AMPHADASE

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

Route-Specific Administration

Injectable Administration
-Hyaluronidase should NOT be administered intravenously due to rapid inactivation. Hyaluronidase may be administered for infiltration use, interstitial use, subcutaneous use, intramuscular use, intraocular use, retrobulbar use, or soft tissue use.
-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 the presence of sodium metabisulfite), and phenytoin are incompatible with hyaluronidase.

Hypersensitivity Test Dose (Amphadase, 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.
-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, store the solution at 15 to 25 degrees Celsius (59 to 77 degrees Fahrenheit) and use within 6 hours. Consult the prescribing information of other drugs for additional storage information.
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.

Other Injectable Administration
Intradermal Administration
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 catheter is in the intradermal 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 intradermal injections of 0.2 mL 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.

Results from an experimental study in humans on the influence of hyaluronidase in bone repair indicate that this enzyme alone in the usual clinical dosage does not deter bone healing.

A mild local injection site reaction is the most frequently reported adverse reaction to hyaluronidase. Immediately after human recombinant hyaluronidase 150 Units SC but before fluid administration among 51 pediatric patients aged 2 months to 10 years, tenderness at the injection site was noted in 22, erythema in 32 (>= 5 cm in 4 of the 32 patients), ecchymosis that was < 2.5 cm in 1, maculopapular rash that was < 2.5 cm in 2, and swelling or edema in 34 (>= 5 cm in 4 of the 34 patients). After SC fluid administration, all of the pediatric patients had swelling at the injection site, and it was >= 5 cm in 29 of the 51. Edema occurs most frequently in association with hypodermoclysis; however, it appears that pain and edema are less severe when hypodermoclysis is performed with fluids administered with hyaluronidase compared to fluids administered with placebo. In adults, the incidence of pain and the incidence and severity of edema were noted to be significantly reduced, while the gravitational infusion rate was significantly higher among adults administered subcutaneous hydration with Lactated Ringers (LR) in conjunction with human recombinant hyaluronidase as compared to those who received LR with placebo. The choice of hydration fluid, volume, and administration rate must be selected using patient specific parameters; ensure appropriate administration technique.

Allergic reactions (e.g., urticaria, angioedema) have been reported in < 0.1% of patients receiving hyaluronidase; anaphylactoid reactions have occurred rarely after intravenous injections. Because venom from insect stings (e.g., wasps, bees) may include hyaluronidase allergens, patients with a history of such allergies may also be sensitive to hyaluronidase. An intradermal test for hyaluronidase hypersensitivity can be performed prior to hyaluronidase administration.

Animal derived hyaluronidase is purified from testicular tissue; it has been reported that testicular atrophy (degeneration) may occur in patients with repeated exposure to such a product as a result of organ-specific antibodies against purified ovine or bovine hyaluronidase. Testicular degeneration would not be expected with use of recombinant human hyaluronidase.

Studies have demonstrated that hyaluronidase is antigenic; repeated injections of relatively large amounts of this enzyme may result in neutralizing antibody formation.

Hypovolemia may occur after subcutaneous administration of hyaluronidase in conjunction with solutions devoid of inorganic electrolytes. To minimize this risk, use solutions containing adequate amounts of inorganic electrolytes, and adjust the volume and rate of fluid administration for patient specific parameters.

An extremely remote risk for viral infection and variant Creutzfeldt-Jakob disease (vCJD) transmission exists with human recombinant hyaluronidase, as it contains albumin. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also exists, but the risk would also be considered extremely remote. No cases of transmission of viral diseases, CJD, or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products. Products derived from 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. Report all infections thought by a physician to have been possibly transmitted by a medication to the manufacturer.

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.

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.

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

Do not inject hyaluronidase into or around 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.

Carefully assess fluid requirements for pediatric patients to avoid hypervolemia. Do not exceed the rate and volume of subcutaneous fluid administration of those employed for intravenous infusion.

While commonly used to treat drug extravasation, hyaluronidase may cause serious side effects with certain drugs. For example, do not use hyaluronidase to enhance the absorption and dispersion of dopamine and/or alpha-agonist drugs.

Description: Hyaluronidase is a parenteral enzyme that hydrolyzes hyaluronic acid in connective tissue allowing greater permeation of local tissues. All hyaluronidase products are approved for use as adjunct therapy to increase the absorption and dispersion of other injected drugs, particularly local anesthetics; for use in hypodermoclysis rehydration, a method of subcutaneous fluid replacement; and for use as an adjunct in subcutaneous urography for improving resorption of radiopaque agents. Beyond FDA-approved indications, hyaluronidase has been used as an adjunct to non-pharmacologic management of extravasation of certain drugs. Hyaluronidase is FDA approved for use in pediatric patients as young as premature neonates.

Hypersensitivity Test Dose:
Intradermal dosage:
Inject 0.02 mL of hyaluronidase intradermally (3 units of Amphadase or Hydase). Monitor patient for response. 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.

For use as an adjuvant to increase the absorption and dispersion of other drugs (e.g., local anesthesia, including infiltration anesthesia):
Regional dosage:
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.
Infants, Children, and Adolescents: 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):
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.
Infants, Children, and Adolescents: 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):
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 1,000 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.
Infants and Children 1 to 2 years: 200 units injected subcutaneously will facilitate absorption of 1,000 mL or more. Do not exceed a maximum fluid volume of 200 mL per single clysis.
Children and Adolescents 3 to 17 years: 200 units injected subcutaneously will facilitate absorption of 1,000 mL or more. Rate and volume of administration should not exceed those employed for intravenous infusion.
Subcutaneous dosage (Amphadase, Hydase, Hylenex):
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 1,000 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.
Infants and Children 1 to 2 years: 150 units injected subcutaneously will facilitate absorption of 1,000 mL or more. Do not exceed a maximum fluid volume of 200 mL per single clysis.
Children and Adolescents 3 to 17 years: 150 units injected subcutaneously will facilitate absorption of 1,000 mL or more. Rate and volume of administration should not exceed those employed for intravenous infusion.

For use as an adjunct in subcutaneous urography for improving resorption of urographic radiopaque contrast agents when intravenous administration cannot be successfully accomplished:
Subcutaneous dosage:
Neonates: 75 units injected subcutaneously over each scapula while the patient is lying prone, then inject contrast medium at the same sites.
Infants, Children, and Adolescents: 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 adjunct for extravasation* of selected drugs:
NOTE: Do not use hyaluronidase to enhance the absorption and dispersion of dopamine and/or alpha-agonist drugs.
Subcutaneous or Intradermal dosage:
Neonates: 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).
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).

Maximum Dosage Limits:
-Neonates
Maximum dosage information is not available.
-Infants
Maximum dosage information is not available.
-Children
Maximum dosage information is not available.
-Adolescents
Maximum dosage information is not available.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

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 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 cases of extravasation, hyaluronidase is used to increase the dispersion and absorption of select agents after unintentional drug infiltration.

Pharmacokinetics: Hyaluronidase is administered intradermally and subcutaneously. 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; hyaluronidase-induced absorption and dispersion of other drugs is not achieved after intravenous administration.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Other Route(s)
Intradermal Route
After intradermal administration of hyaluronidase in adult humans, the drug effect completely dissipates within 48 hours.