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  • CLASSES

    Emollients and Protectants, Other
    Hyaluronidase
    Other Topical Anti-pruritics

    DEA CLASS

    Rx

    DESCRIPTION

    Hydrolyzes hyaluronic acid in connective tissue, which enhances connective tissue permeability
    For increasing the absorption and dispersion of other injected drugs, for hypodermoclysis rehydration, and for improving resorption of radiopaque agents in subcutaneous urography
    Hypersensitivity may occur; skin testing can be performed

    COMMON BRAND NAMES

    Amphadase, Hylenex, Vitrase

    HOW SUPPLIED

    Amphadase/Hylenex/Vitrase Subcutaneous Inj Sol: 1mL, 150USPu, 150U, 200USPu
    Amphadase/Vitrase Intradermal Inj Sol: 1mL, 150USPu, 200USPu

    DOSAGE & INDICATIONS

    For use as an adjuvant to increase the absorption and dispersion of other drugs (e.g., local anesthesia, including infiltration anesthesia).
    For use as an adjunct for ophthalmic anesthesia†.
    Intravitreal dosage†
    Adults

    Clinical trial data documenting dosages used in practice are limited, although use clinically is common; it is estimated that the most common use of hyaluronidase is as a spreading agent for anesthetics in ophthalmologic surgery. Doses of 15 to 300 units of hyaluronidase administered intravitreally in conjunction with various parenteral anesthetics have been reported in the literature. In a Phase III trial for the treatment of vitreous bleeding, an increased incidence of adverse events was noted with an intravitreal dosage of hyaluronidase 75 units, the highest dose evaluated in this study.

    Regional dosage
    Adults, Adolescents, Children, Infants, and Neonates

    150 units (range: 50 to 300 units/dose) added to the injection solution. Do not use hyaluronidase to enhance the dispersion and absorption of dopamine and/or alpha agonist drugs. Consult appropriate references to determine the usual precautions for the use of any other drug with hyaluronidase.

    Subcutaneous dosage (Hylenex only)
    Adults, Adolescents, Children, Infants, and Neonates

    150 units (range: 50 to 300 units/dose) subcutaneous. Do not use hyaluronidase to enhance the dispersion and absorption of dopamine and/or alpha agonist drugs. Consult appropriate references to determine the usual precautions for the use of any other drug with hyaluronidase.

    For hypodermoclysis.
    Subcutaneous dosage (Vitrase only)
    Adults, Adolescents, and Children 3 years and older

    200 units injected subcutaneously will facilitate absorption of 1000 mL or more. Rate and volume of administration should not exceed those employed for intravenous infusion.

    Infants and Children 1 to 2 years

    200 units injected subcutaneously will facilitate absorption of 1000 mL or more. Do not exceed a maximum fluid volume of 200 mL per single clysis.

    Neonates

    Although a specific neonatal dosage is not provided in the product labeling, a dosage of 20 units per 100 mL of administered fluid may be considered based on the recommended dosage for older patients (i.e., 200 units injected subcutaneously will facilitate absorption of 1000 mL or more). The maximum daily volume of clysis is 25 mL/kg/day; the rate of administration should not be greater than 2 mL/minute. The dosage of subcutaneous fluids administered is dependent on the age, weight, and clinical condition of the patient.

    Subcutaneous dosage (Amphadase, Hydase, Hylenex)
    Adults, Adolescents, and Children 3 years and older

    150 units injected subcutaneously will facilitate absorption of 1000 mL or more. Rate and volume of administration should not exceed those employed for intravenous infusion.

    Infants and Children 1 to 2 years

    150 units injected subcutaneously will facilitate absorption of 1000 mL or more. Do not exceed a maximum fluid volume of 200 mL per single clysis.

    Neonates

    Although a specific neonatal dosage is not provided in the product labeling, a dosage of 15 units per 100 mL of administered fluid may be considered based on the recommended dosage for older patients (i.e., 150 units injected subcutaneously will facilitate absorption of 1000 mL or more). The maximum daily volume of clysis is 25 mL/kg/day; the rate of administration should not be greater than 2 mL/minute. The dosage of subcutaneous fluids administered is dependent on the age, weight, and clinical condition of the patient.

    For use as an adjunct in subcutaneous urography for improving resorption of urographic radiopaque contrast agents.
    Subcutaneous dosage
    Adults, Adolescents, Children, Infants, and Neonates

    75 units injected subcutaneously over each scapula while the patient is lying prone, then inject contrast medium at the same sites.

    For use as an antidote for extravasation† of selected drugs, examples include: antineoplastic agents (e.g., vinca alkaloids), osmotic fluids, (e.g., total parenteral nutrition, 10% or greater dextrose injection, calcium salts, mannitol, potassium salts, sodium bicarbonate, aminophylline, radiocontrast media, or hypertonic saline), or irritants (e.g., diazepam, nafcillin, phenytoin, thiopental, or vasopressin).
    NOTE: Use only in the treatment of extravasations where hyaluronidase has been shown to be of benefit. Hyaluronidase is not generally recommended for use as an antidote for extravasation of ischemic agents (e.g., dopamine or alpha-agonists).
    NOTE: Use hyaluronidase as an adjunct to medical management of extravasation; co-therapies may include hot or cold compresses (extravasating agent dependent), elevation of the affected limb, surgical debridement, and wound care.
    NOTE: A preliminary hypersensitivity test dose can be performed prior to use.
    Subcutaneous and Intradermal dosage
    Adults

    Total doses of 150 to 900 units have been used; divide the total dose and inject subcutaneously or intradermally between 5 to 10 sites along the leading edge of the extravasation. Dilute with normal saline to a final concentration of 15 to 150 units/mL depending on the size of the extravasation; larger areas of extravasation require a greater total number of injections to circumvent the site, and therefore more dilute injections must be used to administer the total dose. If a single syringe is used change the needle after each injection.

    Neonates, Infants, Children, and Adolescents

    Usually, 15 to 150 units/dose subcutaneous or intradermally as soon as possible (ideally within 1 hour of the extravasation) either through the catheter if still in place or through 4 to 5 injections of 0.25 or 0.2 mL of a 15 to 150 unit/mL solution in a circumferential pattern along the leading edge of the extravasation. Larger doses have been used and may be appropriate for large extravasations, for example. Adjunctive medical therapy for extravasation should also be considered, including hot or cold compresses (extravasating agent dependent), elevation of the affected limb, surgical debridement, and wound care. Examples of drugs where hyaluronidase may be effective in treating extravasation include: antineoplastic agents (e.g., vinca alkaloids), osmotic fluids, (e.g., total parenteral nutrition, 10% or greater dextrose injection, calcium salts, mannitol, potassium salts, sodium bicarbonate, aminophylline, radiocontrast media, or hypertonic saline), or irritants (e.g., diazepam, nafcillin, phenytoin, thiopental, or vasopressin).

    For the treatment of vitreous hemorrhage†.
    NOTE: A preliminary hypersensitivity test dose can be performed prior to use.
    Intravitreal dosage (Vitrase only)†
    Adults

    Inject 55 units intravitreally. A dose of 7.5 units has also been studied, but efficacy was found to be reduced after 3 months. An increased incidence of adverse events has been noted with an intravitreal dosage of 75 units. Pooled data from 2 Phase III clinical trials evaluating the efficacy of a single 55 unit injection resulted in a statistically significant effect on the primary efficacy endpoint (i.e., clearance of hemorrhage sufficient to see the underlying pathology and completion of treatment when indicated) at month 1 and 2 with the greatest relative treatment effect at 1 month. These results were supported by significant improvements in 3 secondary endpoints (i.e., >= 3-line improvement in best corrected visual acuity [BCVA], hemorrhage density reduction, and therapeutic utility assessment).

    For the treatment of diabetic retinopathy†.
    NOTE: A preliminary hypersensitivity test dose can be performed prior to use.
    Intravitreal dosage (Vitrase only)†
    Adults

    Inject 55 units intravitreally. NOTE: Limited Phase II study data are available. A single dose of Vitrase is used to cause a detachment of the vitreous humor from the retina; data indicate the drug may delay diabetic retinopathy. An increased incidence of adverse events has been noted with an intravitreal dosage of 75 units.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage information is not available.

    Geriatric

    Maximum dosage information is not available.

    Adolescents

    Maximum dosage information is not available.

    Children

    Maximum dosage information is not available.

    Infants

    Maximum dosage information is not available.

    Neonates

    Maximum dosage information is not available.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment needed.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solutions should be clear and colorless.
    Furosemide, benzodiazepines, 2% lidocaine with 1:100,000 or 1:200,000 epinephrine (due to presence of sodium metabisulfite), and phenytoin have been found to be incompatible with hyaluronidase.
     
    Hypersensitivity Test Dose (Vitrase, Amphadase, Hylenex, Hydase)
    A preliminary skin test for hypersensitivity can be performed with any formulation of hyaluronidase prior to the full-dose administration.
    Inject approximately 0.02 mL of hyaluronidase solution intradermally (3 units of Amphadase, Hylenex, or Hydase; 4 units of Vitrase).
    A positive reaction consists of a wheal with pseudopods appearing within 5 minutes and persisting for 20 to 30 minutes and accompanied by localized itching. Transient vasodilation (i.e., erythema) at the site of the test is not a positive reaction. Discontinue if sensitization occurs.
     
    Administration for Absorption and Dispersion of other Drugs
    Absorption and dispersion of other injected drugs may be enhanced by adding 50 to 300 units, most typically 150 units of hyaluronidase, to the injection solution prior to infiltration use, interstitial use, intramuscular use, intraocular use, retrobulbar use, soft tissue use, or subcutaneous use.
    Do not use hyaluronidase to enhance the dispersion and absorption of dopamine and/or alpha agonist drugs. Consult appropriate references regarding physical or chemical incompatibilities before adding hyaluronidase to a solution containing another drug.
    Storage (Vitrase only): If Vitrase is mixed with other drugs, the solution should be stored at 15 to 25 degrees C (59 to 77 degrees F) and used within 6 hours.

    Subcutaneous Administration

    Administration for Hypodermoclysis (Subcutaneous Fluid Administration)
    Lightly pinch the skin up into a small mound and using aseptic technique, insert the needle/catheter into the subcutaneous space.
    Inject hyaluronidase through the catheter hub or injection port closest to the needle/catheter either before (Hylenex, Hydase, Amphadase, or Vitrase) or immediately after (Amphadase, Hydase, or Vitrase) the start of subcutaneous fluid administration.
    Alternatively, hyaluronidase may be added to small volumes of fluid replacement solutions. For infants and children less than 3 years, the volume of a single clysis should be limited to 200 mL. For premature infants and neonates, the dosage should not exceed 25 mL/kg/day.
    As with all parenteral fluid therapy, closely observe the effect on the patient and use the same precautions for restoring fluid and electrolyte balance as when administering intravenous injections.
    For premature infants and neonates, do not exceed an administration rate of 2 mL/minute. For older patients, do not exceed a rate and volume of administration greater than those employed for intravenous infusion. The dosage, administration rate, and solution type must be adjusted carefully to the individual patient.
     
    Administration for Subcutaneous Urography
    With patient in the prone position, subcutaneously inject 75 units of hyaluronidase over each scapula and then inject contrast medium at the same sites.
     
    Administration for Absorption and Dispersion of other Drugs (Hylenex only)
    Inject 50 to 300 units (usually 150 units) subcutaneously immediately before subcutaneous administration of a drug.
     
    Administration to Treat Extravasation
    Determine the desired hyaluronidase concentration, which is dependent on the total dose desired and the extravasation size. If dilution is desired, dilute with normal saline to make, for example, a concentration of 15 units/mL.
    If the catheter is in the subcutaneous space, try to withdraw any extravasated fluid and then inject hyaluronidase undiluted or diluted through the existing catheter. Alternatively, using syringes and 25-gauge needles, make 4 to 5 injections of 0.2 mL subcutaneously of either 150 unit/mL or 15 unit/mL hyaluronidase, for example, along the leading edge of the extravasation site. If a single syringe is used, change the needle after each injection.

    Ophthalmic Administration

    Intravitreal Administration
    Hyaluronidase is not approved by the FDA for intravitreal administration. This route of administration should only be used by specially trained healthcare professionals (i.e., ophthalmologist).
    Specialized references should be consulted for specific procedures and administration techniques; detailed administration instructions are outside the scope of this reference.

    STORAGE

    Amphadase:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    Hydase:
    - Protect from freezing
    - Refrigerate (between 36 and 46 degrees F)
    Hylenex :
    - Do not freeze
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    Vitrase:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    Xclair:
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Hyaluronidase hypersensitivity


    Hyaluronidase hypersensitivity or hypersensitivity to any other ingredient in the formulation is a contraindication to the use of hyaluronidase. Venom from insect stings (e.g., wasps, bees) may include hyaluronidase allergens, so individuals with such allergies may be more likely to exhibit hyaluronidase sensitivity. A preliminary test for sensitivity may be conducted prior to the administration of any hyaluronidase product.

    Extravasation, intravenous administration

    Do not use hyaluronidase for intravenous administration; the enzyme is rapidly inactivated and the effects relative to absorption and dispersion of other drugs are not produced when it is administered intravenously. When considering the administration of any other drug with hyaluronidase, clinicians should be familiar with the precautions pertaining to the other drug and observe them. For example, when epinephrine is injected along with hyaluronidase, precautions related to epinephrine (e.g., cardiovascular disease, thyroid disease, diabetes, digital nerve block, ischemia of the fingers and toes, etc.) should be observed. While commonly used to treat drug extravasation, care must be taken to choose hyaluronidase for the proper clinical scenarios in which it has been proven to be helpful, and to avoid clinical scenarios in which the drug may cause further tissue injury. Do not use hyaluronidase to enhance the absorption and dispersion of dopamine and/or alpha-agonist drugs. Although this list may not be inclusive, furosemide, benzodiazepines, and phenytoin have been found to be incompatible with hyaluronidase; consult appropriate references prior to admixture.

    Ocular exposure, ocular surgery

    Hyaluronidase should not be administered by direct application to the cornea during ocular surgery. Avoid unintended (accidental) ocular exposure.

    Infection

    Hyaluronidase should not be injected into acutely inflamed or infected areas to avoid a potential risk of spreading a localized infection. Do not use hyaluronidase to reduce swelling from bites or stings to avoid a potential risk of spreading a toxin and/or infectious agent. Venom from insect stings (e.g., wasps, bees) may include hyaluronidase allergens, so the administration of hyaluronidase may actually worsen the reaction to the sting in allergic individuals.

    Children, hypervolemia, infants

    Using hyaluronidase for hypodermoclysis (usually performed in children and infants), special care must be taken to avoid overhydration (hypervolemia) in the pediatric patient by controlling the rate and total volume of the clysis.

    Pregnancy

    Studies of hyaluronidase use during human pregnancy as an aid to delivery have been performed without reports of maternal or fetal harm. Administration of hyaluronidase during labor and obstetric delivery was reported to cause no increase in blood loss or differences in cervical trauma. Additionally, studies of hyaluronidase as an aid to conception (assist the in vitro fertilization of human eggs) have not reported maternal or fetal harm.

    Breast-feeding

    There are no data available on the presence of hyaluronidase in human milk, the effects on breastfed infants, or the effects on milk production to inform about the risk of hyaluronidase to an infant during breast-feeding. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for hyaluronidase and any potential adverse effects on the breastfed infant from hyaluronidase.

    Viral infection

    Depending on the product, hyaluronidase is either prepared from bovine or ovine enzymes, or, as is the case with recombinant human hyaluronidase products, contains a small amount of albumin, a derivative of human blood. Products derived from human blood or animal components may carry the remote possibility of contamination or infection with hepatitis, Creutzfeldt-Jakob disease (CJD), or other bacterial or viral pathogens. Patients and clinicians should use hyaluronidase from legal commercial sources only. If the raw material of bovine or ovine derived products is illegally imported from outside the US, there is the potential for contamination with bovine or ovine pathogens. The FDA monitors animal-derived drug and food products; those animal ingredients originating in prohibited countries are prohibited entry into the US. However, these safeguards cover legal importations only. As with other products derived from human blood components, screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents. The manufacturing processes are designed to reduce the risk of transmitting viral infection; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents may be present. Hyaluronidase should be given only if a benefit is expected. All infections thought by a physician to have been possibly transmitted by a medication should be reported to the manufacturer.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / 0-1.0
    seizures / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    ocular hemorrhage / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    erythema / Early / Incidence not known
    edema / Delayed / Incidence not known
    iritis / Delayed / Incidence not known
    testicular atrophy / Delayed / Incidence not known
    antibody formation / Delayed / Incidence not known
    hypovolemia / Early / Incidence not known

    Mild

    urticaria / Rapid / 0-1.0
    injection site reaction / Rapid / Incidence not known
    skin irritation / Early / Incidence not known
    infection / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Amide local anesthetics: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Aminosalicylate sodium, Aminosalicylic acid: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Articaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Aspirin, ASA: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Carisoprodol: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Dipyridamole: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Omeprazole: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Oxycodone: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Pravastatin: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Bismuth Subsalicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Bupivacaine Liposomal: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine; Lidocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Chloroprocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Choline Salicylate; Magnesium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Cocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Conjugated Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Corticotropin, ACTH: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Cortisone: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Dienogest; Estradiol valerate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Diethylstilbestrol, DES: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ester local anesthetics: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Esterified Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Levonorgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Norethindrone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Norgestimate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Progesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estropipate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Etonogestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norgestimate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Levobupivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Lidocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Magnesium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Mepivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Mepivacaine; Levonordefrin: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Mestranol; Norethindrone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Prilocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Prilocaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Procaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Ropivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Salicylates: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Salsalate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Sedating H1-blockers: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Tetracaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.

    PREGNANCY AND LACTATION

    Pregnancy

    Studies of hyaluronidase use during human pregnancy as an aid to delivery have been performed without reports of maternal or fetal harm. Administration of hyaluronidase during labor and obstetric delivery was reported to cause no increase in blood loss or differences in cervical trauma. Additionally, studies of hyaluronidase as an aid to conception (assist the in vitro fertilization of human eggs) have not reported maternal or fetal harm.

    There are no data available on the presence of hyaluronidase in human milk, the effects on breastfed infants, or the effects on milk production to inform about the risk of hyaluronidase to an infant during breast-feeding. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for hyaluronidase and any potential adverse effects on the breastfed infant from hyaluronidase.

    MECHANISM OF ACTION

    Hyaluronidase is a dispersion agent that breaks down hyaluronic acid in connective tissue resulting in increased permeability and enhanced diffusion of concurrently administered parenteral agents. Hyaluronidase hydrolyzes hyaluronic acid by splitting the glucosaminidic bond between C1 of the glucosamine moiety and C4 of glucuronic acid. This temporarily decreases the viscosity of the cellular cement and promotes diffusion of injected fluids or of localized transudates or exudates, thus facilitating their absorption. When no spreading factor is present, material injected subcutaneously spreads very slowly, but hyaluronidase causes rapid spreading of other materials, provided local interstitial pressure is adequate to furnish the necessary mechanical impulse. Such an impulse is normally initiated by injected solutions. The rate of diffusion is proportionate to the amount of enzyme administered, and the extent is proportionate to the volume of solution.
     
    During local anesthesia, hyaluronidase is used to increase the anesthetized area and decrease the time to anesthetic onset of action. During cataract and other intraocular surgery, hyaluronidase is given to decrease the time to onset of local anesthetics and reduce the risk of surgery-related increased intraocular pressure (IOP). In the management of vitreous hemorrhage, hyaluronidase is thought to liquefy vitreous. Liquefaction of the vitreous is thought to increase the diffusion rate of erythrocytes and phagocytes through the vitreous and facilitates red cell lysis and phagocytosis. Improvement of vitreous hemorrhage density and/or clearance of vitreous hemorrhage should allow for better visual acuity and better visualization of the retina for diagnosis of retinal pathology and further treatment, if needed. In cases of extravasation, hyaluronidase is used to increase the dispersion and absorption of select agents after unintentional drug infiltration.

    PHARMACOKINETICS

    Hyaluronidase is administered parenterally by various routes (e.g., intradermal and subcutaneous) but is not given intravenously; the hyaluronidase-induced absorption and dispersion of other drugs is not achieved after intravenous administration. The rate of hyaluronidase-induced diffusion of concurrently administered drugs is proportionate to the amount of enzyme administered, while the extent of diffusion is proportionate to the volume of solution. Knowledge of the mechanisms involved in the clearance of injected hyaluronidase is limited. It is known, however, that the blood of a number of mammalian species brings about the inactivation of hyaluronidase. After intradermal administration of hyaluronidase in adult humans, the drug effect completely dissipates within 48 hours. Studies have demonstrated that hyaluronidase is antigenic; repeated injections of relatively large amounts of this enzyme may result in the formation of neutralizing antibodies.

    Other Route(s)

    Intradermal Route
    The reconstitution of the dermal barrier removed by intradermal injection of hyaluronidase (20, 2, 0.2, 0.02, and 0.002 Units/ml) to adult humans indicated that at 24 hours the restoration of the barrier is incomplete and inversely related to the dosage of enzyme; at 48 hours the barrier is completely restored in all treated areas.
     
    Intravitreous Route
    Pharmacokinetics of hyaluronidase have been assessed in animal studies after intravitreous injection. The plasma half-life is 49 hours. The highest concentrations are achieved in vitreous, retina, and sclera. The half-life in ocular tissues is between 60 and 112 hours.