AMPHADASE

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

2 DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. • Subcutaneous Fluid Administration : Insert needle with aseptic precautions. With tip lying free and movable between skin and muscle, begin clysis; fluid should start in readily without pain or lump. Then inject Amphadase ® (hyaluronidase injection) into rubber tubing close to needle. ( 2.1 ) • 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 hyaluronidase, to the injection solution. ( 2.2 ) • 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 Amphadase ® (hyaluronidase injection) is injected subcutaneously over each scapula, followed by injection of the contrast medium at the same sites. ( 2.3 ) 2.1 Subcutaneous Fluid Administration (Hypodermoclysis) Insert needle with aseptic precautions. With tip lying free and movable between skin and muscle, begin clysis; fluid should start in readily without pain or lump. Then inject Amphadase ® (hyaluronidase injection) into rubber tubing close to needle. An alternate method is to inject Amphadase ® under skin prior to clysis. 150 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. Amphadase ® 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. 2.2 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 hyaluronidase, to the injection solution. 2.3 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 Amphadase ® (hyaluronidase injection) is injected subcutaneously over each scapula, followed by injection of the contrast medium at the same sites.

5 WARNINGS AND PRECAUTIONS • Spread of Localized Infection ( 5.1 ) • Ocular Damage ( 5.2 ) • Enzyme Inactivation with Intravenous Administration ( 5.3 ) 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. 5.3 Enzyme Inactivation with Intravenous Administration Hyaluronidase should not be used for intravenous injections because the enzyme is rapidly inactivated.

4 CONTRAINDICATIONS Hypersensitivity ( 4.1 ) 4.1 Hypersensitivity Hypersensitivity to hyaluronidase or any other ingredient in the formulation is a contraindication to the use of this product.

7 DRUG INTERACTIONS It is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding Amphadase ® 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 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 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; e.g., when epinephrine is injected along with hyaluronidase, the precautions for the use of epinephrine in cardiovascular disease, thyroid disease, diabetes, digital nerve block, ischemia of the fingers and toes etc., should be observed. 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, , 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.

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. There are no available data on Amphadase ® use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Amphadase ® . 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.

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 (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 Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.