VITRASE

1 INDICATIONS AND USAGE VITRASE is an endoglycosidase indicated as an adjuvant: in subcutaneous fluid administration for achieving hydration. ( 1.1 ) for increasing the dispersion and absorption of other injected drugs. ( 1.2 ) for improving resorption of radiopaque agents, in subcutaneous urography. ( 1.3 ) 1.1 Subcutaneous Fluid Administration (Hypodermoclysis) VITRASE ® (hyaluronidase injection) is indicated as an adjuvant in subcutaneous fluid administration for achieving hydration. 1.2 Dispersion and Absorption of Injected Drugs VITRASE is indicated as an adjuvant to increase the dispersion and absorption of other injected drugs. 1.3 Subcutaneous Urography VITRASE is indicated as an adjuvant in subcutaneous urography for improving resorption of radiopaque agents.

2 DOSAGE AND ADMINISTRATION Draw the desired amount of VITRASE into the syringe to obtain target hyaluronidase activity (USP Units) according to table. ( 2.1 ) Before adding VITRASE to a solution containing another drug check appropriate references regarding physical/chemical incompatibilities. ( 7 ) Subcutaneous Fluid Administration : Inject 200 Units of VITRASE prior to clysis. It will facilitate absorption of 1,000 mL or more of solution. The dosage of subcutaneous fluids administered depends upon the age, weight, clinical condition of the patient, and laboratory determinations. Rate and volume of subcutaneous fluid administration should not exceed those employed for intravenous infusion. ( 2.2 , 8.4 ) Increasing absorption and dispersion of injected drugs : Add 50–300 Units (most typically 150 Units) of VITRASE to the injection solution. ( 2.3 ) Subcutaneous urography : With the patient prone, inject 75 Units of VITRASE subcutaneously over each scapula, followed by injection of the contrast medium at the same sites. ( 2.4 ) 2.1 Important Administration Instructions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. VITRASE should be administered as discussed below, since its effects relative to absorption and dispersion of other drugs are not produced when it is administered intravenously. Draw the desired amount of VITRASE into the syringe to obtain the target Hyaluronidase Activity (USP Units) according to the table below. Table 1. Amount of VITRASE Solution Withdrawn Per Target Hyaluronidase Activity Target Hyaluronidase Activity (USP Units) Volume Withdrawn from Vial (mL) 50 Units 0.25 mL 75 Units 0.38 mL 150 Units 0.75 mL 200 Units 1.00 mL After admixture with drug, store at 15°C to 25°C (59°F to 77°F) and use within 6 hours. Consult the Prescribing Information of other drugs for additional storage information. 2.2 Dosage for Subcutaneous Fluid Administration (Hypodermoclysis) Insert needle with aseptic precautions. With tip free and movable between skin and muscle, begin clysis; fluid should start in readily without pain or lump. Then inject VITRASE into rubber tubing close to needle. An alternate method is to inject VITRASE under skin prior to clysis. 200 Units will facilitate absorption of 1,000 mL or more of solution. As with all parenteral fluid therapy, observe effect closely, with 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 given by hypodermoclysis, 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. VITRASE may be added to small volumes of solution (up to 200 mL), such as small clysis for infants or solutions of drugs for subcutaneous injection. For infants and children less than 3 years old, the volume of a single clysis should be limited to 200 mL; and in premature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg of body weight; the rate of administration should not be greater than 2 mL per minute. For older patients, the rate and volume of administration should not exceed those employed for intravenous infusion. 2.3 Dosage for Absorption and Dispersion of Injected Drugs Absorption and dispersion of other injected drugs may be enhanced by adding 50 Units to 300 Units, most typically 150 Units of VITRASE to the injection solution. 2.4 Dosage for Subcutaneous Urography The subcutaneous route of administration of urographic contrast media is indicated when intravenous administration cannot be successfully accomplished, particularly in infants and small children. With the patient prone, 75 Units of VITRASE are injected subcutaneously over each scapula, followed by injection of the contrast medium at the same sites.

4 CONTRAINDICATIONS VITRASE is contraindicated in patients with known hypersensitivity to hyaluronidase or any other ingredient in the formulation. Discontinue VITRASE if sensitization occurs. Hypersensitivity ( 4 )

5 WARNINGS AND PRECAUTIONS Spread of Localized Infection ( 5.1 ) Ocular Cornea Damage ( 5.2 ) Enzyme Inactivation with Intravenous Administration ( 5.3 ) 5.1 Spread of Localized Infection Hyaluronidase should not be injected into or around infected or acutely inflamed area because of the danger of spreading to a localized infection. Hyaluronidase should not be used to reduce the swelling of bites or stings. 5.2 Ocular Cornea Damage VITRASE should not be applied directly to the cornea. 5.3 Enzyme Inactivation with Intravenous Administration VITRASE should not be used for intravenous injections because the enzyme is rapidly inactivated.

7 DRUG INTERACTIONS It is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding VITRASE to a solution containing another drug. Furosemide, benzodiazepines and phenytoin are incompatible with hyaluronidase. ( 7.1 ) Hyaluronidase should not be used to enhance the absorption and dispersion 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, adrenocorticotropic hormone (ACTH), estrogens or antihistamines: Concomitant use may require larger amounts of hyaluronidase for equivalent dispersing effect. ( 7.4 ) 7.1 Incompatibilities Furosemide, benzodiazepines and phenytoin have been found to be incompatible with hyaluronidase. 7.2 Drug-Specific Precautions Hyaluronidase should not be used to enhance the absorption and dispersion 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 Anesthetic Agent 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 incidences of systemic reaction. 7.4 Salicylates, Cortisone, ACTH, Estrogens, Antihistamines Patients receiving large doses of salicylates, cortisone, adrenocorticotropic hormone (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.

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 local injection site reactions. Hyaluronidase has been reported to enhance the adverse reactions associated with co-administered drug products. Edema has been reported most frequently in association with hypodermoclysis. Allergic reactions (e.g., urticaria, 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 Bausch & Lomb Incorporated at 1-800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary Human studies of hyaluronidase as an aid to conception and as an aid to delivery have been conducted without reports of maternal or fetal harm. Non-human animal reproduction studies have not been conducted with VITRASE. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Clinical Considerations Hyaluronidase has been used as a component to aid the in vitro fertilization of human eggs. Administration of hyaluronidase during labor was reported to cause no complications; no increase in blood loss or differences in cervical trauma were observed.