Fungizone

924.08

924.08

215-742-2

DTXSID9022601

Deep yellow prisms or needles from n,n-dimethylformamide|YELLOW TO ORANGE POWDER

A - Alimentary tract and metabolism|G - Genito urinary system and sex hormones|J - Antiinfectives for systemic use

320

log Kow = -2.80 (est)

yellow powder

1.3±0.1 g/cm3

>170 °C (decomp)

1140.365°C at 760 mmHg

643.5±34.3 °C

1.614

H2O: <0.1 g/100 mL at 21 ºC;sterile water: 20 mg/mL as a stock solution.

2-8°C

0mmHg at 25°C

Intravenous-rat LD50: 11.3 mg/kg; peritoneal-mouse LD50: 27.74 mg/kg

Flammable; heat produces toxic nitrogen oxide fumes

D24 +333° (acidic DMF); -33.6° (0.1N methanolic HCl)

ODORLESS OR PRACTICALLY SO

Hydroxyl radical reaction rate constant = 6.5X10-10 cu cm/molec-sec at 25 °C (est)

III

6.1(b)

UN 1759 8/PG 3

3

36/37/38-22-40-23/24/25

26-36/37/39-45-36-60-37

BU2625000

C,Xi,Xn,T

Warehouse ventilated, low temperature and dry

Stable, but may be light sensitive. Incompatible with strong oxidizing agents.

H335

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl amphotericin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Benson JM, Nahata MC; Clinical Use of Systemic Antifungal Agents. Clin Pharm 7 (Jun): 424-38 (1988). The chemistry, pharmacology, mechanism of action, pharmacokinetics, clinical uses, adverse effects, and drug interactions of amphotericin B are reviewed.|Branch RA; Prevention of Amphotericin B Induced Renal Impairment: Review on the Use of Sodium Supplementation. Arch Intern Med 148 (Nov): 2389-94 (1988). The incidence and mechanism of kidney failure attributed to amphotericin B (Fungizone), guidelines for reducing the risk of renal impairment when the drug is used, and the potential use of sodium, either as sodium chloride or ticarcillin disodium, to reduce the risk of nephrotoxicity are discussed.|Gallis HA et al; Amphotericin B: 30 Years of Clinical Experience. Rev Infect Dis12 (2): 308-29 (1990). This paper discusses the clinical uses of amphotericin B, including its application in AIDS related fungal infections, in neutropenic cancer patients who are persistently febrile, and in infections of the central nervous system, lung, peritoneum, genitourinary system, eye, and skin. The paper also reviews the drug's adverse reactions, with a discussion of administration techniques that may reduce these reactions, and its spectrum of activity, pharmacokinetics, and dosage and administration.|Georgiev VS; Treatment and Developmental Therapeutics in Aspergillosis. 1. Amphotericin B and its Derivatives. Respiration 59 (5): 291-302 (1992). The clinical efficacy of amphotericin B, its toxicities and various routes of applications, are discussed. Different combinations of amphotericin B with other drugs have also been reviewed, along with the anti-Aspergillus activity of various other antibiotics and some ester derivatives of amphotericin B.|For more Special Reports (Complete) data for AMPHOTERICIN B (12 total), please visit the HSDB record page.

|Warning|H315 (98.85%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 261 companies from 16 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

most toxic

Mild and transient elevations in liver enzymes occur in up to 20% of patients receiving amphotericin. Clinically apparent hepatotoxicity is rare, but several convincing cases have been published. The liver injury arises as early as 4 to 14 days after starting therapy, typically with a hepatocellular or mixed pattern of enzyme elevation. Most patients have no symptoms or jaundice. Recovery occurs promptly upon stopping therapy. In addition, isolated but dramatic instances of hyperbilirubinemia arising within days of starting amphotericin have been reported with elevations largely in the direct (conjugated) bilirubin fraction. These patients become visually jaundiced but have no constitutional symptoms, minimal if any elevations in serum ALT or alkaline phosphatase levels, and no evidence of frank hepatic injury. Finally, rare instances of acute cholestatic hepatitis with jaundice have been reported in patients receiving amphotericin, but these patients have generally been critically ill and exposed to multiple potentially hepatotoxic agents, so that the attribution to amphotericin has been weak.

Since nephrotoxic effects may be additive, the concurrent or sequential use of amphotericin B and other drugs with similar toxic potentials (eg, aminoglycosides, capreomycin, colistill, cisplatin, cyclosporine, methoxyflurane, pentamidine, polymyxin B, vancomycin) should be avoided, if possible.|Corticosteroids reportedly may enhance the potassium depletion caused by amphotericin B and should not be used concomitantly unless necessary to control adverse reactions to amphotericin B.|Antineoplastic agents (eg, mechlorethamine) may enhance the potential for renal toxicity, bronchospasm, and hypotension in patients receiving amphotericin B and such concomitant therapy should be used only with great caution.|In a randomized, double-blind study that evaluated use of conventional IV amphotericin B and amphotericin B cholesteryl sulfate complex in febrile neutropenic patients with normal baseline serum creatinine concentrations, the incidence of renal toxicity (defined as a doubling or an increase of 1 mg/dL or more from baseline serum creatinine or a 50% or greater decrease from baseline in calculated creatinine clearance) was 31% in adults and pediatric patients who received amphotericin B cholesteryl sulfate complex concomitantly with cyclosporine or tacrolimus compared with 68% in those who received conventional amphotericin B concomitantly with these agents. In adults and pediatric patients who did not receive cyclosporine or tacrolimus therapy, the incidence of renal toxicity was 8% in those who received amphotericin B cholesteryl sulfate complex and 35% in those who received conventional amphotericin B.|For more Interactions (Complete) data for AMPHOTERICIN B (15 total), please visit the HSDB record page.

LD50 Mouse iv 4 mg/kg|LD50 Mouse ip 88 mg/kg

Amphotericin B is an antifungal agent with a broad spectrum of activity against many fungal species. Amphotericin B commonly causes mild to moderate serum aminotransferase elevations and can cause hyperbilirubinemia, but acute, clinically apparent drug induced liver injury from amphotericin B therapy is exceedingly rare.

Antifungal Agents

Ambecides; Antibiotics, Antifungal; Antibiotics, Macrolide; Antiprotozoal Agents|MEDICATION: Antifungal; (VET): Antifungal|MEDICATION (VET): ... Blastomycosis, histoplasmosis.|Parenteral amphotericin B is used as a secondary agent in the treatment of paracoccidioidomycosis caused by Paracoccidioide brasillensis. /NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for AMPHOTERICIN B (19 total), please visit the HSDB record page.

Rash (including maculopapular or vesiculobullous rash), purpura, pruritus, urticaria, sweating, exfoliative dermatitis, erythema multiforme, alopecia, dry skin, and skin discoloration or ulcer, have been reported in patients receiving amphotericin B.|IV administration of conventional amphotericin B, amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal may cause erythema, pain, or inflammation at the injection site. Phlebitis or thrombophlebitis has been reported with conventional IV amphotericin B. The manufacturer of conventional IV amphotericin B and some clinicians suggest that the addition of 500-1000 units of heparin to the amphotericin B infusion, the use of a pediatric scalp-vein needle, or alternate-day therapy may decrease the incidence of thrombophlebitis. Extravasation of the drug causes local irritation.|Conventional IV amphotericin B is associated with a high incidence of adverse effects, and most patients who receive the drug experience potentially severe adverse effects at some time during the course of therapy. Acute infusion reactions (e.g., fever, chills, headache, nausea, vomiting) and nephrotoxicity are the most frequent adverse reactions to conventional IV amphotericin B. Although clinical experience with amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal is limited to date, these drugs appear to be better tolerated than conventional IV amphotericin B. As with conventional IV amphotericin B, the most frequent adverse reactions to amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal are acute infusion reactions; however, data accumulated to date indicate that lipid-based and liposomal formulations of amphotericin B may be associated with a lower overall incidence of adverse effects and a lower incidence of hematologic and renal toxicity than the conventional formulation of the drug.|Acute infusion reactions consisting of fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, and tachypnea may occur 1-3 hours after initiation of IV infusions of conventional amphotericin B, amphotericin B cholesteryl sulfate, amphotericin B lipid complex, or amphotericin B liposomal. These reactions are most severe and occur most frequently with initial doses and usually lessen with subsequent doses. Fever (with or without shaking chills) may occur as soon as 15-20 minutes after IV infusions of conventional amphotericin B are started. The majority of patients receiving conventional IV amphotericin B (50-90%) exhibit some degree of intolerance to initial doses of the drug, even when therapy is initiated with low doses. Although these reactions become less frequent following subsequent doses or administration of the drug on alternate days, they recur if conventional IV amphotericin B therapy is interrupted and then reinstituted.|For more Drug Warnings (Complete) data for AMPHOTERICIN B (18 total), please visit the HSDB record page.

Resistance to amphotericin B has been produced in vitro by serial passage of fungi in the presence of increasing concentrations of the drug, and resistant strains of some fungi (eg, Candida) have been isolated from patients who received long-term therapy with conventional amphotericin B. Amphotericin B-resistant Candida are reported relatively infrequently; however, primary resistance to the drug occurs in some strains of C. lusitaniae and also occurs in C. guilliermondii.|While the clinical importance is unclear, fluconazole-resistant strains of C. albicans that were cross-resistant to amphotericin B have been isolated from a few immunocompromised individuals, including leukemia patients and patients with human immunodeficiency virus (HIV) infection. In addition, a few isolates of Cryptococcus neoformans resistant to fluconazole also have been resistant to amphotericin B.|Fungi resistant to conventional amphotericin B also may be resistant to amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal.

Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes and membrane proteins. (See all compounds classified as Liposomes.)|Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. (See all compounds classified as Antifungal Agents.)|Substances that are destructive to protozoans. (See all compounds classified as Antiprotozoal Agents.)

The pharmacokinetics of amphotericin B vary substantially depending on whether the drug is administered as conventional amphotericin B (formulated with sodium desoxycholate), amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, or amphotericin B liposomal, and pharmacokinetic parameters reported for one amphotericin B formulation should not be used to predict the pharmacokinetics of any other amphotericin B formulation.|Amphotericin B is poorly absorbed from the GI tract and must be given parenterally to treat systemic fungal infections. In one study, immediately after completion of iv infusion of 30 mg of amphotericin B (administered over a period of several hours), average peak serum concentrations were about 1 ug/ml; when the dose was 50 mg, average peak serum concentrations were approximately 2 ug/ml. Immediately after infusion, no more than 10% of the amphotericin B dose can be accounted for in serum. Average minimum serum concentrations (recorded just prior to the next drug infusion) of approximately 0.4 ug/ml have been reported when doses of 30 mg were given daily or when doses of 60 mg were given every other day.|Information on the distribution of amphotericin B is limited, although distribution is apparently multicompartmental. The volume of distribution of the drug following administration of conventional amphotericin B has been reported to be 4 L/kg; the volume of distribution at steady state after administration of amphotericin B cholesteryl sulfate is reported to be 3.8-4.1 L/kg. Amphotericin B concentrations attained in inflamed pleura, peritoneum, synovium, and aqueous humor following IV administration of conventional amphotericin B reportedly are about 60% of concurrent plasma concentrations; the drug also is distributed into vitreous humor, pleural, pericardial, peritoneal, and synovial fluid. Amphotericin B reportedly crosses the placenta and low concentrations are attained in amniotic fluid.|Following IV administration of conventional amphotericin B, CSF concentrations of the drug are approximately 3% of concurrent serum concentrations. To achieve fungistatic CSF concentrations, the drug must usually be administered intrathecally. In patients with meningitis, intrathecal administration of 0.2-0.3 mg of conventional amphotericin B via a subcutaneous reservoir has produced peak CSF concentrations of 0.5-0.8 ug/mL; 24 hours after the dose, CSF concentrations were 0.11-0.29 ug/mL. Amphotericin B is removed from the CSF by arachnoid villi and appears to be stored in the extracellular compartment of the brain, which may act as a reservoir for the drug.|For more Absorption, Distribution and Excretion (Complete) data for AMPHOTERICIN B (14 total), please visit the HSDB record page.

Amphotericin B cholesteryl sulfate complex has a distribution half-life of 3.5 minutes and an elimination half-life of 27.5-28.2 hours. /Amphotericin B cholesteryl sulfate complex/|Following IV administration of conventional amphotericin B in patients whose renal function is normal prior to therapy, the initial plasma half-life is approximately 24 hours. After the first 24 hours, the rate at which amphotericin B is eliminated decreases and an elimination half-life of approximately 15 days has been reported.|Elimination, half life: Neonates: Variable (range, 18 to 62.5 hours). Children: Variable (range, 5.5 to 40.3 hours). Adults: Approximately 24 hours. Terminal half life: Approximately 15 days. NOTE: There is large interindividual variation among neonates in the elimination of amphotericin B. Amphotericin B may persist in the circulation of neonates for up to 17 days after it has been discontinued.|. The half life of elimination of amphotericin B from the lungs /of rats/ was 4.8 days according to serial sacrifices done after a single dose of 3.2 mg of aerosol doses of amphotericin B per kg.

Amphotericin B usually is fungistatic in action at concentrations obtained clinically, but may be fungicidal in high concentrations or against very susceptible organisms. Amphotericin B exerts its antifungal activity principally by binding to sterols (e.g., ergosterol) in the fungal cell membrane. As a result of this binding, the cell membrane is no longer able to function as a selective barrier and leakage of intracellular contents occurs. Cell death occurs in part as a result of permeability changes, but other mechanisms also may contribute to the in vivo antifungal effects of amphotericin B against some fungi. Amphotericin B is not active in vitro against organisms that do not contain sterols in their cell membranes (eg, bacteria).|Binding to sterols in mammalian cells (such as certain kidney cells and erythrocytes) may account for some of the toxicities reported with conventional amphotericin B therapy. At usual therapeutic concentrations of amphotericin B, the drug does not appear to hemolyze mature erythrocytes, and the anemia seen with conventional IV amphotericin B therapy may result from the action of the drug on actively metabolizing and dividing erythropoietic cells.|...Nephrotoxicity associated with conventional IV amphotericin B appears to involve several mechanisms, including a direct vasoconstrictive effect on renal arterioles that reduces glomerular and renal tubular blood flow and a lytic action on cholesterol-rich lysosomal membranes of renal tubular cells. ...

In the event of overdosage with any amphotericin B formulation, therapy with the drug should be discontinued and the patient's clinical status (eg, cardiorespiratory, renal, and liver function, hematologic status, serum electrolytes) monitored. Supportive therapy should be administered as required. ... The patient's condition should be stabilized, including correction of electrolyte abnormalities, prior to reinstituting amphotericin B therapy.|Exchange transfusion may be useful in neonates and infants and should be considered after large iv exposures. In adults, extracorporeal elimination is not expected to be useful because of the drug's low water solubility and high blood-protein binding.|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|If severe respiratory distress, anaphylaxis, or an anaphylactoid reaction occurs in a patient receiving amphotericin B, the drug should be discontinued immediately and the patient given appropriate therapy (eg, epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.

/SIGNS AND SYMPTOMS/ Acute overdosage of conventional amphotericin B may result in cardiorespiratory arrest. Adverse cardiovascular effects, including hypotension, bradycardia, and cardiac arrest, have been reported in several pediatric patients who inadvertently received overdosage of conventional amphotericin B.|/SIGNS AND SYMPTOMS/ Four /of 13/ infants had minimal elimination for /amphotericin B/ between doses, a finding that correlates with rises in serum creatinine (greater than 0.4 mg/dL, 40 umol/L) and blood urea nitrogen (greater than 10 mg/dL, 3.6 mmol/L).|/SIGNS AND SYMPTOMS/ Various adverse cardiopulmonary effects, including hypotension, tachypnea, cardiac failure, cardiac arrest, cardiomyopathy, shock, pulmonary edema, hypersensitivity pneumonitis, arrhythmias (including ventricular fibrillation), dyspnea, and hypertension, have been reported in individuals receiving conventional IV amphotericin B.|/SIGNS AND SYMPTOMS/ If severe respiratory distress, anaphylaxis, or an anaphylactoid reaction occurs in a patient receiving amphotericin B, the drug should be discontinued immediately and the patient given appropriate therapy (eg, epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.|For more Human Toxicity Excerpts (Complete) data for AMPHOTERICIN B (10 total), please visit the HSDB record page.

Abelcet

ESSENTIALLY 100% AS AN ANTIBIOTIC

MYSTECLIN-F /SRP: TETRACYCLINE-AMPHOTERICIN B COMBINATION/.|Amphotericin B is ... formulated for iv infusion by complexing it with the bile salt deoxycholate ... /and/ marketed as a lyophilized powder (FUNGIZONE) containing 50 mg of amphotericin B, 41 mg of deoxycholate, and a small amount of sodium phosphate buffer. The amphotericin B-deoxycholate complex (DOC) forms a colloid in water ... N-acyl and O-acyl derivatives of amphotericin B form water-soluble salts, but none is available commercially.|... /Three/ lipid formulations for iv infusion /are available/. Amphotericin B colloidal dispersion (ABCD, AMPHOTEC, AMPHOCIL) ... /contains/ roughly equimolar amounts of amphotericin B and cholesteryl sulfate ... /In/ a unilamellar vesicle formulation ... (AMBISOME) ... amphotericin B (50 mg) is combined with 350 mg of lipid in an approximately 10% molar ratio. The lipid contains hydrogenated soy lecithin (phosphatidylcholine), cholesterol, and distearoylphosphatidylglycerol in a 10:5:4 molar ratio. The drug is supplied as a lyophilized powder, which is reconstituted with sterile water for injection and then the dose diluted with 5% dextrose solution ... The third lipid formulation is amphotericin B lipid complex (ABLC, ABELCET). This preparation of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol in a 7:3 mixture with approximately 35 mol% amphotericin B forms ribbon-like sheets ...|The amphotericin B-deoxycholate complex (DOC) has been mixed with a 20% lipid emulsion (INTRALIPID) ...|For more Formulations/Preparations (Complete) data for AMPHOTERICIN B (10 total), please visit the HSDB record page.

Polyene antibiotic produced by Streptomycetes nodosus M4575 obtained from soil of the Orinoco river region of Venezuela.|Commercially available as a deoxycholate complex.|Amphotericin B was found in the mycelium of Streptomyces nodosus M-4575 by Gold et al. of the Squibb Institute of Medical Research in 1956. It is produced with another polyene macrolide antibiotic, amphotericin A, and separated by solvent extraction.

A SYNTHETIC AGAR CULTURE MEDIUM WAS DEVELOPED; TURBIDIMETRIC ADJUSTMENT OF CELL SUSPENSIONS RESULTED IN STANDARD REPRODUCIBLE INOCULA, WHICH GAVE SHARP, CLEAR ZONES IN INHIBITION WHEN APPLIED BY AN AGAR OVERLAY METHOD.|Analyte: amphotericin B; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards|Analyte: amphotericin B; matrix: chemical purity; procedure: cylinder-plate method or turbidimetric method with comparison to standards|Analyte: amphotericin B; matrix: pharmaceutical preparation (cream; injection solution; lotion; ointment); procedure: cylinder-plate method or turbidimetric method with comparison to standards (chemical purity)|For more Analytic Laboratory Methods (Complete) data for AMPHOTERICIN B (10 total), please visit the HSDB record page.

SIMPLE MICRO AGAR DIFFUSION METHOD FOR DETERMINATION OF ANTIBIOTIC CONCN IN BLOOD & OTHER BODY FLUIDS.|Analyte: amphotericin B; matrix: cerebral spinal fluid; procedure: high-performance liquid chromatography with ultraviolet detection at 410 nm; limit of detection: 0.5 ng/mL|Analyte: amphotericin B; matrix: blood (serum); procedure: high-performance liquid chromatography with ultraviolet detection at 382 nm; limit of detection: 0.2 ng|Analyte: amphotericin B; matrix: blood (whole); procedure: high-performance liquid chromatography with ultraviolet detection at 405 nm; limit of quantitation: 75 ng/mL|For more Clinical Laboratory Methods (Complete) data for AMPHOTERICIN B (15 total), please visit the HSDB record page.

Human drugs -> Rare disease (orphan)