I have a patient with cavitary pulmonary histoplasmosis who started treatment with itraconazole per ID for such. Eleven days into treatment, he developed fever, nausea/vomiting, diffuse dermal erythema and pruritus, and some pruritic dermal papules. Itraconazole was stopped. Fever and nausea/vomiting resolved within a couple of days, but dermal pruritus, erythema, and papules persisted and gradually resolved over weeks. No other medications started prior to above symptoms. I'm suspicious this was a delayed hypersensitivity reaction to itraconazole. Patient and his ID physician wish to avoid use of amphotericin B but he requires further treatment for histoplasmosis per ID, and ID is tentatively favoring voriconazole if possible. My questions are: 1) is there any utility to patch testing in this situation and if so is there any protocol for patch testing to azole drugs? and 2) whether patch testing is pursued or not, could a graded oral challenge to an alternative azole such as voriconazole be tried and if so is there a recommended inpatient or outpatient protocol for this given the suspected delayed nature of reaction to itraconazole?


This has been asked and answered in previously in "Ask the Expert". Below is the previous responses"

There are allergic or allergic-like reactions to azole antifungals. I have provided a copy of a prior Ask The Expert questions that you may find of value.

To summarize the information, IgE mediated or IgE-like reactions are very unusual with azoles. There are multiple descriptions of using an alternative azole after a patient suffered an adverse event with another agent, suggesting minimal cross reactivity. However, there are case reports of urticaria and even anaphylaxis from azoles. Percutaneous skin testing has been described with 2mg/ml fluconazole and intradermal testing with 0.2 mg/ml and 0.02 mg/ml. Graded dose challenges are also described with alternative agents in subjects with adverse effects. Desensitization with fluconazole using a 2 mg/ml solution has also been described (Jariwala; Rankin; Takahashi).

Voriconazole Testing and Challenge
Q: 11/26/2014
I am looking for the recommended skin prick/ intradermal test concentrations for voriconazole and alternatives (fluconazole, posaconazole, and ketoconazole) and also a protocol for voriconazole graded oral challenge. Do you happen to know what these are?

A: I was unable to locate a protocol for testing or desensitization/graded challenge for voriconazole but there is some information for fluconazole, which you could possibly adapt. Azole antifungals are rarely associated with hypersensitivity reactions although antifungal therapies are associated with dermatologic systemic lupus-like reactions (Drug Allergy: an updated practice parameter. Ann Allergy Asthma Immunol 2010;205:e1-e78)

A suggested oral desensitization protocol for fluconazole, using a 2mg/ml solution, is provided from Jariwala S, Vernon N, Gabriele de V. A novel method for desensitization for fluconazole hypersensitivity in a patient with AIDS. Ann Allergy Asthma Immunol2011;106:542-543. A more rapid modification is provided in this subsequent reference by some of the same authors (Rankin BT, Jariwala S. Ann Allergy Asthma Immunol 2012;108:466). I could not locate any specific recommendations for testing with fluconazole or voriconazole.

This reference provides a desensitization strategy for fluconazole but does not describe testing (Takahashi, Takashi, et al. "Desensitization to fluconazole in an AIDS patient." Annals of Pharmacotherapy 35.5 (2001): 642-643).

An abstract from another reference (Craig, Timothy J., Francis Peralta, and Jagadish Boggavarapu. "Desensitization for fluconazole hypersensitivity." Journal of Allergy and Clinical Immunology 98.4 (1996): 845-846.)
Fluconazole is an azole antifungal agent. Because it can be taken orally, it is preferred over amphotericin B for long-term treatment. Indications for fluconazole are increasing. Reports of hypersensitivity have been described. If adequate alternative therapy is not available, desensitization may be necessary. Desensitization with fluconazole has not been described. The patient described in this report required fluconazole and was successfully desensitized after manifesting a type 1 hypersensitivity reaction. The patient underwent desensitization during a 15-day period. The starting dose was less than 0.001 dose, with doubling each day. During desensitization, the patient experienced a slight transient rash that resolved with continued therapy. After desensitization, he has continued using fluconazole daily without adverse effects. This report indicates that desensitization to fluconazole can be accomplished safely in selected patients. A suggested desensitization protocol is provided.

A quote from another paper is reassuring in the use of voriconazole in subjects with history of reactions to fluconazole (Pinto, Angie, and Raymond C. Chan. "Lack of allergic cross-reactivity between fluconazole and voriconazole." Antimicrobial Agents and Chemotherapy 53.4 (2009): 1715-1716).

“We conclude from our experience with this case and review of the literature that severe hypersensitivity reactions to fluconazole can occur and that voriconazole can be successfully introduced without cross-sensitization occurring. In addition to documenting a systemic allergic reaction to fluconazole, our case demonstrates successful challenge with another azole. Hence, in situations of azole hypersensitivity, clinicians could consider cautious use of another azole before choosing another class of antifungal agent.”

I have attached a question from the Archives of Ask the Expert related to substituting voriconazole in subject with reaction to fluconazole. This question also provides several references. I have also referred your question to Dr. Marianne Castells at Massachusetts General Hospital as she and her group have extensive experience in testing and desensitizing subjects with drug allergy.

Allergic reaction to fluconazole, substitution with voriconazole
Q: I was recently asked by a GI colleague about a 60 y male patient with esophageal candidiasis who developed hives with fluconazole on two occasions. The rash sounds very much like hives (appear quickly, last less than a day) and not like EM or other rash. No other symptoms. I found a report from the Annals of A, A & I (June 2008) with a skin test protocol and desensitization for fluconazole. I found another abstract (unable to get full report) indicating lack of cross-reactivity between fluconazole and voriconazole, but that looked like it was for non-IgE mediated reactions.

I was going to skin test to fluconazole, use the same protocol for voriconazole (using normal control subjects), and if negative, do a graded challenge or test dose to voriconazole.

A: I think that the protocol you have presented for the safe administration of voriconazole to a patient who has had a potential allergic reaction to fluconazole is appropriate. There are a few "editorial" comments that might be reassuring, and perhaps allow a less labor intensive approach.

First of all, voriconazole, at least in relation to IgE-mediated reactions such as urticaria and anaphylaxis, appears to be an extremely safe drug. I have copied below an abstract for you pertaining to the French experience with voriconazole. As you can see from this abstract, there were essentially no reports of urticaria or anaphylaxis to voriconazole. In addition, a search of PubMed failed to reveal any such reactions, and although cutaneous adverse events have clearly been reported to voriconazole, I could find no clear cut mention of either urticaria or anaphylaxis in the package insert.

Also, I think the article you mentioned, which indicates a lack of cross reactivity between fluconazole and voriconazole, is available in its full content free of charge online. I have copied the reference for you below. It is the Pinto and Chan article. It was published in 2009 online, and you should be able to pull it up quite easily.

You are correct in that the patient they described had a reaction that was not IgE-mediated, and not urticarial. This article is somewhat reassuring in that voriconazole can be substituted for itraconazole with little fear of cross sensitivity. The bibliography in this article also cites other evidence supporting this contention.

In addition, I have copied below an abstract regarding the substitution of voriconazole for another azole, itraconazole, in a case of anaphylaxis to itraconazole. Again, this was accomplished without any difficulty whatsoever.

Thus, there is a small but impressive body of literature that confirms not only the relative safety of voriconazole in regards to IgE-mediated events, but also the ability to substitute this drug for other azoles to which there have been reactions.

The only reason I mention this is to first of all reassure you that your plan to substitute voriconazole is appropriate, but also to let you at least consider another option. This option would be to eliminate the skin test to voriconazole and simply proceed with a careful graded challenge procedure. Another reason to consider this is that I could find no previously published case of urticaria or anaphylaxis to voriconazole, nor could I find any protocol for skin testing that would at least give you suggested concentrations.

Regardless, certainly the more cautious approach that you have suggested has an additional safety measure and is a very good option. But clearly it is quite labor intensive. These are just thoughts. And I do want to emphasize to you that the protocol that you have suggested is certainly an excellent and safe way to proceed.

Antimicrob Agents Chemother. 2009 April; 53(4): 1715–1716. Published online 2009 January 21. doi: 10.1128/AAC.01500-08. PMCID: PMC2663085

Antimicrob Agents Chemother. 2009 April; 53(4): 1715–1716. Published online 2009 January 21. American Society for Microbiology Lack of Allergic Cross-Reactivity between Fluconazole and Voriconazol Angie Pinto and Raymond C. Chan

Ann Pharmacother. 2009 Mar;43(3):537-41. Epub 2009 Mar 3.Appearance of anaphylactic shock after long-term intravenous itraconazole treatment.
Chen J, Song X, Yang P, Wang J.
Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
Objective: To report a rare but severe adverse effect of intravenous itraconazole, anaphylactic shock with hypotension and hypoxemia, in a female patient with acute lymphoblastic leukemia (ALL).
Case Summary: A 36-year-old woman with ALL received antifungal therapy for pulmonary fungal infections. On day 17 of itraconazole treatment, she developed hypotension and hypoxemia shock after intravenous administration of itraconazole 200 mg, which was eventually reversed by steroid treatment. On days 18 and 19, the patient developed the same type of shock 2 more times in the course of itraconazole administration. These 2 episodes of shock occurred more quickly after intravenous itraconazole administration (100 mg on day 18, 40 mg on day 19), and were reversed by stopping itraconazole and applying steroid treatment. In the modified antifungal therapy, intravenous administration of itraconazole was replaced by oral administration of voriconazole 200 mg twice daily. Shock did not recur after discontinuation of itraconazole treatment. The Naranjo probability scale showed a probable relationship between itraconazole treatment and shock occurrence.
Discussion: Itraconazole is a widely used antifungal drugs and is well tolerated. However, long-term itraconazole treatment might lead to serious and even life-threatening adverse effects such as anaphylactic shock, as seen in our patient. T cell reduction caused by immunosuppression and itraconazole accumulation in patients with ALL are considered to be important causal factors for this delayed-type hypersensitivity reaction.
Conclusions: Anaphylactic shock represents a previously undocumented severe adverse effect associated with long-term itraconazole treatment; patients receiving this therapy and should be monitored closely,

Ann Pharmacother. 2007 May;41(5):755-63. Epub 2007 Apr 24.Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database.
Eiden C, Peyrière H, Cociglio M, Djezzar S, Hansel S, Blayac JP, Hillaire-Buys D; Network of the French Pharmacovigilance Centers.
Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital, Montpellier, France.
Background: The most common adverse effects of voriconazole reported during clinical trials were disturbances of vision (30% of pts.), skin rashes (17.3%), and elevations in hepatic enzymes level (approximately 10% of pts.; varying with enzymes). However, postmarketing data concerning safety of voriconazole are limited.
Objective: To describe voriconazole adverse drug effects (ADEs) after 4 years of the drug's availability in France and determine their occurrence.
Methods: All cases of ADEs including voriconazole reported to the French Pharmacovigilance Database between 2002 and 2005 were analyzed. For each case, the following data were recorded: age, sex, indication, concomitant disease, concomitant medications, and ADE description. Causality link between voriconazole and ADEs was performed using the Naranjo probability scale.
Results: A total of 227 ADE cases were reported in 178 adults and 9 children (<12 y), with 66% occurring in males. The patients' median age was 49.6 (2-80) years. ADEs included liver function test abnormalities (23%), visual disturbances (18%), skin rashes (17%), neurologic disturbances (14%), cardiovascular events (10%), hematologic disorders (8%), and renal disturbances (4%). Other less commonly identified ADEs included headache, nausea, vomiting, and diarrhea. Drug-drug interactions were observed in 7 cases. According to the Naranjo criteria, 84% of ADEs were classified as possible, 7% as probable, 5% as highly probable, and 4% as doubtful.
Conclusions: Most ADEs found in this study are well documented in the literature, except for cardiac complications, which are rarely reported. Few ADEs related to drug interactions were observed; however, due to the extensive metabolism of voriconazole by cytochrome P450 isoenzymes, clinicians should be aware of potential interactions between voriconazole and other drugs metabolized through this pathway

Phil Lieberman, M.D.

P.S. Dr Castells has responded. Her comments are as follows:
“Regarding fluconazole reactions there has been few reported cases of IgE mediated reactions but I have seen several cases of urticaria and 2 anaphylactic events and skin testing is routinely done with 2 mg/ml solution for prick and 1/100 and 1/10 for intradermal without irritation for controls and positive test for reactors. Fluconazole tablets contain cellulose, povidone and FD&C dye N. 40 among other ingredients and we have not been able to tease apart which component was the culprit. Desensitization has been done for IgE mediated reactions and the protocol is the same as per our 3 bags 12 steps (Castells, Mariana C., et al. "Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases." Journal of Allergy and Clinical Immunology 122.3 (2008): 574-580.) with success. The protocol provided in the reference in 9 days (see above) is for non IgE-medited reactions and I would not recommended it for this case since it presented with hives. Regarding voriconazole the IV formulation is made in water which is irritant and skin test is difficult to interpret and has not been published. The mechanism of Type IV mediated reactions relies on antigen recognition by the TCR and is not cross-reactive for fluconazole and voriconazole and other azoles but IgE mediated reactions depend of epitopes which can be shared by different azoles. In this particular case if skin test is positive desensitization with an IV formulation of fluconazole would be recommended and should be very safe. If skin test is negative a challenge with voriconzole, which tablets have a different content than fluconazole, should be attempted at 1/10, 1/4, 1/2 and the rest of the tablet at 30 min intervals.”

Dr. Castells refers to the “9 days” schedule which is mentioned in one of the references but the table above is for 60 hours. The authors describe a reaction that was urticarial and acute in onset, suggesting IgE mediated reaction. The same authors describe a protocol with dosing every 3 hours and reach therapeutic dose within 36 hours.

All my best.

Dennis K. Ledford, MD, FAAAAI

Skin test to fluconazole
Q: 2/24/2014
Is there a reliable test for identifying an allergy to Diflucan? The patient states she had lip swelling 12-16 hours after use.

A: I am not aware of any validated skin test protocol to fluconazole nor could I find such in the literature. However, there is a published graded challenge test to fluconazole. This graded challenge was performed without significant adverse event. You can find the protocol in Rankin B and Jariwala S. Annals of Allergy, Asthma, and Immunology 2012; 108:466.

Thank you again for your inquiry and we hope this response is helpful to you.

Andrew Murphy, MD, FAAAAI


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