These highlights do not include all the information needed to use HYLENEX recombinant safely and effectively. See full prescribing information for HYLENEX recombinant. HYLENEX recombinant (hyaluronidase) injection for infiltration use, for interstitial use, for intramuscular use, for intraocular use, for peribulbar use, retrobulbar use, for soft tissue use or for subcutaneous use Initial U.S. Approval: 2005
1. Indications and Usage
1.1. Subcutaneous Fluid Administration
HYLENEX recombinant is indicated as an adjuvant in subcutaneous fluid administration for achieving hydration.
1.2. Dispersion and Absorption of Injected Drugs
HYLENEX recombinant is indicated as an adjuvant to increase the dispersion and absorption of other injected drugs.
1.3. Subcutaneous Urography
HYLENEX recombinant is indicated as an adjunct in subcutaneous urography for improving resorption of radiopaque agents.
2. Dosage and administration
2.1. Important Administration Instructions
HYLENEX recombinant should not be administered intravenously. Its effects relative to dispersion and absorption of other drugs are not produced when it is administered intravenously because the enzyme is rapidly inactivated.
HYLENEX recombinant may be administered for infiltration use, interstitial use, intramuscular use, intraocular use, peribulbar use, retrobulbar use, soft tissue use or subcutaneous use. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration.
2.2. Subcutaneous Fluid Administration
Lightly pinch the skin up into a small mound and insert the needle/catheter into the subcutaneous space. Inject 150 USP units of HYLENEX recombinant prior to start of subcutaneous fluid administration to facilitate absorption of up to 1,000 mL or more of solution. Inject HYLENEX recombinant through the catheter hub or injection port closest to the needle/catheter. Begin administration of solution. Solution should start in readily. As with all parenteral fluid therapy, observe effect closely, with the same precautions for restoring fluid and electrolyte balance as in intravenous injections. The dose, the rate of injection, and the type of solution (saline, glucose, Ringer's, etc.) must be adjusted carefully to the individual patient. When solutions devoid of inorganic electrolytes are administered subcutaneously, hypovolemia may occur. This may be prevented by using solutions containing adequate amounts of inorganic electrolytes and/or controlling the volume and speed of administration.
HYLENEX recombinant may be added to small volumes of solution, such as fluid replacement solutions or solutions of drugs for subcutaneous injection. Subcutaneous fluids should be administered as directed by a physician. The dosage of subcutaneous fluids administered is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. The rate and volume of subcutaneous fluid administration should not exceed those employed for intravenous infusion. For premature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg and the rate of administration should not be greater than 2 mL per minute.
2.3. Dispersion and Absorption of Injected Drugs
Hylenex can be used to enhance the dispersion and absorption of other injected or subcutaneously infused drugs by pre-administration of HYLENEX recombinant or by adding 50 units to 300 units, most typically 150 USP units hyaluronidase, to the injection solution prior to infiltration use, interstitial use, intramuscular use, intraocular use, retrobulbar use, soft tissue use or subcutaneous use.
2.4. Subcutaneous Urography
The subcutaneous route of administration of urographic contrast media may be considered when intravenous administration cannot be successfully accomplished, particularly in infants and small children. With the patient prone, inject 75 USP units of HYLENEX recombinant subcutaneously over each scapula, followed by injection of the contrast medium at the same sites.
3. Dosage Forms and Strengths
Injection: 150 USP units/mL as a clear and colorless solution in a single-dose vial.
4. Contraindications
HYLENEX recombinant is contraindicated in patients with known hypersensitivity to hyaluronidase or any of the excipients in HYLENEX recombinant. Discontinue HYLENEX recombinant if sensitization occurs.
5. Warnings and Precautions
5.1. Spread of Localized Infection
Hyaluronidase should not be injected into or around an infected or acutely inflamed area because of the danger of spreading a localized infection.
Hyaluronidase should not be used to reduce the swelling of bites or stings.
5.2. Ocular Damage
Hyaluronidase should not be applied directly to the cornea. It is not for topical use.
6. Adverse Reactions
The following adverse reactions have been identified during post-approval use of hyaluronidase products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most frequently reported adverse reactions have been mild local injection site reactions such as erythema and pain. Hyaluronidase has been reported to enhance the adverse reactions associated with co-administered drug products. Edema has been reported most frequently in association with subcutaneous fluid administration. Allergic reactions (urticaria or angioedema) have been reported in less than 0.1% of patients receiving hyaluronidase. Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred, rarely.
7. Drug Interactions
It is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding HYLENEX recombinant to a solution containing another drug.
7.1. Incompatibilities
Furosemide, the benzodiazepines and phenytoin have been found to be incompatible with hyaluronidase.
Admixture stability studies have shown that 2% lidocaine with 1:100,000 or 1:200,000 epinephrine is incompatible with hyaluronidase due to the presence of sodium metabisulfite, a common additive in anesthetic products containing epinephrine.
7.2. Drug-Specific Precautions
Hyaluronidase should not be used to enhance the dispersion and absorption of dopamine and/or alpha agonist drugs.
When considering the administration of any other drug with hyaluronidase, it is recommended that appropriate references first be consulted to determine the usual precautions for the use of the other drug.
7.3. Local Anesthetics
When hyaluronidase is added to a local anesthetic agent, it hastens the onset of analgesia and tends to reduce the swelling caused by local infiltration, but the wider spread of the local anesthetic solution increases its absorption; this shortens its duration of action and tends to increase the incidence of systemic reaction.
7.4. Salicylates, Cortisone, ACTH, Estrogens and Antihistamines
Patients receiving large doses of salicylates, cortisone, ACTH, estrogens or antihistamines may require larger amounts of hyaluronidase for equivalent dispersing effect, since these drugs apparently render tissues partly resistant to the action of hyaluronidase.
8. Use in Specific Populations
8.1. Pregnancy
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Risk Summary
There are no adequate and well-controlled studies of HYLENEX recombinant administration in pregnant women to inform a drug-associated risk. Subcutaneous administration of HYLENEX recombinant to pregnant mice throughout organogenesis did not produce teratogenic effects at clinically relevant doses. Administration of HYLENEX recombinant to mice in a pre-/postnatal study did not produce adverse effects on offspring at clinically relevant doses.
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Human Data
Limited available data with HYLENEX recombinant in pregnant women have not identified any potential risks.
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Animal Data
In an embryofetal development study, subcutaneous administration of hyaluronidase to pregnant mice throughout organogenesis produced reduced fetal weight and increased numbers of fetal resorptions at daily doses greater or equal to 3 mg/kg (approximately 360,000 USP units/kg). No malformations were produced at any dose up to approximately 18 mg/kg (approximately 2,200,000 USP units/kg). These doses are several orders of magnitude greater than the maximum recommended human dose (5 USP units/kg).
In a pre- and postnatal development study, mice were dosed daily by subcutaneous injection with hyaluronidase at dose levels up to 9 mg/kg (approximately 1,100,000 USP units/kg). The study found no adverse effects on sexual maturation, learning and memory of offspring, or their ability to produce another generation of offspring.
8.2. Lactation
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Risk Summary
There is no information regarding the presence of HYLENEX recombinant in human milk, the effects on the breastfed infants, or the effects on milk production to inform risk of HYLENEX recombinant to an infant during lactation.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HYLENEX recombinant.
8.4. Pediatric Use
Clinical hydration requirements for children can be achieved through administration of subcutaneous fluids facilitated with HYLENEX recombinant.
The dosage of subcutaneous fluids administered is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. The potential for chemical or physical incompatibilities should be kept in mind [see Drug Interactions (7)].
The rate and volume of subcutaneous fluid administration should not exceed those employed for intravenous infusion. For premature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg of body weight, and the rate of administration should not be greater than 2 mL per minute.
During subcutaneous fluid administration, special care must be taken in pediatric patients to avoid over hydration by controlling the rate and total volume of the infusion [see Dosage and Administration (2.1)].
8.5. Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.
11 Description
Hyaluronidase is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is a glycosylated single-chain protein produced by genetically engineered Chinese Hamster Ovary (CHO) cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase has an approximate molecular weight of 61 kDa.
HYLENEX recombinant (hyaluronidase) injection is supplied as a sterile, clear and colorless, nonpreserved, ready-for-use 1 mL solution in a single-dose vial for infiltration use, for interstitial use, for intramuscular use, for intraocular use, for peribulbar use, for retrobulbar use, for soft tissue use, or for subcutaneous use. Each mL contains 150 USP units of hyaluronidase with albumin human (1 mg), dibasic sodium phosphate (1.4 mg), methionine (1.5 mg), polysorbate 80 (0.2 mg), and sodium chloride (8.5 mg). Hydrochloric acid and sodium hydroxide may be added during manufacture to adjust the pH. HYLENEX has an approximate pH of 7.0.
12 Clinical Pharmacology
12.1 Mechanism of Action
Hyaluronidase is a dispersion agent, which modifies the permeability of connective tissue through the hydrolysis of hyaluronic acid, a polysaccharide found in the intercellular ground substance of connective tissue, and of certain specialized tissues, such as the umbilical cord and vitreous humor. Hyaluronic acid is also present in the capsules of type A and C hemolytic streptococci. Hyaluronidase hydrolyzes hyaluronic acid by splitting the glucosaminidic bond between C1 of an N-acetylglucosamine moiety and C4 of a glucuronic acid moiety. This temporarily decreases the viscosity of the cellular cement and promotes dispersion of injected fluids or of localized transudates or exudates, thus facilitating their absorption.
Hyaluronidase cleaves glycosidic bonds of hyaluronic acid and, to a variable degree, some other acid mucopolysaccharides of the connective tissue. The activity is measured in vitro by monitoring the decrease in the amount of an insoluble serum albumin-hyaluronic acid complex as the enzyme cleaves the hyaluronic acid component.
12.2 Pharmacodynamics
In the absence of hyaluronidase, material injected subcutaneously disperses very slowly. Hyaluronidase facilitates dispersion, provided local interstitial pressure is adequate to furnish the necessary mechanical impulse. Such an impulse is normally initiated by injected solutions. The rate and extent of dispersion and absorption is proportionate to the amount of hyaluronidase and the volume of solution.
The reconstitution of the dermal barrier removed by intradermal injection of hyaluronidase (20, 2, 0.2, 0.02, and 0.002 USP units/mL) to adult humans indicated that at 24 hours the restoration of the barrier is incomplete and inversely related to the dosage of hyaluronidase; at 48 hours, the barrier is completely restored in all treated areas.
Results from an experimental study, in humans, on the influence of hyaluronidase in bone repair support the conclusion that hyaluronidase alone, in the usual clinical dosage, does not deter bone healing.
12.3 Pharmacokinetics
Knowledge of the mechanisms involved in the disappearance of injected hyaluronidase is limited. It is known, however, that the components in blood of a number of mammalian species bring about the inactivation of hyaluronidase.
Studies have demonstrated that hyaluronidase is antigenic; repeated injections of relatively large amounts of hyaluronidase preparations may result in the formation of neutralizing antibodies.
13 Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. When hyaluronidase was subcutaneously administered to cynomolgus monkeys in a 39-week general toxicity study, no toxicity to the male or female reproductive systems was reported for measured parameters (i.e., semen analyses, hormone levels, menstrual cycles, gross pathology, histopathology, organ weight data), at dose levels up to 2 mg/kg (approximately 220,000 USP units/kg).
14 Clinical Studies
HYLENEX recombinant facilitated the administration of subcutaneous fluids in pediatric patients with mild to moderate dehydration in an open-label, multicenter, single arm study in fifty-one (51) patients. A subcutaneous injection of 1 mL (150 USP units) of HYLENEX recombinant was immediately followed by subcutaneous infusion of isotonic fluids in either the mid-anterior thigh or the inter-scapular area of the upper back.
The safety and flow rate of subcutaneously administered Lactated Ringer's (LR) solution with and without HYLENEX recombinant was evaluated in a prospective, randomized, double-blinded, placebo-controlled, within-subject, single-center study in fifty-four (54) healthy volunteers. The mean HYLENEX recombinant facilitated infusion rate was 464 mL/hr versus 118 mL/hr for the saline control (p < 0.001, paired t-test).
16 How Supplied/Storage and Handling
HYLENEX recombinant (hyaluronidase) injection is supplied sterile clear and colorless solution as 150 USP units of nonpreserved hyaluronidase per mL in a single-dose glass vial. Discard unused portion.
STORAGE AND HANDLING SECTION
HYLENEX recombinant is supplied in the following packaging:
1 mL single-dose vial (NDC 18657-117-01) available in boxes of 4 (NDC 18657-117-04)
Store unopened in a refrigerator at 2°C to 8°C (36°F to 46°F).
DO NOT FREEZE.
17 Patient Counseling Information
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Important Precautions Regarding HYLENEX recombinant
Instruct patients that HYLENEX recombinant is being used to increase the dispersion and absorption of fluids or other injected drugs, as appropriate to the intended use.
Instruct patients that there may be mild local injection site signs and symptoms, such as redness, swelling, itching, or pain localized to the site of injection.
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What Patients Should Know About Adverse Reactions
Advise patients that the most frequently reported adverse reactions have been mild local injection site reactions such as redness, swelling, itching, or pain.
Anaphylactic-like reactions, and allergic reactions, such as hives, have been reported rarely in patients receiving hyaluronidases.
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Patients Should Inform Their Doctors If Taking Other Medications
Instruct patients that they may not receive furosemide, the benzodiazepines, phenytoin, dopamine and/or alpha agonists with HYLENEX recombinant. These medications have been found to be incompatible with hyaluronidase.
Advise patients that if they are taking salicylates (e.g., aspirin), steroids (e.g., cortisone or estrogens), or antihistamines, they may need to be prescribed larger amounts of hyaluronidase for equivalent dispersing effect.
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Hylenex and the Hylenex logo are trademarks of Halozyme, Inc.
Patents: https://halozyme.com/
Manufactured for and marketed by: Halozyme, Inc., San Diego, CA 92130Distributed by: Antares Pharma, Inc. Ewing, NJ 08628US license 2187For Product Inquiry: 1 855 495-3639
Rev. 01/2024LBL301-06