Amphotericin B

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# Black Box Warning

# Overview
Amphotericin B is a antifungal,  anti-Infective Agent,  antiprotozoal ,  Dermatological Agent and Polyene that is FDA approved for the treatment of invasive aspergillosis, cryptococcosis (torulosis), North American blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, zygomycosis including mucormycosis due to susceptible species of the genera Absidia, Mucor and Rhizopus, and infections due to related susceptible species of Conidiobolus and Basidiobolus, and sporotrichosis.  Amphotericin B may be useful in the treatment of American mucocutaneous leishmaniasis, but it is not the drug of choice as primary therapy.. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include hypotension, thrombophlebitis, injection site pain, diarrhea, indigestion, loss of appetite, nausea, vomiting, normocystic normochromic anemia, arthralgia, myalgia, headache, tachypnea, fever, malaise, and shivering.
The drug is available as conventional amphotericin B (Amphotericin B deoxycholate; AmB-d) or as lipid-based formulations.  Available lipid-based formulations include Amphotericin B Lipid Complex (ABLC; Abelcet), Amphotericin B cholesteryl sulfate complex (Amphotericin B Colloidal Dispersion; ABCD; Amphotec), and Liposomal Amphotericin B (LAmB; AmBisome).

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Amphotericin B for Injection should be administered by slow intravenous infusion. Intravenous infusion should be given over a period of approximately 2 to 6 hours (depending on the dose) observing the usual precautions for intravenous therapy. The recommended concentration for intravenous infusion is 0.1 mg/mL (1mg/10mL). Since patient tolerance varies greatly, the dosage of amphotericin B must be individualized and adjusted according to the patient's clinical status (e.g., site and severity of infection, etiologic agent, cardio-renal function, etc.). A single intravenous test dose (1 mg in 20 mL of 5% dextrose solution) administered over 20 to 30 minutes may be preferred. The patient's temperature, pulse, respiration, and blood pressure should be recorded every 30 minutes for 2 to 4 hours.
- In patients with good cardio-renal function and a well tolerated test dose, therapy is usually initiated with a daily dose of 0.25 mg/kg of body weight. However, in those patients having severe and rapidly progressive fungal infection, therapy may be initiated with a daily dose of 0.3 mg/kg of body weight. In patients with impaired cardio-renal function or a severe reaction to the test dose, therapy should be initiated with smaller daily doses (i.e., 5 to 10 mg). Depending on the patient's cardio-renal status, doses may gradually be increased by 5 to 10 mg per day to final daily dosage of 0.5 to 0.7 mg/kg.
- There are insufficient data presently available to define total dosage requirements and duration of treatment necessary for eradication of specific mycoses. The optimal dose is unknown. Total daily dosage may range up to 1.0 mg/kg per day or up to 1.5 mg/kg when given on alternate days.
- Sporotrichosis: Therapy with intravenous amphotericin B for sporotrichosis has ranged up to nine months with a total dose up to 2.5 g.
- Aspergillosis: Aspergillosis has been treated with amphotericin B intravenously for a period up to 11 months with a total dose up to 3.6 g.
- Rhinocerebral phycomycosis: This fulminating disease generally occurs in association with diabetic ketoacidosis. It is, therefore, imperative that diabetic control be restored in order for treatment with Amphotericin B for Injection to be successful. In contradistinction, pulmonary phycomycosis, which is more common in association with hematologic malignancies, is often an incidental finding at autopsy. A cumulative dose of at least 3 g of amphotericin B is recommended to treat rhinocerebral phycomycosis. Although a total dose of 3 to 4 g will infrequently cause lasting renal impairment, this would seem a reasonable minimum where there is clinical evidence of invasion of deep tissue. Since rhinocerebral phycomycosis usually follows a rapidly fatal course, the therapeutic approach must necessarily be more aggressive than that used in more indolent mycoses.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- Dosage 
Amphotericin B deoxycholate 1 mg/kg/day IV
Amphotericin B lipid formulation 5 mg/kg/day IV
- Amphotericin B deoxycholate 1 mg/kg/day IV
- Amphotericin B lipid formulation 5 mg/kg/day IV
- Dosage: 0.30.7 mg/kg daily IV 
- Dosage:
Amphotericin B deoxycholate 0.71.0 mg/kg IV daily
Lipid formulation amphotericin B 46 mg/kg IV daily
- Amphotericin B deoxycholate 0.71.0 mg/kg IV daily
- Lipid formulation amphotericin B 46 mg/kg IV daily
- Antibiotic Spectrum
Histoplasmosis
Blastomycosis
Coccidioides
- Histoplasmosis
- Blastomycosis
- Coccidioides
- Dosage 
Amphotericin B lipid complex 5 mg/kg IV daily plus flucytosine 25 mg/kg orally 4 times daily
Amphotericin B deoxycholate 0.7 to 1 mg/kg IV daily plus flucytosine- 25 mg/kg orally 4 times daily
- Amphotericin B lipid complex 5 mg/kg IV daily plus flucytosine 25 mg/kg orally 4 times daily
- Amphotericin B deoxycholate 0.7 to 1 mg/kg IV daily plus flucytosine- 25 mg/kg orally 4 times daily
- Dosage 
Amphotericin B deoxycholate: 0.51.0 mg/kg daily IV
Amphotericin B Lipid Formulation: 35 mg/kg daily IV
- Amphotericin B deoxycholate: 0.51.0 mg/kg daily IV
- Amphotericin B Lipid Formulation: 35 mg/kg daily IV
- Dosage: 0.30.6 mg/kg daily for 17 id resistent to Fluconazol

### NonGuideline-Supported Use
- Dosage: One single intravenous dose of 75 mg
- Dosage: 0.6 milligram/kilogram/day IV + 400 mg/day Itraconazol PO

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Amphotericin B in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- Dosage 
Amphotericin B deoxycholate: 0.51.0 mg/kg daily IV
Amphotericin B Lipid Formulation: 35 mg/kg daily IV
- Amphotericin B deoxycholate: 0.51.0 mg/kg daily IV
- Amphotericin B Lipid Formulation: 35 mg/kg daily IV

### NonGuideline-Supported Use
- Dosage: 35 mg/kg daily IV if no urinary tract involvement

# Contraindications
- This product is contraindicated in those patients who have shown hypersensitivity to amphotericin B or any other component in the formulation unless, in the opinion of the physician, the condition requiring treatment is life-threatening and amenable only to amphotericin B therapy.

# Warnings
- Amphotericin B is frequently the only effective treatment available for potentially life-threatening fungal disease. In each case, its possible life-saving benefit must be balanced against its untoward and dangerous side effects. EXERCISE CAUTION to prevent inadvertent Amphotericin B overdose, which may result in potentially fatal cardiac or cardiopulmonary arrest. Verify the product name and dosage especially if dose exceeds 1.5 mg/kg.

# Adverse Reactions

## Clinical Trials Experience
Although some patients may tolerate full intravenous doses of amphotericin B without difficulty, most will exhibit some intolerance, often at less than the full therapeutic dose. Tolerance may be improved by treatment with aspirin, antipyretics (e.g., acetaminophen), antihistamines, or antiemetics. Meperidine (25 to 50 mg IV) has been shown in some patients to decrease the duration of shaking chills and fever that may accompany the infusion of amphotericin B. Administration of amphotericin B on alternate days may decrease anorexia and phlebitis.
Intravenous administration of small doses of adrenal corticosteroids just prior to or during the Amphotericin B infusion may help decrease febrile reactions. Dosage and duration of such corticosteroid therapy should be kept to a minimum.
Addition of heparin (1000 units per infusion), and the use of a pediatric scalp-vein needle may lessen the incidence of thrombophlebitis. Extravasation may cause chemical irritation.
The adverse reactions most commonly observed are:
- Fever (sometimes accompanied by shaking chills usually occurring within 15 to 20 minutes after initiation of treatment)
- Malaise
- Weight loss
- Hypotension
- Tachypnea
- Anorexia
- Nausea
- Vomiting
- Diarrhea
- Dyspepsia
- Cramping epigastric pain
- Normochromic, normocytic anemia.
- Pain at the injection site with or without phlebitis or thrombophlebitis.
- Generalized pain, including muscle and joint pains.
- Headache
- Decreased renal function and renal function abnormalities including
Azotemia
Hypokalemia
Hyposthenuria
Renal tubular acidosis
Nephrocalcinosis. These usually improve with interruption of therapy. However, some permanent impairment often occurs, especially in those patients receiving large amounts (over 5 g) of amphotericin B or receiving other nephrotoxic agents.
In some patients hydration and sodium repletion prior to amphotericin B administration may reduce the risk of developing nephrotoxicity. Supplemental alkali medication may decrease renal tubular acidosis.
- Azotemia
- Hypokalemia
- Hyposthenuria
- Renal tubular acidosis
- Nephrocalcinosis. These usually improve with interruption of therapy. However, some permanent impairment often occurs, especially in those patients receiving large amounts (over 5 g) of amphotericin B or receiving other nephrotoxic agents.
- In some patients hydration and sodium repletion prior to amphotericin B administration may reduce the risk of developing nephrotoxicity. Supplemental alkali medication may decrease renal tubular acidosis.
The following adverse reactions have also been reported:
- Flushing.
- Anaphylactoid and other allergic reactions
- Bronchospasm
- Wheezing
- Cardiac arrest
- Shock
- Cardiac failure
- Pulmonary edema
- Hypersensitivity pneumonitis
- Arrhythmias, including ventricular fibrillation
- Dyspnea
- Hypertension
- Acute liver failure
- Hepatitis
- Jaundice
- Hemorrhagic gastroenteritis
- Melena
- Agranulocytosis
- Coagulation defects
- Thrombocytopenia
- Leukopenia
- Eosinophilia
- Leukocytosis
- Convulsions
- Hearing loss
- Tinnitus
- Transient vertigo
- Visual impairment
- Diplopia
- Peripheral neuropathy
- Encephalopathy
- Acute renal failure
- Anuria
- Oliguria

## Postmarketing Experience
- Rash, in particular maculopapular
- Pruritus
- Skin exfoliation
- Toxic epidermal necrolysis
- Stevens-Johnson syndrome
- Nephrogenic diabetes insipidus

# Drug Interactions
When administered concurrently, the following drugs may interact with amphotericin B:
- Antineoplastic agents: may enhance the potential for renal toxicity, bronchospasm and hypotension. Antineoplastic agents (e.g., nitrogen mustard, etc.) should be given concomitantly only with great caution.
- Corticosteroids and Corticotropin (ACTH): may potentiate amphotericin B-induced hypokalemia which may predispose the patient to cardiac dysfunction. Avoid concomitant use unless necessary to control side effects of amphotericin B. If used concomitantly, closely monitor serum electrolytes and cardiac function.
- Digitalis glycosides: amphotericin B-induced hypokalemia may potentiate digitalis toxicity. Serum potassium levels and cardiac function should be closely monitored and any deficit promptly corrected.
- Flucytosine: while a synergistic relationship with amphotericin B has been reported, concomitant use may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion.
- Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.): in vitro and animal studies with the combination of amphotericin B and imidazoles suggest that imidazoles may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immnocompromised patients.
- Other nephrotoxic medications: agents such as aminoglycosides, cyclosporine, and pentamidine may enhance the potential for drug-induced renal toxicity, and should be used concomitantly only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications.
- Skeletal muscle relaxants: amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine). Serum potassium levels should be monitored and deficiencies corrected.
- Leukocyte transfusions: acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies in animals have revealed no evidence of harm to the fetus due to amphotericin B for injection. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B for injection without obvious effects to the fetus, but the number of cases reported has been small. Because animal reproduction studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, this drug should be used during pregnancy only if clearly indicated.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amphotericin B in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Amphotericin B during labor and delivery.

### Nursing Mothers
- It is not known whether amphotericin B is excreted in human milk. Because many drugs are excreted in human milk and considering the potential toxicity of amphotericin B, it is prudent to advise a nursing mother to discontinue nursing

### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established through adequate and well-controlled studies. Systemic fungal infections have been successfully treated in pediatric patients without reports of unusual side effects. Amphotericin B for Injection when administered to pediatric patients should be limited to the smallest dose compatible with an effective therapeutic regimen.

### Geriatic Use
There is no FDA guidance on the use of Amphotericin B with respect to geriatric patients.

### Gender
There is no FDA guidance on the use of Amphotericin B with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Amphotericin B with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Amphotericin B in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Amphotericin B in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amphotericin B in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Amphotericin B in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral
- Intravenous

### Monitoring
Renal function should be monitored frequently during amphotericin B therapy. It is also advisable to monitor on a regular basis liver function, serum electrolytes (particularly magnesium and potassium, blood counts, and hemoglobin concentrations. Laboratory test results should be used as a guide to subsequent dosage adjustments.

# IV Compatibility
There is limited information regarding IV Compatibility of Amphotericin B in the drug label.

# Overdosage
Amphotericin B overdoses can result in potentially fatal cardiac or cardiopulmonary arrest. If an overdose is suspected, discontinue therapy and monitor the patient's clinical status (e.g., cardiorespiratory, renal, and liver function, hematologic status, serum electrolytes) and administer supportive therapy, as required. Amphotericin B is not hemodialyzable. Prior to reinstituting therapy, the patient's condition should be stabilized (including correction of electrolyte deficiencies, etc.).

# Pharmacology

## Mechanism of Action
- Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols in the cell membrane of susceptible fungi with a resultant change in membrane permeability allowing leakage of intracellular components. Mammalian cell membranes also contain sterols and it has been suggested that the damage to human cells and fungal cells may share common mechanisms.

## Structure
- Amphotericin B is designated chemically as  -33--1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo  nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid. Structural formula:

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Amphotericin B in the drug label.

## Pharmacokinetics
- An initial intravenous infusion of 1 to 5 mg of amphotericin B per day, gradually increased to 0.4 to 0.6 mg/kg daily, produces peak plasma concentrations ranging from approximately 0.5 to 2 mcg/mL. Following a rapid initial fall, plasma concentrations plateau at about 0.5 mcg/mL. An elimination half-life of approximately 15 days follows an initial plasma half-life of about 24 hours. Amphotericin B circulating in plasma is highly bound (>90%) to plasma proteins and is poorly dialyzable. Approximately two thirds of concurrent plasma concentrations have been detected in fluids from inflamed pleura, peritoneum, synovium, and aqueous humor. Concentrations in the cerebrospinal fluid seldom exceed 2.5% of those in the plasma. Little amphotericin B penetrates into vitreous humor or normal amniotic fluid. Complete details of tissue distribution are not known.
Amphotericin B is excreted very slowly (over weeks to months) by the kidneys with 2 to 5% of a given dose being excreted in the biologically active form. Details of possible metabolic pathways are not known. After treatment is discontinued, the drug can be detected in the urine for at least 7 weeks due to the slow disappearance of the drug. The cumulative urinary output over a 7 day period amounts to approximately 40% of the amount of drug infused.

## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Amphotericin B in the drug label.

# Clinical Studies
There is limited information regarding Clinical Studies of Amphotericin B in the drug label.

# How Supplied
- Available as single vials providing 50 mg amphotericin B as a yellow to orange lyophilized cake (which may partially reduce to powder following manufacture). NDC 39822-1055-5. Retain in carton until time of use.

## Storage
- Prior to reconstitution Amphotericin B for Injection USP should be stored under refrigeration, 2  to 8 C (36 to 46 F), protected against exposure to light. The concentrate (5 mg amphotericin B per mL after reconstitution with 10 mL Sterile Water for Injection USP) may be stored in the dark, at room temperature for 24 hours, or at refrigerator temperatures for one week with minimal loss of potency and clarity. Any unused material should then be discarded. Solutions prepared for intravenous infusion (0.1 mg or less amphotericin B per mL) should be used promptly after preparation and should be protected from light during administration.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Amphotericin B in the drug label.

# Precautions with Alcohol
Alcohol-Amphotericin B interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Amphocin
- Fungizone

# Look-Alike Drug Names
There is limited information regarding Amphotericin B Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price