AMPHOTERICIN B 
*■ AMPHOTERICIN B LIPID-BASED PRODUCTS
Pronounciation
- (am-foe-TER-ih-sin)
Trade Name(s)
- Abelcet, AmBisome
* The Black Box Warning applies only to the generic formulation.
AMPHOTERICIN B *■ AMPHOTERICIN B LIPID-BASED PRODUCTS
Pronounciation
Trade Name(s)
* The Black Box Warning applies only to the generic formulation.
Pretesting and baseline studies required; see Precautions and Monitor.
Each product has different biochemical, pharmacokinetic, and pharmacodynamic properties. They are not interchangeable from dose to dose, in a given patient, between each other or conventional amphotericin.
Abelcet (Amphotericin B Lipid Complex Injection)
Adults and pediatric patients:
5 mg/kg/24 hr as an infusion. Repeat daily until clinical response or mycologic cure.
AmBisome (Amphotericin B Liposome for Injection)
Adults, children, and infants over 1 month of age:
All doses are by infusion.
Empirical therapy in febrile, neutropenic patients:
3 mg/kg/24 hr.
Systemic fungal infections (e.g., Aspergillus, Candida, Cryptococcus):
3 to 5 mg/kg/24 hr.
Treatment of cryptococcal meningitis in HIV-infected patients:
6 mg/kg/24 hr.
Visceral leishmaniasis in immunocompetent patients:
3 mg/kg/24 hr on Days 1 through 5. Repeat 3 mg/kg on Day 14 and on Day 21. A repeat course of therapy may be useful if parasitic clearance is not achieved.
Visceral leishmaniasis in immunocompromised patients:
4 mg/kg/24 hr on Days 1 through 5. Repeat 4 mg/kg on Days 10, 17, 24, 31, and 38. During clinical studies parasitic clearance was not achieved or relapse within 6 months occurred in 88.2% of patients. Usefulness of repeat courses not determined.
Generic (Conventional Amphotericin B)
Adults and pediatric patients:
Begin with a test dose of 0.1 mg/kg up to 1 mg maximum dose in 20 mL D5W. Infuse over 20 to 30 minutes. Determine size of therapeutic dose by intensity of reaction over a 2- to 4-hour period. Usual starting dose is 0.25 mg/kg of body weight/24 hr. Gradually increase dose by 5 to 10 mg/day (0.125 to 0.25 mg/kg in pediatric patients) to a final dose of 0.5 to 0.7 mg/kg. Total daily dose may range up to 1 mg/kg/day, or up to 1.5 mg/kg/24 hr may be given on alternate-day therapy. Several months of therapy are usually required and recommended for cure. Dosage must be adjusted to each specific patient. In some instances, higher doses can be used. Do not exceed a total daily dose of 1.5 mg/kg under any circumstances.
Full dose usually required; base on SCr and overall patient condition.
No dose adjustments suggested.
In all situations, gradual dose increases are essential. Whenever medicine is not given for 7 days or longer, restart treatment at lowest dosage level.
Patients with impaired cardio-renal function or a severe reaction to the test dose:
Initiate with smaller daily doses (i.e., 5 to 10 mg).
Patients who experience amphotericin-induced nephrotoxicity:
One source recommends reducing the total daily dose by 50% or administering the dose every other day.
Available in 100-mg (20-mL) vials. Shake vial until all yellow sediment is dissolved. Maintain aseptic technique. Withdraw an exact total daily dose from one or more vials using one or more syringes and 18-gauge needles. Replace needle(s) on syringe(s) with the 5-micron filter(s) supplied with each vial. A new filter must be used for each 400 mg (80 mL) of Abelcet. Empty syringe contents through filter into an infusion of D5W. 4 mL of diluent (D5W) is required for each 1 mL (5 mg) of Abelcet to achieve a final concentration of 1 mg/mL. For pediatric and/or fluid-restricted patients (e.g., patients with cardiovascular disease) reduce diluent by half (approximate concentration of 2 mg/mL).
Reconstitute each 50-mg vial with 12 mL SWFI (without a bacteriostatic agent) to yield 4 mg/mL. Shake vial vigorously for 30 seconds; forms a yellow translucent suspension. Withdraw an exact total daily dose from one or more vials using one or more 20-mL syringes and needles. Replace needle(s) with the 5-micron filter(s) supplied with each vial. A new filter must be used for each 50-mg vial. Empty syringe contents through filter into an infusion of D5W. Use sufficient diluent to achieve a final concentration of 1 to 2 mg/mL, pH 5 to 6. For pediatric patients: may be further diluted to concentrations of 0.2 to 0.5 mg/mL for infants and small children to provide adequate volume for infusion.
A 50-mg vial is initially diluted with 10 mL of SWFI (without a bacteriostatic agent); 5 mg equals 1 mL. Shake well until solution is clear. Further dilute each 1 mg in at least 10 mL of D5W. Dextrose must have a pH above 4.2. Concentration of solution must not be greater than 0.1 mg/mL. Do not use any other diluent. Use a sterile 20-gauge or larger needle at each step of the dilution. Maintain aseptic technique. Larger pore 1-micron filters may be used. Use only fresh solutions without evidence of precipitate or foreign matter. Light sensitive; protect from light during administration.
5-micron filter(s) supplied with each vial. A new filter must be used for each 400 mg (80 mL) of Abelcet. Empty syringe contents through filter into an infusion solution. Do not use an in-line filter.
5-micron filter(s) supplied with each vial. A new filter must be used for each 50-mg vial. Empty syringe contents through filter into an infusion solution. Do not use an in-line filter smaller than 1 micron.
Larger pore 1-micron filters may be used; see Dilution.
Before reconstitution, refrigerate in carton until time of use and protect from light. Do not freeze. Diluted solution is stable 48 hours if refrigerated and an additional 6 hours at room temperature. Discard unused drug.
Unopened vials may be stored at temperatures up to 25° C (77° F). Vials reconstituted with SWFI may be refrigerated for up to 24 hours. Do not freeze. Infusion of fully diluted solution must begin within 6 hours. Discard unused drug.
Before reconstitution, refrigerate vials and protect from light. Do not freeze. Preserve concentrate in refrigerator up to 7 days or 24 hours at room temperature. Use diluted solution promptly.
In all situations, use a separate infusion line or flush an existing line with D5W before and after administration.
Do not mix with any other diluent, drug, or solution. Use only D5W. Manufacturer states that compatibility with any other diluent has not been established.
Other sources suggest a few specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.
Do not mix with any other diluent, drug, or solution. Use only SWFI for reconstitution and D5W for dilution for infusion. Use of any other solution or the presence of a bacteriostatic agent (e.g., benzyl alcohol) may cause precipitation.
Compatibility information not available from manufacturer.
Other sources suggest a few specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.
Rapid infusion may cause hypotension, hypokalemia, arrhythmia, and shock. Infusion reactions can occur with all amphotericin B formulations. See Precautions, Side Effects, and Antidote. With all formulations, flush existing line with D5W before and after administration or use a separate IV line.
Total daily dose as an infusion at 2.5 mg/kg/hr. Contents of diluted solution must be mixed by shaking at least every 2 hours. Do not use an in-line filter.
Total daily dose as an infusion over 2 hours. Use of a controlled infusion device is recommended. Infusion time may be shortened to a minimum of 1 hour for patients who show no evidence of intolerance or infusion-related reactions. Infusion time may be extended for patient discomfort or acute reactions or if infusion volume is not tolerated. Do not use any in-line filter less than 1 micron.
Daily dose over 2 to 6 hours by slow IV infusion. Expected reactions usually less severe with slower rate. A minimum 1-micron filter may be used.
Antifungal antibiotic agents that bind to the sterol component of fungal cell membranes resulting in leakage of cellular contents. May be fungistatic or fungicidal according to body fluid concentration and susceptibility of the fungus. Abelcet is amphotericin B complexed with two phospholipids in a 1:1 drug-to-lipid ratio. AmBisome is amphotericin B intercalated into a liposomal membrane with several components. Assay tests cannot distinguish lipid-based amphotericin from conventional amphotericin B. Modification of amphotericin to the various lipid-based products alters the drug’s functional properties. It allows for increased levels of drug at the site of action (usually areas where the fungi are). Overall effect is increased effectiveness with less toxicity. Not effective against bacteria, rickettsiae, or viruses. Long terminal half-life probably reflects a slow redistribution from tissues. Actual distribution to organs is somewhat selective and may help to decide which product is best to use in a given situation. Route of metabolism not known. Excreted very slowly in the urine.
Treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy.
Empirical therapy for presumed fungal infection in febrile, neutropenic patients. ■ Treatment of patients with aspergillosis, candida, and/or cryptococcus infections refractory to conventional amphotericin B or in patients in whom renal impairment or unacceptable toxicity precludes the use of conventional amphotericin B. ■ Treatment of visceral leishmaniasis. ■ Treatment of cryptococcal meningitis in HIV-infected patients.
Treatment of fungal infections that are progressive and potentially fatal, such as aspergillosis, cryptococcosis, blastomycosis, and disseminated forms of candidiasis, coccidioidomycosis, and histoplasmosis, mucormycosis, and sporotrichosis. These infections must be caused by specific organisms. Not recommended for treatment of noninvasive forms of fungal disease in patients with normal neutrophil counts.
AmBisome has been used to prevent fungal infections in bone marrow transplant patients.
All amphotericin formulations:
Known sensitivity to amphotericin B or any components of its formulations unless a life-threatening situation is present.
All Amphotericin Formulations:
Diagnosis should be positively established by culture or histologic study. ■ Close clinical observation is imperative. Anaphylaxis has occurred; emergency equipment and supplies must be available. ■ Infusion reactions are common and usually occur 1 to 3 hours after the start of the infusion. Frequency and severity of reactions generally diminish with subsequent doses. Pretreatment with antipyretics, antihistamines (e.g., diphenhydramine), and/or selective use of corticosteroids may be indicated. ■ Use caution in patients receiving leukocyte transfusions; may cause acute pulmonary toxicity. Separate times of administration as much as possible. ■ Nephrotoxicity is the usual dose-limiting factor for use of conventional amphotericin B. Impairment may improve with dose reduction or alternate-day therapy, but some residual dysfunction is possible. Lipid-based formulations are associated with less nephrotoxicity. Most studies show equivalent or superior effectiveness compared with conventional amphotericin. Introduction of lipid-based products to patients with increased CrCl and BUN from conventional amphotericin has decreased the CrCl and BUN.
Renal toxicity is dose dependent but has been consistently less nephrotoxic than conventional amphotericin B.
Incidence of renal toxicity significantly lower than with conventional amphotericin B.
Should be used primarily for treatment of patients with progressive and potentially life-threatening fungal infections. It should not be used to treat noninvasive forms of fungal disease such as oral thrush, vaginal candidiasis, and esophageal candidiasis in patients with normal neutrophil counts. ■ To prevent overdose, verify product name and dose, especially if dose exceeds 1.5 mg/kg.■ Therapy is often initiated in infusion centers. ■ A small amount of heparin added to the infusion may reduce the incidence of thrombophlebitis. ■ Meperidine (Demerol), nonsteroidal anti-inflammatory agents (e.g., ibuprofen), or hydrocortisone before administration may prevent febrile reactions, including chills; corticosteroids not recommended for concomitant use in other situations because they exaggerate hypokalemia. ■ Prophylactic antiemetics and antihistamines are also appropriate.
All amphotericin formulations: Obtain baseline CBC, PT, serum electrolytes, renal (e.g., creatine kinase, BUN, SCr) and liver function (e.g., ALT, AST) tests. Repeat frequently during therapy; recommended weekly. Monitor PT as indicated during therapy. ■ Discontinue or reduce dose until renal function improves if increase in BUN or SCr is clinically significant. Side effects (e.g., hypokalemia, hypomagnesemia, impaired renal function) may be life threatening. ■ Monitor vital signs and I&O. Record every 30 minutes for up to 4 hours after infusion is complete. ■ Monitor for S/S of hypersensitivity or infusion reactions (e.g., chest pain, dizziness, dyspnea, fever, flushing, hypotension, nausea, pruritus, rash, rigors, urticaria). ■ Encourage fluids to maintain hydration.
All amphotericin formulations:
Review all medical conditions and medications before beginning treatment. ■ Discomfort associated with infusion. ■ Promptly report S/S of an acute reaction (e.g., anorexia, chills, fever, headache, hypotension, nausea or vomiting, shortness of breath). ■ Long-term therapy required to effect a cure. ■ Report diarrhea, fever, increased or decreased urination, loss of appetite, sore throat, stomach pain, and any unusual bleeding or bruising, tiredness, or weakness. ■ Maintain adequate hydration.
All amphotericin formulations:
Category B: has been used successfully during pregnancy but adequate studies not available. Use only if clearly needed. ■ Safety for use in breast-feeding and pediatric patients not established. Discontinue nursing. ■ Conventional amphotericin B has been used in pediatric patients. Lipid-based preparations have been used in pediatric patients without any unexpected side effects. Safety of use of AmBisome in infants under 1 month of age not established.
Consider age-related impaired body functions. Lipid-based preparations have been used without unexpected side effects.
Drug interaction studies have not been done for lipid-based preparations, but interactions similar to conventional amphotericin B are expected. ■ Corticosteroids will increase hypokalemia and may cause arrhythmias. Use with caution only if indicated to control drug reactions or, if necessary, monitor serum electrolytes and cardiac function closely. ■ Hypokalemic effect may be increased with thiazides, may potentiate digoxin toxicity, and/or may enhance the curariform effect of neuromuscular blocking agents; monitor serum potassium levels. ■ Avoid use or use extreme caution with other nephrotoxic drugs (e.g., aminoglycosides, selected antibiotics [e.g., vancomycin], anesthetics, antituberculars [e.g., capreomycin], diuretics, pentamidine). Nephrotoxic effects are additive. Frequent monitoring of renal function indicated if any other nephrotoxic drug must be used. ■ Nephrotoxicity and myelotoxicity are both increased when given concurrently with zidovudine. ■ Potentiates nephrotoxicity of cyclosporine; alternate immunosuppressive therapy recommended. ■ Concurrent use with antineoplastic agents (e.g., cisplatin, methotrexate) or radiation therapy may increase renal toxicity and incidence of bronchospasm and hypotension. ■ Enhances antifungal effects of flucytosine and other anti-infectives. May increase toxicity. ■ Antagonism between amphotericin B and imidazole antifungals (e.g., ketoconazole, miconazole, fluconazole) has been reported. ■ Acute pulmonary toxicity occurred in patients receiving leukocyte transfusion; separate administration times as much as possible. ■ False elevations of serum phosphate may occur if patient samples are analyzed using the PHOSm assay.
Most side effects similar to conventional amphotericin B but occur with less frequency and intensity. Acute reactions, including fever and chills, may occur within 1 to 3 hours of starting the infusion. Infusion-related cardiorespiratory reactions may include dyspnea, hypertension, hyperventilation, hypotension, hypoxia, tachycardia, and vasodilation. Arrhythmia, bronchospasm, and shock can occur. Anaphylaxis and cardiac arrest from overdose have been reported.
Common even at doses below therapeutic; may begin to occur within 15 to 20 minutes: anorexia, chills, convulsions, diarrhea, fever, headache, phlebitis, vomiting. Anaphylactoid reactions, anemia, cardiac disturbances (including fibrillation and arrest), coagulation defects, hypertension, hypokalemia, hypotension, and numerous other side effects occur fairly frequently. Renal function impaired in 80% of patients. May reverse after treatment ends, but some permanent damage likely.
Agranulocytosis, angioedema, bronchospasm, cyanosis/hypoventilation, edema, erythema, hemorrhagic cystitis, pulmonary edema, rhabdomyolysis.
All Amphotericin Formulations:
Notify the physician of all side effects. Many are reversible if the drug is discontinued. Some will respond to symptomatic treatment. Acute reactions (e.g., fever, chills, hypotension, nausea, and vomiting) usually lessen with subsequent doses. These acute infusion-related reactions can be managed by pretreatment with antipyretics, antihistamines, and/or corticosteroids or reduction of the rate of infusion and prompt treatment with antihistamines and/or corticosteroids and meperidine (Demerol) for chills. If anaphylaxis or serious respiratory distress occurs, discontinue amphotericin and treat as necessary. Give no further infusions. Hemodialysis not effective in overdose. Discontinue if BUN and alkaline phosphatase are abnormal. Dantrolene has been used to prevent (50 mg PO) or treat (50 mg IV) severe, shaking chills.
Administration of conventional amphotericin B on alternate days may decrease the incidence of some side effects. Urinary alkalinizers may minimize renal tubular acidosis.
Overdose has caused cardiac arrest. Discontinue drug and treat symptomatically.