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Amphotericin B Cholesteryl Sulfate Complex

Pronunciation

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

Index Terms

  • ABCD
  • Amphotericin B Colloidal Dispersion

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension Reconstituted, Intravenous:

Amphotec: 50 mg (1 ea [DSC]); 100 mg (1 ea [DSC]) [contains edetate disodium, hydrochloric acid, lactose, sodium cholesteryl sulfate, tromethamine]

Brand Names: U.S.

  • Amphotec [DSC]

Pharmacologic Category

  • Antifungal Agent, Parenteral

Pharmacology

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).

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 (Walsh 2008)

Half-Life Elimination

~28 hours; prolonged with higher doses

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

Effective in patients with serious Candida species infections

Contraindications

Hypersensitivity to amphotericin B or any component of the formulation (unless the benefits outweigh the possible risk to the patient)

Dosing: Adult

Note: Lipid-based amphotericin formulations (Amphotec) may be confused with conventional formulations (desoxycholate [Amphocin, Fungizone]). Lipid-based and conventional formulations are not interchangeable and have different dosing recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.

Aspergillosis (invasive), treatment: Usual dosage range: 3-4 mg/kg/day. Note: 6 mg/kg/day has been used for treatment of life-threatening invasive aspergillosis in immunocompromised patients (Bowden, 2002).

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 with or without diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone 50-100 mg with or without a nonsteroidal and diphenhydramine (Paterson, 2008).

Test dose: For patients receiving their first dose in a new treatment course, a small amount (10 mL of the final preparation, containing between 1.6-8.3 mg) infused over 15-30 minutes is recommended. The patient should then be observed for an additional 30 minutes.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment: No dosage adjustment provided in manufacturer’s labeling. However, no pharmacokinetic changes were noted in patients with mild-to-moderate impairment.

Severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied).

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 D5W.

Administration

Initially infuse at 1 mg/kg/hour. Rate of infusion may be increased with subsequent doses as patient tolerance allows (minimum infusion time: 2 hours). 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 with or without diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone 50-100 mg with or without a nonsteroidal and diphenhydramine (Paterson, 2008). If the patient experiences rigors during the infusion, meperidine may be administered. If severe respiratory distress occurs, the infusion should be immediately discontinued.

Compatibility

Stable in D5W; incompatible with NS.

Y-site administration: Incompatible with alfentanil, amikacin, ampicillin, ampicillin/sulbactam, atenolol, aztreonam, buprenorphine, butorphanol, calcium chloride, calcium gluconate, carboplatin, cefazolin, cefepime, ceftazidime, ceftriaxone, chlorpromazine, cimetidine, ciprofloxacin, cisatracurium, cisplatin, cyclophosphamide, cyclosporine, diazepam, digoxin, diphenhydramine, dobutamine, dopamine, doxorubicin, doxorubicin liposome, droperidol, enalaprilat, esmolol, famotidine, fluconazole, fluorouracil, gentamicin, haloperidol, heparin, hydromorphone, hydroxyzine, imipenem/cilastatin, labetalol, leucovorin calcium, lidocaine, magnesium sulfate, meperidine, mesna, metoclopramide, metoprolol, metronidazole, miconazole, midazolam, mitoxantrone, morphine, nalbuphine, naloxone, ondansetron, paclitaxel, pentobarbital, phenobarbital, phenytoin, piperacillin, piperacillin/tazobactam, potassium chloride, prochlorperazine, promethazine, propranolol, ranitidine, remifentanil, sodium bicarbonate, ticarcillin/clavulanate potassium, tobramycin, vancomycin, vecuronium, verapamil, vinorelbine.

Compatibility in syringe: Incompatible with ceftriaxone.

Storage

Store intact vials at 15°C to 30°C (59°F to 86°F). 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 D5W are stable for 24 hours at 2°C to 8°C (36°F to 46°F).

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminoglycosides: Amphotericin B may enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May diminish the therapeutic effect of Amphotericin B. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Cardiac Glycosides: Amphotericin B may enhance the adverse/toxic effect of Cardiac Glycosides. Monitor therapy

Colistimethate: Amphotericin B may enhance the nephrotoxic effect of Colistimethate. Consider therapy modification

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Amphotericin B. Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Amphotericin B. Monitor therapy

CycloSPORINE (Systemic): Amphotericin B may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dronabinol: May increase the serum concentration of Amphotericin B. Specifically, dronabinol may displace amphotericin B from its protein-binding sites, leading to an increased concentration of active, unbound drug. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. 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. Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of Amphotericin B. Avoid combination

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Sodium Stibogluconate: Amphotericin B may enhance the cardiotoxic effect of Sodium Stibogluconate. Consider therapy modification

Adverse Reactions

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.

>10%:

Cardiovascular: Hypotension, tachycardia

Central nervous system: Chills

Endocrine & metabolic: Hypokalemia

Gastrointestinal: Vomiting

Hepatic: Hyperbilirubinemia

Renal: Increased serum creatinine

Miscellaneous: Fever

5% to 10%:

Cardiovascular: Chest pain, facial edema, hypertension

Central nervous system: Abnormality in thinking, drowsiness, headache, insomnia

Dermatologic: Diaphoresis, pruritus, skin rash

Endocrine & metabolic: Hyperglycemia, hypocalcemia, hypomagnesemia, hypophosphatemia

Gastrointestinal: Abdominal pain, diarrhea, enlargement of abdomen, hematemesis, nausea, stomatitis, xerostomia

Hematologic & oncologic: Anemia, hemorrhage, thrombocytopenia

Hepatic: Abnormal hepatic function tests, increased serum alkaline phosphatase, jaundice

Neuromuscular & skeletal: Back pain, muscle rigidity, tremor

Respiratory: Dyspnea, epistaxis, hypoxia, increased cough, rhinitis

<5% (Limited to important or life-threatening): Acidosis, atrial arrhythmia, cardiac arrest, cardiac failure, gastrointestinal hemorrhage, hepatic failure, injection site reaction, oliguria, pain at injection site, pleural effusion, renal failure, seizure, syncope, ventricular arrhythmia

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; the patient should not receive further infusions. During the initial dosing, the drug should be administered under close clinical observation.

• Infusion reactions: Acute infusion reactions, sometimes severe, may occur 1-3 hours after starting infusion. These reactions are usually more common with the first few doses and generally diminish with subsequent doses. Pretreatment with antihistamines/corticosteroids and/or decreasing the rate of infusion can be used to manage reactions. Avoid rapid infusion.

Disease-related concerns:

• Heart failure: In a scientific statement from the American Heart Association, amphotericin has been determined to be an agent that may cause direct myocardial toxicity (magnitude: moderate/major) (AHA [Page 2016]).

Monitoring Parameters

Liver function tests, serum electrolytes (especially potassium and magnesium), BUN, serum creatinine, CBC, prothrombin time; temperature, I/O; signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes)

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Amphotericin crosses the placenta and enters the fetal circulation. Amphotericin B is recommended for the treatment of serious systemic fungal diseases in pregnant women; refer to current guidelines (IDSA [Pappas 2016]; King 1998; Pilmis 2015).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, lack of appetite, weight loss, muscle pain, joint pain, or abdominal pain. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), shortness of breath, chills, severe dizziness, passing out, fast breathing, tachycardia, severe headache, bruising, or bleeding (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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