Hyaluronidase

Mechanism of Action

Hyaluronidase is an enzyme that degrades hyaluronic acid, a glycosaminoglycan component of the extracellular matrix that contributes to tissue viscosity and resists fluid dispersion. Hyaluronic acid is a large, hygroscopic, linear polymer composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine.[2][18] Hyaluronidase temporarily and reversibly depolymerizes hyaluronic acid, thereby reducing extracellular matrix viscosity and increasing tissue permeability, which facilitates the dispersion and absorption of injected fluids and medications. Recombinant human hyaluronidase cleaves β-1,4 glycosidic linkages between N-acetylglucosamine and glucuronic acid residues.[3]

rHuPH20 formulations are available for therapeutic administration through subcutaneous injections.[1][9] When this enzyme is coadministered with other biotherapeutics such as insulin, immunoglobulins, or chemotherapy agents, it increases the bioavailability of the target drug by degrading hyaluronic acid in the interstitial space and facilitating the dispersion of the medication.[1] The time to reach Cmax decreases when hyaluronidase is coadministered with the target drug, indicating improved absorption and faster entry into systemic circulation due to hyaluronic acid degradation.[1] rHuPH20 has been used to increase infusion volume, reduce infusion frequency, and decrease the number of infusion sites for injectable pharmaceuticals.[3]

Administration

Hyaluronidase is available under the brand names Amphadase (derived from bovine testicle) and Hylenex (recombinant, preservative-free), both at 150 USP units/mL, in single-dose vials. Vitrase (derived from ovine testicle, preservative-free) is supplied as a sterile, clear, and colorless solution containing 200 USP units/mL in a single-dose glass vial with a rubber stopper and aluminum seal. Unopened vials should be stored in a refrigerator at 2 °C to 8 °C (36 °F to 46 °F). Any unused portion should be discarded. 

Typically, hyaluronidase is administered subcutaneously at doses ranging from 50 to 300 units.[3] When using this enzyme to enhance the dispersion of another pharmaceutical agent, the agent can be administered in one of two ways. Hyaluronidase may be injected first into the subcutaneous tissue, followed by sequential injection of the second agent using the same needle. Alternatively, hyaluronidase may be coadministered with the other agent in a single injection.[1] Studies have been conducted in which pegylated recombinant human hyaluronidase (PEGPH20) was injected directly into tumors to degrade local hyaluronic acid and improve delivery of cytotoxic agents.[9]

• Subcutaneous fluid administration: Insert the needle using aseptic technique. Ensure that the tip is positioned freely between the skin and the muscle before initiating clysis. The fluid should flow readily without causing pain or forming a lump. Inject hyaluronidase into the rubber tubing near the needle. For subcutaneous fluid administration, 150 units of Hylenex, 150 units of Amphadase, or 200 units of Vitrase should be administered prior to hypodermoclysis to facilitate the absorption of 1000 mL or more of fluid. The total volume of subcutaneous fluids should be individualized based on the patient’s age, body weight, clinical status, and relevant laboratory parameters. The rate and volume of administration should not exceed those recommended for intravenous infusion.

• Absorption and dispersion of injected drugs: The absorption and dispersion of other injected drugs can be enhanced by adding 50 to 300 units of hyaluronidase (most commonly 150 units) to the injection solution. 

• Subcutaneous urography: Use the subcutaneous route to administer urographic contrast media when intravenous access is not feasible, especially in infants and small children. With the patient in the prone position, inject 75 units of hyaluronidase subcutaneously over each scapula, then administer the contrast medium at the same sites.

Specific Patient Populations

Pregnancy considerations: Available data are insufficient to assess fetal risk. Clinicians should weigh the potential risks and benefits when prescribing hyaluronidase during pregnancy. Hyaluronidase has been used to facilitate in vitro fertilization of human oocytes. Administration during labor has not been associated with complications, and studies have reported no increase in blood loss or differences in cervical trauma.

Breastfeeding considerations: No human data are available to evaluate the effects of hyaluronidase on milk production in lactating mothers. Clinicians should weigh the potential risks and benefits when prescribing hyaluronidase to breastfeeding women.

Pediatric patients: The dosage of subcutaneous fluids should be determined based on the patient's age, weight, and clinical condition. For premature infants or neonates, the daily dose should not exceed 25 mL/kg body weight, and the administration rate should remain below 2 mL/min. Carefully monitor pediatric patients to prevent overhydration by controlling both the infusion rate and total volume. 

Older patients: No overall differences in safety or effectiveness have been identified between younger adult patients and geriatric patients.

Adverse Effects

Hyaluronidase may increase the risk of adverse reactions when used with other drugs. Edema is the most frequently reported adverse effect associated with hypodermoclysis. Other reported adverse effects include injection site reactions, headache, fatigue, nausea, and fever. Severe adverse reactions include hypersensitivity reactions, anaphylaxis, hyperviscosity, and thromboembolism. Recombinant human hyaluronidase carries a boxed warning for thrombosis. Risk factors for precipitating thrombosis include hypercoagulable conditions, prolonged immobilization, advanced age, and cardiovascular disease. Adequate hydration before administration is recommended to reduce the risk of these adverse reactions. 

Animal-derived hyaluronidase is immunogenic and may cause allergic reactions. rHuPH20 is better tolerated and is less likely to cause an allergic reaction. Approximately 6% of the population has anti-rHuPH20 antibodies that are non-neutralizing and not associated with clinically significant consequences.[3] Accumulating evidence from clinical trials and postmarketing surveillance indicates that rHuPH20 acts locally, with no detectable systemic absorption, and demonstrates a favorable tolerability profile across diverse populations, including pediatric, geriatric, and pregnant patients. Available data further suggest a low immunogenic potential, as treatment-emergent antibodies have not been associated with clinically significant adverse outcomes.[19]

Despite this reassuring safety profile, hypersensitivity reactions remain an important consideration. A 2024 systematic review involving 106 patients identified prior hyaluronidase exposure and sensitization through insect or wasp venom as potential risk factors for the development of allergic responses. Overall, reported allergy rates are low, occurring in fewer than 0.1% of treated individuals, although rare cases of anaphylaxis have been described, particularly following retrobulbar or intravenous administration. In most instances, prompt management with systemic corticosteroids, with or without antihistamines, leads to rapid and complete resolution of symptoms.[20]

Drug-Drug Interactions

• Local anesthetics: Hyaluronidase accelerates the onset and shortens the duration of effect, and may increase the incidence of systemic reactions.

• Adrenocorticotropic hormone, cortisone, estrogens, salicylates, or antihistamines: Large doses may require greater amounts of hyaluronidase to achieve an equivalent dispersing effect, as these medicines apparently render tissues partly resistant to hyaluronidase's action.

• Incompatibilities: Admixture stability studies have shown that hyaluronidase is incompatible with 2% lidocaine containing 1:100,000 or 1:200,000 epinephrine due to the presence of sodium metabisulfite, a common additive in epinephrine-containing anesthetic products.

• General precautions: When administering any other drug with hyaluronidase, clinicians should consult appropriate references to determine the standard precautions for the concomitant drug. For example, if epinephrine is administered with hyaluronidase, all standard precautions for epinephrine should be observed, particularly in patients with digital nerve block, cardiovascular disease, diabetes, thyroid disease, or ischemia of the fingers or toes.

Contraindications

Contraindications include hypersensitivity to hyaluronidase or any component of the formulation. Use caution when administering hyaluronidase to patients at increased risk for thrombosis. Furosemide, benzodiazepines, and phenytoin are incompatible with hyaluronidase. Hyaluronidase should not be administered to enhance the absorption or dispersion of alpha-agonist drugs or dopamine.

Warnings and Precautions

• Do not inject hyaluronidase into or near infected or acutely inflamed areas, as this may facilitate the spread of infection. Hyaluronidase is not recommended for the treatment of swelling due to bites or stings.
• Avoid direct application of hyaluronidase to the cornea.
• Do not administer hyaluronidase intravenously, as the enzyme is quickly inactivated in the bloodstream.

Monitoring

The injection site location should be documented, and acute changes should be monitored. Renal function and vital signs should be monitored during the infusion. If hyaluronidase is used to manage extravasation, the extravasation site should be closely monitored for swelling, pain, redness, or blistering. If the affected area is visible, its boundaries should be marked so that any increase in size or spread can be tracked.

Toxicity

Toxicity due to hyaluronidase is rare. When the enzyme is injected intravenously, it is rapidly degraded, and its enzymatic activity ceases. Tissue inflammation may result from local hyaluronidase toxicity.[21] The most serious complications of hyaluronidase therapy are thrombosis and hypersensitivity reactions. The medication should be discontinued immediately if either of these occurs.

Enhancing Healthcare Team Outcomes

Prescribing clinicians should recognize the benefits of hyaluronidase use in appropriate clinical settings. Clinicians should collaborate with pharmacists to determine the appropriate dose and method of administration. Hyaluronidase should be administered by qualified healthcare professionals, and patients should be monitored for serious complications. Patients should be adequately hydrated before administration of the dose and monitored for signs of thrombosis, anaphylaxis, and injection-site reactions. In the inpatient setting, nursing staff should monitor vital signs and assess for acute changes.

When using hyaluronidase for labeled indications, healthcare providers should know that intravenous administration is ineffective. This enzyme rapidly degrades in the bloodstream, thereby losing its beneficial effects. The individual administering the subcutaneous injection (typically a nursing staff member) should examine the injection site to ensure it is free of infection. Administration of hyaluronidase in inflamed or infected tissues may facilitate the spread of infection. Effective communication among patients and healthcare providers is essential within an interprofessional care team. Nurses should monitor for changes in patient health status and notify the attending clinician. Nursing staff are typically responsible for medication administration. Patients should also receive education on drug delivery methods and potential adverse reactions if self-administration at home is anticipated.

Adjunctive use of hyaluronidase with injectable medications improves treatment efficacy. Pharmacists should consult with the prescribing clinician regarding potential dose adjustments and perform dose verification and medication reconciliation. Improved systemic absorption may allow lower doses and less frequent administration of concomitant medications, thereby improving patient adherence and satisfaction.[1] An interprofessional approach involving clinicians, nursing staff, and pharmacists is essential to optimize hyaluronidase use and achieve optimal outcomes.