HYLENEX RECOMBINANT

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.

HYLENEX recombinant is an endoglycosidase indicated as an adjuvant in subcutaneous fluid administration for achieving hydration ( 1.1 ) to increase the dispersion and absorption of other injected drugs ( 1.2 ) in subcutaneous urography for improving resorption of radiopaque agents ( 1.3 ) 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.

See Full Prescribing Information for all approved routes of administration. ( 2.1 ) Subcutaneous Fluid Administration : Inject 150 USP units HYLENEX recombinant prior to subcutaneous fluid administration. It will facilitate absorption of 1,000 mL or more of solution. 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. ( 2.2 ) Increasing Dispersion and Absorption of Injected or Subcutaneously Infused Drugs : Inject 50 units to 300 units (most typically 150 USP units) HYLENEX recombinant prior to drug administration. Alternatively, add 50 units to 300 units (most typically 150 USP units) HYLENEX recombinant to the injection solution. ( 2.3 ) Subcutaneous Urography : Inject 75 USP units HYLENEX recombinant subcutaneously over each scapula, followed by injection of the contrast medium at the same sites. ( 2.4 ) 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.

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. Hypersensitivity ( 4 )

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. Allergic and anaphylactic-like reactions have been reported, rarely. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Halozyme,ºInc. at 1-877-877-1679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

It is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding HYLENEX recombinant to a solution containing another drug. Furosemide, the benzodiazepines and phenytoin are incompatible with hyaluronidase. ( 7.1 ) Hyaluronidase should not be used to enhance the dispersion and absorption of dopamine and/or alpha agonist drugs. ( 7.2 ) Local anesthetics: Hyaluronidase hastens onset and shortens duration of effect, increases incidence of systemic reactions. ( 7.3 ) Large doses of salicylates, cortisone, ACTH, estrogens or antihistamines may require larger amounts of hyaluronidase for equivalent dispersing effect. ( 7.4 ) 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.

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.