How often do patients receiving Ambisome experience anaphylaxis? Is it common to pre-medicate patients with diphenhydramine? Are there other adverse effects the diphenhydramine is mitigating? (References state MAY pre-medicate with acetaminophen and/or diphenhydramine; traditional amphotericin B had much more adverse effects. We are questioning if patients need to receive pre-medication with diphenhydramine due to its adverse effects and low risk of anaphylaxis).

Comment by InpharmD Researcher

While anaphylaxis with liposomal amphotericin B (Ambisome) is rare, infusion-related reactions such as chest pain, dyspnea, flushing, and urticaria can occur in about 20% of patients (with one study reporting rates from 0 to 100%), typically within the first few minutes of infusion. These reactions are often linked to complement activation from the liposomal carrier than the drug itself and usually respond to temporarily stopping the infusion and giving diphenhydramine. While diphenhydramine can help reduce histamine-mediated effects like flushing or hives, its routine use as premedication is supported by limited evidence and is not specifically recommended for all patients receiving Ambisome. More comprehensive premedication strategies are generally reserved for conventional amphotericin B in those with prior severe infusion reactions.

Background

Lipid formulations of amphotericin B demonstrate reduced acute and chronic toxicity compared to conventional amphotericin B deoxycholate. However, in approximately 20% of cases (range, 0%–100%), these formulations can still trigger acute, infusion-related reactions. These reactions include symptoms such as chest pain, dyspnea, hypoxia, severe pain in the abdomen, flank, or legs, flushing, and urticaria. Notably, when compared to infusion reactions associated with conventional amphotericin B, a significant majority (85%) of the reactions to lipid formulations occur within the first five minutes of infusion and can be rapidly resolved by temporarily halting the infusion and administering intravenous diphenhydramine. The data suggested that these reactions were more likely attributed to the liposomal formulation rather than the drug itself, possibly due to complement activation. The practice of premedicating with diphenhydramine has been found effective in reducing the incidence of these acute reactions. The available evidence suggests that while liposomal amphotericin B is a valuable therapeutic option, it is essential to be vigilant for these reactions, particularly during the initial infusion. [1], [2]

A guideline developed by the National Institutes of Health, the HIV Medicine Association, and the Infectious Diseases Society of America discussed the prevention and treatment of opportunistic infections in adults and adolescents with HIV. The panel states that patients treated with liposomal amphotericin B should be monitored vigilantly for dose-dependent nephrotoxicity, electrolyte disturbances, and infusion-related adverse reactions, which are classified as a strong recommendation with moderate quality evidence (AII). Infusion-related adverse events might be reduced by pre-treatment with acetaminophen or diphenhydramine, although this recommendation carries a weaker evidence base (CIII). To mitigate the risk of glomerular function decline, administering 1 liter of saline an hour before the drug infusion is advised, backed by moderate evidence (BIII). Notably, liposomal or lipid-associated formulations of amphotericin B are associated with a lower incidence of nephrotoxicity compared to amphotericin B deoxycholate. [3]

While the guidelines highlight the need for close monitoring of nephrotoxicity and electrolyte disturbances with all amphotericin B formulations, specific premedication strategies are primarily recommended for traditional amphotericin B in patients with a history of severe infusion-related reactions. These include administering 500–1,000 mL of normal saline before infusion to reduce nephrotoxicity, as well as pre-treatment with acetaminophen (650 mg) and diphenhydramine (25–50 mg) or hydrocortisone (50–100 mg) given 30 minutes before infusion to help mitigate infusion-related adverse effects. Meperidine (25–50 mg), titrated during infusion, is also suggested after the first occurrence of rigors to help prevent recurrence. In contrast, the same premedication recommendations are not explicitly provided for liposomal amphotericin B. [3]

A 2021 narrative review explores the infusion-related adverse effects (IRAEs) associated with amphotericin B, focusing on the utility of pre-medications to prevent such reactions. The review assessed the effects of different formulations, such as amphotericin B deoxycholate and lipid-based formulations, on IRAEs, finding that while pre-medications are common, their routine use may not be warranted as IRAEs occur even among patients receiving these preventive treatments. In comparing amphotericin B deoxycholate to lipid-based formulations, the review noted that the lipid formulations might present a lower or similar risk for IRAEs. The investigation into pre-medications revealed no consistent benefit in preventing these reactions, with instances of IRAEs reported regardless of their use. The review highlighted that different pre-medication regimens (e.g., acetaminophen, diphenhydramine, and corticosteroids) were often employed without a significant reduction in IRAEs. Furthermore, studies comparing infusion rates concluded that shorter infusion times did not significantly escalate the risk of IRAEs but might lead to a swifter onset of such events. Overall, the review suggests reevaluating the necessity of routine pre-medications, given the occurrence of IRAEs across different amphotericin B formulations and treatment protocols. [4]

Relevant Prescribing Information

Warnings [1]
Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including AmBisome. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of AmBisome.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

How often do patients receiving Ambisome experience anaphylaxis? Is it common to pre-medicate patients with diphenhydramine? Are there other adverse effects the diphenhydramine is mitigating?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-2 for your response.

Immediate hypersensitivity reaction following liposomal amphotericin-B (AmBisome) infusion
Design	Case series
Case 1	A 43-year-old man from Bangladesh presented with prolonged fever, anorexia, and progressive weight loss, and was diagnosed with kala-azar (visceral leishmaniasis) confirmed by a positive Rk-39 test and LD bodies on splenic aspirate. He had moderate anemia and an enlarged spleen. Initial treatment with intravenous AmBisome (5 mg/kg daily for 3 days) was started. After a test dose was uneventfully tolerated, the first full dose was administered without issue. However, during the second infusion, the patient developed a severe adverse reaction characterized by restlessness, shortness of breath, hypotension (60/20 mmHg), and tachycardia. Immediate cessation of AmBisome and administration of intramuscular adrenaline, intravenous diphenhydramine, and hydrocortisone resolved his symptoms within 20 minutes. Despite prophylactic treatment with diphenhydramine and hydrocortisone, a subsequent attempt to administer AmBisome resulted in a similar reaction. Consequently, oral miltefosine was used instead, successfully treating his leishmaniasis over a 28-day course.
Case 2	An 11-year-old girl was admitted with a 3-month history of fever, anorexia, and weight loss. She presented with a fever of 38°C and an enlarged spleen palpable at 4 cm below the costal margin. Laboratory investigations showed severe anemia with a hemoglobin level of 4.8 g/dL. A diagnosis of kala-azar was confirmed by the presence of positive Leishman-Donovan bodies in a splenic aspirate. She had no history of allergic reactions to any drugs. She received three units of whole blood, which increased her hemoglobin to 7.8 g/dL. Her blood pressure was initially low at 90/70 mmHg, with a heart rate of 90/min and a respiratory rate of 20/min. Treatment was initiated with intravenous AmBisome (liposomal amphotericin B). During the test dose of AmBisome, she developed chills, rigors, facial flushing, puffiness, chest tightness, and respiratory distress. These symptoms were promptly managed with intravenous antihistamines and hydrocortisone.
Study Author Conclusions	In our experience, AmBisome can cause severe hypersensitivity reactions that warrant proper support and close supervision.

References:

Nath P, Basher A, Harada M, et al. Immediate hypersensitivity reaction following liposomal amphotericin-B (AmBisome) infusion. Trop Doct. 2014;44(4):241-242. doi:10.1177/0049475514543655

Asystolic Cardiac Arrest following Liposomal Amphotericin B Infusion: Anaphylaxis or Compliment Activation-Related Pseudoallergy?
Design	Case report
Case presentation	A 64-year-old patient presented with a 2-week history of headache, photophobia, vomiting, confusion, and a diffuse rash, with serological evidence supporting diagnoses of neurosyphilis and possible cryptococcal meningitis. She was initiated on intravenous benzylpenicillin, liposomal amphotericin B (LAmB; AmBisome®) at 4 mg/kg/day, and flucytosine. Five minutes after completing the initial LAmB infusion (320 mg over one hour), the patient developed lightheadedness, paraesthesia, bradycardia (heart rate 20 bpm), and progressed to asystolic cardiac arrest, requiring CPR and two doses of intravenous adrenaline. She achieved return of spontaneous circulation, was intubated, and recovered without neurological deficit. Serial tryptase levels supported mast cell activation. Skin prick and intradermal testing to LAmB were negative at lower concentrations, and testing at higher concentrations was declined. This case illustrates a rare, severe hypersensitivity reaction to LAmB, raising diagnostic consideration of IgE-mediated anaphylaxis or complement activation-related pseudoallergy (CARPA). Such reactions to LAmB are uncommon, and literature review identifies few reports of anaphylaxis or cardiac toxicity. Diphenhydramine premedication is not universally standard but may be employed selectively, particularly in patients at risk of infusion-related symptoms; however, its role in mitigating severe reactions such as those described remains unclear and requires further investigation.
Study Author Conclusions	To our knowledge, this is the first published occurrence of skin prick and intradermal testing for LAmB allergy. However, whilst SPT (at 1:10 concentration) and IDT was performed at up to 1:100 concentration, maximal non-irritating concentrations are unknown. Clinicians should be aware of the potential for either IgE or non-IgE mediated mast cell reactions in the setting of LAmB, and further research is required into the immunopathogenesis of these reactions.

References:

Drewett GP, Copaescu A, DeLuca J, Holmes NE, Trubiano JA. Asystolic cardiac arrest following liposomal amphotericin B infusion: anaphylaxis or compliment activation-related pseudoallergy?. Allergy Asthma Clin Immunol. 2021;17(1):80. Published 2021 Jul 29. doi:10.1186/s13223-021-00582-x