Adverse reactions have been reported in adults and pediatric patients. Overall, the adult patients treated with ONCASPAR^Ò had a somewhat higher incidence of known L-asparaginase toxicities, except for hypersensitivity reactions, than the pediatric patients treated with ONCASPAR^Ò .

Excluding hypersensitivity reactions, the most frequently occurring known L-asparaginase related toxicities and adverse experiences reported for the 174 patients in clinical studies were chemical hepatotoxicities and coagulopathies, the majority of which did not result in any significant clinical events. The incidence of significant clinical events included clinical pancreatitis (1%), hyperglycemia requiring insulin therapy (3%), and thrombosis (4%).

The following adverse reactions related to ONCASPAR^Ò were reported for 174 patients in five clinical studies. The adverse reactions reported most frequently (greater than 5%) were allergic reactions (which may have included rash, erythema, edema, pain, fever, chills, urticaria, dyspnea, or bronchospasm), SGPT increase, nausea and/or vomiting, fever, and malaise.

The adverse reactions reported occasionally (greater than 1% but less than 5%) were anaphylactic reactions, dyspnea, injection site hypersensitivity, lip edema, rash, urticaria, abdominal pain, chills, pain in the extremities, hypotension, tachycardia, thrombosis, anorexia, diarrhea, jaundice, abnormal liver function test, decreased anticoagulant effect, disseminated intravascular coagulation, decreased fibrinogen, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia, increased thromboplastin, injection site pain, injection site reaction, bilirubinemia, hyperglycemia, hyperuricemia, hypoglycemia, hypoproteinemia, peripheral edema, increased SGOT, arthralgia, myalgia, convulsion, headache, night sweats, and paresthesia.

The adverse reactions reported rarely (less than 1%) were bronchospasm, petechial rash, face edema, lesional edema, sepsis, septic shock, chest pain, endocarditis, hypertension, constipation, flatulence, gastrointestinal pain, hepatomegaly, increased appetite, liver fatty deposits, coagulation disorder, increased coagulation time, decreased platelet count, purpura, increased amylase, edema, excessive thirst, hyper-ammonemia, hyponatremia, weight loss, bone pain, joint disorder, confusion, dizziness, emotional lability, somnolence, increased cough, epistaxis, upper respiratory infection, erythema simplex, pruritus, hematuria, increased urinary frequency, and abnormal kidney function.

The following ONCASPAR^Ò related adverse reactions have been observed in patients with hematologic malignancies, primarily acute lymphoblastic leukemia (approximately 75%), non-Hodgkins lymphoma (approximately 13%), acute myelogenous leukemia (approximately 3%), and a variety of solid tumors (approximately 9%):

HYPERSENSITIVITY REACTIONS: A variety of hypersensitivity reactions have occurred. These reactions may be acute or delayed, and include acute anaphylaxis, bronchospasm, dyspnea, urticaria, arthralgia, ery-thema, induration, edema, pain, tenderness, hives, swelling, lip edema, chills, fever, and skin rashes (SEE WARNINGS AND CONTRAINDICATIONS).

PANCREATIC FUNCTION: Pancreatitis, sometimes fulminant and fatal, has occurred. Increased serum amy-lase and lipase have also occurred.

LIVER FUNCTION: A variety of liver function abnormalities have been observed, including elevations of SGOT, SGPT, and bilirubin (direct and indirect). Jaundice, ascites, and hypoalbuminemia, which may be associated with peripheral edema, have been observed. These abnormalities usually are reversible on discontinuance of therapy, and some reversal may occur during the course of therapy. Fatty changes in the liver and liver failure have occurred.

HEMATOLOGIC: Hypofibrinogenemia, prolonged prothrombin times, prolonged partial thromboplastin times, and decreased antithrombin III have been observed. Superficial and deep venous thrombosis, sagit-tal sinus thrombosis, venous catheter thrombosis, and atrial thrombosis have occurred. Leukopenia, agranulocytosis, pancytopenia, thrombocytopenia, disseminated intravascular coagulation, severe hemolytic anemia, and anemia have been observed. Clinical hemorrhage (which may be fatal), easy bruis-ability, and ecchymosis have also been observed.

METABOLIC: Mild to severe hyperglycemia has been observed in low incidence, and usually responds to discontinuation of ONCASPAR^Ò and the judicious use of intravenous fluid and insulin. Hypoglycemia, increased thirst and hyponatremia, uric acid nephropathy, hyperuricemia, hypoproteinemia, and peripheral edema have also been observed. Hypoalbuminemia, proteinuria, weight loss, and metabolic acidosis have occurred. Therapy with ONCASPAR^Ò is associated with an increase in blood ammonia during the conversion of L-asparagine to aspartic acid by the enzyme.

NEUROLOGIC: Status epilepticus and temporal lobe seizures, somnolence, coma, malaise, mental status changes, dizziness, emotional lability, headache, lip numbness, finger paresthesia, mood changes, night sweats, and a Parkinson-like syndrome have occurred. Mild to severe confusion, disorientation, and paresthesia have also occurred. These side effects usually have reversed spontaneously after treatment was stopped.

RENAL: Increased BUN, increased creatinine, urinary frequency, hematuria due to thrombocytopenia, severe hemorrhagic cystitis, renal dysfunction, and renal failure have been observed.

CARDIOVASCULAR: Chest pain, subacute bacterial endocarditis, hypertension, severe hypotension, and tachycardia have occurred.

DIGESTIVE: Anorexia, constipation, decreased appetite, diarrhea, indigestion, flatulence, gas, gastrointestinal pain, mucositis, hepatomegaly, elevated gamma-glutamyltranspeptidase, increased appetite, mouth tenderness, severe colitis, and nausea and/or vomiting have been observed.

MUSCULOSKELETAL: Diffuse and local musculoskeletal pain, arthralgia, joint stiffness, and cramps have occurred.

RESPIRATORY: Cough, epistaxis, severe bronchospasm, and upper respiratory infection have been observed. SKIN/APPENDAGES: Itching, alopecia, fever blister, purpura, hand whiteness and fungal changes, nail whiteness and ridging, erythema simplex, jaundice, and petechial rash have occurred.

GENERAL: Localized edema, injection site reactions (including pain, swelling, or redness), malaise, infection, sepsis, fatigue, and septic shock may occur.

Unfavorable interactions of L-asparaginase with some antitumor agents have been demonstrated.¹ It is recommended, therefore, that ONCASPAR^Ò be used in combination regimens only by physicians familiar with the benefits and risks of a given regimen. Depletion of serum proteins by ONCASPAR^Ò may increase the toxicity of other drugs which are protein bound. Additionally, during the period of its inhibition of protein synthesis and cell replication, ONCASPAR^Ò may interfere with the action of drugs such as methotrexate, which require cell replication for their lethal effects. ONCASPAR^Ò may interfere with the enzymatic detoxification of other drugs, particularly in the liver. Physicians using a given treatment regimen should be thoroughly familiar with its benefits and risks.

Imbalances in coagulation factors have been noted with the use of ONCASPAR^Ò predisposing to bleeding and/or thrombosis. Caution should be used when administering any concurrent anticoagulant therapy, such as coumadin, heparin, dipyridamole, aspirin, or non-steroidal anti-inflammatories.

REFERENCES

1. Capizzi, RL and Holcenberg, JS. Asparaginase. In: Holland and Frei (eds). Cancer Med third edition, Lea and Febiger, Phila. PA, 1993.

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