Oncaspar Drug Information

First Line Acute Lymphoblastic Leukemia (ALL) ONCASPAR ® is indicated as a component of a multi-agent chemotherapeutic regimen for the first-line treatment of pediatric and adult patients with ALL.

Recommended Dosage Patients 21 Years of Age or Younger

The recommended dose of ONCASPAR for patients up to and including 21 years of age is 2,500 International Units/m 2 intramuscularly or intravenously no more frequently than every 14 days.

Recommended Premedication

Premedicate patients with acetaminophen, an H-1 receptor blocker (such as diphenhydramine), and an H-2 receptor blocker (such as famotidine) 30-60 minutes prior to administration of ONCASPAR to decrease the risk and severity of both infusion and hypersensitivity reactions.

Recommended Monitoring and Dosage Modifications for Adverse Reactions Monitor patients at least weekly, with bilirubin, transaminases, glucose and clinical examinations until recovery from the cycle of therapy. If an adverse reaction should occur, modify treatment according to Table 1. Table 1.

Action Infusion Reaction/Hypersensitivity Reaction

Preparation and Administration Administer ONCASPAR in a healthcare setting with appropriate medical support and resuscitation equipment to manage hypersensitivity reactions, should they occur. ONCASPAR is a clear and colorless solution. Visually inspect parenteral drug products for particulate matter, cloudiness, or discoloration prior to administration.

If any of these are present, discard the vial. When ONCASPAR is administered intramuscularly: Limit the volume at a single injection site to 2 mL. If the volume to be administered is greater than 2 mL, use multiple injection sites.

When ONCASPAR is administered intravenously: Dilute ONCASPAR with 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, using aseptic technique. After dilution, administer immediately into a running infusion of either 0.9% Sodium Chloride, USP or 5% Dextrose Injection, USP, respectively. Administer over a period of 1-2 hours.

Do not infuse other drugs through the same intravenous line during administration of ONCASPAR. The diluted solution should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours.

Protect infusion bags from direct sunlight. ONCASPAR does not contain a preservative. Use only one dose per vial; discard unused product.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. The most common grade 3 and 4 adverse reactions (>5%) included: hypoalbuminemia, elevated transaminase, febrile neutropenia, hypertriglyceridemia, hyperglycemia, bilirubin increased, pancreatitis, abnormal clotting studies, embolic and thrombotic events, hypersensitivity, sepsis, and infections. In Study CCG-1962, detailed safety information was collected for pre-specified adverse reactions identified as asparaginase induced adverse reactions and for grade 3 and 4 nonhematologic adverse reactions according to the Children's Cancer Group (CCG) Toxicity and Complication Criteria.

Incidence of Selected Grades 3 and 4 Adverse Reactions in Study CCG-1962 0 The safety of ONCASPAR was investigated in Study DFCI 11-001, an open label, randomized, active-controlled multicenter clinical trial that included 119 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma treated with ONCASPAR in combination with the Dana Farber Cancer Institute (DFCI) ALL Consortium backbone therapy. The median age on enrollment was 4 years (range, 1-18 years). The majority of patients were male (60%) and white (75%).

Most patients were considered standard risk ALL (59%) and had B-cell lineage ALL (87%). The median number of doses of ONCASPAR during the study was 16 doses (one dose during induction therapy then administered every two weeks during post induction therapy). The median duration of exposure to ONCASPAR was 8 months.

Table 3 summarizes the incidence of selected Grades ≥3 adverse reactions that occurred in 2 or more patients receiving ONCASPAR. Table 3. Incidence of Selected Grades ≥3 Adverse Reactions in Patients Receiving ONCASPAR With Multi-Agent Chemotherapy in Study DFCI 11-001 3 Previously Treated ALL Adverse reaction information was obtained from 5 clinical trials that enrolled a total of 174 patients with relapsed ALL who received ONCASPAR as a single agent or in combination with multi-agent chemotherapy.

The toxicity profile of ONCASPAR in patients with previously treated relapsed ALL is similar to that reported above with the exception of clinical allergic reactions (see Table 3 ). The most common adverse reactions of ONCASPAR were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to ONCASPAR treatment were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

Allergic Reactions Allergic reactions include the following: bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, and urticaria. Among 58 ONCASPAR-treated patients enrolled in Study CCG-1962, clinical allergic reactions were reported in 2 patients (3%). One patient experienced a grade 1 allergic reaction and the other grade 3 hives; both occurred during the first delayed intensification phase of the study (see Table 4 ).

Among 62 patients with relapsed ALL and prior hypersensitivity reactions to asparaginase, 35 patients (56%) had a history of clinical allergic reactions to native Escherichia (E.) coli L-asparaginase, and 27 patients (44%) had a history of clinical allergic reactions to both native E. coli and native Erwinia L-asparaginase. Twenty (32%) of these 62 patients experienced clinical allergic reactions to ONCASPAR (see Table 4 ). Table 4.

Incidence of Clinical Allergic Reactions, Overall and by Severity Grade Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other asparaginase products may be misleading. In Study CCG-1962, ONCASPAR treated patients were assessed for evidence of binding antibodies using an enzyme-linked immunosorbent assay (ELISA) method. In study CCG-1962, there is insufficient information to determine whether the development of antibodies is associated with an increased risk of clinical allergic reactions or altered pharmacokinetics (i.e., loss of asparaginase activity).

The presence of ADA correlated with the occurrence of hypersensitivity reactions.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ONCASPAR. 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. Blood and lymphatic system disorders: Coagulopathy.

Gastrointestinal disorders: Hepatic impairment, pancreatic cyst, pancreatitis. Hepatic: Veno-occlusive disease. Immune system disorders: Anaphylactic shock, hypersensitivity reaction.

Investigations: Blood cholesterol increased. Metabolism and nutrition disorders: Hyperglycemia, hyperammonemia. Musculoskeletal and connective tissue disorders: Osteonecrosis.

Vascular disorders: Hemorrhage including central nervous system hemorrhage, thrombosis including superior sagittal sinus thrombosis.

Glucocorticoids Pegaspargase may increase the risk of glucocorticoid-induced toxicities, including osteonecrosis through a potential increase in exposure of dexamethasone.

Pregnancy Risk summary Based on published literature studies with L-asparaginase in pregnant animals, ONCASPAR can cause fetal harm when administered to a pregnant woman. There are no available data on ONCASPAR use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published literature studies in pregnant animals suggest asparagine depletion may cause harm to the animal offspring (see Data ).

Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are respectively. Data Animal Data Animal reproduction studies have not been conducted with ONCASPAR to evaluate its effect on reproduction and fetal development.

Published literature studies in which pregnant rabbits were administered L-asparaginase or pregnant rats were deprived of dietary asparagine suggested harm to the animal offspring.

Pediatric Use The safety and effectiveness of ONCASPAR in the treatment of ALL have been established in pediatric patients. Use of ONCASPAR in these age groups is supported by evidence of efficacy as first-line treatment from one adequate and well-controlled trial, and evidence of efficacy for treatment of patients with hypersensitivity to asparaginase from four adequate and well-controlled trials, and safety data from 7 total trials.

ONCASPAR is contraindicated in patients with a: History of serious hypersensitivity reactions, including anaphylaxis, to ONCASPAR or to any of the excipients. History of serious thrombosis with prior L-asparaginase therapy. History of pancreatitis, including pancreatitis related to prior L-asparaginase therapy.

History of serious hemorrhagic events with prior L-asparaginase therapy. Severe hepatic impairment. History of serious hypersensitivity reactions to ONCASPAR.

History of pancreatitis with prior L-asparaginase therapy. Severe hepatic impairment.

Three patients received 10,000 International Units/m 2 of ONCASPAR as an intravenous infusion. One patient experienced a slight increase in liver enzymes. A second patient developed a rash 10 minutes after the start of the infusion, which was controlled with the administration of an antihistamine and by slowing down the infusion rate.

A third patient did not experience any adverse reactions. There is no specific antidote for ONCASPAR overdosage. In case of overdose, monitor patients closely for signs and symptoms of adverse reactions, and appropriately manage with symptomatic and supportive treatment.