Hyaluronidase is an enzyme that plays a role in the breakdown of hyaluronic acid, a substance found in the extracellular matrix of connective tissues, skin, and the eyes. Hyaluronic acid is a glycosaminoglycan, a type of molecule that is an essential component of the extracellular matrix and contributes to the structure and hydration of tissues.

Hyaluronidase (Hylenex) is an enzyme formulation that degrades hyaluronic acid. It is used to enhance the tissue penetration of drugs by increasing cell membrane permeability.

Indications of Hyaluronidase (Hylenex):

• Absorption and dispersion of injected drugs:
  • It is given as an adjuvant to increase the absorption and dispersion of other injected drugs.
• Subcutaneous fluid administration:
  • It is indicated 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.
• Off Label Use of Hyaluronidase in Adults:
  • Extravasation management
  • Local anesthetic adjuvant

Hyaluronidase (Hylenex) dose in adults:

Skin test:

• Hyaluronidase is a substance used in skin tests, where a small amount is injected just under the skin's surface.
• The typical dose is 0.02 mL of a solution containing 3 units (Amphadase and Hylenex) or 4 units (Vitrase) per mL.
• A positive reaction to the test is when a raised bump with finger-like projections appears within 5 minutes and lasts for 20-30 minutes, accompanied by localized itching.
• It's important to note that temporary redness is not considered a positive reaction.
• For situations like managing fluid leaks outside blood vessels (extravasation), a skin test is not required before using hyaluronidase.

Hyaluronidase (Hylenex) dose in Dehydration:

• In cases of dehydration, hyaluronidase can be used through a method called hypodermoclysis, which involves injecting it under the skin.
• The typical dose is either 150 or 200 units.
• After the injection, isotonic fluid (a solution with the same concentration of salts as your body fluids) is given under the skin, and the amount should be at least 1000 mL.
• Hyaluronidase can also be added to smaller volumes (up to 200 mL) of replacement fluid.
• It's important to control the rate and volume of this process, ensuring they don't exceed the levels used for intravenous (IV) fluid infusion.

Hyaluronidase (Hylenex) dose in the dispersion/absorption enhancement of injected drugs:

• To enhance the dispersion and absorption of injected drugs, hyaluronidase can be used subcutaneously (SubQ).
• The typical dose ranges from 50 to 300 units, with the usual dose being 150 units.
• This dose can be administered either before giving the drug or by adding hyaluronidase to the drug injection solution.

Hyaluronidase (Hylenex) dose in extravasation management (off-label):

• Various Drugs (Aminophylline, Amiodarone, Calcium Solutions, Dextrose <50%, Nafcillin, Parenteral Nutrition/Amino Acid (4.25%), Potassium Solutions, Sodium Chloride (>1%)):
  • Administration: Intradermal or SubQ
  • Dose: Inject a total of 1 to 1.7 mL (15 units/mL) as five separate 0.2 to 0.3 mL injections into the area of extravasation at the leading edge in a clockwise manner.
• Contrast Media Extravasation:
  • Note: There is conflicting information regarding hyaluronidase in contrast media extravasation management.
  • Dose: 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 into the area of extravasation at the leading edge in a clockwise manner.
• Dextrose 50% Extravasation:
  • Dose: Injection of a total of 1 mL (150 units/mL) as five separate 0.2 mL injections administered along the leading edge of erythema.
• Mannitol:
  • Administration: SubQ
  • Dose: Administer multiple injections of 0.5 to 1 mL (15 units/mL) around the periphery of the extravasation or inject a total of 1 to 1.7 mL (15 units/mL) as five separate 0.2 to 0.3 mL injections into the area of extravasation at the leading edge in a clockwise manner.
• Paclitaxel Extravasation:
  • Administration: IV or SubQ
  • Dose: Administer 1 to 6 mL (150 units/mL) into the existing IV line or inject subcutaneously in a clockwise manner around the area of extravasation. The usual dose is 1 mL hyaluronidase for each 1 mL of extravasated drug; may repeat several times over the next 3 to 4 hours.
• Sodium Bicarbonate Extravasation:
  • Administration: SubQ
  • Dose: Administer 4 to 5 separate 0.2 mL injections (15 units/mL) around the area of extravasation or inject a total of 1 to 1.7 mL (15 units/mL) as five separate 0.2 to 0.3 mL injections into the area of extravasation at the leading edge in a clockwise manner.
• 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 the existing IV line; the usual dose is 1 mL hyaluronidase for each 1 mL of extravasated drug.
  • If Needle/Cannula Has Been Removed (SubQ): Inject 1 to 6 mL (150 units/mL) in a clockwise manner using 1 mL for every 1 mL of drug extravasated or administer 1 mL (150 units/mL) as five separate 0.2 mL injections into the extravasation site.

Hyaluronidase (Hylenex) Retrobulbar/peribulbar block (adjuvant in bupivacaine-lidocaine mixture) (off-label):

• Procedure: Retrobulbar or peribulbar block.
• Adjuvant Dose (Hyaluronidase):
  • Either 3.75 units (150 units/mL concentration) or 7.5 units (150 units/mL concentration).
• Mixture for Injection:
  • A 1:1 mixture of bupivacaine 0.75% and lidocaine 2%.
• Total Volume:
  • Administer a total of 6 to 8 mL of the mixture.
• Administration:
  • Divide the total volume evenly between retrobulbar and peribulbar injections.
• Reference:
  • The dosing recommendation comes from the study by Kallio in 2000.

This combination is used in ophthalmic procedures to provide local anesthesia for surgeries around the eye.

Hyaluronidase dose in children:

Skin test:

• Type of Test:
  • Intradermal: A tiny amount (0.02 mL) of a solution containing 3 units (for Amphadase and Hylenex) or 4 units (for Vitrase) is injected just under the skin.
• Solution Strength:
  • Concentration: The solution has either 150 units/mL (for Amphadase and Hylenex) or 200 units/mL (for Vitrase).
• Positive Reaction:
  • Appearance: A positive reaction is when a raised bump with finger-like projections (wheal with pseudopods) shows up within 5 minutes and stays for 20 to 30 minutes. It might also come with localized itching. Transient erythema (temporary redness) is not counted as a positive reaction.
• When It's Used:
  • Extravasation Management: If the doctor needs to manage a fluid leak outside blood vessels (extravasation), they don't have to do a skin test first. They can go ahead and use hyaluronidase without testing the skin.

Hyaluronidase (Hylenex) Dose for Dehydration: Hypodermoclysis:

When babies, kids, or teens are dehydrated and need fluids, a method called hypodermoclysis can be used. Here's how it works:

• Injection before Fluids:
  • Amount: Either 150 units or 200 units, injected under the skin (SubQ).
  • Next Step: After the injection, give isotonic fluid (like saline) under the skin at a rate suitable for the child's age, weight, and how sick they are. The 150 units help absorb at least 1,000 mL of the fluid. If the infusion lasts more than 24 hours, additional doses (up to 3 total) can be given every 24 hours.
• Added to Replacement Fluids:
  • Amount: The dose depends on how much fluid needs to be infused. For example, 150 units of hyaluronidase helps with the absorption of at least 1,000 mL of fluid. In some cases, for very small babies needing less fluid (up to 100 mL), 15 units are added for every 100 mL of replacement fluid. The maximum daily dose is 150 units per day.
• Limits on Fluid Volume:
  • For Infants and Children under 3 years: The amount of fluid in a single session should not go over 200 mL.
  • For Children 3 years and older, including Adolescents: The rate and amount of fluid in a single session should not be more than what's typically used when giving fluids through a vein (IV).

Hyaluronidase (Hylenex) dose in the dispersion/absorption enhancement of injected drugs:

• Injection Method:
  • Under the Skin (SubQ): A small amount, somewhere between 50 and 300 units, is injected. The usual amount is 150 units.
• Timing:
  • When to Inject: The hyaluronidase can be injected either before giving the medicine or mixed with the medicine before injecting it.
• Consult Compatibility:
  • Mixing Precaution: Before combining hyaluronidase with the medicine, it's important for the doctor to check if they are compatible. This means they work well together without causing problems.

Hyaluronidase (Hylenex) dose in the treatment of extravasation:

• Injection Method:
  • Under the Skin (SubQ) or Just Beneath the Skin (Intradermal): Hyaluronidase is injected in small amounts, around 0.2 mL each, using 4 to 5 separate injections.
• Timing:
  • When to Inject: It's important to do this as soon as possible, preferably within 1 hour of noticing the extravasation.
• Concentration Choice:
  • Solution Strength: The concentration of hyaluronidase can be either 15 units/mL or 150 units/mL. Some centers decide based on the risk of the medicine causing tissue issues or the volume of the leaked medicine. For smaller volumes (less than 100 mL), a less concentrated solution (15 units/mL) is sometimes used.

So, by injecting hyaluronidase at the site of the leakage, doctors try to prevent or minimize any potential harm caused by the medicine that went outside of where it was supposed to go.

Hyaluronidase (Hylenex) dose in Urography:

• Dose:
  • Amount: 75 units of hyaluronidase are injected over each scapula (shoulder blade).
• Procedure:
  • Follow-up Injection: After injecting hyaluronidase, a contrast medium (a substance that enhances the visibility of structures in the body during imaging) is injected at the same site where hyaluronidase was administered.
• Patient Position:
  • Recommended Position: The patient should be in the prone position (lying face down) during the administration of the hyaluronidase and contrast medium.

This process is part of the urography procedure, which helps in obtaining clear images of the urinary system.

Hyaluronidase (Hylenex) Pregnancy Risk Category: C

• Hyaluronidase, when used to assist in delivery or conception, did not show any harmful effects on the mother or the baby.
• It was found safe during labor, causing no extra bleeding or differences in injury to the cervix.
• In studies, it has been looked at as a potential help before a procedure called intracytoplasmic sperm injection (ICSI), which is part of in vitro fertilization (IVF) for human eggs.
• Researchers found it to be safe and evaluated its use in these reproductive processes without observing any adverse events (DeVos 2008; Evison 2009; Majumdar 2013; Moura 2017; Worrilow 2013).

Hyaluronidase use during breastfeeding:

• It's uncertain whether hyaluronidase is present in breast milk when used for medical reasons.
• The manufacturer suggests that the decision about breastfeeding during treatment should take into account the potential risk of the baby being exposed to the medication, the advantages of breastfeeding for the infant, and the benefits of the treatment for the mother.
• Therefore, it's crucial for healthcare providers and mothers to carefully weigh these factors and make an informed decision about breastfeeding while undergoing hyaluronidase therapy.

Hyaluronidase (Hylenex) Dose adjustment in renal disease:

• The manufacturer's instructions do not include any specific adjustments to the dosage of the medication for individuals with kidney (renal) impairment.
• This implies that, according to the available information, the standard dosage recommendations apply to individuals with or without renal impairment.

Hyaluronidase (Hylenex) Dose adjustment in liver disease:

• The manufacturer's labeling for hyaluronidase does not include specific dosage adjustments for individuals with hepatic (liver) impairment.
• This suggests that, based on the available information, the standard dosage recommendations apply to individuals with or without hepatic impairment.

Side effects of Hyaluronidase (Hylenex):

• Cardiovascular:
  • Edema
• Local:
  • Injection site reaction

Contraindications to Hyaluronidase (Hylenex):

• If someone is sensitive or allergic to hyaluronidase or any part of the medication, it's not a good idea for them to use it.
• This is because their body might react negatively to the medication, and it could cause unwanted side effects.

Warnings and precautions

Hypersensitivity

• If someone has a known history of being allergic to bee stings, using hyaluronidase requires caution.
• This is because hyaluronidase is a part of bee venom, and individuals with a history of bee sting allergy may have an increased risk of being sensitive to hyaluronidase as well.

Sensitization:

• If someone using hyaluronidase develops sensitization, meaning they show signs of becoming overly sensitive or allergic to the medication, it's recommended to stop using it.
• In such cases, a skin test may be conducted to check for hypersensitivity and to help determine the cause of the reaction.

Hyaluronidase: Drug Interaction

Monitoring parameters:

Extravasation Management: Off-Label Use

• Document and Monitor:
  • Keep a record of the extravasation site.
  • Regularly check and observe the area where the medication leaked outside the blood vessel.

This off-label use involves managing the unintended leakage of medication, and careful documentation and monitoring of the extravasation site are essential steps in the process.

How to administer Hyaluronidase (Hylenex)?

Guidelines for Hyaluronidase Use: Extravasation Management

• Stop Infusion:
  • If extravasation occurs, halt the vesicant infusion immediately.
  • Disconnect the IV line, but leave the needle/cannula in place.
  • Gently aspirate the extravasated solution from the IV line; do not flush the line.
• Elevate and Monitor:
  • For vinca alkaloid extravasation, keep the needle/cannula in place and elevate the extremity.
  • For other vesicants, if appropriate, remove the needle/cannula and elevate the extremity.

Hyaluronidase Administration: Local Use (Intradermal or SubQ)

• Preparation:
  • Mix 0.1 mL of hyaluronidase (150 units/mL) with 0.9 mL of normal saline (NS) to create a final concentration of 15 units/mL.
• Administration:
  • Administer a total of 1 to 1.7 mL (15 units/mL) in 5 separate 0.2 to 0.3 mL injections.
  • Inject both intradermally and/or subcutaneously into the extravasation site.

Hyaluronidase Use for Vinca Alkaloids:

• If Needle/Cannula in Place:
  • Administer 1 to 6 mL of hyaluronidase (150 units/mL) into the existing IV line.
  • Usual dose: 1 mL of hyaluronidase for each 1 mL of extravasated drug.
• If Needle/Cannula Removed:
  • Inject 1 to 6 mL (150 units/mL) subcutaneously in a clockwise manner.
  • Alternatively, administer 1 mL (150 units/mL) in 5 separate 0.2 mL subcutaneous injections into the extravasation site.

Retrobulbar/Peribulbar Administration (Off-Label Use):

• Preparation:
  • Combine hyaluronidase with a 1:1 mixture of bupivacaine 0.75% and lidocaine 2% according to standard anesthetic technique.

These guidelines provide instructions for managing extravasation and administering hyaluronidase in various scenarios, emphasizing proper preparation and administration techniques.

Mechanism of action of Hyaluronidase (Hylenex):

• Hyaluronidase works by changing the permeability of connective tissue.
• It does this by breaking down hyaluronic acid, a key component that acts like a cement in tissues, creating a barrier to the movement of liquids.
• By hydrolyzing hyaluronic acid, hyaluronidase reduces this resistance and allows better distribution and absorption of locally injected or leaked IV medications.
• In simple terms, it helps medications spread more effectively in the targeted area, enhancing their overall impact.

Onset of Action:

• SubQ (Under the Skin): Immediate. When used to manage extravasation (leakage of fluids), there is typically a noticeable decrease in swelling within 15 to 30 minutes after administration (Zenk 1981b).

Duration:

• 24 to 48 hours (variable). The effectiveness of hyaluronidase can vary, but its impact usually lasts for a period of 24 to 48 hours.

International Brand Names of Hyaluronidase:

• Amphadase
• Hylenex
• Vitrase
• Facidase
• H-lase
• Hyalase
• Hyalasedessau
• Hyalozima
• Hyaluronidase Choay
• Hyanid
• Hyase
• Hyason
• Hylase
• Hylorase
• Hynidase
• Jaluran
• Lasonil
• Longidaza
• Lydase
• Lyrase
• Malinda
• Nydase
• Penetrase
• Permease
• Sprase
• Unidasa
• Vitrase

Hyaluronidase Injection Brand Names in Pakistan: