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Hyaluronidase

Pronunciation

(hye al yoor ON i dase)

Index Terms

  • Wydase

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Amphadase: 150 units/mL (1 mL) [contains edetate disodium, thimerosal]

Solution, Injection [preservative free]:

Hylenex: 150 units/mL (1 mL [DSC]) [contains albumin human, edetate disodium]

Hylenex: 150 units/mL (1 mL) [contains albumin human, polysorbate 80]

Vitrase: 200 units/mL (1.2 mL)

Generic: 150 units/mL (1 mL)

Brand Names: U.S.

  • Amphadase
  • Hylenex
  • Vitrase

Pharmacologic Category

  • Antidote, Extravasation
  • Enzyme

Pharmacology

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 substances.

Onset of Action

SubQ: Immediate; when used for extravasation, there is usually a reduction in swelling within 15-30 minutes after administration (Zenk, 1981b)

Duration of Action

24-48 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: Unlabeled

Management of specific drug extravasations (eg, aminophylline, calcium salts, contrast agents, dextrose, epipodophyllotoxins, mannitol, nafcillin, parenteral nutrition, phenytoin, potassium salts, vinca alkaloids); local anesthetic adjuvant in bupivacaine-lidocaine mixture for retrobulbar/peribulbar block

Contraindications

Hypersensitivity to hyaluronidase or any component of the formulation

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: 50-300 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, calcium solutions, dextrose 10%, nafcillin, parenteral nutrition, potassium solutions, and radiocontrast media extravasation: Intradermal or SubQ: Inject a total of 1 mL (15 units/mL) as five separate 0.2 mL injections (using a 25-gauge needle) into area of extravasation at the leading edge in a clockwise manner (MacCara, 1983; Zenk, 1981b)

Contrast media extravasation: 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, 2009).

Mannitol: SubQ: Administer multiple injections of 0.5-1 mL (15 units/mL) around the periphery of the extravasation (Kumar, 2003)

Paclitaxel: IV: Administer 1-6 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 3-4 hours (Ener, 2004)

Sodium bicarbonate: SubQ: Administer 4-5 separate 0.2 mL injections (15 units/mL) around area of extravasation (Hurst, 2004)

Vinca alkaloid (vinblastine, vincristine, vindesine, vinorelbine) extravasation:

If needle/cannula still in place: IV: After gently aspirating to remove extravasated vesicant, administer 1-6 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 1-6 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 6-8 mL of mixture divided evenly between retrobulbar and peribulbar injections (Kallio, 2000).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Skin test: 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 20-30 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

Premature Infants: Volume of a single clysis/day should not exceed 25 mL/kg and the rate of administration should not exceed 2 mL/minute

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: 50-300 units (usual dose: 150 units) either injected prior to drug administration or added to injection solution (consult compatibility reference prior to mixing)

Subcutaneous urography: Infants and Children: 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

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Extravasation management (off-label use): To make 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); 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 5 x 0.2 mL (15 units/mL) intradermally and/or subcutaneously into area of extravasation (MacCara, 1983).

Vinca alkaloids: If needle/cannula still in place, administer 1-6 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 1-6 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).

Compatibility

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D51/4NS, D51/2NS, D5NS, D5W, D10W, LR, 1/2NS, NS.

Y-site administration: Note: Not to be administered intravenously (for approved indications). Incompatible with hydromorphone.

Compatibility in syringe: Incompatible with hydromorphone.

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: Dipivefrin; 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; 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% (Limited to important or life-threatening): anaphylactic-like reactions (retrobulbar block or IV injections), anaphylaxis, hypersensitivity reaction

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: 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 Risk Factor

C

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies (not conducted with all products). Administration during labor did not cause any increase in blood loss or differences in cervical trauma. It is not known whether it affects the fetus if used during labor. Hyaluronidase has been evaluated for use prior to intracytoplasmic sperm injection (ICSI) to increase male fertility (DeVos, 2008; Evison, 2009).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber severe injection site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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