Hyaluronidase


Article Author:
Rachel Gilson


Article Editor:
Anoosh Zafar Gondal


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


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Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
9/15/2019 3:51:38 PM

Indications

Many patients with chronic diseases require injections as part of their prolonged medical therapy. Hyaluronidase has been shown to enhance the systemic delivery of injectable medications and provide better treatment outcomes for these patients. Examples of current medications being using in combination with hyaluronidase include, but are not limited to: insulin in diabetes, beta interferons in multiple sclerosis, biotherapeutics in rheumatoid arthritis, immunoglobulin replacement therapy in primary immunodeficiencies, and monoclonal antibodies in cancer treatment.[1] Hyaluronidase is currently used for several other types of medical management as well. 

FDA approved indications[1][2][3][4][5][4]:

  • Absorption and dispersion enhancer of injected drugs
  • Subcutaneous fluid administration for hydration therapy - hypodermoclysis
  • Subcutaneous urography to improve absorption of radiopaque agents 

Non-FDA approved uses[6][7][2][8][9][8][2]:

  • Extravasation of medications from intravenous lines management
  • Adjunct to local anesthetic eye blocks for ophthalmic surgery
  • Keloid scar treatment – involves cryosurgery followed by injections with hyaluronidase, triamcinolone, and 5-fluorouracil
  • Reversing cosmetic facial fillers composed of hyaluronic acid

Hyaluronidase is an enzyme that degrades the glycosaminoglycan hyaluronan, more commonly known as hyaluronic acid. Hyaluronic acid is a component of the extracellular matrix that absorbs water and has a gel-like consistency.[3] The structure of hyaluronic acid impedes fluid movement and reduces the volume of injectable drugs into the subcutaneous space. Hyaluronidase is a natural enzyme that catalyzes the degradation of hyaluronic acid through depolymerization.[3]

Recombinant human hyaluronidase (rHuPH20) has been manufactured for therapeutic administration through subcutaneous injections.[1][8] When this enzyme is co-administered with other biotherapeutics such as insulin, immunoglobulins, or chemotherapy agents, it has been shown to increase the target drug bioavailability by breaking down hyaluronic acid in the interstitial space and allowing dispersion of the medication.[1] The time to reach Cmax decreases when hyaluronidase is co-administered with the target drug, which means that the medication is better absorbed and enters systemic circulation at a faster rate with the aid of hyaluronic acid degradation.[1] Recombinant human hyaluronidase (rHuPH20) has been used to increase the volume of infusion, reduce the frequency of infusions, and decrease the number of infusion sites of injectable pharmaceuticals.[3]

Mechanism of Action

Hyaluronic acid is a glycosaminoglycan that contributes to the extracellular matrix of connective tissues. It is a large, viscous, and hygroscopic molecule that blocks the flow of fluids entering the vasculature from a subcutaneous space.[3] Hyaluronic acid is a linear polymer made of thousands of simple disaccharides stacked on one another, which contributes to the hydrophilic properties of the molecule.[10][2] Hyaluronic acid has a relatively short half-life of 15 to 20 hours. Hyaluronidase is an enzyme that temporarily and reversibly depolymerizes hyaluronic acid; this creates microchannels in the interstitial matrix that allows fluids to flow through. Recombinant human hyaluronidase is specific for cleaving the beta 1-4 linkage of the glycosaminoglycan.[3]

Administration

Typical administration of hyaluronidase is via subcutaneous injection with doses ranging from 50 to 300 units/mL.[3] When using this enzyme to enhance the dispersion of another pharmaceutical agent, the administration is possible in one of two ways. It may be injected first into the subcutaneous tissue, and then the second agent may be injected sequentially with the same needle. Or it may be co-administered with the other agent in a single injection.[1] There have been studies conducted with injecting pegylated recombinant human hyaluronidase (PEGPH20) directly into a tumor with the attempts to degrade the local hyaluronic acid and improve cytotoxic agent delivery.[8]

Adverse Effects

The most frequently encountered adverse effects are injection site reaction, headache, fatigue, nausea, and fever. Severe reactions can include hypersensitivity reactions, anaphylaxis, hyperviscosity, and thromboembolism. Recombinant human hyaluronidase comes with a black box warning of thrombosis. Risk factors for precipitating thrombosis are hypercoagulable conditions, prolonged immobilization, advanced age, and cardiovascular disease. It is essential to hydrate adequately before administering the dose to prevent these adverse reactions.

Animal-derived hyaluronidase is immunogenic and may cause allergic reactions. Human recombinant hyaluronidase (rHuPH20) is better tolerated and is less likely to cause an allergic reaction. Approximately 6% of the population have anti-rHuPH20 antibodies that are non-neutralizing and have no clinically significant consequences.[3]

There is insufficient data available to assess fetal risk in pregnancy, nor is there human data available to evaluate the effects on milk production in lactating mothers. It is essential to weigh the risks versus benefits when prescribing to pregnant or breastfeeding women.

Contraindications

Contraindications to this medication include hypersensitivity to this drug class or components of the injection. Caution is necessary when administering this drug to someone who is at increased risk for thrombosis.

Monitoring

It is essential to document location and monitor the injection site for acute changes. It is also recommended to monitor renal function and vital signs during the infusion.

Toxicity

Toxicity due to hyaluronidase is rare. If the enzyme gets injected intravenously, it immediately degrades, and enzymatic activity halts. Tissue inflammation may result from local hyaluronidase toxicity. [11] The most feared complications of hyaluronidase therapy are thrombosis or a hypersensitivity reaction, immediately discontinue the medication if either one of these occurs. 

Enhancing Healthcare Team Outcomes

Prescribing clinicians should recognize the benefit of using hyaluronidase in certain medical conditions. They should collaborate with the pharmacist to achieve an appropriate dose and method of administration. It is essential that hyaluronidase is administered by a medical professional and that patients undergo monitoring for serious complications. Patients must be adequately hydrated before dosage administration and monitored for signs of thrombosis, anaphylaxis, and injection site reaction. If hyaluronidase use is in the inpatient setting, the nursing staff monitors patient vital signs and assesses for any acute changes.

When using hyaluronidase for labeled indications, health care providers should know that it is ineffective to deliver the medication intravenously. This enzyme rapidly degrades in the bloodstream, and the beneficial effects terminate. Also, the person administering the subcutaneous injection (typically nursing) should examine the injection site and note that it is clear of any infections. The administration of hyaluronidase in inflamed or infected tissues could precipitate the spread of the local infection.

Communication is key between the patient and all healthcare providers. Nurses should note any changes in the patient's health status and notify the attending physician. Nursing will also almost always have the task of administering the medications. The patient should also receive instruction on drug delivery methods, and possible adverse reactions should they be able to administer self-injections at home.

The adjuvant therapy of adding hyaluronidase with injectable medications has improved the efficacy of many treatments. Pharmacists should consult with the prescribing/ordering clinician regarding potential dose adjustments, as well as performing their usual function of checking doses and performing medication reconciliation. Patients require smaller dosages of their medications and can receive less frequent injections due to better systemic absorption, which contributes to overall improved patient compliance and satisfaction with treatment.[1]  But as can be seen above, an interprofessional approach involving the physicians, nursing staff, and pharmacist are necessary to optimize the use of hyaluronidase and achieve optimal results. [Level V]


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Hyaluronidase - Questions

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A 17-year-old male is admitted to the emergency department for diabetic ketoacidosis. He is started on insulin therapy and administered a dextrose solution intravenously. Several hours after admission, the patient is complaining of excruciating pain in his antecubital fossa around the intravenous site. Physical examination reveals the skin around the intravenous line has become violaceous with a mottled appearance. Which of the following drugs may help prevent tissue necrosis caused by the extravasation of concentrated dextrose solution?



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A 63-year-old female presents to the emergency department 30 minutes after receiving cosmetic injectable fillers at her dermatologist's office. She reports increasing facial pain on the left. Physical exam reveals a reticulate, violaceous discoloration of the skin overlying her left zygoma with extreme tenderness to palpation. In addition to gentle massage, heat, and nitroglycerin paste, what is the next best step in the management of this patient?



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A 6-year-old male presents to the emergency department with a 4-day history of nausea, vomiting, and diarrhea. He is lethargic but still responsive to questions asked. Physical exam reveals sunken eyes, cracked lips, and decreased skin turgor. Attempts made to establish peripheral intravenous access are unsuccessful. The decision is made to initiate subcutaneous hydration. What is the mechanism of action of the medication used to facilitate faster absorption of the injected fluids?



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A female with multiple sclerosis has been receiving beta interferon injections for the last two years. Despite treatment, she continues to have relapsing and remitting flare-ups of her disease. The reason seems to be that the systemic concentration of her medication is not reaching a therapeutic level. A decision is made to add a new medication to her current regiment that will aid in the uptake of beta interferon. What is the preferred delivery method for this new medication?



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A 65-year-old male is undergoing a novel treatment for pancreatic adenocarcinoma. His specialist is injecting hyaluronidase directly into the pancreatic tumor in order to achieve better uptake of the chemotherapy in the cancer cells. Within minutes of administration of the hyaluronidase, the patient becomes diaphoretic, begins wheezing, and his blood pressure drops to 86/50 mmHg, while his heart rate is measured at 140/min. What is the next best step in the management of this patient?



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Hyaluronidase - References

References

Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities., Bittner B,Richter W,Schmidt J,, BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy, 2018 Jul 24     [PubMed]
Hyaluronidases: A Therapeutic Enzyme., Khan N,Niazi ZR,Rehman F,Akhtar A,Khan MM,Khan S,Khan S,, Protein and peptide letters, 2018 Jun 29     [PubMed]
Use of hyaluronidase as an adjunct to local anaesthetic eye blocks to reduce intraoperative pain in adults., Rüschen H,Aravinth K,Bunce C,Bokre D,, The Cochrane database of systematic reviews, 2018 Mar 2     [PubMed]
Recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin infusion in primary immunodeficiency diseases., Wasserman RL,, Immunotherapy, 2017 Sep     [PubMed]
Targeting the Tumor Stroma: the Biology and Clinical Development of Pegylated Recombinant Human Hyaluronidase (PEGPH20)., Wong KM,Horton KJ,Coveler AL,Hingorani SR,Harris WP,, Current oncology reports, 2017 Jul     [PubMed]
Eisert L,Nast A, Treatment of extensive, recalcitrant keloids using a combination of intralesional cryosurgery, triamcinolone, 5-fluorouracil and hyaluronidase. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2019 May 27;     [PubMed]
Spandorfer PR,Mace SE,Okada PJ,Simon HK,Allen CH,Spiro DM,Friend K,Harb G,Lebel F, A randomized clinical trial of recombinant human hyaluronidase-facilitated subcutaneous versus intravenous rehydration in mild to moderately dehydrated children in the emergency department. Clinical therapeutics. 2012 Nov;     [PubMed]
Maytin EV, Hyaluronan: More than just a wrinkle filler. Glycobiology. 2016 Jun;     [PubMed]
Juhász MLW,Levin MK,Marmur ES, The Kinetics of Reversible Hyaluronic Acid Filler Injection Treated With Hyaluronidase. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2017 Jun;     [PubMed]
Zamora-Alejo K,Moore S,Leatherbarrow B,Norris JH,Lake DB,Malhotra R,Selva D,Goggin M, Hyaluronidase toxicity: a possible cause of postoperative periorbital inflammation. Clinical     [PubMed]
Corbett M,Marshall D,Harden M,Oddie S,Phillips R,McGuire W, Treating extravasation injuries in infants and young children: a scoping review and survey of UK NHS practice. BMC pediatrics. 2019 Jan 7;     [PubMed]

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