AMPHOTERICIN B

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

Route-Specific Administration

Oral Administration
Oral Liquid Formulations
-Administer the oral suspension between meals to permit prolonged contact with the oral lesions.
-If the patient is old enough to swish the liquid, swish in the mouth for as long as possible before swallowing or spitting. Alternatively, apply to lesions with a nonabsorbent swab or with an oral dropper.

Extemporaneous Compounding-Oral
Compounded Oral Suspension (20 mg/ml)
NOTE: Extemporaneously prepared amphotericin B oral suspension is not approved by the FDA. Very limited data are available.
One published case report used a suspension prepared by the following method :
-A 20 mg/ml (100 mg/5 ml) suspension was made by wetting 1.2 g of amphotericin B bulk powder with glycerin, adding 3% flavoring, and then adding sufficient quantity of simple syrup to make a final volume of 60 ml.
-Storage: The suspension was given an expiration date of 30 days; however, specific stability data are not available.
-Shake well prior to administering.
For neonates and infants, a 100 mg/ml suspension may be more appropriate to deliver the recommended dosage. Preparation instructions for a 100 mg/ml suspension that could be prepared by a compounding pharmacy have been described.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Amphotericin B intravenous products are not interchangeable; assure the appropriate product has been selected. Lipid formulations of amphotericin B require higher doses than conventional amphotericin B; therefore, verify the product name and dose prior to drug administration. Serious adverse events can occur if the incorrect product is selected.
Intravenous Administration
Test Dose Protocol
-If a test dose is desired, the FDA-approved product labeling recommends reconstituting 1 mg in 20 ml of D5W and infusing over 20-30 minutes. However, this test dose regimen is intended for adult patients; in pediatric patients, a test dose of 0.1 mg/kg (Max: 1 mg) has been used. Final concentration for administration is 0.05 mg/ml. The test dose should be given 2-4 hours prior to the first therapeutic dose.

Reconstitution
-Reconstitute 50 mg vial with 10 ml of sterile water for injection without bacteriostatic agent to give a concentration of 5 mg/ml.
-Immediately shake the vial until the solution is clear. Further dilution is required prior to administration.
-Storage: Reconstituted solution is stable for 24 hours at room temperature or for 7 days in the refrigerator. Protect from light.

Dilution
-For infusion, dilute reconstituted product with D5W to a final concentration of 0.1 mg/ml.
-Do not dilute with any non-dextrose solution; the FDA-approved product labeling recommends dilution with D5W with a pH > 4.2.-Neonates: Administering amphotericin to neonates often presents a nutritional challenge due to the length of infusion and incompatibility with total parenteral nutrition (TPN). If the patient has only one IV line available and TPN must be held during amphotericin administration, some experts recommend preparing amphotericin in a dextrose solution of a concentration that can provide an appropriate amount of carbohydrate calories during the course of the infusion. Amphotericin B is compatible in D5W, D10W, D15W, and D20W.

- Solutions should be administered promptly after preparation; protect from light during administration.

Intermittent IV Infusion
-Flush intravenous line with D5W to infusion. If this cannot be done, then a separate IV line must be used. Amphotericin B is not compatible with saline or electrolyte-containing solutions.

-Rapid IV infusion (< 1 hour) must be avoided; severe adverse effects may occur.
-Infuse IV over 2-6 hours. Slowing the infusion rate may minimize adverse effects.
-An inline membrane filter may be used if mean pore diameter is >= 1 micron.
-Protect drug from light during infusion.

Intrathecal Administration
NOTE: Amphotericin B is not approved by the FDA for intrathecal administration.
NOTE: Drug administration via the intrathecal route should only be performed by practitioners skilled in this method of administration. Aseptic technique must be used, and the final volume for administration must be appropriate for the patient's age and size.

Neonates
Limited data are available.
-Reconstitute lyophilized amphotericin B with sterile water for injection without bacteriostatic agent to a final concentration of 0.25 mg/ml.
-Withdraw desired dose. Further dilute dose with a reasonable amount of patient's own CSF prior to administration.-In one case report of a term neonate (birth weight = 2.9 kg), a final volume of 2 ml was used for administration.

-Administer slowly.

Non-neonatal Patients
-Reconstitute 50 mg of lyophilized amphotericin B with 50 ml of sterile water for injection without bacteriostatic agent to provide a concentration of 1 mg/ml. Withdraw desired dose.
-Further dilute dose with an appropriate amount of patient's own CSF prior to administration. The final concentration for administration should be no greater than 0.25 mg/ml. -Common volumes reported in the literature range from 3-6 ml; 2 ml has been used in a neonate.

-Administer slowly. A rate no faster than 1 mg/min has been recommended for adults ; a slower rate may be necessary for children.



Inhalation Administration
NOTE: Amphotericin B is not approved by the FDA for inhalational administration.
-Reconstitute amphotericin B lyophilized powder for injection with sterile water for injection without a bacteriostatic agent. Concentrations used have varied from 1-5 mg/ml. Use a concentration appropriate to deliver the prescribed dose in an appropriate volume for the nebulizer being used (e.g. final volume of 5-10 ml for many nebulizers).
-Most nebulizers generate particles with a diameter of < 5 micro-m, which is necessary for pulmonary deposition. Aerosols generated by ultra-sonic devices contain a greater number of large particles.
-Administer via a face mask nebulizer.

Nephrotoxicity is one of the most common adverse events associated with conventional IV amphotericin B. Although most cases of renal impairment are reversible or improve with cessation of therapy, permanent injury can also occur. The incidence of nephrotoxicity is typically less in infants and young children compared with adults. Nephrotoxicity (CrCl decrease of >= 20%) was reported in 58% of children who received amphotericin B in one study (n = 130). In another study in neonates (n = 92), nephrotoxicity (increase in serum creatinine of >= 0.4 mg/dl) occurred in 16% of patients. Nephrotoxicity is manifest in many forms including azotemia, hypokalemia, hyposthenuria, nephrolithiasis (specifically nephrocalcinosis), renal tubular acidosis (RTA), and acute renal failure (unspecified). Renal tubular acidosis may be present without concurrent systemic acidosis. Although the exact mechanism of renal toxicity has not been defined, amphotericin B can cause a decrease in glomerular filtration rate (GFR) and renal blood flow. Factors that may increase the risk of nephrotoxicity include elevations in daily dose, duration of therapy, concomitant nephrotoxic drugs, abnormal baseline renal function, and bone marrow transplantation. Proper hydration and sodium loading have been reported to minimize renal impairment. In neonates, a sodium intake of > 4 mEq/kg/day has been associated with a lower incidence of renal dysfunction. In addition to hypokalemia, other electrolyte abnormalities that may occur include hypomagnesemia, hypocalcemia, and hyperkalemia. Other adverse renal effects include anuria, elevated serum creatinine, and oliguria. Cases of nephrogenic diabetes insipidus have been reported during post-marketing use. Closely monitor patents' renal function and serum electrolytes (particularly potassium and magnesium) during therapy.

Infusion-related reactions are common (up to 70% of patients) with conventional IV amphotericin B; the most common include headache (8%), chills (30-74%), fever (16%), tachypnea, flushing, decreased blood pressure, decreased appetite, and nausea/vomiting. With subsequent doses, the intensity of these reactions usually decreases, and slower infusion rates may lessen the risk. Amphotericin B has been shown to stimulate prostaglandin synthesis, which may account for the infusion-related reactions. Avoiding rapid infusion rates and pretreatment with antipyretics, antihistamines, meperidine, and corticosteroid therapies may decrease acute infusion-related reactions. Serious cardiovascular adverse effects have also occurred and have most commonly been associated with rapid administration. These events have included cardiac arrest, arrhythmia exacerbation (including ventricular fibrillation), heart failure, hypertension, and hypotension. Caution is warranted to prevent an inadvertent overdose (based on product selection) that can result in potentially fatal cardiac or cardiorespiratory arrest.

Amphotericin B is irritating to the veins. Slowing the infusion rate may help alleviate the injection site reaction. The addition of heparin (1 unit/mL) has been reported to help with pain at the injection site and minimize phlebitis. The FDA-approved labeling also suggests that alternate-day therapy or use of a scalp-vein needle may decrease local reactions. Extravasation of amphotericin B causes local irritation.

Gastrointestinal adverse reactions, such as anorexia, cramping, diarrhea, dyspepsia, epigastric or abdominal pain, hemorrhagic gastroenteritis, melena, nausea and vomiting, and weight loss, have occurred in some patients receiving treatment with conventional IV amphotericin B.

A normocytic, normochromic anemia occurs in many patients receiving conventional IV amphotericin B. This reaction is believed to be caused by a suppressive effect on erythropoietin production. Usually, this condition does not require transfusions and blood counts generally return to baseline after discontinuation of therapy. Other hematologic effects, including agranulocytosis, coagulopathy, eosinophilia, leukopenia, leukocytosis, and thrombocytopenia have been reported in patients receiving conventional IV amphotericin B. Monitor patients' complete blood counts (CBC) during therapy. Evaluation of platelet counts in pediatric patients with fungal infections can be challenging; thrombocytopenia often accompanies systemic fungal infection, especially in neonates.

Elevated hepatic enzymes, hyperbilirubinemia, and increased alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) have been reported in patients receiving conventional IV amphotericin B. Rarely, acute hepatic failure, hepatitis, and jaundice have also been reported. Monitor hepatic function during amphotericin B therapy. In neonates with pre-existing hyperbilirubinemia, more frequent monitoring may be appropriate.

Anaphylaxis or anaphylactoid reactions, bronchospasm, dyspnea, and wheezing have been reported in patients receiving conventional IV amphotericin B. If severe respiratory distress, anaphylaxis or an anaphylactoid reaction occurs, the drug should be discontinued immediately and the patient given appropriate therapy as indicated. Less frequent adverse effects associated with conventional IV amphotericin B consist of hypersensitivity pneumonitis, pulmonary edema, and shock. Acute pulmonary reactions have occurred in patients receiving amphotericin B during or shortly after leukocyte transfusions; it is recommended to temporarily separate these infusions and to monitor pulmonary function.

Dermatologic adverse events that have been reported in patients receiving treatment with conventional IV amphotericin B include rash (unspecified), maculopapular rash, and pruritus. Cases of skin exfoliation, Stevens-Johnson syndrome, and toxic epidermal necrolysis 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.

Adverse neurologic reactions that have been reported in patients receiving conventional IV amphotericin B include diplopia, encephalopathy, hearing loss, leukoencephalopathy, malaise, peripheral neuropathy, seizures or convulsions, tinnitus, transient vertigo, and visual impairment. Headache has also occurred in some patients and is associated with acute infusion-related reactions.

Intrathecal administration of amphotericin B can cause headache and blurred vision and, in some cases, difficulty in urination. Polyneuropathy and/or paresthesias can occur in some patients, which are exhibited by numbness, tingling, pain, or weakness. Arachnoiditis is also possible.

Intravenous administration of amphotericin B has been associated with musculoskeletal adverse events including generalized pain, arthralgia, and myalgia.

Nebulized amphotericin B has been associated with cough, dysgeusia (altered taste), nausea/vomiting, wheezing and dysphagia. Patients (adults) with a history of asthma have experienced significant decreases in peak flow values as compared to non-asthmatic patients who received nebulized amphotericin B.

Although rare, anaphylaxis has been reported with amphotericin B products. The use of amphotericin B is contraindicated in patients who have had a prior hypersensitivity reaction to the drug except for life-threatening situations that require amphotericin B therapy. If severe respiratory distress occurs during administration of amphotericin B, stop the infusion and institute appropriate medical therapy.

Acute pulmonary reactions have occurred in patients receiving intravenous amphotericin B and leukocyte transfusions simultaneously. If both amphotericin B and leukocyte transfusions are necessary, separate the administration of these infusions as much as possible and monitor pulmonary function.

Intravenous amphotericin B should be primarily used for the treatment of severe fungal infections; it should not be used to treat non-serious fungal infections.

There is a potential for overdose or poisoning with conventional intravenous amphotericin B due to confusion with the dosing of the various amphotericin B products. Lipid formulations of amphotericin B are given in higher doses than conventional amphotericin B doses; therefore, verify the product name and dose prior to drug administration, especially if the conventional amphotericin B dose prescribed exceeds 1.5 mg/kg. Caution is warranted to prevent an inadvertent overdose (based on product selection) that can result in potentially fatal cardiac or cardiorespiratory arrest.

Use amphotericin B cautiously in patients with preexisting renal disease because it can cause additional renal impairment; however, the incidence and degree of renal impairment associated with amphotericin B use is typically less severe in pediatric patients compared to adults. Factors that may increase the risk of nephrotoxicity include concurrent nephrotoxic medications (e.g., diuretics, aminoglycosides, cisplatin), cumulative dose, duration of therapy, abnormal baseline renal function, and bone marrow transplantation. Hydration and sodium repletion prior to amphotericin B administration may reduce the risk of developing nephrotoxicity in some patients. In neonates, a sodium intake of > 4 mEq/kg/day has been associated with a lower incidence of renal dysfunction. Supplemental alkali medication may decrease renal tubular acidosis complications.

Use caution when administering amphotericin B to patients with electrolyte imbalance including hypokalemia, hypomagnesemia, hypocalcemia, and hyponatremia. Significant renal electrolyte loss (especially potassium) may occur with administration of amphotericin B. In addition, pre-existing electrolyte imbalance may increase the risk of amphotericin-associated renal toxicity. Ideally, correct electrolyte imbalances prior to initiating amphotericin therapy. Monitor serum electrolytes carefully during amphotericin B treatment and replace as appropriate.

Intravenous amphotericin B is associated with infusion-related reactions that can be severe. Acute reactions may include fever, chills, rigors, hypotension, anorexia, nausea, vomiting, headache, and tachypnea and often occur within 1 to 3 hours after beginning the infusion. Although these reactions are typically most severe during the first few doses, monitor patients carefully during all amphotericin infusions. Slowing the infusion rate may help reduce infusion-related reactions; pre-medication with antipyretics, anti-histamines, meperidine (for rigors), and/or corticosteroids may prevent or minimize the reaction in some patients. Rapid administration must be strictly avoided; serious hypotension, hypokalemia, arrhythmias, and shock have occurred with rapid infusion rates. Amphotericin B is also irritating to the veins. Slowing the infusion rate may also help alleviate injection site reactions. Although not standard of care, the addition of heparin (1 unit/ml) has been reported to help with the pain at the injection site and phlebitis.

Use amphotericin B with caution in patients with hematological disease including patients with preexisting anemia, leukopenia, or thrombocytopenia; amphotericin B use has been associated with anemia, leukopenia, and thrombocytopenia and may worsen pre-existing blood cell count abnormalities. Monitor CBC and platelets during amphotericin B therapy. Evaluation of platelet counts in pediatric patients with fungal infections can be challenging; thrombocytopenia often accompanies systemic fungal infection, especially in neonates.

Monitor serum bilirubin concentrations in patients at risk for jaundice (e.g., neonates with hyperbilirubinemia). Amphotericin B has been associated with hyperbilirubinemia.

Description: Amphotericin B is a parenteral antifungal agent produced as a fermentation by-product of Streptomyces nodosus, a soil actinomycete. Amphotericin B is an older drug of the polyene class similar to nystatin. Despite having many well-known adverse reactions and toxicities and the introduction of several newer antifungal agents onto the market, amphotericin B remains the drug of choice for many serious systemic fungal infections; however, because of an improved toxicity profile, the lipid formulations of amphotericin B have replaced conventional amphotericin B as the preferred agent for many fungal infections. The exception to this common preference is the use of amphotericin for neonatal candidiasis. Because the kidney and urinary tract are commonly involved in disseminated neonatal candidiasis, conventional amphotericin B is often preferred over lipid formulations. Infusion-related reactions and nephrotoxicity are among the most common adverse reactions and warrant careful monitoring. Although nephrotoxicity is still a significant concern in pediatric patients, clinical studies have demonstrated less nephrotoxicity with amphotericin B in infants and young children compared with adults. Although not FDA-approved in children, amphotericin B is used off-label in pediatric patients as young as neonates.

General dosing information:
Initiation of therapy
-A test dose (0.1 mg/kg/dose; Max: 1 mg/dose) may be given prior to therapy and is suggested in the FDA-approved labeling. The test dose should be given 2 to 4 hours prior to the first therapeutic dose. Many clinicians do not utilize a test dose; true hypersensitivity reactions to amphotericin B are rare. Some authors suggest that the recommendation of giving a test dose stems from when amphotericin B products were less pure compared to formulations available today. Test dosing is not recommended in neonates as immediate adverse reactions are not common in this group and the benefit of attaining therapeutic concentrations as soon as possible is often desirable.
-Some clinicians initiate amphotericin B therapy with a lower initial dose (i.e., 0.25 to 0.5 mg/kg/day, increased by 0.25 mg/kg/day increments to the goal dose). Others initiate therapy with the full dose. Most guidelines recommend initiating therapy with the full dose. In addition, lower initial doses are not recommended in neonates as immediate adverse reactions are not common in this group and the benefit of attaining therapeutic concentrations faster outweighs potential risks.
Pre-medication regimens
-Fever, chills, or rigor: To decrease infusion-related reactions, premedication regimens including antipyretics (e.g., acetaminophen), antihistamines (e.g., diphenhydramine), meperidine, and steroids have been used. Of note, steroids should be used cautiously due to the potentiation of hypokalemia.
-Nephrotoxicity prophylaxis: Hydration and sodium repletion/sodium loading prior to amphotericin B administration may reduce the risk of nephrotoxicity. Supplemental alkali medication may decrease renal tubular acidosis; the suggested alkali medications have not been described. Evidence on the efficacy of sodium loading to reduce or reverse amphotericin B-associated nephrotoxicity are lacking in children. One study suggested a sodium intake more than 4 mEq/kg/day in extremely low birth weight infants receiving amphotericin B.

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: Absidia sp., Aspergillus fumigatus, Aspergillus sp., Basidiobolus sp., Blastomyces dermatitidis, Candida albicans, Candida sp., Coccidioides immitis, Conidiobolus sp., Cryptococcus neoformans, Cryptococcus sp., Histoplasma capsulatum, Leishmania braziliensis, Leishmania donovani, Leishmania infantum, Leishmania mexicana, Leishmania sp., Leishmania tropica, Mucor mucedo, Mucor sp., Rhizopus sp., Rhodotorula sp., Sporothrix schenckii
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: Acanthamoeba castellanii, Acanthamoeba polyphaga, Acremonium sp., Entomophthora sp., Naegleria fowleri, Naegleria sp., Paracoccidioides brasiliensis, 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 the treatment of CNS disease caused by Cryptococcus, see Cryptococcus meningitis.
-for the treatment of CNS infections due to Candida sp.:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours. Continue treatment until all signs and symptoms and cerebrospinal fluid (CSF) and radiologic abnormalities have resolved. Remove intraventricular devices. Guidelines recommend amphotericin B deoxycholate as preferred therapy. Concomitant flucytosine therapy is not routinely recommended but may be considered as salvage therapy for those who do not respond to amphotericin B alone.
Infants, Children, and Adolescents: Conventional amphotericin B is not recommended as routine therapy for invasive Candida infections; liposomal amphotericin B is the preferred treatment.
Intrathecal dosage:
Neonates: Very limited data are available; not routinely recommended. In a case report of a single term infant (birth weight = 2.9 kg) 0.05 mg/dose intrathecally followed by a second dose 3 days later.
-for treatment of CNS infections due to Coccidioides sp.:
Intravenous dosage:
Infants and Children: 0.5 to 1 mg/kg/dose IV every 24 hours. Guidelines for opportunistic infections in persons living with HIV recommend intravenous amphotericin B plus intrathecal amphotericin B as an alternative regimen for infections unresponsive to fluconazole. Continue with fluconazole or itraconazole for lifelong suppressive therapy. Guidelines for the treatment of Coccidioides sp. recommend reserving intravenous amphotericin B for refractory cases.
Adolescents: 0.7 to 1 mg/kg/dose IV every 24 hours. Utility of intravenous amphotericin B in clinical cases of coccidioidal meningitis is unclear; reserve for treatment of refractory cases.
Intrathecal dosage:
Infants and Children: 0.01 to 0.05 mg/dose intrathecally followed by a gradual dose escalation (0.025 to 0.1 mg/day) until appearance of patient intolerance. Most patients tolerate a maximum dose of approximately 0.5 mg/treatment and many tolerate only a maximum of 0.2 mg/treatment. Initial frequency is often daily, followed by a reduction in intervals after cerebrospinal fluid (CSF) improvement (i.e., few times weekly, then weekly, then every few weeks). In a study in 6 children (19 to 74 months), intrathecal doses were initiated at 0.05 mg/day and increased to patient tolerance; however, no doses exceeded 0.25 mg/day per site. Guidelines for opportunistic infections in persons living with HIV recommend intravenous amphotericin B plus intrathecal amphotericin B as an alternative regimen for infections unresponsive to fluconazole. Guidelines for the treatment of Coccidioides sp. suggest intrathecal amphotericin B for immunocompetent patients experiencing failure with initial IV fluconazole therapy.
Adolescents: 0.01 to 1.5 mg intrathecally 1 to 3 times weekly, depending on method of administration. For lumbar delivery by barbotage or by mixing drug with 5 mL of 10% Dextrose Injection, 0.01 to 0.025 mg initially and increase as tolerated to target dose of 0.5 mg. For cisternal therapy, 0.25 mg or less in 0.5 mL or smaller volumes. Maintenance doses of 0.01 to 1.5 mg have been used. For ventricular administration by an Omaya reservoir, 0.01 mg initially and increase to maintenance dose of 1.5 mg. The frequency of dosing and duration of therapy are generally 3 times per week for the first 3 months, then 1 to 2 times per week for several months, then once every several weeks, depending on the cerebrospinal fluid (CSF) cell count. Guidelines for opportunistic infections in persons living with HIV suggest intrathecal amphotericin B when IV triazole antifungals are not effective. Intravenous fluconazole is the preferred therapy. Guidelines for the treatment of Coccidioides sp. suggest intrathecal amphotericin B for immunocompetent patients experiencing failure with initial IV fluconazole therapy or pregnant females in their first trimester. After the first pregnancy trimester, a triazole may be used or intrathecal amphotericin B may be continued.

For the treatment of candidemia* and invasive candidiasis* (non-CNS):
NOTE: For CNS disease, see meningitis indication.
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours as first-line therapy. 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: 1 mg/kg/dose IV every 24 hours as an alternative. 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 fluconazole-refractory oropharyngeal candidiasis (thrush)*:
NOTE: Amphotericin B deoxycholate should not be used in noninvasive infections, such as oropharyngeal candidiasis (thrush), in patients with normal neutrophil counts.
Intravenous dosage:
Infants, Children, and Adolescents: 0.3 mg/kg/dose IV every 24 hours for up to 28 days as an alternative.
Oral dosage:
Neonates: 100 mg PO 4 times daily for up to 28 days as an alternative. There are limited data in neonates; however, a study in 63 children (premature infants to 12 years of age) with oropharyngeal candidiasis reported an excellent or good response in 86% of patients who received amphotericin B oral suspension. Bioavailability is poor after oral administration, and swabbing the lesion with a nonabsorbent swab or applying directly to the lesion using a dropper are the preferred methods of application for neonates. Therefore, significant systemic exposure is not expected.
Infants, Children, and Adolescents: 100 mg PO 4 times daily for up to 28 days as an alternative. There are limited data in children; however, a study in 63 children (premature infants to 12 years of age) with oropharyngeal candidiasis reported an excellent or good response in 86% of patients who received amphotericin B oral suspension. Patients should swish the suspension for as long as reasonably possible before swallowing or spitting. If swabbing the lesion is the desired method of application, a nonabsorbent swab should be used.

For the treatment of esophageal candidiasis*, including fluconazole-refractory disease:
NOTE: Amphotericin B deoxycholate should not be used in noninvasive infections, such as esophageal candidiasis, in patients with normal neutrophil counts.
-for the treatment of esophageal candidiasis* in persons without HIV:
Intravenous dosage:
Infants, Children, and Adolescents: 0.3 to 0.7 mg/kg/dose IV every 24 hours for 14 to 21 days as an alternative for patients who cannot tolerate oral therapy or for fluconazole-refractory disease.
-for the treatment of esophageal candidiasis in persons living with HIV:
Intravenous dosage:
Infants and Children: 0.3 to 0.7 mg/kg/dose IV every 24 hours for 14 to 21 days as an alternative.
Adolescents: 0.6 mg/kg/dose IV every 24 hours for 14 to 21 days as an alternative.

For the treatment of Candida respiratory infections (i.e., 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. 1 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest amphotericin B deoxycholate as the preferred therapy for neonatal candidiasis.
Infants, Children, and Adolescents: Growth of Candida sp. from the respiratory tract typically reflects colonization and rarely requires antifungal therapy. Clinical practice guidelines do not include amphotericin B deoxycholate for invasive candidiasis infections. A lipid formulation amphotericin B is preferred.

For the treatment of intraabdominal infections due to candidiasis*, including neonatal necrotizing enterocolitis*:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours. Amphotericin B deoxycholate is the preferred therapy for neonatal candidiasis, including necrotizing enterocolitis.
Infants, Children, and Adolescents: 1 mg/kg/dose IV every 24 hours. Guidelines do not include amphotericin B deoxycholate for invasive candidiasis infections.

For the treatment of Candida bone and joint infections*, including osteomyelitis* and infectious arthritis*):
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest amphotericin B deoxycholate as the preferred therapy for neonatal candidiasis. 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: Clinical practice guidelines do not include amphotericin B deoxycholate for invasive candidiasis infections. A lipid formulation amphotericin B is preferred.

For the treatment of asymptomatic candiduria* and Candida urinary tract infection (UTI)*, including cystitis* and pyelonephritis*:
-for the treatment of asymptomatic candiduria* in very low-birth-weight infants (weighing less than 1.5 kg):
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours for 14 days as first-line therapy. 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 patients.
-for the treatment of asymptomatic candiduria* in persons undergoing urologic procedures:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours for several days before and after the urologic procedure.
Infants, Children, and Adolescents: 0.3 to 0.6 mg/kg/dose IV every 24 hours for several days before and after the urologic procedure.
-for the treatment of cystitis*:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours for 14 days as first-line therapy.
Infants, Children, and Adolescents: 0.3 to 0.6 mg/kg/dose IV every 24 hours for 1 to 7 days for C. glabrata or C. krusei.
Intravesicular dosage (bladder irrigation):
Neonates: Data are limited. 50 mcg/mL solution in Sterile Water for Irrigation as a continuous or intermittent irrigation has been recommended. For intermittent irrigation, instill an appropriate volume for the patient's size into the bladder; clamp catheter for 1 to 2 hours then drain bladder. Repeat 3 to 4 times daily for 2 to 7 days or until cultures are negative. The bladder capacity of neonates is variable, and a standard method of calculating bladder capacity in this population has not been validated. One neonatal reference states that bladder capacity is approximately 5 to 10 mL/kg. A retrospective study of infants younger than 1 year, found a mean bladder capacity of approximately 30 mL (range, 10 to 100 mL) for neonates (gestational ages not reported). A review of free voiding studies found a median bladder capacity in preterm infants (32 weeks gestation) of 12 mL and 52 mL in term infants at 3 months of age. Guidelines suggest amphotericin B deoxycholate bladder irrigation may be useful for symptomatic cystitis due to fluconazole-resistant species, such as C. glabrata and C. krusei.
Infants, Children, and Adolescents: Data are limited. Various regimens have been used and range from continuous irrigation to intermittent instillation up to 4 times daily. 50 mg per 1 L of Sterile Water for Irrigation administered by continuous bladder irrigation for 5 days has been used. A rate of 40 mL/hour has been used in adults; however, this rate must be individualized to an appropriate rate for the patient's age or size. Alternately, dilute 20 to 60 mg in Sterile Water for Irrigation to yield 100 to 200 mcg/mL. Instill an appropriate volume for the size of the patient's bladder; clamp the catheter for 60 to 120 minutes then drain bladder. Irrigate bladder 3 to 4 times daily for 2 to 5 days. Estimating bladder capacity in pediatric patients, particularly infants and young children, must be individualized. A study of infants younger than 12 months (mean age, 8.2 months) found a mean bladder capacity of 46.8 mL. The following equations have been recommended to estimate bladder capacity: for children younger than 2 years, bladder capacity (ounces) = (2 x age [years]) + 2, and for children 2 years and older, bladder capacity (ounces) = (age [years] / 2) + 6. However, some data suggest that the equation for children younger than 2 years overestimates bladder capacity for infants. Guidelines suggest amphotericin B deoxycholate bladder irrigation may be useful for symptomatic cystitis due to fluconazole-resistant species, such as C. glabrata and C. krusei.
-for the treatment of ascending pyelonephritis*:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours for 14 days as first-line therapy.
Infants, Children, and Adolescents: 0.3 to 0.6 mg/kg/dose IV every 24 hours for 1 to 7 days for C. glabrata or C. krusei. Consider adding flucytosine for C. glabrata.
-for the treatment of urinary fungal balls*:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours for 14 days as first-line therapy.
Infants, Children, and Adolescents: 0.3 to 0.6 mg/kg/dose IV every 24 hours for 1 to 7 days.
Local renal irrigation dosage (irrigation of renal pelvis):
Neonates: Data are very limited. Two case reports describe the use of amphotericin B irrigation at a concentration of 50 mcg/mL through nephrostomy catheters. A 3-month-old infant (30 week gestational age at birth with 2-month NICU stay) was treated with amphotericin B deoxycholate irrigation through percutaneous nephrostomy catheters for obstructive bilateral fungal balls caused by C. albicans. In addition to systemic therapy, amphotericin B deoxycholate was administered by slow, continuous irrigation or as intermittent doses given every 5 hours. In a second case, a 3-week-old neonate with bladder exstrophy was treated with amphotericin B deoxycholate irrigation through nephrostomy catheters 3 times daily in addition to various systemic antifungal treatments for bilateral aspergilloma. 25 to 50 mg in 200 to 500 mL of Sterile Water for Irrigation as irrigation through nephrostomy tubes.
Infants, Children, and Adolescents: 25 to 50 mg in 200 to 500 mL of Sterile Water for Irrigation as irrigation through nephrostomy tubes.

For the treatment of invasive aspergillosis*:
Intravenous dosage:
Neonates: 1 to 1.5 mg/kg/dose IV every 24 hours is the general dosage recommended by the American Academy of Pediatrics (AAP). Although specific neonatal recommendations are not available, guidelines do not include amphotericin B deoxycholate for invasive aspergillosis infections. Voriconazole is recommended as primary therapy with a lipid formulation amphotericin B as alternative or salvage therapy.
Infants, Children, and Adolescents: 1 to 1.5 mg/kg/dose IV every 24 hours is the general dosage recommended by the American Academy of Pediatrics (AAP). Guidelines do not include amphotericin B deoxycholate for invasive aspergillosis infections. Voriconazole is recommended as primary therapy with a lipid formulation amphotericin B as alternative or salvage therapy.

For the treatment of allergic bronchopulmonary aspergillosis* (ABPA):
Respiratory (Inhalation) dosage:
Children and Adolescents: Limited data are available. Case reports and small case series have described 5 to 10 mg inhaled by nebulizer twice daily in persons with cystic fibrosis (CF) with refractory allergic bronchopulmonary aspergillosis (ABPA). A case series of 7 patients with CF (younger than 18 years; n = 4) reports the use of 25 mg inhaled by nebulizer 3 times weekly; 5 of 7 patients were able to successfully wean from systemic steroids without ABPA relapse for at least 12 months.

For the treatment of ocular fungal infections*, including endophthalmitis* and chorioretinitis* caused by susceptible organisms:
-for the treatment of Aspergillus endophthalmitis:
Intravitreal dosage:
Infants, Children, and Adolescents: 5 to 10 mcg by intravitreal injection to the affected eye(s). Clinical practice guidelines suggest intravitreal amphotericin B deoxycholate in combination with systemic therapy 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 Candida endophthalmitis* and chorioretinitis*:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours. Clinical practice guidelines suggest amphotericin B deoxycholate as the preferred therapy for neonatal candidiasis. Treat for at least 4 to 6 weeks, with duration depending on stabilization or resolution of lesions.
Intravitreal dosage:
Neonates: 5 to 10 mcg/0.1 mL Sterile Water for Injection by intravitreal injection to the affected eye(s) for at least 4 to 6 weeks, with duration depending on stabilization or resolution of lesions. Clinical practice guidelines suggest intravitreal amphotericin B deoxycholate in combination with systemic therapy for chorioretinitis macular involvement or vitritis.
Infants, Children, and Adolescents: 5 to 10 mcg/0.1 mL Sterile Water for Injection by intravitreal injection to the affected eye(s) for at least 4 to 6 weeks, with duration depending on stabilization or resolution of lesions. Clinical practice guidelines suggest intravitreal amphotericin B deoxycholate in combination with systemic therapy for chorioretinitis macular involvement or vitritis.

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)*:
-for the treatment of Aspergillus cardiovascular system infections:
Intravenous dosage:
Neonates: 1 to 1.5 mg/kg/dose IV every 24 hours is the general dosage recommended by the American Academy of Pediatrics (AAP). Although specific neonatal recommendations are not available, guidelines do not include amphotericin B deoxycholate for invasive aspergillosis infections. Voriconazole is recommended as primary therapy with a lipid formulation amphotericin B as alternative or salvage therapy.
Infants, Children, and Adolescents: 1 mg/kg/dose IV every 24 hours with or without flucytosine for 4 to 6 weeks and surgical resection is recommended by endocarditis guidelines. Aspergillosis guidelines do not include amphotericin B deoxycholate for invasive aspergillosis infections. Voriconazole is recommended as primary therapy with a lipid formulation amphotericin B as alternative or salvage therapy.
-for the treatment of Candida cardiovascular system infections:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours. Guidelines suggest amphotericin B deoxycholate as the preferred therapy for neonatal candidiasis. 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: 1 mg/kg/dose IV every 24 hours with or without flucytosine for 4 to 6 weeks and surgical resection is recommended by endocarditis guidelines. Candidiasis guidelines do not include amphotericin B deoxycholate for invasive candidiasis infections. A lipid formulation amphotericin B is preferred. 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 empirical therapy for presumed fungal infection in patients with febrile neutropenia*:
Intravenous dosage:
Infants, Children, and Adolescents: 0.6 to 1.2 mg/kg/dose IV every 24 hours. 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 fungal prophylaxis* (e.g., candidiasis prophylaxis*, aspergillosis prophylaxis*) in immunosuppressed patients:
Intravenous dosage:
Infants, Children, and Adolescents: Various regimens have been used. 0.5 mg/kg/dose IV 3 times/week was compared to oral voriconazole for fungal prophylaxis in patients 15 years and younger with acute leukemia undergoing induction therapy (n = 100). A significant difference in efficacy was not found between the regimens, and oral voriconazole was thought to be more convenient. In another study, 0.2 mg/kg/dose (Max: 10 mg/dose) IV was compared to fluconazole in patients (ages 4 to 63 years) undergoing hematopoietic stem cell transplantation. No significant difference was found between the groups in regard to proven or suspected fungal infections, survival at 100 days post-transplant, or death attributable to fungal infection.
Nebulized dosage:
Adolescents: Data are limited. Doses of 5 to 10 mg (diluted in 5 to 10 mL of Sterile Water for Injection) administered by nebulizer over 10 to 20 minutes and given 1 to 3 times daily have been used in patients after lung transplantation and neutropenic patients after bone marrow transplantation or intensive chemotherapy. In a retrospective study (n = 611) of older adolescent and adult stem cell transplant recipients, 25 mg by nebulizer once daily was used. Most studies have found a reduction in invasive fungal infections with nebulized amphotericin B deoxycholate ; however, some data have shown no benefit.

For the treatment of moderately severe to severe blastomycosis*:
NOTE: For CNS disease, see meningitis indication.
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours for 1 to 2 weeks or until improvement is noted.
Infants, Children, and Adolescents: 0.7 to 1 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: 0.7 to 1 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*:
NOTE: For CNS involvement, see meningitis.
-for the treatment of severe severe pulmonary or nonmeningeal, extrapulmonary coccidioidomycosis* in persons without HIV:
Intravenous dosage:
Infants and Children: 0.5 to 1 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.
Adolescents: 0.7 to 1 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: 0.5 to 1 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: 0.7 to 1 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 CNS cryptococcal infections, including cryptococcal meningitis* and cerebral cryptococcomas:
-Persons living with HIV:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. Alternatively, amphotericin B deoxycholate 1 to 1.5 mg/kg/dose IV every 24 hours 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 Childen: 1 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. In resource-limited settings, amphotericin B deoxycholate with flucytosine for 1 week followed by high-dose fluconazole for 1 week is recommended as the preferred induction regimen. Alternatively, amphotericin B deoxycholate 1 to 1.5 mg/kg/dose IV every 24 hours 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: 0.7 to 1 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. In resource-limited settings, amphotericin B deoxycholate with flucytosine for 1 week followed by high-dose fluconazole for 1 week is recommended as the preferred induction regimen. Alternatively, amphotericin B deoxycholate 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.
-Organ transplant recipients:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B deoxycholate for 4 to 6 weeks as an alternative single agent induction therapy 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: 1 mg/kg/dose IV every 24 hours for 4 to 6 weeks as an alternative single agent induction therapy 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: 1 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B deoxycholate in combination with flucytosine for at least 4 weeks as a preferred induction therapy. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If amphotericin B deoxycholate 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: 1 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 4 weeks as a preferred induction therapy. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If amphotericin B deoxycholate 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: For the treatment of CNS infections, see cryptococcal meningitis.
-Persons living with HIV:
Intravenous dosage:
Neonates: 0.7 to 1 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: 0.7 to 1 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: 0.7 to 1 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 2 weeks as a preferred induction therapy. In resource-limited settings, amphotericin B deoxycholate with flucytosine for 1 week followed by high-dose fluconazole for 1 week is recommended as the preferred induction regimen. Alternatively, amphotericin B deoxycholate 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.
-Organ transplant recipients:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B deoxycholate for 4 to 6 weeks as an alternative single agent induction therapy for patients unable to tolerate flucytosine. 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: 1 mg/kg/dose IV every 24 hours for 4 to 6 weeks as an alternative single agent induction therapy for patients unable to tolerate flucytosine. 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: 1 mg/kg/dose IV every 24 hours. Although specific neonatal recommendations are not available, guidelines suggest amphotericin B deoxycholate in combination with flucytosine for at least 4 weeks as a preferred induction therapy. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If amphotericin B deoxycholate is given as a single agent, consider lengthening induction therapy for at least 2 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: 1 mg/kg/dose IV every 24 hours in combination with flucytosine for at least 4 weeks as a preferred induction therapy. For patients at low risk for therapy failure, consider induction therapy for only 2 weeks. If amphotericin B deoxycholate is given as a single agent, consider lengthening induction therapy for at least 2 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 moderately severe to severe disseminated (nonmeningeal) or pulmonary histoplasmosis*:
-for the treatment of pulmonary histoplasmosis:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours for 1 to 2 weeks followed by itraconazole for a total of 12 weeks. Clinical practice guidelines suggest amphotericin B deoxycholate as the preferred treatment.
Infants, Children, and Adolescents: 1 mg/kg/dose IV every 24 hours for 1 to 2 weeks followed by itraconazole for a total of 12 weeks. Clinical practice guidelines suggest amphotericin B deoxycholate as the preferred treatment.
-for the treatment of disseminated (nonmeningeal) histoplasmosis:
Intravenous dosage:
Neonates: 1 mg/kg/dose IV every 24 hours for 4 to 6 weeks, or alternately, for 2 to 4 weeks followed by itraconazole for a total of 12 weeks. Longer treatment may be required in patients with persistent immunodeficiency. Treat for at least 2 weeks or longer if clinical improvement is delayed followed by itraconazole for 12 months, or alternately, for 4 to 6 weeks for HIV-infected children. While liposomal amphotericin B is preferred treatment in HIV-infected children, clinical practice guidelines suggest amphotericin B deoxycholate as the preferred treatment in non-HIV-infected children.
Infants and Children: 1 mg/kg/dose IV every 24 hours for 4 to 6 weeks, or alternately, for 2 to 4 weeks followed by itraconazole for a total of 12 weeks. Longer treatment may be required in patients with persistent immunodeficiency. Treat for at least 2 weeks or longer if clinical improvement is delayed followed by itraconazole for 12 months, or alternately, for 4 to 6 weeks for HIV-infected children. While liposomal amphotericin B is preferred treatment in HIV-infected children, clinical practice guidelines suggest amphotericin B deoxycholate as the preferred treatment in non-HIV-infected children.
Adolescents: 0.7 to 1 mg/kg/dose IV every 24 hours for 1 to 2 weeks followed by itraconazole for a total of 12 weeks as an alternative to a lipid formulation amphotericin B in patients who are at a low risk for nephrotoxicity. For HIV-infected patients, treat for at least 2 weeks or until clinically improved followed by itraconazole for at least 12 months. Longer treatment may be required in patients with persistent immunodeficiency. Clinical practice guidelines suggest liposomal amphotericin B as a preferred treatment.

For the treatment of leishmaniasis*:
-for the treatment of cutaneous leishmaniasis*:
Intravenous dosage:
Infants, Children, and Adolescents: 0.5 to 1 mg/kg/dose IV every 24 hours or every other day for a cumulative total of 15 to 30 mg/kg.
-for the treatment of mucosal leishmaniasis*:
Intravenous dosage:
Infants, Children, and Adolescents: 0.5 to 1 mg/kg/dose IV every 24 hours or every other day for a cumulative total of 20 to 45 mg/kg.
-for the treatment of visceral leishmaniasis*:
Intravenous dosage:
Infants and Children: 1 mg/kg/dose IV every 24 hours or every other day for a cumulative total of 15 to 20 doses as an alternative to liposomal amphotericin B. Amphotericin B deoxycholate is not recommended when there are contraindications to or toxicity with liposomal amphotericin B except in patients who develop liposome-induced complement activation-related pseudoallergy (CARPA).
Adolescents: 1 mg/kg/dose IV every 24 hours or every other day for a cumulative total of 15 to 20 doses as an alternative to liposomal amphotericin B. A total dose of 1.5 to 2 g, then chronic maintenance therapy with a lipid formulation amphotericin B, or alternately, pentavalent antimony is suggested for HIV-infected patients. For patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. Amphotericin B deoxycholate is not recommended when there are contraindications to or toxicity with liposomal amphotericin B except in patients who develop liposome-induced complement activation-related pseudoallergy (CARPA).

For the treatment of mucormycosis (phycomycosis*):
Intravenous dosage:
Infants, Children, and Adolescents: 1 to 1.5 mg/kg/dose IV every 24 hours. In case reports, treatment typically continued for 6 weeks.

For the treatment of visceral or disseminated sporotrichosis*:
Intravenous dosage:
Infants, Children, and Adolescents: 0.7 mg/kg/dose IV every 24 hours until favorable response. Continue step-down therapy with itraconazole to complete a total of at least 12 months of therapy.

For the treatment of talaromycosis* in HIV-infected patients:
Intravenous dosage:
Adolescents: 0.7 mg/kg/day IV for 2 weeks as alternative therapy, then itraconazole for consolidation therapy and chronic suppressive therapy.

Maximum Dosage Limits:
Safety and efficacy have not been established in pediatric patients; however, doses up to 1.5 mg/kg/day IV are used off-label for all age groups.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that dosage adjustments are not needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in most patients with renal impairment are not available. Some experts recommend no dosage adjustment; however, use with caution in patients with renal impairment as amphotericin B is nephrotoxic and may worsen renal dysfunction.

Neonates
Some experts recommend extending the dosage interval to every 48 hours if serum creatinine is more than 1.5 mg/dL or if serum creatinine rises more than 0.3 mg/dL per day.

Intermittent hemodialysis
Amphotericin B is not efficiently removed by hemodialysis; dosage adjustments are not necessary in patients receiving hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Amphotericin B is a polyene antifungal that binds to sterols in the cell membranes of both fungal and human cells. It is usually fungistatic in vivo but can have fungicidal activity at high concentrations or against extremely susceptible organisms. Its higher affinity for ergosterol, the sterol found in fungal cell membranes, over cholesterol, the sterol found in human cell membranes, allows amphotericin B to be used systemically. As a result of this binding, membrane integrity is impaired, causing the loss of intracellular potassium and other cellular contents.

Some adverse reactions to amphotericin B, such as electrolyte loss and nephrotoxicity, are an extension of its pharmacologic action, while infusion-related reactions may be related to stimulation and release of prostaglandin synthesis as amphotericin B is a potent inducer of prostaglandin E2 synthesis in vitro. Anemia may be secondary to an inhibition of erythropoietin production or may be due to renal toxicity. Although the exact mechanism of renal toxicity has not been defined, amphotericin B can cause a decrease in glomerular filtration rate (GFR) and renal blood flow. A proposed mechanism involves the effects of amphotericin B on membrane permeability as pathological changes of tubular lesions were observed in a study (n = 26). Another proposed mechanism is amphotericin B-induced activation of an intrarenal mechanism called tubuloglomerular feedback (TGF); TGF regulates proximal and distal tubule delivery of ions, which results in afferent arteriolar vasoconstriction. TGF can be blocked by sodium loading or with the administration of furosemide or theophylline. However, single-nephron studies suggest that the theory involving TGF may be questionable. Other possible mechanisms include direct toxic effects to the afferent arterioles and tubules and direct renal and systemic vasoconstriction, which may be related to inhibition of nitric oxide or atrial natriuretic peptide systems or potentially to enhanced adenosine release in the kidneys. Vasoconstriction due to amphotericin B may also be calcium-dependent.

Pharmacokinetics: Amphotericin B is primarily given intravenously; limited data are available for use by oral, intrathecal, and inhalation routes. Distribution of amphotericin B is believed to follow a 3-compartment model. The volume of distribution is highly variable, ranging from approximately 0.5 to 4 L/kg depending on the patient population. Amphotericin B is 90-95% protein-bound, primarily to lipoproteins. Distribution into body fluids other than blood are typically low; amphotericin B concentrations in pleural, peritoneal, and synovial fluids have been reported to be less than half or up to two thirds concurrent plasma concentrations. Penetration into the cerebrospinal fluid (CSF) is poor in adults (2-4% of serum concentrations); however, in a small study of neonates, CSF concentrations were reported to be 40-90% of serum concentrations.

Metabolism of amphotericin B is unknown. Amphotericin B is excreted very slowly (over weeks to months) by the kidneys. Approximately 2-5% of a dose is eliminated renally as unchanged drug; over a 7-day period approximately 40% of a dose is excreted in the urine. The initial elimination half-life in adults with normal renal function is approximately 24-48 hours; however, the terminal phase half-life can be as long as 15 days, probably due to slow release of the drug from peripheral compartments.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Absorption after oral administration is poor (< 5%).

Intravenous Route
Peak concentrations after typical doses are usually in the 0.3-2 mcg/ml range ; however, many variables influence peak concentrations, including dose, duration of infusion, and volume of distribution. Like volume of distribution, peak concentrations are highly variable in pediatric patients.

Inhalation Route
Using a conventional nebulizer, 10-20% of a dose will reach the lungs; however, delivery is variable and highly dependent on the nebulizer used.


-Special Populations
Pediatrics
Neonates
Amphotericin pharmacokinetics are highly variable in neonates. Unlike older populations, penetration into the CSF is relatively good (40-90% of serum concentrations). The following pharmacokinetic parameters have been reported from small studies of neonates (total n = 18; majority of patients were premature; weight 580-3325 g) :
half-life: 14.8-22.1 hours (median)
volume of distribution (Vd): 1.5-2.49 L/kg (median)
clearance: 12-18 ml/min/1.73 m2 (median)

Infants, Children, and Adolescents
Similar to neonates, amphotericin pharmacokinetics are highly variable in infants and children. Clearance of amphotericin B significantly decreases with increasing age. In a study of 12 pediatric patients (mean age, 6.6 years (range, 4 months to 14 years), mean total clearance was 0.57 ml/kg/min in children 8 months to 9 years of age compared to 0.25 ml/kg/min in children > 9 years of age. The following pharmacokinetic parameters were reported for the overall study group :
half-life: 11.9-33.2 hours (range)
volume of distribution (Vd): 0.23-1.91 L/kg (range)
clearance: 0.22-0.79 ml/min/kg (range; NOTE: units are per kg, not per standardized BSA)

Renal Impairment
Amphotericin B is poorly removed by dialysis.