AMBISOME (Brand for AMPHOTERICIN B LIPOSOME)

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

NOTE: Amphotericin B liposomal (LAmB) is not dosed the same as conventional amphotericin B (amphotericin B deoxycholate) or other lipid formulations. Further, amphotericin B lipid formulations may not be substituted for one another. The differences in the chemical composition and lipid component of these products can substantially affect their functional properties.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration. After reconstitution, liposomal amphotericin B is a yellow, translucent suspension.
Intravenous Administration
Reconstitution
-Add 12 mL of Sterile Water for Injection, USP to each vial to yield a 4 mg/mL suspension. Do not reconstitute with saline, add saline to the reconstituted suspension, or mix with other medications. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause a precipitate to form.
-Immediately after adding the Sterile Water for Injection, shake the vial vigorously for 30 seconds to completely disperse the product. The suspension should be yellow and translucent. Visually inspect vial for particulate matter and continue shaking until completely dispersed.
-Storage: The reconstituted product may be stored for up to 24 hours at 2 to 8 degrees C (36 to 46 degrees F). Do not freeze.

Dilution
-Calculate the amount of reconstituted suspension to be further diluted and withdraw this amount into a sterile syringe.
-Attach the provided 5-micron filter to the syringe; inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection. Use only 1 filter per vial.
-The suspension must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL before administration. For infants and small children, lower concentrations (0.2 to 0.5 mg/mL) may be appropriate to provide sufficient volume for infusion.-ISMP Recommended Standard Concentration for Neonates: 1 mg/mL

-Storage: Begin injection within 6 hours of dilution.

Intermittent IV infusion
-Flush existing intravenous line with 5% Dextrose Injection before infusion. If this is not feasible, infuse through a separate line.
-An in-line membrane filter may be used provided the mean pore diameter of the filter is not less than 1 micron.
-Administer by intravenous infusion using a controlled infusion device over approximately 120 minutes. May reduce infusion time to approximately 60 minutes in patients who tolerate the infusion. If the patient experiences discomfort during infusion, the duration of infusion may be increased.

Anaphylaxis, anaphylactoid reactions, and angioedema have been reported rarely in patients receiving amphotericin B liposomal injection (LAmB). 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 liposomal injection (LAmB) is associated with a lower risk of nephrotoxicity (0-19%) when compared to conventional amphotericin B and has been used in patients with preexisting renal impairment. The incidence of nephrotoxicity (defined as a 100% increase in baseline serum creatinine) was lower with LAmB compared with ABLC (14-15% vs. 42%) in a clinical study of febrile neutropenic patients. Nephrotoxicity is manifest in many forms including azotemia, hypokalemia, hyposthenuria, nephrolithiasis (specifically nephrocalcinosis), 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 LAmB 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 LAmB-induced nephrotoxicity than those with lower concentrations. Azotemia (7.4-21%), increased serum creatinine (18.5-39.4%), hypokalemia (6.7-51.1%), hypomagnesemia (15.3-48.9%), hyponatremia (8.5-11.6%), hypernatremia (4.1%), and hypocalcemia (4.9-18.4%) have been reported in patients receiving LAmB. Other electrolyte disturbances that were reported in 2-10% of patients include hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, and hypophosphatemia. Other adverse renal effects include acute renal failure (unspecified) (2-10%), anuria, decreased renal function, dysuria (2-10%), hematuria (14%), toxic nephropathy (2-10%), and urinary incontinence (2-10%). Cases of hemorrhagic cystitis have been observed during the post-marketing period. Additionally, nephrogenic diabetes insipidus has been reported in association with LAmB in a critically ill adult bone marrow transplant recipient being treated for fungal pneumonia. Patient management should involve laboratory monitoring of renal function and serum electrolytes (particularly potassium and magnesium serum concentrations).

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 26.7-47.9% of patients receiving amphotericin B liposomal injection (LAmB). Other hematologic effects experienced by LAmB recipients include coagulopathy (2-10%), bleeding (e.g., vaginal bleeding) (2-10%), decreased and increased prothrombin times (2-10%), ecchymosis (2-10%), leukopenia (15.1-17%), petechiae (2-10%), and thrombocytopenia (5.8-12.8%). Cases of agranulocytosis were reported during the post-marketing period. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.

Intravenous administration of amphotericin B liposomal injection (LAmB) can cause an injection site reaction that includes symptoms such as pain and inflammation at the injection site (2-10%). During clinical trials, phlebitis developed in 9.3-10.6% of LAmB infusion recipients. Cases of erythema, potentially related to infusion, have been observed during the post-marketing period. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.

Gastrointestinal (GI) adverse reactions, such as abdominal enlargement (2-10%), abdominal pain (7-19.8%), anorexia (9.6-14%), diarrhea (10.5-30.3%), dyspepsia (2-10%), dysphagia (2-10%), constipation (14.9-15.1%), eructation (2-10%), fecal incontinence (2-10%), GI bleeding (9.9%), gingival bleeding (2-10%), hematemesis (2-10%), hemorrhoids (2-10%), flatulence (2-10%), ileus (2-10%), mucositis (2-10%), nausea (16.3-39.7%) and vomiting (10.5-31.8%), stomatitis (2-10%), and xerostomia (2-10%), have occurred in recipients of LAmB during clinical trials.

Infusion-related reactions have been reported with the administration of amphotericin B liposomal injection (LAmB). Infusion-related reactions are toxicities occurring during or shortly after administration of LAmB and include symptoms such as nausea/vomiting (8-14%/4-16%), chills and rigors (6-48.1%), fever (7-23.5%), increased and decreased blood pressure (2.3-8.6% and 3.5%, respectively), tachycardia (2.3-9.9%), shortness of breath (4.7-9.9%), decreased oxygenation (0.3-1.2%), and hyperventilation (1.2%). The severity with which these reactions occur is usually most intense during the first administration and decreases in strength with subsequent doses. 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 is lower following administration of LAmB than with conventional amphotericin B. In a large, double-blind study of adult and pediatric febrile neutropenic patients, infusion-related reactions occurred less often with the first dose of LAmB (6-18%) than with the first dose of conventional amphotericin B (8-54%). Infusion-related reactions also occurred less frequently in children compared with adults. There have been a few reports of patients experiencing flush, pain in the back (with or without chest tightness), and chest pain within a few minutes after initiation of IV infusions of LAmB. These reactions were occasionally severe but disappeared when the infusion was stopped. 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. Slowing the rate of infusion is not helpful. Infusion-related reactions can be more severe if administration occurs shortly after platelet or granulocyte transfusions.

Respiratory adverse reactions that have been reported during clinical trials with amphotericin B liposomal injection include asthma (2-10%), atelectasis (2-10%), increased cough (2.1-17.8%), dyspnea (4.7-23%), epistaxis (8.6-14.9%), hemoptysis (2-10%), hiccups (2-10%), hypoxia (0.3-7.6%), nasal dryness (2-10%), pulmonary edema (2-10%), respiratory alkalosis (2-10%), respiratory failure (2-10%), and rhinitis (11.1%). In addition, in patients receiving leukocyte infusions with amphotericin B, pulmonary toxicity has been reported. Cases of pulmonary edema, bronchospasm, and hypoventilation with cyanosis have been reported during the post-marketing period. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.

The most common cardiovascular adverse reactions reported during general clinical trials with amphotericin B liposomal (LAmB) injection included chest pain (unspecified) (8.2-12%), edema (12.3-14.3%), hypertension (2.3-19.8%), hypotension (3.5-14.3%), hypervolemia (8.2-12.2%), peripheral edema (14.6%), pleural effusion (12.5%), and sinus tachycardia (2.3-18.5%). Other adverse reactions reported by 2-10% of LAmB recipients included arrhythmia exacerbation, atrial fibrillation, bradycardia, cardiac arrest, fluid retention, flushing, cardiomegaly, orthostatic hypotension, peripheral vasodilation, valvular heart disease, and vascular disorder.

Hepatotoxicity has been associated with amphotericin B liposomal injection (LAmB) treatment. During clinical trials, elevated hepatic enzymes and cases of hyperbilirubinemia developed in 4.3-14.6% and 8.5-18.1% of patients, respectively. Other hepatic adverse events experienced by 2-10% of LAmB recipients included hepatocellular damage, hepatomegaly, and hepatic veno-occlusive disease (VOD). Health care providers are advised to monitor the hepatic function of patients receiving LAmB therapy.

The most common neurologic adverse reactions associated with amphotericin B liposomal injection (LAmB) therapy include anxiety (7.4-13.7%), asthenia (6.2-13.1%), confusion (8.6-12.9%), dizziness (7-8.5%), headache (9.4-19.8%), and insomnia (17-22.1%). Other neurologic adverse events experienced by 2-10% of LAmB recipients include abnormal thinking, agitation, coma, depression, dysesthesia, drowsiness, hallucinations, malaise, nervousness, paresthesias, seizures, and tremor.

During amphotericin B liposomal injection (LAmB) clinical trials, the most frequently reported dermatologic adverse events included hyperhidrosis (7%), pruritus (10.8%), and rash (unspecified) (4.7-24.8%). Other dermatologic adverse events experienced by 2-10% of LAmB recipients included alopecia, bullous rash, purpura, maculopapular rash, vesicular rash, skin discoloration, skin ulcer, urticaria, and xerosis.

Generalized pain and back pain were experienced by 14% and 12%, respectively, of amphotericin B liposomal injections (LAmB) recipients during clinical trials. Other musculoskeletal adverse events occurring in 2-10% of patients treated with LAmB included arthralgia, bone pain, dystonic reaction, myalgia, and neck pain. Rhabdomyolysis was reported during the post-marketing period. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.

Ophthalmic adverse events experienced by 2-10% of amphotericin B liposomal injection (LAmB) recipients during clinical trials included conjunctivitis, ocular hemorrhage, and xerophthalmia (dry eyes).

Infections developed in 11.1-12.8% of amphotericin B liposomal injection (LAmB) recipients during clinical trials. Specific infection type/sites included cellulitis (2-10%), herpes simplex (2-10%), influenza-like symptoms (2-10%), pharyngitis (2-10%), pneumonia (2-10%), sepsis (7.4-14%), and sinusitis (2-10%). Other immunologic reactions experienced by patients receiving treatment with LAmB included blood product transfusion reactions (8.6-18.4%), cell mediated immunological reactions (2-10%), and graft versus host disease (2-10%).

Metabolic adverse events experienced by recipients of amphotericin B liposomal injection (LAmB) during clinical trials included elevated alkaline phosphatase (7.1-22.2%), elevated lactate dehydrogenase (2-10%), elevated nonprotein nitrogen (2-10%), elevated amylase (2-10%), hyperglycemia (8.2-23%), hypoproteinemia (2-10%), and metabolic acidosis (2-10%).

Amphotericin B liposomal injection (LAmB) is contraindicated in patients with a known hypersensitivity to amphotericin B or any other component in the formulation. Anaphylaxis has been reported with LAmB; thus, administer LAmB only under close observation by medically trained personnel. If a severe anaphylactic reaction occurs during administration of LAmB, 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 LAmB, exercise caution to prevent inadvertent overdose; if an overdose occurs, discontinue therapy and administer supportive measures. In addition, acute pulmonary toxicity has been reported in patients receiving amphotericin B and leukocyte transfusions; concomitant use of leukocyte transfusions and LAmB should be avoided.

Administer amphotericin B liposomal injection (LAmB) with caution to patients with preexisting renal impairment or renal failure. Although LAmB has an improved safety profile when compared to conventional amphotericin B, nephrotoxicity can still develop. In clinical trials that included children, the incidence of renal toxicity, defined as a 100% increase in baseline serum creatinine, ranged from 0-19% for doses of LAmB of 1-3 mg/kg/day. The incidence of renal toxicity for conventional amphotericin B in the same studies ranged from 23-37% for doses of 0.6-1 mg/kg/day. According to the manufacturer, LAmB has been successfully administered to patients with preexisting renal disease; no dose adjustment recommendations are given. Renal function should be monitored during LAmB therapy.

Amphotericin B liposomal injection (LAmB) 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 LAmB therapy.

Amphotericin B liposomal injection (LAmB) is known to cause anemia, leukopenia, and thrombocytopenia; administer the drug with caution in patients with preexisting hematological disease including patients with preexisting anemia, leukopenia, and thrombocytopenia. In addition, monitor CBC and platelets during LAmB therapy. A clinical study of LAmB therapy in cryptococcal meningitis patients demonstrated an increased incidence of anemia, leukopenia, and thrombocytopenia as the dose was increased from 3 mg/kg/day to 6 mg/kg/day.

Use caution when administering amphotericin B liposomal injection (LAmB) to patients with an electrolyte imbalance including hypokalemia, hypomagnesemia, hypocalcemia, and hyponatremia. Serum electrolyte abnormalities may occur after administration of LAmB. Monitor serum electrolytes during LAmB treatment.

Administer amphotericin B liposomal injection (LAmB) with caution to patients with preexisting cardiac disease including patients with preexisting tachycardia, hypotension, and hypertension. In clinical studies, patients have experienced chest pain, tachycardia, hypotension, and hypertension after LAmB infusions.

Description: Amphotericin B is a polyene antifungal isolated 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 liposomal injection (LAmB) is amphotericin B intercalated into a unilamellar bilayer liposomal membrane that has a diameter of less than 100 nm and consists of hydrogenated soy phosphatidylcholine (HSPC), cholesterol, distearoylphosphatidylglycerol, and alpha tocopherol. Incorporating amphotericin B into a liposomal membrane decreases the toxicity and alters the pharmacokinetic properties of the drug without diminishing its efficacy. In studies involving patients with persistent fever and neutropenia, LAmB showed comparable success rates with fewer adverse events when compared to conventional amphotericin B. Similarly, in studies of AIDS patients with Cryptococcus and Histoplasma capsulatum infections, treatment with LAmB resulted in equivalent success rates and fewer adverse events when compared to conventional amphotericin B. LAmB is approved for empiric therapy in febrile, neutropenic patients with presumed fungal infections; for the treatment of Cryptococcal meningitis in HIV infected patients; for the treatment of patients with Aspergillus, Candida, or Cryptococcus species infections refractory to conventional amphotericin B or in patients where renal impairment or unacceptable toxicity precludes the use of conventional amphotericin B; and for the treatment of visceral leishmaniasis. LAmB is also used for antifungal prophylaxis in high-risk patients (cancer or solid organ/hematopoietic stem cell transplantation patients) and for other invasive fungal infections (e.g., blastomycosis, coccidioidomycosis, histoplasmosis). Conventional amphotericin B is still considered the first-line therapy for neonatal invasive fungal infections. Amphotericin B liposomal is FDA approved for use in pediatric patients as young as 1 month of age.

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 flavus, Aspergillus fumigatus, Aspergillus sp., Blastomyces dermatitidis, Candida albicans, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida sp., Candida tropicalis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Leishmania infantum, Paracoccidioides brasiliensis
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.

This drug may also have activity against the following microorganisms: Talaromyces marneffei
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

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*: 3 to 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when voriconazole is contraindicated or not tolerated. 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: 3 to 5 mg/kg/dose IV every 24 hours. Guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when voriconazole is contraindicated or not tolerated. 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 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 Candida sp. in patients refractory to or intolerant of amphotericin B deoxycholate:
Intravenous dosage:
Neonates*: 3 to 5 mg/kg/dose IV every 24 hours. Doses up to 7 mg/kg/dose IV every 24 hours have been successfully used in neonates with systemic candidiasis. In general, concurrent flucytosine therapy is not routinely recommended in neonates but may be considered as salvage therapy in patients who do not respond to initial amphotericin therapy. Continue treatment until all signs and symptoms and cerebrospinal fluid (CSF) and radiologic abnormalities have resolved. Remove intraventricular devices.
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours. Guidelines suggest 5 mg/kg/dose IV every 24 hours as an alternative to amphotericin B deoxycholate with or without flucytosine. May use fluconazole as step-down therapy after achieving response to initial therapy. Continue treatment until all signs and symptoms and cerebrospinal fluid (CSF) and radiologic abnormalities have resolved. Remove intraventricular devices.
-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. Doses up to 7 mg/kg/dose IV every 24 hours have been successfully used in neonates with systemic 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 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications.
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 refractory to or intolerant of amphotericin B deoxycholate:
NOTE: For CNS disease, see meningitis indication.
Intravenous dosage:
Neonates*: 3 to 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, clinical practice guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. 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: 3 to 5 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. 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 and chorioretinitis, in patients refractory to or intolerant of amphotericin B deoxycholate:
-for the treatment of Candida endophthalmitis and chorioretinitis:
Intravenous dosage:
Neonates*: 3 to 5 mg/kg/dose IV every 24 hours. Doses up to 7 mg/kg/dose IV every 24 hours have been successfully used in neonates with systemic 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. With macular involvement or vitritis, intravitreal amphotericin B deoxycholate or voriconazole is suggested in addition to systemic therapy. Treat for at least 4 to 6 weeks, with duration depending on stabilization or resolution of lesions.
Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours with or without flucytosine. Clinical practice guidelines suggest liposomal amphotericin B as alternative therapy for fluconazole- or voriconazole-resistant strains. With macular involvement or vitritis, intravitreal amphotericin B deoxycholate or voriconazole is suggested in addition to systemic therapy. Treat for at least 4 to 6 weeks, with duration depending on stabilization or resolution of lesions.
-for the treatment of Aspergillus endophthalmitis:
Intravenous dosage:
Neonates*: 3 to 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, clinical practice guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. 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: 3 to 5 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. 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 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. Doses up to 7 mg/kg/dose IV every 24 hours have been successfully used in neonates with systemic 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. 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*: 3 to 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: 3 to 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.

For the treatment of respiratory infections (i.e., pneumonia, tracheobronchitis, sinusitis) in patients 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. In cases where pneumonia is associated with disseminated infection, 3 to 5 mg/kg/dose IV every 24 hours. Doses up to 7 mg/kg/dose IV every 24 hours have been successfully used in neonates with systemic 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*: 3 to 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, clinical practice guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. 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: 3 to 5 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. 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 Candida intraabdominal infections:
Intravenous dosage:
Neonates*: 3 to 5 mg/kg/dose IV every 24 hours as an alternative. Doses up to 7 mg/kg/dose IV every 24 hours have been successfully used in neonates with systemic 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: 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 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. Doses up to 7 mg/kg/dose IV every 24 hours have been successfully used in neonates with systemic 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 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*: 3 to 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, clinical practice guidelines suggest a lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. 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: 3 to 5 mg/kg/dose IV every 24 hours as initial and salvage therapy when triazoles are contraindicated or not tolerated. 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 in patients with febrile neutropenia:
Intravenous dosage:
Infants, Children, and Adolescents: 3 mg/kg/dose IV every 24 hours. In a study of 82 children, liposomal amphotericin B doses were increased to 5 mg/kg/day after 5 days of persistent fever and inadequate clinical response. 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.

For fungal prophylaxis* (e.g., candidiasis prophylaxis*, aspergillosis prophylaxis*) in high-risk patients:
-in patients undergoing solid organ or hematopoietic stem cell transplantation:
Intravenous dosage:
Infants, Children, and Adolescents: Various regimens may be used depending on local protocols; 1 to 2 mg/kg/dose IV every 24 hours is common. A treatment duration of 5 days has been used for patients immediately after liver transplantation. For hematopoietic stem cell transplant (HSCT) recipients, prophylaxis has been given during the neutropenic phase after HSCT and until neutrophil recovery (median, 14 days). Higher doses (3 mg/kg/day for first 100 days after transplantation) have also been reported in HSCT recipients.
-in patients with malignancy and not undergoing a hematopoietic stem cell transplantation:
Intravenous dosage:
Infants, Children, and Adolescents: 2.5 mg/kg/dose IV twice weekly.

For the treatment of CNS cryptococcal infections, including cryptococcal meningitis and cerebral cryptococcomas:
NOTE: LAmB has been designated an orphan drug by the FDA for this indication.
-Persons living with HIV:
Intravenous dosage:
Neonates*: 6 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, liposomal amphotericin B 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: 6 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, liposomal amphotericin B 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: 3 to 4 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, liposomal amphotericin B 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 at 4 to 6 mg/kg/dose IV every 24 hours until clinical response. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy. The FDA-approved dosage is 6 mg/kg/dose IV every 24 hours.
-Organ transplant recipients*:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest liposomal amphotericin B in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, liposomal amphotericin B may be given as a single agent for 4 to 6 weeks for patients unable to tolerate flucytosine. For cerebral cryptococcomas, give induction therapy for at least 6 weeks. For persistence or relapse of cryptococcal infection, 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, liposomal amphotericin B may be given as a single agent for 4 to 6 weeks for patients unable to tolerate flucytosine. For cerebral cryptococcomas, give induction therapy for at least 6 weeks. For persistence or relapse of cryptococcal infection, 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 liposomal amphotericin B in combination with flucytosine for at least 4 weeks as an alternative induction therapy for patients who are intolerant of amphotericin B deoxycholate. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If liposomal amphotericin B is given as a single agent, consider lengthening induction therapy for at least 2 weeks. In patients with neurological complications or cerebral cryptococcomas, give induction therapy for at least 6 weeks. For persistence or relapse of cryptococcal infection, 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 4 weeks as an alternative induction therapy for patients who are intolerant of amphotericin B deoxycholate. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If liposomal amphotericin B is given as a single agent, consider lengthening induction therapy for at least 2 weeks. In patients with neurological complications or cerebral cryptococcomas, give induction therapy for at least 6 weeks. For persistence or relapse of cryptococcal infection, 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:
NOTE: LAmB has been designated an orphan drug by the FDA for this indication.
NOTE: For the treatment of CNS infections, see cryptococcal meningitis.
-Persons living with HIV:
Intravenous dosage:
Neonates*: 3 to 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: 3 to 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: 3 to 4 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, liposomal amphotericin B 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 at 4 to 6 mg/kg/dose IV every 24 hours until clinical response. Follow induction therapy with consolidation therapy with fluconazole for at least 8 weeks, and then chronic suppressive therapy. The FDA-approved dosage is 3 to 5 mg/kg/dose IV every 24 hours.
-Organ transplant recipients:
Intravenous dosage:
Neonates*: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest liposomal amphotericin B in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, liposomal amphotericin B 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, liposomal amphotericin B 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. The FDA-approved dosage is 3 to 5 mg/kg/dose IV every 24 hours.
-Non-HIV, nontransplant patients:
Intravenous dosage:
Neonates*: 5 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest liposomal amphotericin B in combination with flucytosine for at least 4 weeks as an alternative induction therapy for patients who are intolerant of amphotericin B deoxycholate. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If liposomal amphotericin B is given as a single agent for patients unable to tolerate flucytosine, 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 in combination with flucytosine for at least 4 weeks as an alternative induction therapy for patients who are intolerant of amphotericin B deoxycholate. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If liposomal amphotericin B is given as a single agent for patients unable to tolerate flucytosine, 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. The FDA-approved dosage is 3 to 5 mg/kg/dose IV every 24 hours.

For the treatment of moderately severe to severe blastomycosis*:
NOTE: For CNS infections, see meningitis indication.
Intravenous dosage:
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* 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*:
NOTE: LAmB has been designated an orphan drug by the FDA for this indication.
NOTE: For CNS disease, see meningitis indication.
-for the treatment of pulmonary histoplasmosis:
Intravenous dosage:
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 liposomal amphotericin B as alternate therapy in patients unable to tolerate amphotericin B deoxycholate.
-for the treatment of disseminated histoplasmosis:
Intravenous dosage:
Infants and Children: 3 to 5 mg/kg/dose IV every 24 hours for at least 2 weeks or longer if clinical improvement is delayed. Continue step-down therapy with itraconazole for 12 months for HIV-infected children. If itraconazole is not tolerated, liposomal amphotericin B may be given alone for 4 to 6 weeks. While liposomal amphotericin B is preferred treatment in HIV-infected children, guidelines suggest amphotericin B deoxycholate as the preferred treatment in non-HIV-infected children.
Adolescents: 3 mg/kg/dose IV every 24 hours for 1 to 2 weeks followed by itraconazole for at least 12 months. 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 liposomal amphotericin B as a preferred treatment.

For the treatment of leishmaniasis:
NOTE: LAmB has been designated an orphan drug by the FDA for this indication.
-for the treatment of cutaneous leishmaniasis*:
Intravenous dosage:
Infants, Children, and Adolescents: 3 mg/kg/dose IV every 24 hours on days 1 through 5 and on day 10 or on days 1 through 7 for a cumulative total of 18 to 21 mg/kg.
HIV-infected Adolescents: 2 to 4 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. Chronic maintenance therapy may be indicated in immunocompromised patients with multiple relapses.
-for the treatment of mucosal leishmaniasis*:
Intravenous dosage:
Infants, Children, and Adolescents: 3 mg/kg/dose IV every 24 hours for a cumulative total of 20 to 60 mg/kg.
-for the treatment of visceral leishmaniasis:
Intravenous dosage:
Immunocompetent Infants, Children, and Adolescents: 3 mg/kg/dose IV on days 1, 2, 3, 4, 5, 14, and 21, for a cumulative total of 21 mg/kg as preferred therapy. For patients who do not achieve parasitic clearance with the recommended dose, repeating the course of therapy may be useful; higher doses or a longer course may be considered. Other regimens with a total dose of 18 to 21 mg/kg have been used effectively. For patients who acquired the infection in East Africa, total doses of 40 mg/kg or more may be needed.
Immunocompromised Infants and Children: 4 mg/kg/dose IV on days 1, 2, 3, 4, 5, 10, 17, 24, 31, and 38, or 2 to 4 mg/kg/dose IV every 24 hours for 10 days, for a cumulative total of 20 to 60 mg/kg, as preferred therapy. For patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended; higher doses or a longer course may be considered. Combination therapy with miltefosine may be considered in HIV-infected patients with refractory cases. Chronic maintenance therapy is recommended in HIV-infected patients.
Immunocompromised Adolescents: 4 mg/kg/dose IV on days 1, 2, 3, 4, 5, 10, 17, 24, 31, and 38, or 2 to 4 mg/kg/dose IV every 24 hours for 10 days, for a cumulative total of 20 to 60 mg/kg, as preferred therapy. For patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended; higher doses or a longer course may be considered. Chronic maintenance therapy with a lipid formulation amphotericin B, or alternately, pentavalent antimony is recommended in HIV-infected patients is recommended in HIV-infected patients. Chronic maintenance therapy is recommended in HIV-infected patients.

For the treatment of talaromycosis* in HIV-infected patients:
Intravenous dosage:
Adolescents: 3 to 5 mg/kg/day IV for 2 weeks, then itraconazole for consolidation therapy and chronic suppressive therapy.

For secondary leishmaniasis prophylaxis* (i.e., long-term suppressive therapy) in HIV-infected patients:
Intravenous dosage:
Adolescents: 4 mg/kg/dose IV every 2 to 4 weeks 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. Doses up to 7 mg/kg/dose IV every 24 hours have been successfully used in neonates with systemic candidiasis. 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.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 7 mg/kg/day IV have been used off-label.
-Infants
6 mg/kg/day IV.
-Children
6 mg/kg/day IV.
-Adolescents
6 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; it appears that no dosage adjustments are needed.

Intermittent hemodialysis or Peritoneal dialysis
Liposomal amphotericin B 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 liposomal injection (LAmB), 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 attributed 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 liposomal injection (LAmB) is administered intravenously. Pharmacokinetic parameters for LAmB should not be used to predict the pharmacokinetics of any other amphotericin B formulation. The clinical relevance of pharmacokinetic differences between LAmB 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. Peak concentrations are achieved approximately 2.5 hours after administration. Higher peak concentrations, smaller volume of distribution, and slower clearance are reported with LAmB compared with conventional amphotericin B. Lipid formulations also have a slower onset of action. Good tissue penetration has been demonstrated in adult studies.

Metabolism of amphotericin B following administration of LAmB is unknown. Excretion of amphotericin B after administration of LAmB has not been studied. The terminal elimination half-life of amphotericin B is longer after administration of the liposomal formulation (mean 4-6 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 following repeated dosing.


-Special Populations
Pediatrics
Neonates
Pharmacokinetic data of liposomal amphotericin B in neonates are unavailable.

Infants and Children
Very limited pharmacokinetic data in infants and children have revealed some differences in pharmacokinetic properties of liposomal amphotericin B between small children and adults. In a study (n = 14) of once-weekly high-dose liposomal amphotericin B (10 mg/kg/dose) for antifungal prophylaxis in infants and children (4.5 months to 9 years of age), volume of distribution (Vd) and clearance values were approximately 4.2 L/kg and 0.06-0.07 L/kg/hr, respectively, which are higher than those reported in adults. Vd and clearance were directly related to body weight. Elimination half-life was also shorter than that reported in adults (43-55 hours vs. 152 hours); however, in this study the pharmacokinetics of the active portion of the drug were measured (non-lipid complexed amphotericin), which makes it difficult to compare with other pharmacokinetic data.