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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
(For additional information see "Hyaluronidase: Pediatric drug information")
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, treatment to facilitate subcutaneous fluid replacement: Infants, Children, and Adolescents:
SubQ following SubQ infusion: SubQ: Dose dependent on volume to be infused; administer into rubber tubing close to needle after initiation of subcutaneous isotonic fluid; fluid administration rate is dependent upon age, weight, and clinical condition of the patient, as well as laboratory determinations.
Amphadase: 150 units facilitates absorption of ≥1,000 mL of solution.
Vitrase: 200 units facilitates absorption of ≥1,000 mL of solution.
SubQ prior to SubQ infusion: SubQ: Dose dependent on volume to be infused; administer into rubber tubing close to needle prior to initiation of subcutaneous isotonic fluid; fluid administration rate is dependent upon age, weight, and clinical condition of the patient, as well as laboratory determinations.
Amphadase, Hylenex: 150 units facilitates absorption of ≥1,000 mL of solution.
Vitrase: 200 units facilitates absorption of ≥1,000 mL of solution.
Added to SubQ replacement solution: SubQ: Dose dependent on volume to be infused, generally recommended for smaller volumes (eg, 200 mL); rate and volume of a single clysis should not exceed those used for infusion of IV fluids.
Amphadase, Hylenex: 150 units facilitates absorption of ≥1,000 mL of solution.
Vitrase: 200 units facilitates absorption of ≥1,000 mL of solution.
Dispersion/absorption enhancement of injected drugs: Children and Adolescents: Amphadase, Hylenex, Vitrase: 50 to 300 units added to injection solution (consult compatibility reference prior to mixing); some preparations (Hylenex) may be administered SubQ prior to drug needing dispersed.
Dispersion of subcutaneous immunoglobulin: Limited data available: Hylenex: Children ≥2 years and Adolescents: 75 units of hyaluronidase per gram of immunoglobulin; hyaluronidase added to dose of subcutaneous immunoglobulin. Dosing based on open-label prospective studies in patients with primary immunodeficiencies requiring immunoglobulin (Wasserman 2012; Wasserman 2016a; Wasserman 2016b).
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; hyaluronidase exerts its effects locally and is rapidly inactivated in the blood; adverse effects would not be expected.
There are no dosage adjustments provided in the manufacturer's labeling; hyaluronidase exerts its effects locally and is rapidly inactivated in the blood; adverse effects would not be expected.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Amphadase: 150 units/mL (1 mL) [contains edetate (edta) disodium, thimerosal (thiomersal)]
Solution, Injection [preservative free]:
Hylenex: 150 units/mL (1 mL) [contains albumin human, polysorbate 80]
Vitrase: 200 units/mL (1.2 mL) [contains lactose]
No
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).
Parenteral: Do not administer IV (enzyme is rapidly inactivated and desired effects will not be produced)
Extravasation management: May administer undiluted (150 units/mL) or dilutions may be used. Infiltrate area of extravasation with 4 to 5 small injections at the leading edge; use 25-, 27-, or 30-gauge needles and change needle between each skin entry to prevent bacterial contamination and minimize pain (Kuensting 2010; Sokol 1998; Zenk 1981b).
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.
Extravasation management; Local anesthetic adjuvant
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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
Hypersensitivity to hyaluronidase or any component of the formulation
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).
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.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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. Risk D: Consider therapy modification
Antihistamines: May diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Corticosteroids (Systemic): 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. Risk D: 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. Risk D: Consider therapy modification
Estrogen Derivatives: May diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Local Anesthetics: Hyaluronidase may enhance the adverse/toxic effect of Local Anesthetics. Risk C: 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. Risk X: Avoid combination
Salicylates: May diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
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).
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.
It is not known if hyaluronidase is present in breast milk following therapeutic administration.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Extravasation management (off-label use): Document and monitor extravasation site.
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.
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: 24 to 48 hours (variable)
Solution (Amphadase Injection)
150 units/mL (per mL): $66.96
Solution (Hylenex Injection)
150 units/mL (per mL): $66.96
Solution (Vitrase Injection)
200 units/mL (per mL): $113.98
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