AmBisome

AmBisome Instructions
Common name: AmBisome
Trade name: AmBisome
All names: AmBisome, AmBisome

Indications:
Applicable to patients with deep fungal infections; patients who cannot use effective doses of amphotericin B due to kidney damage or drug toxicity, or patients who have received ineffective treatment.

Dosage:
It is recommended to give a test dose before a new course of treatment. A small infusion of AmBisome (e.g., 1 mg) may be taken for approximately 10 minutes, then discontinued, and the patient carefully observed for the next 30 minutes. If there is no severe allergic or anaphylactoid reaction, the AmBisome dose can be continued.

Treatment of fungal diseases
Treatment is usually carried out at a dose of 1.0mg/kg body weight per day, and gradually increased to 3.0mg/kg as needed. Currently, data are insufficient to define the total dose and duration of treatment required to resolve fungal disease. However, the usual cumulative dose of AmBisome is 1.0-3.0 g of amphotericin B over 3-4 weeks. The dosage of amphotericin B as AmBisome must be adjusted to the specific requirements of each patient.

Mucormycosis
The recommended starting dose is 5mg/kg/day. The duration of treatment should be determined on an individual basis. Clinical practice typically uses treatment courses of up to 6 to 8 weeks; deep-seated infections, prolonged chemotherapy, or neutropenia may require longer treatment periods.
Although doses greater than 5 mg/kg, up to doses of 10 mg/kg, have been used in clinical trials and clinical practice, data on the safety and efficacy of AmBisome in the treatment of mucormycosis at these higher doses remain limited. Therefore, a benefit:risk assessment should be performed at the individual patient level to determine whether the potential benefits of treatment are considered to outweigh the known increased risk of toxicity at higher AmBisome doses.

Treatment of Visceral Leishmaniasis
A total dose of 21.0-30.0 mg/kg body weight given over 10-21 days can be used to treat visceral leishmaniasis. Details on optimal dosing and eventual development of resistance are incomplete. This product should be administered under strict medical supervision.
Empirical Treatment of Febrile Neutropenia
The recommended daily dose is 3 mg/kg body weight per day. Treatment should be continued until the recorded temperature returns to normal for 3 consecutive days. In any case, treatment should be discontinued after a maximum of 42 days.

Children
Systemic fungal infections in children and presumed fungal infections in children with febrile neutropenia have been successfully treated with AmBisome, but no unusual adverse events have been reported. AmBisome has been studied in pediatric patients aged one month to 18 years. The doses used in these clinical studies are the same as those used in adults (on a mg/kg body weight basis).
Due to a lack of safety and efficacy data, AmBisome is not recommended for use in children younger than 1 month of age.

Geriatric patients
No changes in dose or dosing frequency are required.

Renal Impairment
In clinical trials, AmBisome has been administered to a large number of patients with preexisting renal insufficiency at a starting dose of 1-3 mg/kg/day, without the need for dose or dosing frequency adjustments.

Hepatic Impairment
There are no data to recommend doses for patients with hepatic impairment.

Adverse reactions:
Blood and lymphatic system disorders
Rare:
Thrombocytopenia
Unknown:
Anemia

Immune system disorders
Rare:
anaphylactoid reactions
Unknown:
anaphylactic reactions
hypersensitivity reactions

Metabolism and nutritional disorders
Very common:
Hypokalemia
Common:
Hyponatremia
Hypocalcemia
Hypomagnesemia
Hyperglycemia

Nervous system disorders
Common
Headache
Rare
convulsions

Cardiac disease
Common:
Tachycardia
Unknown:
Cardiac arrest
Arrhythmia

Vascular disease
Common:
Hypotension
vasodilation
flushing
Respiration

Thoracic and mediastinal disorders
Common:
dyspnea
Rare:
bronchospasm

Gastrointestinal disease Disease
Very common:
Nausea
Vomiting
Common:
Diarrhea
Abdominal pain

Hepatobiliary disease
Common:
Abnormal liver function tests
Hyperbilirubinemia
Elevated alkaline phosphatase

Skin and subcutaneous diseases
Common:
Skin rash
Unknown:
Angioedema

Musculoskeletal and connective tissue disorders
Common:
Low back pain
Unknown:
Rhabdomyolysis (associated with hypokalemia)
Musculoskeletal pain (called arthralgia or bone pain)

Kidney and urinary tract disorders
Common:
Muscle Elevated anhydride
Elevated blood urea
Unknown:
Renal failure
Renal insufficiency

General disorders and administration site conditions
Very common:
Severe
Fever
Common:
Chest pain

Contraindications:
This product is contraindicated in patients who are allergic to any of its ingredients. Patients with a history of allergies should only use this product unless their doctor believes that the benefits of using this product outweigh the risks of allergy.

Precautions:
Anaphylaxis and Anaphylactoid Reactions
Anaphylaxis and anaphylactoid reactions have been reported in association with AmBisome infusion. Anaphylaxis, including serious infusion-related reactions, may occur during administration of amphotericin-containing products, including AmBisome. Therefore, it is still recommended to give a test dose before a new course of treatment. If a severe allergic reaction or anaphylactoid/anaphylactoid reaction occurs, the infusion should be discontinued immediately and the patient should not receive further infusions of AmBisome.

Infusion-Related Reactions
Other serious infusion-related reactions may occur while taking amphotericin B-containing products, including AmBisome. Although infusion-related reactions are generally not serious, precautions should be considered to prevent or treat these reactions in patients receiving AmBisome. Successful prevention or treatment has been reported with slower infusion rates (over 2 hours) or conventional doses of diphenhydramine, acetaminophen, pethidine, and/or hydrocortisone.

Nephrotoxicity
AmBisome has been shown to be much less toxic than traditional amphotericin B, especially in terms of nephrotoxicity. However, adverse renal effects may still occur.
In studies comparing AmBisome at 3 mg/kg daily with higher doses (5, 6, or 10 mg/kg daily), significantly higher rates of serum creatinine, hypokalemia, and hypomagnesemia were found in the high-dose group.
In particular, caution should be exercised when prolonged treatment is required. Laboratory evaluation of serum electrolytes (especially potassium and magnesium) and renal, hepatic, and hematopoietic function should be performed regularly at least once weekly. This is particularly important in patients receiving concomitant nephrotoxic drugs. Renal function should be monitored closely in these patients. Due to the risk of hypokalemia, appropriate potassium supplementation may be required during AmBisome administration. If a clinically significant decrease in renal function or worsening of other parameters occurs, dose reduction, treatment interruption, or discontinuation of treatment should be considered.

Pulmonary Toxicity
Acute pulmonary toxicity has been reported in patients receiving amphotericin B (as sodium deoxycholate complex) during or shortly after leukocyte transfusion. It is recommended that these infusions be spaced as long as possible and lung function should be monitored.

For Diabetics
AmBisome contains approximately 900 mg of sucrose in each vial. This should be taken into consideration when treating patients with diabetes.

Storage:
Store in the dark below 25 degrees Celsius

Mechanism of action:
Amphotericin B is a macrocyclic polyene antifungal antibiotic produced by Streptomyces nodosus. Amphotericin B is bacteriostatic or fungicidal, depending on the concentration obtained in body fluids and the susceptibility of the fungus. This molecule is thought to work by binding to sterols in the fungal cell membrane, causing changes in membrane permeability that allow a variety of small molecules to leak. Mammalian cell membranes also contain sterols, and it has been suggested that amphotericin B damage to human and fungal cells may share a common mechanism. The lipophilic portion of amphotericin allows the molecule to be integrated into the lipid bilayer of liposomes. Liposomes are closed spherical vesicles formed from a variety of amphipathic substances such as phospholipids.

Efficacy and Safety:
AmBisome has established efficacy in numerous clinical trials for the treatment of systemic fungal infections, empiric therapy of unexplained fever in neutropenic patients, and treatment of visceral leishmaniasis. These studies included a randomized study of AmBisome compared with conventional amphotericin B in established Aspergillus and Candida infections in which the efficacy of both drugs was equivalent. In adult and pediatric febrile neutropenic patients with presumed fungal infections, results from a randomized, double-blind clinical trial indicate that AmBisome administered at a dose of 3 mg/kg/day is as effective as conventional amphotericin B. Treatment of visceral leishmaniasis has been clearly demonstrated in a large number of immunocompetent and immunocompromised patients.

Invasive filamentous fungal infections (IFFI), including Aspergillus.
Efficacy of AmBisome has been demonstrated in a prospective, randomized, multicenter study as a primary first-line treatment for immunocompromised, primarily neutropenic adults and children with proven or possible IFFI (>30 days) (AmBiLoad study).
Monitor patients for 12 weeks. A standard dose regimen of 3 mg/kg/day (N = 107) was compared with a loading dose regimen of 10 mg/kg/day (N = 94) during the first 14 days of treatment. In the modified intention-to-treat analysis, favorable overall response rates were 50% in the standard-dose group and 46% in the loading-dose group. The difference is not statistically significant. The median time to fever resolution was similar in the standard-dose and loading-dose groups (6 days and 5 days, respectively). Twelve weeks after the first injection of AmBisome, the survival rate was 72% in the standard dose group and 59% in the loading dose group, with no statistically significant difference.

Invasive Candidiasis
AmBisome (3 mg/kg/day) was as effective as micafungin (100 mg/day [body weight > 40 kg] or 2 mg/kg/day [body weight ≤ 40 kg]) as first-line treatment for candidemia and infiltrative candidiasis in a randomized, double-blind, multinational, non-inferiority study in adults and children. The median duration of administration of AmBisome and micafungin was 15 days. The overall overall favorable response rate was 89.5% (170/190) in the AmBisome arm and 89.6% (181/202) in the micafungin arm (per protocol analysis set). The pediatric substudy of 98 patients, including 57 children under 2 years of age (including 19 preterm infants), showed good overall response rates: 88.1% (37/42) with AmBisome and 85.4% (35/41) superior to micafungin.

Invasive Mucormycosis (Zygomycosis)
There are no large-scale randomized clinical trials of mucormycosis.
The Zygomycosis Working Group of the European Federation of Medical Mycology (ECMM) prospectively collected cases of patients with zygomycosis, in which 130 patients received liposomal amphotericin B (L-AMB) alone or in combination. Among patients who received it as the only antifungal drug, the survival rate was 68%. Among cured patients, the median treatment duration was 55 days (range 14-169 days) and the median daily dose was 5 mg/kg (range 3-10 mg/kg), (Skiada et al; Clin Microbiol Infect 2011;17(12:1859-67).
In a prospective study of high-dose (10 mg/kg/day) liposomal amphotericin B for the initial treatment of mucormycosis, the median duration of treatment in 29 patients receiving 10 mg/kg/day was 13.5 days (range, 0-28 days). The primary endpoint was treatment success at week 4 or end of treatment (if earlier), with response in 12 (36%) of 33 evaluable patients, including 18% complete response; response rate increased to 45% at week 12, and survival was 62% at week 12 and 47% at week 24 (Lanternier et al; J Antimicrob Chemother 2015; 70(11):3116-23).

Children
The pharmacodynamic profile of AmBisome in pediatric patients is consistent with that described in adult patients.