Fungizone (Amphotericin B)

FUNGIZONE® INTRAVENOUS

Squibb

Amphotericin B

Antifungal

Indications And Clinical Uses: Amphotericin B is specifically intended for the treatment of disseminated mycotic infections, including coccidioidomycosis; cryptococcosis (torulosis); disseminated candidiasis, histoplasmosis, South American leishmaniasis, North and South American blastomycosis; mucormycosis (phycomycosis) caused by species of the genera Mucor, Rhizopus, Absidia, Entomophthora, and Basidiobolus, sporotrichosis (S. schenckii), and aspergillosis (A. fumigatus).

Other Clinical Uses: Limited studies have shown that amphotericin B powder for injection may be useful when administered by routes other than i.v. for the treatment of certain types of fungal infections.

Bladder Irrigation: Successful treatment of fungal infections of the bladder by amphotericin B has been noted in the literature.

The basic method used for bladder irrigation is as follows: 15 mg Fungizone powder is dissolved in 100 to 400 mL of sterile water and injected via catheter after complete emptying of the bladder. The patient is then asked to retain the solution for as long as possible. An alkalizing mixture should be given every 4 hours. The treatment may be repeated until the culture is negative and the symptoms have disappeared.

Aerosol: Amphotericin B has also been administered by aerosol (nebulizer) for the treatment of pulmonary fungal infections. A preparation suitable for administration by aerosol is prepared as follows: Dissolve a 50 mg vial of Fungizone in a bottle of Alevaire or in 10 mL of distilled or sterile water. Administer 1 to 2 mL of this solution (5 to 10 mg amphotericin B) 3 to 4 times daily for a period of 1 to 2 weeks.

Eye Infections: Several studies have been done using topical administration of amphotericin B for fungal infections of the eye. Such use has shown a low degree of efficacy after prolonged therapy and is not recommended unless there is no other alternative. It is unlikely to be of value except in superficial infections.

Reconstitute a 50 mg vial of amphotericin B by adding 10 mL of sterile water, giving a concentration of 5 mg/mL. Shake until the solution is clear. Further dilution of 1 mL of this solution to a concentration of 1 mg/mL using sterile water provides a solution suitable for use in the eye. Dosage varies from 2 drops every hour to 1 drop every 4 to 6 hours. Intervals between administration may be lengthened as improvement occurs. Amphotericin B has been reported in some instances to be toxic to the eye when applied locally and may cause local irritation and discomfort.

Solutions of 1.5 mg/mL up to 4.0 mg/mL have also been used. Normal (isotonic) saline is not recommended for dilution since it may cause precipitation of amphotericin B.

Higher concentrations can lead to serious damage to the eye and must not be used.

Ear infections: There is little evidence to support the efficacy of such use.

Contra-Indications: In those persons 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.

Manufacturers’ Warnings In Clinical States: Amphotericin B should be administered primarily to patients with progressive, potentially fatal infections. This potent drug should not be used to treat the common apparent forms of fungal diseases which show only positive skin or serologic tests.

Amphotericin B is frequently the only available treatment for potentially fatal fungal diseases. In each case, its possible life-saving benefit must be balanced against its untoward and dangerous side effects.

Precautions: General: Prolonged therapy with amphotericin B is usually necessary. Adverse reactions are quite common when the drug is given parenterally at therapeutic dosage levels. Some of these reactions are potentially dangerous. Hence, amphotericin B should be used only in hospitalized patients or those under close clinical observation by medically trained personnel, and should be reserved for those patients in whom a diagnosis of the progressive, potentially fatal forms of susceptible mycotic infections has been firmly established preferably by positive culture or histologic study.

Rapid i.v. infusion, over less than 1 hour, particularly in patients with renal insufficiency, has been associated with hyperkalemia and arrhythmias, and should, therefore, be avoided (see Dosage).

Leukoencephalopathy has been reported following use of amphotericin B in patients who received total body irradiation.

Urinalysis and BUN determinations should be performed at least weekly during therapy, as should serum creatinine or endogenous creatinine clearance tests. If the BUN level exceeds 40 mg/100 mL or the serum creatinine level exceeds 3 mg/100 mL, administration of amphotericin B should, whenever feasible, be discontinued or dosage markedly reduced, until the level returns to near normal limits (usually in 1 or 2 weeks). Some authorities suggest that the serum creatinine clearance rate permits better evaluation of renal function.

Weekly hemograms and serum potassium and magnesium determinations are also advisable. Low serum magnesium levels have also been noted during treatment with amphotericin B. Therapy should be discontinued if the results of liver function tests are abnormal (elevated BSP, alkaline phosphatase and bilirubin).

Whenever medication is interrupted for a period longer than 7 days, therapy should be resumed by starting with the lowest dosage level, e.g., 0.25 mg/kg/day of body weight and increased gradually to an optimum level as outlined in Dosage.

Drug Interactions: Corticosteroids and corticotropin (ACTH) may potentiate amphotericin B-induced hypokalemia and should not be administered concomitantly unless they are necessary to control drug reactions. Since deep fungal infections sometimes emerge in patients undergoing therapy with antibiotics and antineoplastic agents such as nitrogen mustard, they should not be given concomitantly with amphotericin B if avoidable. Other nephrotoxic agents (e.g., cisplatin, pentamidine, aminoglycosides and cyclosporine) may enhance the potential for renal toxicity and should not be given concomitantly except with great caution.

Concomitant administration of flucytosine may increase the toxicity of flucytosine possibly by increasing its cellular uptake and/or impairing its renal excretion.

Though not observed in all studies, acute pulmonary reactions have been observed in patients given amphotericin B during or shortly after leukocyte transfusions, thus it is advisable to separate these infusions as far as possible and to monitor pulmonary function.

Caution should be observed when agents whose effects or toxicity may be increased by hopokalemia (e.g., digitalis glycosides, skeletal muscle relaxants and antiarrhythmic agents) are administered concomitantly.

Pregnancy: Reproduction studies in animals have revealed no evidence of harm to the fetus due to amphotericin B. 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 administered during pregnancy with caution and only if the potential benefit to the mother outweighs the potential risk to the fetus.

Lactation: It is not known whether amphotericin B is excreted in human milk. Likewise, data are in conflict as to the extent of oral absorption, if any. 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.

Children: Safety and effectiveness in pediatric patients have not been established through adequate and well-controlled studies. Systemic fungal infections have been treated in pediatric patients without reports of unusual side effects.

Adverse Reactions: While a few patients may tolerate full i.v. doses of amphotericin B without difficulty, most will exhibit some intolerance, often at less than the full therapeutic dosage. The adverse reactions most commonly observed are:

General (Body as a Whole): fever (sometimes accompanied by shaking chills occurring within 15 to 20 minutes after initiation of treatment), malaise and weight loss.

Digestive: anorexia, nausea, vomiting, diarrhea, dyspepsia and cramping epigastric pain.

Hematologic: reversible normochromic and normocytic anemia.

Local: local venous pain at the injection site with or without phlebitis or thrombophlebitis.

Musculoskeletal: generalized pain, including muscle and joint pains.

Neurologic: headache.

Renal: decreased renal function and renal function abnormalities including azotemia, hyposthenuria, renal tubular acidosis and nephrocalcinosis, an increase in the serum creatinine level, a decrease in the serum creatinine clearance rate or a decrease in the phenol-sulfonphthalein (PSP) excretion is commonly observed. Hypokalemia with or without concomitant impairment of renal function has often been observed. Potassium replacement may be considered by oral or parenteral route. Concomitant diuretic therapy may be a predisposition for renal impairment whereas sodium repletion or supplementation may reduce the occurrence of nephrotoxicity.

Renal damage is often accompanied by the appearance of granular and hyaline casts, and sometimes by microhematuria. Renal dysfunction is usually reversible on discontinuation of therapy, but serious and permanent renal damage has been reported in patients given large doses for prolonged periods; especially in those receiving a total dose exceeding 5 g.

The following adverse reactions have also been reported.

General (Body as a Whole): flushing.

Allergic: anaphylactoid and other allergic reactions.

Cardiovascular: cardiovascular toxicity including arrhythmias, ventricular fibrillation, cardiac arrest, hypertension and hypotension.

Dermatologic: maculopapular rash and pruritus (without rash).

Digestive: acute liver failure, jaundice, liver function test abnormalities, melena or hemorrhagic gastroenteritis and hepatotoxicity.

Hematologic: coagulation defects, thrombocytopenia, leukopenia, agranulocytosis, eosinophilia, leukocytosis.

Neurologic: hearing loss, tinnitus, transient vertigo, blurred vision or diplopia, peripheral neuropathy, encephalopathy, convulsions and other neurologic symptoms.

Pulmonary: dyspnea, bronchospasm, noncardiac pulmonary edema and hypersensitivity pneumonitis.

Renal: hypomagnesemia, hyperkalemia, acute renal failure, anuria and oliguria.

Fever, nausea, vomiting, hadache and malaise sometimes subside with continued administration. Reactions to amphotericin B may be made less severe by administration of an antipyretic, e.g., ASA, an antihistaminic and/or an antiemetic prior to and concurrently with amphotericin B, or by modifying the rate of infusion. Addition of a small amount of heparin, rotation of the injection site, the use of a pediatric scalp-vein needle and alternate day therapy may lessen the incidence of thrombophlebitis and anorexia. Supplemental alkali medication may decrease renal tubular acidosis complications. Extravasation may cause chemical irritation.

I.V. or i.m. administration of small doses of adrenal corticosteroids just prior to, or during the amphotericin B infusion may decrease febrile reactions. The dosage and duration of such corticosteroid therapy should be kept to a minimum (see Precautions).

If a severe reaction occurs during the course of an infusion, therapy should be interrupted for about 15 minutes to allow the patient to recover. If the reaction recurs, therapy should be resumed at a lower dosage the next day. Blood transfusions may be required when reversible normocytic, normochromic anemia occurs during prolonged therapy.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Amphotericin B overdoses can result in cardiorespiratory 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.). tag_DosageDosage

Dosage And Administration: Amphotericin B should be administered by slow i.v. infusion, given over a period of approximately 6 hours, observing the usual precautions for i.v. therapy. The recommended concentration for i.v. infusion is 0.1 mg/mL (1 mg/10 mL).

Since tolerance to amphotericin B varies individually, dosage must be adjusted to the specific requirements of each patient. Therapy is usually initiated with a total daily dose of 0.25 mg/kg of body weight and gradually increased as tolerance permits. There are insufficient data presently available to define total dosage requirements and duration of treatment necessary for eradication of mycoses such as phycomycoses. The optimal dose is unknown. The total daily dose may range up to a level of 1 mg/kg of body weight. Dosage may range up to 1.5 mg/kg when an alternate day regimen is used.

Caution: Under no circumstances should a total daily dosage of 1.5 mg/kg be exceeded. Amphotericin B overdoses can result in cardiorespiratory arrest (see Overdose: Symptoms and Treatment).

Duration of therapy depends on such factors as the etiologic agent, anatomic locations of the lesions, stage and severity of the infection and ability of the patient to tolerate amphotericin B. Several months of therapy are usually necessary; a shorter period of therapy may produce an inadequate response and lead to a relapse.

Therapy with i.v. amphotericin B for sporotrichosis has ranged up to nine months. The usual dose per injection is 20 mg.

Aspergillosis has been treated with amphotericin B administered i.v. for a period up to 11 months with a total dose of up to 3.6 g.

Rhinocerebral phycomycosis, a fulminating disease, generally occurs in association with diabetic ketoacidosis. Therefore, it is imperative that rapid restoration of diabetic control be instituted before successful treatment can be accomplished. 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. Although a total dose of 3 to 4 g will sometimes cause lasting renal impairment, this would seem a reasonable minimum where there is clinical evidence of invasion of the deep tissues. Since rhinocerebral phycomycosis usually follows a rapidly fatal course, the therapeutic approach must necessarily be more aggressive than that used in indolent mycoses.

Preparation of Solutions: Reconstitute the dry powder as follows: An initial concentrate of 5 mg amphotericin B/mL is first prepared by adding 10 mL Sterile Water for Injection USP without a bacteriostatic agent to the vial of dry powder and shaking the vial until the liquid is clear.

The infusion liquid, providing 0.1 mg amphotericin B/mL is then obtained by further dilution (1:50) with 5% Dextrose Injection USP of pH above 4.2 to a volume of 500 mL. The pH of each container of Dextrose Injection should be ascertained before use. Commercial Dextrose Injection usually has a pH above 4.2; however, if it is below 4.2, 1 or 2 mL of sterile buffer should be added to the Dextrose Injection before it is used to dilute the concentrated solution of amphotericin B. The Dextrose Injection should then be retested to ascertain that the pH has been adjusted to the required range.

The recommended buffer has the following composition: dibasic sodium phosphate (anhydrous) 1.59 g, monobasic sodium phosphate (anhydrous) 0.96 g, water for injection USP q.s. 100 mL.

The buffer should be sterilized before it is added to the Dextrose Injection, either by filtration through a bacterial retentive stone, mat or membrane (maximum pore size of 0.45 microns), or by autoclaving for 30 minutes at 15 pounds pressure (121°C).

Caution: Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in the antibiotic or in materials used to prepare it for administration. All entries into the vial or into the diluents must be made with a sterile needle. Do not reconstitute with saline solutions.

The use of any diluent other than the ones recommended or the presence of a bacteriostatic agent (e.g., benzyl alcohol) in the diluent may cause precipitation of the antibiotic. Do not use the initial concentrate or the infusion solution if there is any evidence of precipitation or foreign matter in either one.

An in-line membrane filter may be used for i.v. infusion of amphotericin B; however, the mean pore diameter of the filter should not be less than 1.0 micron in order to assure passage of the antibiotic dispersion.

Storage: Store dry powder in the refrigerator (2 to 8°C), protected against exposure to light. The concentrate (5 mg amphotericin B per mL after reconstitution with 10 mL of sterile water for injection USP) may be stored in the dark at room temperature for 24 hours, or in the refrigerator (2 to 8°C) for 1 week with minimal loss of potency and clarity. Any unused material should then be discarded. Solutions prepared for i.v. infusion (0.1 mg or less amphotericin B/mL) should be used promptly after preparation and should be protected from light during administration.

Availability And Storage: A sterile, lyophilized powder in 20 mL vials providing 50 mg amphotericin B. Nonmedicinal ingredients: sodium desoxycholate and sodium phosphate.

FUNGIZONE® INTRAVENOUS Squibb Amphotericin B Antifungal

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