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.

2.1 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.

Always use aseptic precautions. Lightly pinch the skin up into a small mound and insert the needle/catheter into the subcutaneous space. Inject HYLENEX recombinant through the catheter hub or injection port closest to the needle/catheter. Begin administration of solution. Solution should start in readily.

2.2 Subcutaneous Fluid Administration

Inject 150 U of HYLENEX recombinant prior to start of subcutaneous fluid administration to facilitate absorption of up to 1,000 mL or more of solution. 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 50-300 U, most typically 150 U 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 U of HYLENEX recombinant subcutaneously over each scapula, followed by injection of the contrast medium at the same sites.

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.

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.

8.1 Pregnancy

Pregnancy Category C. In an embryo-fetal study, mice have been dosed daily by subcutaneous injection with recombinant human hyaluronidase at dose levels up to 2,200,000 U/kg. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which represents several orders of magnitude over the suggested human dose range of 50-300 U of HYLENEX recombinant (0.8-5 U/kg in a 60 kg subject).

In a pre- and postnatal development study, mice have been dosed daily by subcutaneous injection with recombinant human hyaluronidase at dose levels up to 1,100,000 U/kg. The study found no adverse effects on sexual maturation, learning and memory of offspring, or their ability to produce another generation of offspring.

It is also not known whether HYLENEX recombinant can cause fetal harm when administered to a pregnant woman. HYLENEX recombinant should be given to a pregnant woman only if clearly needed.

8.2 Labor and Delivery

Administration of hyaluronidase during labor was reported to cause no complications: no increase in blood loss or differences in cervical trauma were observed.

8.3 Nursing Mothers

It is not known whether hyaluronidase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when hyaluronidase is administered to a nursing woman.

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.

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 U/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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Hyaluronidase is found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase.

Human studies on the effect of intravaginal hyaluronidase in sterility due to oligospermia indicated that hyaluronidase may have aided conception. Thus, it appears that hyaluronidase may not adversely affect fertility in females. In addition, when recombinant human hyaluronidase was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.

Store unopened in a refrigerator at 2° to 8°C (36° to 46° F).

DO NOT FREEZE.

17.1 Important Precautions Regarding HYLENEX recombinant

Instruct patient 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 patient that there may be mild local injection site signs and symptoms, such as redness, swelling, itching, or pain localized to the site of injection.

17.2 What Patients Should Know About Adverse Reactions

Patients should be advised 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.

17.3 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.

Patients should be advised 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.