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Vitrase® Fun Facts James Lewin, PharmD Postdoctoral Fellow/Vitrase Lead “Fun Fact”: The Warnings and

Precautions section of the Vitrase® (hyaluronidase) package insert states “Hyaluronidase should not be used to reduce the swelling of bites or stings.” Contrary to some clinicians’ beliefs, this warning is not related to the risk of cross-reactivity to the hyaluronidase in bee venom, but rather to the fact that Vitrase, via its mechanism of action, poses a threat of spreading a localized infection. 1,2 Sample Case Study: A physician wants to use Vitrase in a patient who has a documented allergy to bee stings. She is seeking your advice because her colleague stated that Vitrase is contraindicated in patients who are allergic to bees. Background info: Hyaluronidase is one of at least eight biologically active components in honeybee venom (honeybee will be referred to as “bee” for the remainder of the article) and is one of the major allergens found in the venom.3 The amino acid sequence (also called the primary structure) of bee venom hyaluronidase is very different from that of mammalian, testicular hyaluronidase: researchers did not discover that the two enzymes were even related until technology allowed for identification of crystalline structures, which showed the 3-dimensional configuration of the proteins.4,5 Although the crystalline structure showed that bee venom hyaluronidase has the same critical amino acids in the active site of the enzyme, immunological cross-reactivity depends primarily on the amino acid sequence.5 In an effort to better understand the extent of the differences between bee venom and mammalian hyaluronidase, I spoke to ISTA’s Vitrase expert, Bruce Aird (Principal Scientist, Research & Development). Bruce stated that if you run a homology-checking program to compare the amino acid sequences of the bee venom and mammalian, testicular hyaluronidase, it comes back showing very little relationship. Of note, data have not been published regarding these sequence homology comparisons when using ovine-based hyaluronidase as the mammalian enzyme source; therefore, Bruce and I compared the amino acid sequences of ovine, testicular hyaluronidase and bee venom hyaluronidase to gauge the degree of similarity between their respective identities. When the immune system detects a foreign protein, it clips the protein into very small sequences that contain no more than eight amino acid residues. Antibodies learn to recognize these sequences as antigens, and if the antigen is reintroduced, the antibodies will promote an immune response against it. We determined that ovine and bee venom hyaluronidase enzymes share only 27.7% direct identity in their amino acid sequences. There are four stretches of sequence with enough direct identity to have an impact immunologically — meaning that about 5% of the actual sequence might generate a common immune-reactive peptide for antigen presentation; thus, albeit improbable, there is a slight chance that cross-reactivity could occur. There are no known cases of cross-reactivity between these two enzymes per a literature search via multiple databases: PubMed, Embase, Ovid/Medline, and International Pharmaceutical Abstracts. Recommendation to clinician:  Consult with the physician: (1) discuss the relationship, or lack thereof, between the structures of ovine, testicular hyaluronidase and bee venom hyaluronidase; (2) inform the clinician that the

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patient does not have a known hypersensitivity specifically to hyaluronidase; there are other bee venom components, such as phospholipase A2 and acid phosphatase, that could be the source of the patient’s hypersensitivity reactions.3 If the clinician decides to move forward with the use of Vitrase: strongly recommend performing a preliminary skin test. Provide a copy of the package insert and direct the physician to the “Laboratory Tests” section: The skin test is performed by injecting approximately 0.02 mL (4 Units) of a 200 Unit/mL solution of Vitrase intradermally. A positive reaction consists of a wheal with pseudopods appearing within 5 minutes and persisting for 20 to 30 minutes, accompanied by localized itching. Transient vasodilation at the site of the test does not constitute a positive reaction.1 If the patient has a positive reaction to the skin test: Vitrase and other hyaluronidase formulations are contraindicated.1

The author would like to acknowledge Bruce Aird (Principal Scientist, Research & Development) for assisting with the development of this report. References: 1. Vitrase [package insert]. Irvine, CA: ISTA Pharmaceuticals, Inc; 2004. 2. Lee A, Grummer SE, Kriegel D, et al. Hyaluronidase. Dermatol Surg. 2010;36:1071-1077. 3. Peiren N, de Graaf DC, Evans JD, et al. Genomic and transcriptional analysis of protein heterogeneity of the honeybee venom allergen Api m 6. Insect Mol Biol. 2006;15(5):577-581. 4. Gmachl M, Kreil G. Bee venom hyaluronidase is homologous to a membrane protein of mammalian sperm. Proc Natl Acad Sci. 1993;90:3569-3573. 5. Markovic´-Housley Z, Miglierini G, Soldatova L, et al. Crystal Structure of Hyaluronidase, a Major Allergen of Bee Venom. Structure. 2000;8:1025-1035.