ABELCET

General Administration Information
For storage information, see the specific product information within the How Supplied section.

NOTE: Amphotericin products are not interchangeable. Amphotericin B lipid complex (ABLC) is dosed differently than conventional amphotericin B (amphotericin B deoxycholate) and other lipid formulations. Serious toxicities have occurred after the inadvertent substitution of one amphotericin product for another. Carefully check to ensure that the correct amphotericin product is being used.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration.
Intravenous Administration
Filtration and Dilution
-Prepare the admixture (ABLC suspension) by shaking the vial gently until there is no evidence of yellow sediment at the bottom of the vial.
-Transfer the appropriate amount of drug from the required number of vials into one or more sterile syringes using an 18-gauge needle.
-Remove the 18-gauge needle and attach the provided 5-micron filter needle to the syringe; inject the syringe contents through the filter needle, into the appropriate amount of D5W. Each filter needle may be used on the contents of no more than four 100 mg vials.
-ABLC should be diluted with D5W to a final concentration not to exceed 2 mg/ml (usual concentration = 1 mg/ml). DO NOT USE SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES.
-Storage: The diluted ready-for-use admixture is stable for up to 48 hours at 2-8 degrees C (36-46 degrees F) and an additional 6 hours at room temperature. Do not freeze.

Intermittent IV Infusion
-Flush intravenous line with D5W injection prior to infusion. If this cannot be done, then a separate IV line must be used. DO NOT USE AN IN-LINE FILTER.
-Prior to infusion, shake the bag until the contents are thoroughly mixed.
-The rate of infusion should not exceed 2.5 mg/kg/hr. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours.

Infusion-related reactions have been reported with the administration of amphotericin B lipid complex (ABLC). Infusion-related reactions are toxicities occurring during or shortly after (within 1-2 hours) administration of ABLC and include symptoms such as chills , fever, rigors, decreased blood pressure, bronchospasm, arrhythmias, and shock. In a study of 46 pediatric patients (3 months to 18 years) receiving ABLC, fever and chills were reported in 11% and 7% of patients, respectively. The severity with which these reactions occur is usually most intense during the first administration and decrease in strength with subsequent doses. In a clinical study of 78 pediatric and adult patients with febrile neutropenia who received ABLC, fever and chills/rigors occurred in 58% and 80% of patients on day 1 of therapy, respectively. The frequencies decreased to 51% and 45%, respectively, on days 2-5 of therapy. The mechanism for this adverse event is unknown; however, the infusion-related reactions may be a result of prostaglandin synthesis stimulated by amphotericin B. The incidence of infusion-related reactions associated with ABLC has been shown to be higher than with amphotericin B liposomal injection (LAmB). In a clinical study of pediatric and adult febrile neutropenic patients, 5 mg/kg/day of ABLC resulted in an 88% incidence of infusion-related reactions with the first dose of treatment. In this same study, patients receiving LAmB at 3 mg/kg/day and 5 mg/kg/day experienced infusion-related reactions at a rate of 51% and 48% respectively. Although several medications frequently are prescribed to suppress these reactions prior to administration of an amphotericin B dose, only hydrocortisone, meperidine, and ibuprofen have been shown to be effective. Infusion-related reactions can be more severe if administration occurs shortly after platelet or granulocyte transfusions.

Anaphylaxis or anaphylactoid reactions (< 0.1%), bronchospasm, dyspnea (7%), and wheezing have been reported in patients receiving treatment with amphotericin B lipid complex (ABLC). If severe respiratory distress, anaphylaxis or an anaphylactoid reaction occurs, the drug should be discontinued immediately and the patient given appropriate therapy as indicated. Cases of anaphylaxis have been reported when patients are switched from conventional amphotericin B to lipid formulations or when patients are switched between different amphotericin B lipid formulations.

Amphotericin B lipid complex (ABLC) is associated with a lower risk of nephrotoxicity (approximately 40% lower) when compared to conventional amphotericin B and has been used in patients with preexisting renal impairment. In an analysis of 548 pediatric patients (0-20 years; median age, 9 years; 99 patients < 2 years; 44 patients < 3 months) treated with ABLC from the Collaborative Exchange of Antifungal Research (CLEAR) database, elevations of serum creatinine > 1.5 x baseline were reported in 24.8% of patients and elevations > 2.5 x baseline were reported in 8.8% of patients. Patients in the 0-3 month age group experienced a lower frequency (6.8% and 2.3%, respectively). In a clinical study of febrile neutropenic patients (>= 2 years of age) receiving ABLC, the incidence of nephrotoxicity, defined as a 100% increase in baseline serum creatinine, was 42% for ABLC compared with 14-15% for liposomal amphotericin B (LAmb). However, a meta-analysis of other studies revealed a similar rate of nephrotoxicity between ABLC and LAmb. Nephrotoxicity is manifest in many forms including azotemia, hypokalemia, renal tubular acidosis (RTA), and frank renal failure. Renal tubular acidosis may be present without concurrent systemic acidosis and azotemia can develop after only a few doses. Although renal function can return to baseline in several days if ABLC therapy is held, irreversible renal tubular necrosis can develop, especially after prolonged therapy, large cumulative doses, or concomitant therapy with other nephrotoxic drugs. It appears that patients with higher serum low-density lipoprotein (LDL) concentrations are more susceptible to ABLC-induced nephrotoxicity than those with lower concentrations. Cases of azotemia, increased serum creatinine (11%), hyperuricemia, hypokalemia (5%), hyperkalemia, hypomagnesemia, hypophosphatemia, hypercalcemia, and hypocalcemia have been reported in patients receiving ABLC. Other adverse renal effects reported in patients receiving ABLC include anuria, decreased renal function, dysuria, oliguria, and renal failure (unspecified) (5%). Health care providers are advised to monitor renal function and serum electrolytes concentrations (particularly potassium and magnesium) in patients receiving treatment with ABLC.

A normocytic, normochromic anemia occurs in most patients receiving conventional amphotericin B. This reaction is believed to be caused by a suppressive effect on erythropoietin production. Usually, this condition does not require transfusions and generally returns to baseline within several months following discontinuation of therapy. Anemia has also been reported in 4% of patients receiving amphotericin B lipid complex (ABLC) during clinical trials. Other hematologic effects include leukopenia (4%) and thrombocytopenia (5%). Cases of coagulopathy, eosinophilia, and leukocytosis were reported during open-label, uncontrolled clinical trials; however, because these events occurred in uncontrolled trials, neither a frequency nor a definitive causal relationship can be established.

Cases of cardiac arrest (6%), respiratory failure (8%), chest pain (unspecified) (3%), hypertension (5%), and hypotension (8%) have been associated with the use of amphotericin B lipid complex (ABLC) during clinical trials. Other cardiorespiratory adverse events reported during open-label, uncontrolled clinical trials include heart failure, pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, pulmonary embolism, cardiomyopathy, pleural effusion, and arrhythmia exacerbation including ventricular fibrillation; however, because these events occurred in uncontrolled trials, neither a frequency nor a definitive causal relationship can be established. There is a potential for increased pulmonary toxicities in patients receiving leukocyte transfusions with amphotericin B infusions; therefore, concomitant administration of leukocyte transfusions and ABLC is not recommended.

Intravenous administration of amphotericin B lipid complex (ABLC) can cause an injection site reaction that includes symptoms such as pain and inflammation at the injection site. Phlebitis has also been associated with ABLC treatment during uncontrolled clinical trials.

Gastrointestinal (GI) adverse reactions, such as abdominal pain, anorexia, abdominal cramping, diarrhea (6%), dyspepsia, epigastric pain, GI bleeding (4%), melena, nausea (3-9%), vomiting (3-8%), and weight loss, have occurred in patients receiving amphotericin B lipid complex (ABLC) during clinical trials.

Hepatotoxicity has been associated with amphotericin B lipid complex (ABLC) therapy. During clinical trials, recipients of ABLC experienced elevated bilirubin concentrations or hyperbilirubinemia (4%), elevated hepatic enzymes, elevated alkaline phosphatase and lactate dehydrogenase, acute hepatic failure, hepatitis, jaundice, hepatomegaly, and hepatic veno-occlusive disease (VOD). Additionally, biliary disorders, such as cholangitis and cholecystitis, have developed in ABLC-treated patients. Health care providers are advised to monitor hepatic function in patients receiving treatment with ABLC.

Adverse neurologic reactions have been reported in patients receiving amphotericin B lipid complex (ABLC). Headache, noted in 6% of ABLC recipients, was the most frequently reported neurologic event during clinical trials. Other events observed in open-label, uncontrolled clinical trials included cerebral vascular accident (stroke), diplopia, encephalopathy, extrapyramidal syndrome, hearing loss, malaise, peripheral neuropathy, seizures, tinnitus, transient vertigo, and visual impairment; however, because these events occurred in uncontrolled trials, neither a frequency nor a definitive causal relationship can be established.

Rash (unspecified) was reported by 4% of amphotericin B lipid complex (ABLC) recipients during clinical trials. Other dermatologic adverse events reported during open-label, uncontrolled trials included maculopapular rash, pruritus, exfoliative dermatitis, and erythema multiforme; however, because these events occurred in uncontrolled trials, neither a frequency nor a definitive causal relationship can be established.

Generalized pain was experienced by 5% of amphotericin B lipid complex (ABLC) recipients during clinical trials. Other events observed in open-label, uncontrolled clinical trials included arthralgia, bone pain, musculoskeletal pain, and myasthenia; however, because these events occurred in uncontrolled trials, neither a frequency nor a definitive causal relationship can be established.

Metabolic adverse events associated with amphotericin B lipid complex (ABLC) therapy during open-label, uncontrolled clinical trials include metabolic acidosis, hyperamylasemia, hyperglycemia, and hypoglycemia; however, because these events occurred in uncontrolled trials, neither a frequency nor a definitive causal relationship can be established.

Adverse events experienced by recipients of amphotericin B lipid complex (ABLC) during clinical trials include multiple organ failure (11%), infection and sepsis (5-7%), and asthma.

Amphotericin B lipid complex (ABLC) is contraindicated in patients with a known hypersensitivity to amphotericin B or any other component in the formulation. Anaphylaxis has been reported with the use of ABLC; thus, administer ABLC only under close observation by medically trained personnel. If a severe anaphylactic reaction occurs during administration of ABLC, the drug should be immediately discontinued and the patient should not receive further doses of amphotericin B.

Cardiorespiratory arrest has been reported in patients receiving an overdose of amphotericin B. When administering ABLC, exercise caution to prevent inadvertent overdose; if an overdose occurs, discontinue therapy and administer supportive measures.

Acute pulmonary toxicity has been reported in patients receiving amphotericin B and leukocyte transfusions; concomitant use of leukocyte transfusions and amphotericin B lipid complex (ABLC) should be avoided.

Administer amphotericin B lipid complex (ABLC) with caution to patients with preexisting renal impairment or renal failure. Although ABLC has an improved safety profile when compared to conventional amphotericin B, nephrotoxicity can still develop. In a study of febrile neutropenic pediatric and adult patients receiving ABLC, the incidence of renal toxicity, defined as a 100% increase in baseline serum creatinine, was 42%. According to the manufacturer, ABLC has been successfully administered to patients with preexisting renal disease; no dose adjustment recommendations are given. However, renal function should be monitored during ABLC therapy.

Amphotericin B lipid complex (ABLC) has not been studied in patients with hepatic disease; administer the drug with caution in patients with preexisting hepatic impairment or hepatic failure. Monitor liver function tests during ABLC therapy, particularly serum bilirubin concentrations in patients at risk for jaundice (e.g., neonates with hyperbilirubinemia), as ABLC has been associated with hyperbilirubinemia.

Administer amphotericin B lipid complex (ABLC) with caution in patients with preexisting hematological disease including anemia, leukopenia, and thrombocytopenia. ABLC has been shown to cause anemia, leukopenia, and thrombocytopenia in clinical trials. Monitor CBC and platelets during ABLC therapy.

Use caution when administering amphotericin B lipid complex (ABLC) to patients with an electrolyte imbalance including hyperkalemia, hypokalemia, hypomagnesemia, hypercalcemia, and hypocalcemia. Serum electrolyte abnormalities may occur after administration of ABLC. Monitor serum electrolytes during ABLC therapy.

Administer amphotericin B lipid complex (ABLC) with caution to patients with preexisting cardiac disease including patients with preexisting hypotension and hypertension. In clinical studies, patients have experienced cardiac arrest, chest pain, hypotension, and hypertension after ABLC infusions.

Infusion-related reactions have been reported with the administration of amphotericin B lipid complex (ABLC). Acute reactions may include fever, chills, rigors, decreased blood pressure, bronchospasm, arrhythmias, and shock and usually occur during or shortly after (within 1-2 hours) administration of ABLC. The severity with which these reactions occur is usually most intense during the first administration and decrease in strength with subsequent doses. Although several medications frequently are prescribed to suppress these reactions prior to administration of an amphotericin B dose, only hydrocortisone, meperidine, and ibuprofen have been shown to be effective. Infusion-related reactions can be more severe if administration occurs shortly after platelet or granulocyte transfusions.

Description: Amphotericin B is a polyene antifungal first isolated in 1955 from Streptomyces nodosus. Amphotericin B maintains a broad spectrum of activity with a low potential for resistance, yet despite its efficacy, the usefulness of amphotericin B has been limited by its severe toxicities. To improve the tolerability of amphotericin B, lipid-based formulations have been developed. Amphotericin B lipid complex (ABLC) is composed of ribbon-like structures with a size ranging from 1600 to 11000 nm and a 1:1 molar ration of amphotericin B-to-phospholipid [L-alpha-dimyristoylphosphatidylcholine (DMPC) and L-alpha-dimyristoylphosphatidylglycerol (DMPG)]. Incorporating amphotericin B into a lipid complex decreases the toxicity and alters the pharmacokinetic properties of the drug without diminishing its efficacy. Data from 2 open-label studies involving pediatric patients refractory to or intolerant of conventional amphotericin B demonstrated effectiveness of ABLC in the treatment of invasive fungal infections. In addition, treatment with ABLC has resulted in significantly lower incidences of nephrotoxicity when compared to conventional amphotericin B. ABLC is indicated for the treatment of invasive fungal infections (e.g., aspergillosis, candidiasis, cryptococcosis) in patients who are refractory to or intolerant of conventional amphotericin B therapy. ABLC is also used for empirical therapy in febrile neutropenic patients. Conventional amphotericin B is still considered the first-line therapy for neonatal invasive fungal infections. ABLC is FDA-approved for use in pediatric patients as young as neonates.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Aspergillus fumigatus, Aspergillus sp., Blastomyces dermatitidis, Candida albicans, Candida guilliermondii, Candida sp., Candida stellatoidea, Candida tropicalis, Coccidioides immitis, Cryptococcus sp., Histoplasma sp.
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of CNS infections, including meningitis:
NOTE: For CNS infections caused by Cryptococcus, see Cryptococcus meningitis.
-for the treatment of CNS infections due to Aspergillus sp. in patients refractory to or intolerant of amphotericin B deoxycholate:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B lipid complex as salvage therapy.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. Guidelines suggest amphotericin B lipid complex as salvage therapy.
-for the treatment of CNS infections due to Blastomyces dermatitidis*:
Intravenous dosage:
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours for 4 to 6 weeks. Continue step-down therapy with an oral azole for at least 12 months and until resolution of CSF abnormalities.
-for the treatment of CNS infections due to Histoplasma capsulatum*:
Intravenous dosage:
Infants and Children: 5 mg/kg/dose IV every 24 hours for 4 to 6 weeks. Continue step-down therapy with itraconazole for at least 12 months and until resolution of cerebrospinal fluid (CSF) abnormalities. Guidelines suggest liposomal amphotericin B as preferred treatment.
Adolescents: 5 mg/kg/dose IV every 24 hours for 4 to 6 weeks. Continue step-down therapy with itraconazole for at least 12 months and until resolution of abnormal cerebrospinal fluid (CSF) findings. Guidelines suggest liposomal amphotericin B as preferred treatment.

For the treatment of candidemia and invasive candidiasis (non-CNS), including chronic disseminated (hepatosplenic candidiasis), in patients refractory to or intolerant of amphotericin B deoxycholate:
NOTE: For CNS disease, see meningitis indication.
-for the treatment of candidemia and invasive candidiasis (non-CNS):
Intravenous dosage:
Neonates: 3 to 5 mg/kg/dose IV every 24 hours as an alternative to an echinocandin or fluconazole if there is resistance or intolerance. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. In general, amphotericin B deoxycholate is preferred in neonates; lipid formulation amphotericin B should be used with caution in neonates, particularly in the presence of urinary tract involvement. Amphotericin B lipid complex has been successfully used in neonates with disseminated candidiasis, including in premature neonates, in a dosage range of 3.2 to 6.5 mg/kg/dose (mean 5 mg/kg/dose) IV every 24 hours.
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours as an alternative to an echinocandin or fluconazole if there is resistance or intolerance. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications.
-for the treatment of chronic disseminated (hepatosplenic candidiasis):
Intravenous dosage:
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours for several weeks, followed by oral fluconazole.

For the treatment of invasive aspergillosis in patients who are refractory to or intolerant of amphotericin B deoxycholate:
NOTE: For CNS disease, see meningitis indication.
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, clinical practice guidelines suggest amphotericin B lipid complex as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours. In an analysis of data from pediatric patients (median age, 9 years; 99 patients younger than 2 years; 44 patients younger than 3 months) treated with amphotericin B lipid complex for invasive fungal infections (median dose 4.92 mg/kg/day), the overall response rate (cured plus improved plus stable) was 71.4% for the 255 evaluable patients with documented fungal infections. The response rate for Aspergillus infections was 59.4%. Clinical practice guidelines suggest amphotericin B lipid complex as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

For the treatment of fungal ophthalmic infection, including endophthalmitis, caused by Aspergillus sp. in patients refractory to or intolerant of amphotericin B deoxycholate:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, clinical practice guidelines suggest amphotericin B lipid complex as salvage therapy. Intravitreal amphotericin B deoxycholate or voriconazole is suggested in addition to systemic therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours. In an analysis of data from pediatric patients (median age, 9 years; 99 patients younger than 2 years; 44 patients younger than 3 months) treated with amphotericin B lipid complex for invasive fungal infections (median dose 4.92 mg/kg/day), the overall response rate (cured plus improved plus stable) was 71.4% for the 255 evaluable patients with documented fungal infections. The response rate for Aspergillus infections was 59.4%. Clinical practice guidelines suggest amphotericin B lipid complex as salvage therapy. Intravitreal amphotericin B deoxycholate or voriconazole is suggested in addition to systemic therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

For the treatment of esophageal candidiasis* in persons living with HIV:
Intravenous dosage:
Adolescents: 3 to 4 mg/kg/dose IV every 24 hours for 14 to 21 days as an alternative.

For the treatment of cardiovascular system infections, including endocarditis, myocarditis, pericarditis, suppurative thrombophlebitis*, and infected pacemaker*, implantable cardiac defibrillator (ICD)*, or ventricular assist devices (VAD)* in patients who are refractory to or intolerant of amphotericin B deoxycholate:
-for the treatment of Candida cardiovascular system infections:
Intravenous dosage:
Neonates: 3 to 5 mg/kg/dose IV every 24 hours. Amphotericin B lipid complex has been successfully used in neonates with disseminated candidiasis, including in premature neonates, in a dosage range of 3.2 to 6.5 mg/kg/dose (mean 5 mg/kg/dose) IV every 24 hours. Guidelines suggest a lipid formulation amphotericin B as an alternative to an echinocandin or fluconazole if there is resistance or intolerance. In general, amphotericin B deoxycholate is preferred in neonates; lipid formulation amphotericin B should be used with caution in neonates, particularly in the presence of urinary tract involvement. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal. When valve replacement or hardware removal is not possible or for prosthetic valve endocarditis, chronic suppressive therapy with fluconazole is recommended after initial treatment. Treat suppurative thrombophlebitis for at least 2 weeks after candidemia (if present) has cleared.
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal. When valve replacement or hardware removal is not possible or for prosthetic valve endocarditis, chronic suppressive therapy with fluconazole is recommended after initial treatment. Treat suppurative thrombophlebitis for at least 2 weeks after candidemia (if present) has cleared.
-for the treatment of Aspergillus cardiovascular system infections:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Specific neonatal recommendations are not available. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. After surgical replacement of an infected valve, consider lifelong antifungal therapy.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. After surgical replacement of an infected valve, consider lifelong antifungal therapy. In an analysis of data from pediatric patients (median age, 9 years; 99 patients younger than 2 years; 44 patients younger than 3 months) treated with amphotericin B lipid complex for invasive fungal infections (median dose 4.92 mg/kg/day), the overall response rate (cured plus improved plus stable) was 71.4% for the 255 evaluable patients with documented fungal infections. The response rate for Aspergillus infections was 59.4%.

For the treatment of respiratory infections (i.e., pneumonia, tracheobronchitis, sinusitis) in patients who are refractory to or intolerant of amphotericin B deoxycholate:
-for the treatment of Candida pneumonia:
Intravenous dosage:
Neonates: Growth of Candida sp. from the respiratory tract typically reflects colonization and rarely requires antifungal therapy. Restrict treatment to pneumonia associated with disseminated infection. 3 to 5 mg/kg/dose IV every 24 hours. Amphotericin B lipid complex has been successfully used in neonates with disseminated candidiasis, including in premature neonates, in a dosage range of 3.2 to 6.5 mg/kg/dose (mean 5 mg/kg/dose) IV every 24 hours. Clinical practice guidelines suggest a lipid formulation amphotericin B as an alternative to amphotericin B deoxycholate or fluconazole for neonatal candidiasis. In general, amphotericin B deoxycholate is preferred in neonates; lipid formulation amphotericin B should be used with caution in neonates, particularly in the presence of urinary tract involvement.
Infants, Children, and Adolescents: Growth of Candida sp. from the respiratory tract typically reflects colonization and rarely requires antifungal therapy. In cases where pneumonia is associated with disseminated infection, 3 to 5 mg/kg/dose IV every 24 hours.
-for the treatment of invasive pulmonary, sinus, or tracheobronchial aspergillosis:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, clinical practice guidelines suggest amphotericin B lipid complex as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. In lung transplant recipients with tracheobronchial aspergillosis (TBA) associated with anastomotic endobronchial ischemia or ischemic reperfusion injury, inhaled amphotericin B is suggested in addition to systemic therapy; treat for at least 3 months or until TBA is resolved, whichever is longer. Surgery alone may be used to treat Aspergillus fungal ball of the paranasal sinus.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours. In an analysis of data from pediatric patients (median age, 9 years; 99 patients younger than 2 years; 44 patients younger than 3 months) treated with amphotericin B lipid complex for invasive fungal infections (median dose 4.92 mg/kg/day), the overall response rate (cured plus improved plus stable) was 71.4% for the 255 evaluable patients with documented fungal infections. The response rate for Aspergillus infections was 59.4%. Clinical practice guidelines suggest amphotericin B lipid complex as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. In lung transplant recipients with tracheobronchial aspergillosis (TBA) associated with anastomotic endobronchial ischemia or ischemic reperfusion injury, inhaled amphotericin B is suggested in addition to systemic therapy; treat for at least 3 months or until TBA is resolved, whichever is longer. Surgery alone may be used to treat Aspergillus fungal ball of the paranasal sinus.

For the treatment of intraabdominal infections due to candidiasis:
Intravenous dosage:
Neonates: 3 to 5 mg/kg/dose IV every 24 hours as an alternative.
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours as an alternative.

For the treatment of bone and joint infections, including osteomyelitis and infectious arthritis, in patients who are refractory to or intolerant of amphotericin B deoxycholate:
-for the treatment of Candida osteomyelitis or infectious arthritis:
Intravenous dosage:
Neonates: 3 to 5 mg/kg/dose IV every 24 hours. Amphotericin B lipid complex has been successfully used in neonates with disseminated candidiasis, including in premature neonates, in a dosage range of 3.2 to 6.5 mg/kg/dose (mean 5 mg/kg/dose) IV every 24 hours. Clinical practice guidelines suggest 3 to 5 mg/kg/dose IV every 24 hours as an alternative to amphotericin B deoxycholate or fluconazole for neonatal candidiasis. In general, amphotericin B deoxycholate is preferred in neonates; lipid formulation amphotericin B should be used with caution in neonates, particularly in the presence of urinary tract involvement. Treat for at least 2 weeks followed by fluconazole for 6 to 12 months for osteomyelitis or 4 weeks for infectious arthritis. Surgical debridement may be helpful in some cases of osteomyelitis and is recommended for all cases of septic arthritis. For infection involving a prosthetic device, device removal in addition to antifungal therapy is recommended.
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest a lipid formulation amphotericin B as an alternative to fluconazole. Treat for at least 2 weeks followed by fluconazole for 6 to 12 months for osteomyelitis or 4 weeks for infectious arthritis. Surgical debridement may be helpful in some cases of osteomyelitis and is recommended for all cases of septic arthritis. For infection involving a prosthetic device, device removal in addition to antifungal therapy is recommended.
-for the treatment of Aspergillus osteomyelitis or infectious arthritis:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, clinical practice guidelines suggest amphotericin B lipid complex as salvage therapy. Treat for at least 8 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. Longer courses (greater than 6 months) are frequently necessary.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours. In an analysis of data from pediatric patients (median age, 9 years; 99 patients younger than 2 years; 44 patients younger than 3 months) treated with amphotericin B lipid complex for invasive fungal infections (median dose 4.92 mg/kg/day), the overall response rate (cured plus improved plus stable) was 71.4% for the 255 evaluable patients with documented fungal infections. The response rate for Aspergillus infections was 59.4%. Clinical practice guidelines suggest amphotericin B lipid complex as salvage therapy. Treat for at least 8 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement. Longer courses (greater than 6 months) are frequently necessary.

For empirical therapy for presumed fungal infection in patients with febrile neutropenia* or nonneutropenic patients at risk of fungal infection* (e.g. critically ill patients with risk factors for invasive candidiasis and no other known cause of fever):
Intravenous dosage:
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours. Clinical practice guidelines for candidiasis suggest 3 to 5 mg/kg/day IV of a lipid formulation amphotericin B as an alternative to an echinocandin or fluconazole if there is resistance or intolerance. Aspergillosis clinical practice guidelines suggest empirical therapy for high-risk patients with prolonged neutropenia who remain persistently febrile despite broad-spectrum antibiotic therapy. In neutropenic patients with cancer, empiric antifungal therapy is suggested for patients with persistent or recurrent fever after 4 to 7 days of antibiotics and whose overall duration of neutropenia is expected to be more than 7 days. If already receiving antifungal prophylaxis, consider switching to a different class of mold active agent. Caspofungin or liposomal amphotericin B is a preferred agent for empiric antifungal therapy in children with cancer and/or undergoing hematopoietic stem cell transplantation.

For the treatment of CNS cryptococcal infections, including cryptococcal meningitis and cerebral cryptococcomas, in patients who are refractory to or intolerant of amphotericin B deoxycholate:
-Persons living with HIV:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours in combination with flucytosine for 2 weeks as a preferred induction therapy. Alternatively, amphotericin B lipid complex may be given as a single agent or with high-dose fluconazole for patients unable to tolerate flucytosine. For treatment failure or relapse, continue induction therapy until clinical response. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
Infants and Children: 5 mg/kg/dose IV every 24 hours in combination with flucytosine for 2 weeks as a preferred induction therapy. Alternatively, amphotericin B lipid complex may be given as a single agent or with high-dose fluconazole for patients unable to tolerate flucytosine. For treatment failure or relapse, continue induction therapy until clinical response. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
Adolescents: 5 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as an alternative induction therapy. For treatment failure or relapse, continue induction therapy until clinical response. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
-Organ transplant recipients:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B lipid complex in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, amphotericin B lipid complex may be given as a single agent for patients unable to tolerate flucytosine. If amphotericin B lipid complex is given as a single agent, give induction therapy for 4 to 6 weeks. For cerebral cryptococcomas, give induction therapy for at least 6 weeks. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, amphotericin B lipid complex may be given as a single agent for patients unable to tolerate flucytosine. If amphotericin B lipid complex is given as a single agent, give induction therapy for 4 to 6 weeks. For cerebral cryptococcomas, give induction therapy for at least 6 weeks. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
-Non-HIV, nontransplant patients:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B lipid complex with flucytosine for at least 4 weeks as an alternative induction therapy. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If amphotericin B lipid complex is given as a single agent, consider lengthening induction therapy for at least 2 weeks. In patients with neurological complications or cerebral cryptococcomas, extend induction therapy for a total of 6 weeks. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours with flucytosine for at least 4 weeks as an alternative induction therapy. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If amphotericin B lipid complex is given as a single agent, consider lengthening induction therapy for at least 2 weeks. In patients with neurological complications or cerebral cryptococcomas, extend induction therapy for a total of 6 weeks. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.

For the treatment of disseminated (nonmeningeal) or pulmonary cryptococcosis in patients refractory to or intolerant of amphotericin B deoxycholate:
NOTE: For the treatment of CNS infections, see cryptococcal meningitis.
-Persons living with HIV:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours with or without flucytosine. Duration of therapy dependent on site and severity of infection and clinical response.
Infants and Children: 5 mg/kg/dose IV every 24 hours with or without flucytosine. Duration of therapy dependent on site and severity of infection and clinical response.
Adolescents: 5 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as an alternative induction therapy. For treatment failure or relapse, continue induction therapy until clinical response. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
-Organ transplant recipients:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B lipid complex in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, amphotericin B lipid complex may be given as a single agent for 4 to 6 weeks for patients unable to tolerate flucytosine. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, amphotericin B lipid complex may be given as a single agent for 4 to 6 weeks for patients unable to tolerate flucytosine. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
-Non-HIV, nontransplant patients:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B lipid complex with flucytosine for at least 4 weeks as an alternative induction therapy. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If amphotericin B lipid complex is given as a single agent, consider lengthening induction therapy for at least 2 weeks. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours for at least 4 weeks as an alternative induction therapy. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If amphotericin B lipid complex is given as a single agent, consider lengthening induction therapy for at least 2 weeks. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy.

For the treatment of moderately severe to severe blastomycosis:
NOTE: For CNS infections, see meningitis indication.
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours.
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours for 1 to 2 weeks or until improvement is noted. Continue step-down therapy with itraconazole to complete a total of 12 months of therapy.
Immunosuppressed Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours for 1 to 2 weeks or until improvement is noted. Continue step-down therapy with itraconazole to complete a total of at least 12 months of therapy. Lifelong suppressive therapy may be required.

For the treatment of severe pulmonary or nonmeningeal, extrapulmonary coccidioidomycosis:
-for the treatment of severe pulmonary or nonmeningeal, extrapulmonary coccidioidomycosis in persons without HIV who are refractory to or intolerant of other therapies:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours.
Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours until clinical improvement, followed by fluconazole or itraconazole. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.
-for the treatment of severe pulmonary or nonmeningeal, extrapulmonary coccidioidomycosis in persons living with HIV:
Intravenous dosage:
Infants and Children: 5 mg/kg/dose IV every 24 hours until clinical improvement, followed by fluconazole or itraconazole for at least 12 months then long-term suppressive therapy. Some experts will also add an azole to amphotericin B during the acute phase of treatment.
Adolescents: 3 to 5 mg/kg/dose IV every 24 hours until clinical improvement, followed by fluconazole or itraconazole for at least 12 months then long-term suppressive therapy; discontinuation is dependent on clinical and serological response. Some experts will also add an azole to amphotericin B during the acute phase of treatment.

For the treatment of moderately severe to severe pulmonary or disseminated histoplasmosis in patients refractory to or intolerant of amphotericin B deoxycholate:
-for the treatment of pulmonary histoplasmosis:
Intravenous dosage:
Neonates: 3 to 5 mg/kg/dose IV every 24 hours for 1 to 2 weeks. Continue step-down therapy with itraconazole for a total of 12 weeks. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B lipid complex as alternate therapy in patients unable to tolerate amphotericin B deoxycholate.
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours for 1 to 2 weeks. Continue step-down therapy with itraconazole for a total of 12 weeks. Guidelines suggest amphotericin B lipid complex as alternate therapy in patients unable to tolerate amphotericin B deoxycholate.
-for the treatment of disseminated histoplasmosis:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours for for at least 2 weeks or longer if clinical improvement is delayed. Continue step-down therapy with itraconazole for 12 months for HIV-infected patients. Although specific neonatal recommendations are not available, guidelines suggest liposomal amphotericin B as the preferred treatment in HIV-infected children and amphotericin B deoxycholate as the preferred treatment in non-HIV-infected children.
Infants and Children: 5 mg/kg/dose IV every 24 hours for for at least 2 weeks or longer if clinical improvement is delayed. Continue step-down therapy with itraconazole for 12 months for HIV-infected patients. Guidelines suggest liposomal amphotericin B as the preferred treatment in HIV-infected children and amphotericin B deoxycholate as the preferred treatment in non-HIV-infected children.
Adolescents: 5 mg/kg/dose IV every 24 hours for 1 to 2 weeks. For HIV-infected patients, continue step-down therapy with itraconazole for at least 12 months. Longer treatment may be required in patients with persistent immunodeficiency. Guidelines suggest amphotericin B lipid complex as an alternate treatment to liposomal amphotericin B.

For the treatment of visceral leishmaniasis*:
Intravenous dosage:
Immunocompetent Infants, Children, and Adolescents: 2 to 3 mg/kg/dose IV every 24 hours for 5 to 10 days as an alternative to liposomal amphotericin B. In general, this formulation is not recommended, but may be considered with patients who develop liposome-induced complement activation-related pseudoallergy (CARPA).
Immunocompromised Infants and Children: 3 to 5 mg/kg/dose IV every 24 hours for 10 days as an alternative to liposomal amphotericin B. In general, this formulation is not recommended, but may be considered with patients who develop liposome-induced complement activation-related pseudoallergy (CARPA).
Immunocompromised Adolescents: 2 to 5 mg/kg/dose IV every 24 hours for 10 days or 4 mg/kg/dose IV on days 1, 2, 3, 4, 5, 10, 17, 24, 31, and 38, for a cumulative total of 20 to 60 mg/kg, as an alternative to liposomal amphotericin B. In general, this formulation is not recommended, but may be considered with patients who develop liposome-induced complement activation-related pseudoallergy (CARPA). Chronic maintenance therapy with a lipid formulation amphotericin B, or alternately, pentavalent antimony is recommended in HIV-infected patients.

For secondary leishmaniasis prophylaxis* (i.e., long-term suppressive therapy) in HIV-infected patients:
Intravenous dosage:
Adolescents: 3 mg/kg/dose IV every 21 days until a sustained (at least 3 to 6 months) increase in CD4 count to more than 200 to 350 cells/mm3 in response to antiretroviral therapy; however, indefinite prophylaxis may be used. Prophylaxis is recommended in patients with visceral disease and in some patients with multiple cutaneous relapses.

For the treatment of asymptomatic candiduria:
-for the treatment of asymptomatic candiduria in neutropenic persons:
Intravenous dosage:
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours for 14 days as an alternative to an echinocandin or fluconazole if there is resistance or intolerance. Candiduria may be the only microbiological documentation of disseminated candidiasis in neutropenic persons; therefore, candiduria should be treated as disseminated candidiasis in these persons.
-for the treatment of asymptomatic candiduria in very-low-birth-weight infants (weight less than 1.5 kg):
Intravenous dosage:
Neonates: 3 to 5 mg/kg/dose IV every 24 hours for 14 days as an alternative to an echinocandin or fluconazole if there is resistance or intolerance. Candiduria may be the only microbiological documentation of disseminated candidiasis in very-low-birth-weight infants; therefore, candiduria should be treated as disseminated candidiasis in these infants. In general, amphotericin B deoxycholate is preferred in neonates; lipid formulation amphotericin B should be used with caution in neonates, particularly in the presence of urinary tract involvement. Amphotericin B lipid complex has been successfully used in neonates with disseminated candidiasis, including in premature neonates, in a dosage range of 3.2 to 6.5 mg/kg/dose (mean 5 mg/kg/dose) IV every 24 hours.

Maximum Dosage Limits:
-Neonates
5 mg/kg/day IV. Doses up to 6.5 mg/kg/day IV have been used rarely, but are typically not recommended.
-Infants
5 mg/kg/day IV.
-Children
5 mg/kg/day IV.
-Adolescents
5 mg/kg/day IV.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; renal toxicity associated with ABLC is dose-dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient.

Intermittent hemodialysis or Peritoneal dialysis
Amphotericin B lipid complex (ABLC) is not efficiently removed by hemodialysis or peritoneal dialysis; dosage adjustments are not necessary in patients receiving these types of dialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Amphotericin B, the active ingredient in amphotericin B lipid complex (ABLC), binds to sterols in cell membranes of both fungal and human cells. As a result of this binding, membrane integrity of the cells is impaired, causing loss of intracellular potassium and other cellular contents. Altered permeability of ergosterol-containing membranes, characteristic of fungal cell membranes, occurs at low amphotericin B concentrations; however, beyond a certain concentration threshold, amphotericin B induces leakage of cellular contents through human cholesterol-containing membranes. Some adverse reactions to amphotericin B, such as electrolyte loss and nephrotoxicity, are an extension of this pharmacologic action. Amphotericin B is usually fungistatic in vivo but can have fungicidal activity at high concentrations or against extremely susceptible organisms.

Pharmacokinetics: Amphotericin B lipid complex (ABLC) is administered intravenously. Pharmacokinetic parameters for ABLC should not be used to predict the pharmacokinetics of any other amphotericin B formulation. The clinical relevance of pharmacokinetic differences between ABLC and other amphotericin B formulations has not been determined. Further, the interpretation of serum or tissue amphotericin B concentrations is complicated by the fact that many assays to measure amphotericin B concentrations do not distinguish free amphotericin B and amphotericin B that is lipid-complexed, liposome-encapsulated, or protein-bound. ABLC is widely distributed (primarily to spleen, liver, and lung) with a large volume of distribution (approximately 12.4 L/kg) reported in adults. It is minimally distributed to the kidney and heart.

Metabolism of amphotericin B following administration of ABLC is unknown. Amphotericin B is excreted very slowly by the kidneys. The terminal elimination half-life of amphotericin B is longer after administration of the lipid-complexed formulation (mean 7 days) when compared to conventional amphotericin B (mean 4 days). The long terminal half-life reflects slow redistribution from the tissues. Despite being excreted slowly, there is little accumulation in the blood after repeated dosing. Limited pharmacokinetic data in children reported that steady state was attained by day 7 of therapy.

Affected cytochrome P450 isoenzymes: none


-Special Populations
Pediatrics
Neonates
The pharmacokinetics of amphotericin B lipid complex appear to be similar to those of adults based on limited pharmacokinetic data available in neonates. In a population pharmacokinetic study in 28 neonates (mean gestational age 27 weeks, range 24-41 weeks), the final parameter estimates for clearance, volume of distribution, and elimination half-life were 0.399 L/hr/kg, 10.5 L/kg, and 395 hours, respectively. These values were similar to those reported in adults (0.27-0.41 L/hr/kg; 12.4 L/kg, and 395 hours, respectively); however, the clearance observed in neonates was approximately twice as high as that observed in children > 1 year of age (0.218 L/hr/kg).

Children and Adolescents
There are limited pharmacokinetic data available in children; however, the pharmacokinetics of amphotericin B lipid complex are not expected to be different in children compared with adults. The mean clearance reported from pharmacokinetic data from 3 children was 0.218 L/hr/kg.

Hepatic Impairment
Pharmacokinetic data are unavailable in patients with hepatic impairment.

Renal Impairment
Pharmacokinetic data for amphotericin B lipid complex are unavailable in patients with renal impairment or patients receiving dialysis. However, amphotericin B is not eliminated by hemodialysis when administered as amphotericin B deoxycholate.