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Pronunciation:

(am foe TER i sin bee lye po SO mal)

U.S. Brand Names:

AmBisome®

Synonyms:

L-AmB

Generic Available:

Canadian Brand Names:

AmBisome®

Use:

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 desoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B desoxycholate. Treatment of cryptococcal meningitis in HIV-infected patients. Treatment of visceral leishmaniasis.

Use - Unlabeled/Investigational:

Effective in patients with serious Candida species infections

Pregnancy Risk Factor:

Lactation:

Excretion in breast milk unknown/contraindicated

Contraindications:

Hypersensitivity to amphotericin B or any component of the formulation unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk

Warnings/Precautions:

Although amphotericin B (liposomal) has been shown to be significantly less toxic than amphotericin B desoxycholate, adverse events may still occur. Patients should be under close clinical observation during initial dosing. As with other amphotericin B-containing products, anaphylaxis has been reported. Facilities for cardiopulmonary resuscitation should be available during administration, and the drug should be administered by medically-trained personnel. Acute reactions (including fever and chills) may occur 1-2 hours after starting infusions; reactions are more common with the first few doses and generally diminish with subsequent doses. Immediately discontinue infusion if severe respiratory distress occurs; the patient should not receive further infusions. Safety and efficacy have not been established in patients <1 year of age.

Adverse Reactions:

Percentage of adverse reactions is dependent upon population studied and may vary with respect to premedications and underlying illness. Incidence of decreased renal function and infusion-related events are lower than rates observed with amphotericin B deoxycholate.

>10%:

Cardiovascular: Peripheral edema (15%), edema (12% to 14%), tachycardia (9% to 18%), hypotension (7% to 14%), hypertension (8% to 20%), chest pain (8% to 12%), hypervolemia (8% to 12%)

Central nervous system: Chills (29% to 48%), insomnia (17% to 22%), headache (9% to 20%), anxiety (7% to 14%), pain (14%), confusion (9% to 13%)

Dermatologic: Rash (5% to 25%), pruritus (11%)

Endocrine & metabolic: Hypokalemia (31% to 51%), hypomagnesemia (15% to 50%), hyperglycemia (8% to 23%), hypocalcemia (5% to 18%), hyponatremia (8% to 12%)

Gastrointestinal: Nausea (16% to 40%), vomiting (10% to 32%), diarrhea (11% to 30%), abdominal pain (7% to 20%), constipation (15%), anorexia (10% to 14%)

Hematologic: Anemia (27% to 48%), blood transfusion reaction (9% to 18%), leukopenia (15% to 17%), thrombocytopenia (6% to 13%)

Hepatic: Increased alkaline phosphatase (7% to 22%), increased BUN (7% to 21%), bilirubinemia (9% to 18%), increased ALT (15%), increased AST (13%), abnormal liver function tests (not specified) (4% to 13%)

Local: Phlebitis (9% to 11%)

Neuromuscular & skeletal: Weakness (6% to 13%), back pain (12%)

Renal: Increased creatinine (18% to 40%), hematuria (14%)

Respiratory: Dyspnea (18% to 23%), lung disorder (14% to 18%), increased cough (2% to 18%), epistaxis (8% to 15%), pleural effusion (12%), rhinitis (11%)

Miscellaneous: Sepsis (7% to 14%), infection (11% to 12%)

2% to 10%:

Cardiovascular: Arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, facial swelling, flushing, postural hypotension, valvular heart disease, vascular disorder

Central nervous system: Agitation, abnormal thinking, coma, convulsion, depression, dysesthesia, dizziness (7% to 8%), hallucinations, malaise, nervousness, somnolence

Dermatologic: Alopecia, bruising, cellulitis, dry skin, maculopapular rash, petechia, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, vesiculobullous rash

Endocrine & metabolic: Acidosis, increased amylase, fluid overload, hypernatremia (4%), hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hypophosphatemia, hypoproteinemia, increased lactate dehydrogenase, increased nonprotein nitrogen

Gastrointestinal: Constipation, dry mouth, dyspepsia, enlarged abdomen, eructation, fecal incontinence, flatulence, gastrointestinal hemorrhage (10%), hematemesis, hemorrhoids, gum/oral hemorrhage, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis

Genitourinary: Vaginal hemorrhage

Hematologic: Coagulation disorder, hemorrhage, decreased prothrombin, thrombocytopenia

Hepatic: Hepatocellular damage, hepatomegaly, veno-occlusive liver disease

Local: Injection site inflammation

Neuromuscular & skeletal: Arthralgia, bone pain, dystonia, myalgia, neck pain, paresthesia, rigors, tremor

Ocular: Conjunctivitis, dry eyes, eye hemorrhage

Renal: Abnormal renal function, acute kidney failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence

Respiratory: Asthma, atelectasis, cough, dry nose, hemoptysis, hyperventilation, lung edema, pharyngitis, pneumonia, respiratory alkalosis, respiratory insufficiency, respiratory failure, sinusitis, hypoxia (6% to 8%)

Miscellaneous: Allergic reaction, cell-mediated immunological reaction, flu-like syndrome, graft versus host disease, herpes simplex, hiccup, procedural complication (8% to 10%), diaphoresis (7%)

Postmarketing and/or case reports: Angioedema, erythema, urticaria, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis

Overdosage/Toxicology:

The toxicity due to overdose has not been defined. Repeated daily doses up to 7.5 mg/kg 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.

Drug Interactions:

Increased nephrotoxicity: Aminoglycosides, cyclosporine, other nephrotoxic drugs

Potentiation of hypokalemia: Corticosteroids, corticotropin

Increased digitalis and neuromuscular-blocking agent toxicity due to hypokalemia

Decreased effect: Pharmacologic antagonism may occur with azole antifungal agents (eg, miconazole, ketoconazole)

Pulmonary toxicity has occurred with concomitant administration of amphotericin B and leukocyte transfusions

Stability:

Unopened vials should be stored at temperatures 25°C (77°F). Must be reconstituted using sterile water for injection, USP (without a bacteriostatic agent). Follow package insert instructions carefully for preparation. 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.

Must be diluted with 5% dextrose injection to a final concentration of 1-2 mg/mL prior to administration. Lower concentrations (0.2-0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion.

Injection should commence within 6 hours of dilution with 5% dextrose injection.

An in-line membrane filter may be used for the intravenous infusion; provided, THE MEAN PORE DIAMETER OF THE FILTER SHOULD NOT BE LESS THAN 1 (one) MICRON.

Compatibility:

Compatible: Stable in D5W. Incompatible: NS, ¹/2NS, or other saline-containing solutions

Mechanism of Action:

Binds to ergosterol altering cell membrane permeability in susceptible fungi and causing leakage of cell components with subsequent cell death. Proposed mechanism suggests that amphotericin causes an oxidation-dependent stimulation of macrophages (Lyman, 1992).

Pharmacodynamics/Kinetics:

Distribution: Vd: 131 L/kg

Half-life elimination: Terminal: 174 hours

Dosage:

Children and Adults: I.V.:

Note: Premedication: For patients who experience chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related immediate reactions, premedicate with the following drugs, 30-60 minutes prior to drug administration: a nonsteroidal (eg, ibuprofen, choline magnesium trisalicylate) with or without diphenhydramine; or acetaminophen with diphenhydramine; or hydrocortisone 50-100 mg. If the patient experiences rigors during the infusion, meperidine may be administered.

Empiric therapy: Recommended initial dose: 3 mg/kg/day

Systemic fungal infections (Aspergillus, Candida, Cryptococcus): Recommended initial dose of 3-5 mg/kg/day

Cryptococcal meningitis in HIV-infected patients: 6 mg/kg/day

Treatment of visceral leishmaniasis:

Immunocompetent patients: 3 mg/kg/day on days 1-5, and 3 mg/kg/day on days 14 and 21; a repeat course may be given in patients who do not achieve parasitic clearance

Immunocompromised patients: 4 mg/kg/day on days 1-5, and 4 mg/kg/day on days 10, 17, 24, 31, and 38

Dosing adjustment in renal impairment: None necessary; effects of renal impairment are not currently known

Hemodialysis: No supplemental dosage necessary

Peritoneal dialysis effects: No supplemental dosage necessary

Continuous arteriovenous or venovenous hemofiltration: No supplemental dosage necessary

Administration:

Should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 2 hours. Infusion time may be reduced to approximately 1 hour in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased. Administer at a rate of 2.5 mg/kg/hour. Existing intravenous line should be flushed with D5W prior to infusion (if not feasible, administer through a separate line). An in-line membrane filter (not less than 1 micron) may be used.

Monitoring Parameters:

Renal function (monitor frequently during therapy), electrolytes (especially potassium and magnesium), liver function tests, temperature, PT/PTT, CBC; monitor input and output; monitor for signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes, etc)

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug can only be administered intravenously. You will be monitored during infusion. Report immediately any chills, chest pain, respiratory difficulty, tightness in throat, or other adverse reaction. Personal hygiene is very important to help reduce the spread and recurrence of lesions. Most skin lesions require 1-3 weeks of therapy. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause hypotension (use caution when changing from lying or sitting position to standing or when climbing stairs); or nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report any hearing loss, skin rash, dizziness or weakness, muscle or bone pain, changes in color of urine or stool, persistent GI distress, alteration in voiding or bowel patterns, CNS disturbances, pain at injection site, or other adverse reactions. Breast-feeding precaution: Do not breast-feed.

Additional Information:

Amphotericin B (liposomal) is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. Amphotericin B (liposomal) consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the amphotericin B liposomal liposomes. Amphotericin B (liposomal) contains true liposomes that are <100 nm in diameter.

Anesthesia and Critical Care Concerns/Other Considerations:

This product is significantly more expensive than conventional amphotericin B; Infectious Disease consult is recommended. AmBisome® is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. AmBisome® consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the AmBisome® liposomes. AmBisome® contains true liposomes that are less than 100 nm in diameter.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Facial swelling, postural hypotension, mucositis, stomatitis, and ulcerative stomatitis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Dental Comment:

Amphotericin B, liposomal is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. Amphotericin B, liposomal consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the amphotericin B liposomes. Amphotericin B, liposomal contains true liposomes that are <100 nm in diameter.

Mental Health: Effects on Mental Status:

Sedation is common; may cause delirium

Mental Health: Effects on Psychiatric Treatment:

May cause bone marrow suppression; use caution with clozapine and carbamazepine

Dosage Forms:

Injection, powder for reconstitution: 50 mg

International Brand Names:

AmBisome® (CA)

References

Edwards JE Jr, Bodey GP, Bowden RA, et al, "International Conference for the Development of a Consensus on the Management and Prevention of Severe Candidal Infections,"Clin Infect Dis, 1997, 25(1):43-59.

Eggimann P, Francioli P, Bille J, et al, "Fluconazole Prophylaxis Prevents Intra-Abdominal Candidiasis in High-Risk Surgical Patients,"Crit Care Med, 1999, 27(6):1066-72.

Emminger W, Graninger W, Emminger-Schmidmeir W, et al, "Tolerance of High Doses of Amphotericin B by Infusion of a Liposomal Formulation in Children With Cancer,"Ann Hematol, 1994, 68:27-31.

Fichtenbaum CJ, Zackin R, Rajicic N, et al, "Amphotericin B Oral Suspension for Fluconazole-Refractory Oral Candidiasis in Persons With HIV Infection. Adult AIDS Clinical Trials Group Study Team 295,"AIDS, 2000, 14(7):845-52.

Hiemenz JW and Walsh TJ, "Lipid Formulations of Amphotericin B: Recent Progress and Future Directions,"Clin Infect Dis, 1996, 22(Suppl 2):133-44.

Lyman CA and Walsh TJ, "Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications,"Drugs, 1992, 44(1):9-35.

Mora-Duarte J, Betts R, Rotstein C, et al, "Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis,"N Engl J Med, 2002, 347(25):2020-9.

Patel R, "Antifungal Agents. Part I. Amphotericin B Preparations and Flucytosine,"Mayo Clin Proc, 1998, 73(12):1205-25.

Rex JH, Bennett JE, Sugar AM, "A Randomized Trial Comparing Fluconazole With Amphotericin B for the Treatment of Candidemia in Patients Without Neutropenia. Candidemia Study Group and the National Institute,"N Engl J Med, 1994, 331(20):1325-30.

Rex JH, Pappas PG, Karchmer AW, et al, "A Randomized and Blinded Multicenter Trial of High-Dose Fluconazole Plus Placebo Versus Fluconazole Plus Amphotericin B as Therapy for Candidemia and Its Consequences in Nonneutropenic Subjects,"Clin Infect Dis, 2003, 36(10):1221-8.

Rex JH, Walsh TJ, Sobel JD, et al, "Practice Guidelines for the Treatment of Candidiasis. Infectious Diseases Society of America,"Clin Infect Dis, 2000, 30(4):662-78.

Ringden O, Andstrom E, Remberger M, et al, "Safety of Liposomal Amphotericin B (AmBisome®) In 187 Transplant Recipients Treated With Cyclosporin,"Bone Marrow Transplant, 1994, 14(Suppl 5):10-4.

Slain D, "Lipid-Based Amphotericin B for the Treatment of Fungal Infections,"Pharmacotherapy, 1999, 19(3):306-23.

Walsh TJ, Finberg RW, Arndt C, et al, "Liposomal Amphotericin B for Empirical Therapy in Patients With Persistent Fever and Neutropenia,"N Engl J Med, 1999, 340:764-71.

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