rigors, fever, nausea, vomiting, and cardiorespiratory events may still be seen with AmBisome.

Abelcet is not indicated for empirical treatment of febrile neutropenic patients.

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18. How does AmBisome compare with Abelcet in terms of nephrotoxicity?

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%)

Dose-limiting renal toxicity may still be observed with AmBisome even though significantly less nephrotoxicity was observed at dosages of 3 mg/kg/day and 5 mg/kg/day compared to Abelcet at a dosage of 5 mg/kg/day.

Abelcet is not indicated for empirical treatment of febrile neutropenic patients.

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19. How does AmBisome compare to other lipid-complex Amphotericin B containing products ?

Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated drug or non-lipid associated drug. In addition, different liposomal or lipid-complex products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect the functional properties of these drug products.

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20. How is AmBisome stored?

Unopened vials of lyophilized material are to be stored at temperatures up to 25º C (77º F).

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21. Are there any warnings regarding the use of AmBisome?

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.

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AmBisome^® is a registered trademark of Gilead Sciences, Inc.
Abelcet^® is a registered trademark of Enzon Pharmaceuticals, Inc.