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Medication Safety Issues
Safety issues:
Lipid-based amphotericin formulations (Amphotec®) may be confused with conventional formulations (Amphocin®, Fungizone®)
Large overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products. Single daily doses of conventional amphotericin formulation never exceed 1.5 mg/kg.
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(am foe TER i sin bee kole LES te ril SUL fate KOM plecks)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
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
B
Lactation
Excretion in breast milk unknown/contraindicated
Breast-Feeding Considerations
Due to limited data, consider discontinuing nursing during therapy.
Contraindications
Hypersensitivity to amphotericin B or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Anaphylaxis: Has been reported with 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.
Special populations:
• Neutropenic patients: 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: Creatinine increased
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.
Drug Interactions
Aminoglycosides: Amphotericin B may enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May diminish the therapeutic effect of Amphotericin B. Risk C: Monitor therapy
Colistimethate: Amphotericin B may enhance the nephrotoxic effect of Colistimethate. Risk D: Consider therapy modification
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Amphotericin B. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Amphotericin B. Risk C: Monitor therapy
CycloSPORINE: Amphotericin B may enhance the nephrotoxic effect of CycloSPORINE. Risk C: Monitor therapy
Flucytosine: Amphotericin B may enhance the adverse/toxic effect of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. Risk C: Monitor therapy
Gallium Nitrate: Amphotericin B may enhance the nephrotoxic effect of Gallium Nitrate. Risk X: Avoid combination
Saccharomyces boulardii: Antifungal Agents may diminish the therapeutic effect of Saccharomyces boulardii. Risk D: Consider therapy modification
Storage
Store intact vials under refrigeration. After reconstitution, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F) and used within 24 hours. 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.
Reconstitution
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. Further dilute amphotericin B colloidal dispersion with dextrose 5% in water.
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
A regimen of 6 mg/kg/day has been used for treatment of life-threatening invasive mold infections in immunocompromised patients; maximum: 7.5 mg/kg/day.
Initially infuse at 1 mg/kg/hour. Rate of infusion may be increased with subsequent doses to 3 mg/kg/hour as patient tolerance allows. Treatment should continue as patient tolerance allows, until complete resolution of microbiologic and clinical evidence of fungal disease.
Administration: I.V.
For a patient who experiences chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related 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. If severe respiratory distress occurs, the infusion should be immediately discontinued.
Administration: I.V. Detail
Avoid injection faster than 1 mg/kg/hour.
Monitoring Parameters
Liver function tests, electrolytes, BUN, Cr, temperature, CBC, I/O, signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes)
Patient Education
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. You will be monitored closely during and after infusion; report immediately any pain or swelling at infusion site, chills, nausea, chest pain, swelling of face or mouth, difficulty breathing, muscle cramping, acute anxiety, or other infusion reactions. Maintain adequate hydration 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; unusual chills or fever; persistent nausea, vomiting, or abdominal pain; sore throat; excessive fatigue; swelling of extremities or unusual weight gain; difficulty breathing; pain at infusion site; muscle cramping or weakness; or other adverse reactions. Breast-feeding precaution: Do not breast-feed.
Geriatric Considerations
The pharmacokinetics and dosing of amphotericin have not been studied in the elderly. It appears that use is similar to young adults. Caution should be exercised and renal function and desired effect monitored closely.
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
Clinical Pearls/Comments:
Prevention of infusion-related reactions: Patients may be premedicated with acetaminophen 650 mg and diphenhydramine 25-50 mg 30 minutes prior to infusion. Hydrocortisone can be used if patient has experienced rigors with amphotericin in the past. Meperidine can also be used for the treatment of rigors during the infusion.
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 B formulation are comparable. Consequently, Amphotec® should be restricted to those patients who cannot tolerate or who fail a standard amphotericin B formulation. This product is significantly more expensive than conventional amphotericin B; infectious diseases 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
Nursing: Physical Assessment/Monitoring
Assess culture and sensitivity report and patient's previous exposure to amphotericin B prior to starting therapy. Assess potential for interactions with other medications patient may be taking (eg, other nephrotoxic drugs). See Administration for specific infusion directions and premedication recommendations prior to administering first dose. Patient should be monitored closely for infusion related reactions (eg, anaphylaxis, chills, fever, nausea, vomiting, rigors, hypotension, acute respiratory distress) and cardiopulmonary resuscitation should be available. If acute respiratory distress occurs, infusion should be stopped and prescriber notified. Assess results of laboratory tests, therapeutic effectiveness, and adverse response (see Adverse Reactions) frequently during therapy. Teach patient possible side effects/appropriate interventions and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Amphotec®: 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.
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, and 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
Lexi-Comp.com
Last full review/revision July 2009
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