Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Amphadase: 150 units/mL (1 mL) [contains edetate disodium, thimerosal]
Solution, Injection [preservative free]:
Hylenex: 150 units/mL (1 mL) [contains albumin human, polysorbate 80]
Vitrase: 200 units/mL (1.2 mL) [contains lactose]
Pharmacology
Mechanism of Action
Enzymatically modifies the permeability of connective tissue through hydrolysis of hyaluronic acid, one of the chief components of tissue cement which offers resistance to diffusion of liquids through tissues; hyaluronidase increases the distribution/dispersion and absorption of locally injected or extravasated IV medications.
Pharmacokinetics/Pharmacodynamics
Onset of Action
SubQ: Immediate; when used for extravasation, there is usually a reduction in swelling within 15 to 30 minutes after administration (Zenk 1981b)
Duration of Action
24 to 48 hours (variable)
Use: Labeled Indications
Absorption and dispersion of injected drugs: As an adjuvant to increase the absorption and dispersion of other injected drugs.
Subcutaneous fluid administration: As an adjuvant in subcutaneous fluid administration (hypodermoclysis) for achieving hydration.
Subcutaneous urography: As an adjunct in subcutaneous urography for improving resorption of radiopaque agents.
Use: Off Label
Extravasation managementcyes
Based on the Oncology Nursing Society (ONS) and the European Society for Medical Oncology (ESMO) and European Oncology Nursing Society (EONS), and other clinical experiences, hyaluronidase may be used for extravasation management of several drug extravasations (eg, amiodarone, aminophylline, calcium salts, dextrose, epipodophyllotoxins, mannitol, nafcillin, parenteral nutrition, phenytoin, potassium salts, vinca alkaloids) ESMO/EONS [Perez Fidalgo 2012], Le 2014, Macara 1983, ONS [Polovich 2009], Reynolds 2014, Schulmeister 2011, Weigand 2009, Zenk 1981b.
Local anesthetic adjuvantb
Data from three prospective, randomized, double-blinded studies using hyaluronidase as an adjuvant for local anesthetic administration (eg, peribulbar block) including a pharmacokinetic study supports the use of hyaluronidase in this setting Kallio, 2000, Moharib 2002, Nathan 1996, Van Den Berg 2001. Clinical experience also suggests the utility of hyaluronidase as an adjuvant for local anesthetic administration Barash 2010, Lai 2003.
Contraindications
Hypersensitivity to hyaluronidase or any component of the formulation
Dosage and Administration
Dosing: Adult
Skin test: Intradermal: 0.02 mL (Amphadase 3 units, Hylenex 3 units, or Vitrase 4 units) of a 150 units/mL (Amphadase, Hylenex) or 200 units/mL (Vitrase) solution. Positive reaction consists of a wheal with pseudopods appearing within 5 minutes and persisting for 20-30 minutes with localized itching (transient erythema is not considered a positive reaction). Skin testing is not necessary prior to use for extravasation management.
Dehydration: Hypodermoclysis: SubQ: 150 or 200 units followed by subcutaneous isotonic fluid administration ≥1000 mL or may be added to small volumes (≤200 mL) of subcutaneous replacement fluid. Rate and volume of a single clysis should not exceed those used for infusion of IV fluids.
Dispersion/absorption enhancement of injected drugs: SubQ: 50 to 300 units (usual dose: 150 units) either injected prior to drug administration or added to injection solution (consult compatibility reference prior to mixing)
Extravasation management (off-label use): Note: Administer as soon as extravasation is recognized. Do not use for extravasation of vasoconstrictors (eg, dopamine, norepinephrine [manage with phentolamine]). For extravasation management, skin testing is not necessary prior to use. The concentration of doses used to manage extravasation ranges from 15 units/mL to 150 units/mL; refer to specific vesicant (below) for a description of doses/concentrations used in published case reports and/or reviews:
Aminophylline, amiodarone, calcium solutions, dextrose <50%, nafcillin, parenteral nutrition/amino acid (4.25%), potassium solutions, and sodium chloride (>1%): Intradermal or SubQ: Inject a total of 1 to 1.7 mL (15 units/mL) as 5 separate 0.2 to 0.3 mL injections (using a 25-gauge needle) into area of extravasation at the leading edge in a clockwise manner (Fox 2017; MacCara 1983; Reynolds 2014; Zenk 1981b).
Contrast media extravasation: Information conflicts regarding hyaluronidase in contrast media extravasation management; the American College of Radiology (ACR) Manual on Contrast Media does not recommend hyaluronidase (ACR 2018), while other sources suggest its utility (Bellin 2002; Reynolds 2014). If using hyaluronidase, inject a total of 1 to 1.7 mL (15 units/mL) as five separate 0.2 to 0.3 mL intradermal or SubQ injections (using a 25-gauge needle) into area of extravasation at the leading edge in a clockwise manner (MacCara 1983; Reynolds 2014; Zenk 1981b) or the injection of a total of 5 mL (150 units/mL) as five separate 1 mL injections around the extravasation site has been also used successfully (Rowlett 2012).
Dextrose 50% extravasation: Injection of a total of 1 mL (150 units/mL) as five separate 0.2 mL injections administered along the leading edge of erythema has also been used successfully for dextrose 50% extravasation (Wiegand 2010).
Mannitol: SubQ: Administer multiple injections of 0.5 to 1 mL (15 units/mL) around the periphery of the extravasation (Kumar 2003) or Intradermal or SubQ: Inject a total of 1 to 1.7 mL (15 units/mL) as 5 separate 0.2 to 0.3 mL injections (using a 25-gauge needle) into area of extravasation at the leading edge in a clockwise manner (Reynolds 2014).
Paclitaxel: IV: Clinical experience suggests hyaluronidase may be used in the management of paclitaxel extravasations (Perez Fidalgo 2012; Stanford 2003); data is limited. If using hyaluronidase, administer 1 to 6 mL (150 units/mL) into existing IV line, and/or, if needle/cannula has been removed, inject subcutaneously in a clockwise manner around area of extravasation. Usual dose is 1 mL hyaluronidase for each 1 mL of extravasated drug; may repeat several times over the next 3 to 4 hours (Ener 2004; Perez Fidalgo 2012).
Sodium bicarbonate: SubQ: Administer 4 to 5 separate 0.2 mL injections (15 units/mL) around area of extravasation (Hurst 2004) or Intradermal or SubQ: Inject a total of 1 to 1.7 mL (15 units/mL) as 5 separate 0.2 to 0.3 mL injections (using a 25-gauge needle) into area of extravasation at the leading edge in a clockwise manner (Reynolds 2014).
Vinca alkaloid (vinblastine, vincristine, vindesine, vinorelbine) extravasation:
If needle/cannula still in place: IV: After gently aspirating to remove extravasated vesicant, administer 1 to 6 mL hyaluronidase (150 units/mL) into existing IV line; the usual dose is 1 mL hyaluronidase for each 1 mL of extravasated drug (Perez Fidalgo 2012; Schulmeister 2011).
If needle/cannula has been removed: SubQ: Inject 1 to 6 mL (150 units/mL) in a clock wise manner using 1 mL for every 1 mL of drug extravasated (Schulmeister 2011) or administer 1 mL (150 units/mL) as 5 separate 0.2 mL injections (using a 25-gauge needle) into the extravasation site (Polovich 2009).
Retrobulbar/peribulbar block (adjuvant in bupivacaine-lidocaine mixture) (off-label use): 3.75 units (150 units/mL concentration) or 7.5 units (150 units/mL concentration) for every 1 mL of a 1:1 mixture of bupivacaine 0.75% and lidocaine 2%; administer a total of 6 to 8 mL of mixture divided evenly between retrobulbar and peribulbar injections (Kallio 2000).
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Skin test: Infants, Children, and Adolescents: Intradermal: 0.02 mL (Amphadase 3 units, Hylenex 3 units, or Vitrase 4 units) of a 150 units/mL (Amphadase, Hylenex) or 200 units/mL (Vitrase) solution. Positive reaction consists of a wheal with pseudopods appearing within 5 minutes and persisting for 20 to 30 minutes with localized itching (transient erythema is not considered a positive reaction). Skin testing is not necessary prior to use for extravasation management.
Dehydration: Hypodermoclysis: Infants, Children, and Adolescents:
SubQ prior to infusion: SubQ: 150 units or 200 units, followed by subcutaneous isotonic fluid administration at a rate appropriate for age, weight, and clinical condition of the patient; 150 units facilitates absorption of ≥1,000 mL of solution. If the infusion is continued greater than 24 hours, additional doses have been administered at 24 hour intervals up to a total of 3 doses (Allen 2009)
Added to replacement solution: Dose dependent on volume to be infused; 150 units of hyaluronidase facilitates the absorption of ≥1,000 mL of fluid; for patients (ie, young infants) who require smaller volumes for replacement fluid (≤100 mL), 15 units added for every 100 mL of replacement fluid has been used at some centers; maximum daily dose: 150 units/day
Maximum clysis volumes:
Infants and Children <3 years: Volume of a single clysis should not exceed 200 mL
Children ≥3 years and Adolescents: Rate and volume of a single clysis should not exceed those used for infusion of IV fluids
Dispersion/absorption enhancement of injected drugs: Children and Adolescents: SubQ: 50 to 300 units (usual dose: 150 units) either injected prior to drug administration or added to injection solution (consult compatibility reference prior to mixing)
Extravasation: Limited data available: Infants, Children, and Adolescents: SubQ, intradermal: Use 4 to 5 separate 0.2 mL injections of a 15 or 150 units/mL solution into the extravasation site at the leading edge as soon as possible (preferably within 1 hour) after extravasation is recognized (Hurst 2004; Le 2014; Reynolds 2014; Sokol 1998; Wiegand 2010). Note: Some centers may determine concentration of hyaluronidase based upon the medication risk of tissue toxicity (risk determined by pH, osmolarity, known tissue toxicity) or by volume of extravasation, so for smaller volumes (<100 mL), a less concentrated solution (15 units/mL) has been used (Hurst 2004; MacCara 1983; Sokol 1998; Wiegand 2010)
Urography, subcutaneous: Infants, Children, and Adolescents: SubQ: 75 units over each scapula followed by injection of contrast medium at the same site; patient should be in the prone position during drug administration
Reconstitution
Extravasation management (off-label use): To prepare a 15 units/mL concentration, mix 0.1 mL (of 150 units/mL) with 0.9 mL NS.
Administration
Do not administer IV for labeled uses (enzyme is rapidly inactivated and desired effects will not be produced).
Extravasation management (off-label use): Stop vesicant infusion immediately and disconnect IV line (leave needle/cannula in place); if appropriate, gently aspirate extravasated solution from the IV line (do NOT flush the line). Keep needle/cannula in place for vinca alkaloid extravasation, if appropriate, remove needle/cannula for other vesicants; elevate extremity.
Hyaluronidase administration:
Local administration (intradermal or subQ): Using a 150 units/mL concentration, mix 0.1 mL (of 150 units/mL) with 0.9 mL NS in 1 mL syringe to make final concentration of 15 units/mL; administer a total of 1 to 1.7 mL (15 units/mL) as 5 separate 0.2 to 0.3 mL intradermally and/or subcutaneously into area of extravasation (MacCara 1983; Reynolds 2014).
Vinca alkaloids: If needle/cannula still in place, administer 1 to 6 mL hyaluronidase (150 units/mL) into the existing IV line; the usual dose is 1 mL hyaluronidase for each 1 mL of extravasated drug (Perez Fidalgo 2012, Schulmeister 2011). If needle/cannula has been removed, inject 1 to 6 mL (150 units/mL) subcutaneously in a clockwise manner using 1 mL for 1 mL of drug extravasated (Schulmeister 2011) or administer 1 mL (150 units/mL) as 5 separate 0.2 mL injections (25-gauge needle) subcutaneously into the extravasation site (Polovich 2009).
Retrobulbar/peribulbar administration (off-label use): After combining hyaluronidase with a 1:1 mixture of bupivacaine 0.75% and lidocaine 2%, administer according to standard anesthetic technique (Kallio 2000).
Storage
Amphadase, Hylenex: Store intact vials in refrigerator at 2°C to 8°C (36°F to 46°F); do not freeze.
Vitrase: Store intact vials in refrigerator at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. If adding to other injectable solutions, store admixture at 15°C to 25°C (59°F to 77°F) and use within 6 hours.
Drug Interactions
Alpha-/Beta-Agonists: Hyaluronidase may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of alpha-/beta-agonists. Use of hyaluronidase for other purposes in patients receiving alpha-/beta-agonists may be considered as clinically indicated. Exceptions: EPINEPHrine (Nasal); EPINEPHrine (Oral Inhalation); Isometheptene; Pseudoephedrine. Consider therapy modification
Antihistamines: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving antihistamines (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification
Corticosteroids: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Exceptions: Beclomethasone (Nasal); Budesonide (Nasal); Ciclesonide (Nasal); Desonide; DexAMETHasone (Ophthalmic); Difluprednate; Flunisolide (Nasal); Fluocinolone (Ophthalmic); Fluticasone (Nasal); Hydrocortisone (Ophthalmic); Loteprednol; Mometasone (Nasal); PrednisoLONE (Ophthalmic); Triamcinolone (Nasal); Triamcinolone (Ophthalmic). Consider therapy modification
DOPamine: Hyaluronidase may enhance the adverse/toxic effect of DOPamine. Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of dopamine. Use of hyaluronidase for other purposes in patients receiving dopamine may be considered as clinically indicated. Consider therapy modification
Estrogen Derivatives: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification
Local Anesthetics: Hyaluronidase may enhance the adverse/toxic effect of Local Anesthetics. Exceptions: Benzocaine; Benzydamine; Cocaine (Topical); Dibucaine; Dyclonine; Ethyl Chloride; Hexylresorcinol; Lidocaine (Ophthalmic); Lidocaine (Topical); Pramoxine; Proparacaine; Tetracaine (Ophthalmic); Tetracaine (Topical). Monitor therapy
Phenylephrine (Systemic): Hyaluronidase may enhance the vasoconstricting effect of Phenylephrine (Systemic). Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of phenylephrine. Use of hyaluronidase for other purposes in patients receiving phenylephrine may be considered as clinically indicated. Avoid combination
Salicylates: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving salicylates (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification
Adverse Reactions
Frequency not defined.
Cardiovascular: Edema
Local: Injection site reaction
<1%, postmarketing, and/or case reports: Anaphylactic-like reactions (retrobulbar block or IV injections), anaphylaxis, angioedema, hypersensitivity reaction, urticaria
Warnings/Precautions
Concerns related to adverse effects:
- Hypersensitivity: Use with caution in patients with reported history of bee sting allergy; hyaluronidase is an active component in bee venom (Lee 2010).
- Sensitization: Discontinue if sensitization occurs (a skin test may be performed to determine hypersensitivity).
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Dosage form specific issues:
- Albumin: Some products may contain albumin; albumin carries an extremely remote risk for transmission of viral diseases, Creutzfeldt-Jakob disease (CJD) and variant CJD (vCJD). No cases of transmission of viral diseases, CJD, or vCJD have been identified for licensed albumin or albumin contained in other licensed products.
Other warnings/precautions:
- Administration: For labeled indications, do not administer intravenously (enzyme is rapidly inactivated and desired effects will not be produced); do not inject in or around infected or inflamed areas; may spread localized infection. Do not apply directly to the cornea; not for topical use.
- Appropriate use: Hyaluronidase is ineffective for extravasation management of vasoconstrictors (eg, dopamine, epinephrine, norepinephrine, phenylephrine, vasopressin) or to reduce swelling of bites or stings; do not use in these settings.
Monitoring Parameters
Extravasation management (off-label use): Document and monitor extravasation site.
Pregnancy
Pregnancy Considerations
Adverse maternal or fetal events were not observed when used as an aid to delivery or an aid to conception. Administration during labor did not cause any increase in blood loss or differences in cervical trauma.
Hyaluronidase has been evaluated for use prior to intracytoplasmic sperm injection (ICSI) to aid the in vitro fertilization of human eggs (DeVos 2008; Evison 2009; Majumdar 2013; Moura 2017; Worrilow 2013).
Patient Education
What is this drug used for?
- It is used to help other drugs get into the body.
- It may be given to you for other reasons. Talk with the doctor.
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Severe injection site irritation
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
