Amphotericin B Cholesteryl Sulfate Complex

Pronunciation

(am foe TER i sin bee kole LES te ril SUL fate KOM plecks)

U.S. Brand Names

Amphotec®

Synonyms

ABCD; Amphotericin B Colloidal Dispersion

Generic Available

Canadian Brand Names

Amphotec®

Use

Treatment of invasive aspergillosis in patients who have failed amphotericin B deoxycholate treatment, or who have renal impairment or experience unacceptable toxicity which precludes treatment with amphotericin B deoxycholate in effective doses.

Use - Unlabeled/Investigational

Effective in patients with serious Candida species infections

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to amphotericin B or any component of the formulation

Warnings/Precautions

Anaphylaxis has been reported with other amphotericin B-containing drugs. Facilities for cardiopulmonary resuscitation should be available during administration due to the possibility of anaphylactic reaction. If severe respiratory distress occurs, the infusion should be immediately discontinued. During the initial dosing, the drug should be administered under close clinical observation. Infusion reactions, sometimes, severe, usually subside with continued therapy - manage with decreased rate of infusion and pretreatment with antihistamines/corticosteroids; pulmonary reactions may occur in neutropenic patients receiving leukocyte transfusions; separation of the infusions as much as possible is advised.

Adverse Reactions

>10%: Central nervous system: Chills, fever

1% to 10%:

Cardiovascular: Hypotension, tachycardia

Central nervous system: Headache

Dermatologic: Rash

Endocrine & metabolic: Hypokalemia, hypomagnesemia

Gastrointestinal: Nausea, diarrhea, abdominal pain

Hematologic: Thrombocytopenia

Hepatic: LFT change

Neuromuscular & skeletal: Rigors

Renal: Elevated creatinine

Respiratory: Dyspnea

Note: Amphotericin B colloidal dispersion has an improved therapeutic index compared to conventional amphotericin B, and has been used safely in patients with amphotericin B-related nephrotoxicity; however, continued decline of renal function has occurred in some patients.

Overdosage/Toxicology

Symptoms of overdose include renal dysfunction, anemia, thrombocytopenia, granulocytopenia, fever, nausea, and vomiting. Treatment is supportive.

Drug Interactions

Increased nephrotoxicity: Aminoglycosides, cyclosporine, other nephrotoxic drugs

Potentiation of hypokalemia: Corticosteroids, corticotropin

Increased digitalis and neuromuscular-blocking agent toxicity due to hypokalemia

Decreased effect: Pharmacologic antagonism may occur with azole antifungal agents (eg, miconazole, ketoconazole)

Pulmonary toxicity has occurred with concomitant administration of amphotericin B and leukocyte transfusions

Stability

Store intact vials under refrigeration.

Reconstitute 50 mg and 100 mg vials with 10 mL and 20 mL of SWI, respectively. The reconstituted vials contain 5 mg/mL of amphotericin B. Shake the vial gently by hand until all solid particles have dissolved. After reconstitution, the solution should be refrigerated at 2°C to 8°C/36°F to 46°F and used within 24 hours.

Further dilute amphotericin B colloidal dispersion with dextrose 5% in water. Concentrations of 0.1-2 mg/mL in dextrose 5% in water are stable for 14 days at 4°C and 23°C if protected from light, however, due to the occasional formation of subvisual particles, solutions should be used within 48 hours.

Incompatible with sodium chloride solutions

Compatibility

Stable in D5W; incompatible with NS

Y-site administration: Compatible: Acyclovir, aminophylline, cefoxitin, ceftizoxime, clindamycin, dexamethasone sodium phosphate, fentanyl, furosemide, ganciclovir, granisetron, hydrocortisone sodium succinate, ifosfamide, lorazepam, mannitol, methotrexate, methylprednisolone sodium succinate, nitroglycerin, sufentanil, trimethoprim/sulfamethoxazole, vinblastine, vincristine, zidovudine. Incompatible: Alfentanil, amikacin, ampicillin, ampicillin/sulbactam, atenolol, aztreonam, bretylium, buprenorphine, butorphanol, calcium chloride, calcium gluconate, carboplatin, cefazolin, cefepime, cefoperazone, ceftazidime, ceftriaxone, chlorpromazine, cimetidine, cisatracurium, cisplatin, cyclophosphamide, cyclosporine, cytarabine, diazepam, digoxin, diphenhydramine, dobutamine, dopamine, doxorubicin, doxorubicin liposome, droperidol, enalaprilat, esmolol, famotidine, fluconazole, fluorouracil, gatifloxacin, gentamicin, haloperidol, heparin, hydromorphone, hydroxyzine, imipenem/cilastatin, labetalol, leucovorin, lidocaine, magnesium sulfate, meperidine, mesna, metoclopramide, metoprolol, metronidazole, midazolam, mitoxantrone, morphine, nalbuphine, naloxone, ofloxacin, ondansetron, paclitaxel, pentobarbital, phenobarbital, phenytoin, piperacillin, piperacillin/tazobactam, potassium chloride, prochlorperazine, promethazine, propranolol, ranitidine, remifentanil, sodium bicarbonate, ticarcillin, ticarcillin/clavulanate, tobramycin, vancomycin, vecuronium, verapamil, vinorelbine

Mechanism of Action

Binds to ergosterol altering cell membrane permeability in susceptible fungi and causing leakage of cell components with subsequent cell death. Proposed mechanism suggests that amphotericin causes an oxidation-dependent stimulation of macrophages (Lyman, 1992).

Pharmacodynamics/Kinetics

Distribution: Vd: Total volume increases with higher doses, reflects increasing uptake by tissues (with 4 mg/kg/day = 4 L/kg); predominantly distributed in the liver; concentrations in kidneys and other tissues are lower than observed with conventional amphotericin B

Half-life elimination: 28-29 hours; prolonged with higher doses

Dosage

Children and Adults: I.V.:

Premedication: For patients who experience chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related immediate reactions, premedicate with the following drugs, 30-60 minutes prior to drug administration: a nonsteroidal (eg, ibuprofen, choline magnesium trisalicylate) with or without diphenhydramine; or acetaminophen with diphenhydramine; or hydrocortisone 50-100 mg. If the patient experiences rigors during the infusion, meperidine may be administered.

Range: 3-4 mg/kg/day (infusion of 1 mg/kg/hour); maximum: 7.5 mg/kg/day

Administration

Avoid injection faster than 1 mg/kg/hour. For a patient who experiences chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related reactions, premedication with the following drugs, 30-60 minutes prior to drug administration: A nonsteroidal (eg, ibuprofen, choline magnesium trisalicylate) with or without diphenhydramine; or acetaminophen with diphenhydramine, or hydrocortisone 50-100 mg. If the patient experiences rigors during the infusion, meperidine may be administered. If severe respiratory distress occurs, the infusion should be immediately discontinued.

Monitoring Parameters

Liver function tests, electrolytes, BUN, Cr, temperature, CBC, I/O, signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes)

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This medication can only be administered by infusion and therapy may last several weeks. Maintain good personal hygiene to reduce spread and recurrence of lesions. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause postural hypotension (use caution when changing from lying or sitting position to standing or when climbing stairs); or nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report chest pain or palpitations; CNS disturbances; skin rash; chills or fever; persistent nausea, vomiting, or abdominal pain; sore throat; excessive fatigue; swelling of extremities or unusual weight gain; respiratory difficulty; pain at infusion site; muscle cramping or weakness; or other adverse reactions. Breast-feeding precaution: Do not breast-feed.

Additional Information

Controlled trials which compare the original formulation of amphotericin B to the newer liposomal formulations (ie, Amphotec®) are lacking. Thus, comparative data discussing differences among the formulations should be interpreted cautiously. Although the risk of nephrotoxicity and infusion-related adverse effects may be less with Amphotec®, the efficacy profiles of Amphotec® and the original amphotericin formulation are comparable. Consequently, Amphotec® should be restricted to those patients who cannot tolerate or fail a standard amphotericin B formulation.

Anesthesia and Critical Care Concerns/Other Considerations

Patients may be premedicated with acetaminophen and diphenhydramine 30 minutes prior to infusion. Meperidine (Demerol®) may help reduce rigors.

Controlled trials which compare the original formulation of amphotericin B to the newer liposomal formulations (ie, Amphotec®) are lacking. Thus, comparative data discussing differences among the formulations should be interpreted cautiously. Although the risk of nephrotoxicity and infusion-related adverse effects may be less with Amphotec®, the efficacy profiles of Amphotec® and the original amphotericin formulation are comparable. Consequently, Amphotec® should be restricted to those patients who can not tolerate or who fail a standard amphotericin B formulation. This product is significantly more expensive than conventional amphotericin B; Infectious Disease consult is recommended.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

May cause bone marrow suppression; use caution with clozapine and carbamazepine

Dosage Forms

Injection, powder for reconstitution: 50 mg, 100 mg

References

Edwards JE Jr, Bodey GP, Bowden RA, et al, "International Conference for the Development of a Consensus on the Management and Prevention of Severe Candidal Infections," Clin Infect Dis , 1997, 25(1):43-59.

Eggimann P, Francioli P, Bille J, et al, "Fluconazole Prophylaxis Prevents Intra-Abdominal Candidiasis in High-Risk Surgical Patients," Crit Care Med , 1999, 27(6):1066-72.0n

Fichtenbaum CJ, Zackin R, Rajicic N, et al, "Amphotericin B Oral Suspension for Fluconazole-Refractory Oral Candidiasis in Persons With HIV Infection. Adult AIDS Clinical Trials Group Study Team 295," AIDS , 2000, 14(7):845-52.

Hiemenz JW and Walsh TJ, "Lipid Formulations of Amphotericin B: Recent Progress and Future Directions," Clin Infect Dis , 1996, 22(Suppl 2):133-44.

Lister J, "Amphotericin B Lipid Complex (Abelcet®) in the Treatment of Invasive Mycoses: The North American Experience," Eur J Haematol Suppl , 1996, 57:18-23.

Lyman CA and Walsh TJ, "Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications," Drugs , 1992, 44(1):9-35.

Mora-Duarte J, Betts R, Rotstein C, et al, "Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis," N Engl J Med , 2002, 347(25):2020-9.

Patel R, "Antifungal Agents. Part I. Amphotericin B Preparations and Flucytosine," Mayo Clin Proc , 1998, 73(12):1205-25.

Prentice HG, Hann IM, Herbrecht R, et al, "A Randomized Comparison of Liposomal Versus Conventional Amphotericin B for the Treatment of Pyrexia of Unknown Origin in Neutropenic Patients," Br J Haematol , 1997, 98(3):711-8.

Rex JH, Bennett JE, Sugar AM, "A Randomized Trial Comparing Fluconazole With Amphotericin B for the Treatment of Candidemia in Patients Without Neutropenia. Candidemia Study Group and the National Institute," N Engl J Med , 1994, 331(20):1325-30.

Rex JH, Pappas PG, Karchmer AW, et al, "A Randomized and Blinded Multicenter Trial of High-Dose Fluconazole Plus Placebo Versus Fluconazole Plus Amphotericin B as Therapy for Candidemia and Its Consequences in Nonneutropenic Subjects," Clin Infect Dis , 2003, 36(10):1221-8.

Rex JH, Walsh TJ, Sobel JD, et al, "Practice Guidelines for the Treatment of Candidiasis. Infectious Diseases Society of America," Clin Infect Dis , 2000, 30(4):662-78.

Slain D, "Lipid-Based Amphotericin B for the Treatment of Fungal Infections," Pharmacotherapy , 1999, 19(3):306-23.

International Brand Names

Amphotec® (CA)

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