Asparlas Drug Information

Acute Lymphoblastic Leukemia ASPARLAS is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years.

Recommended Dosage

The recommended dose of ASPARLAS is 2,500 units/m 2 given intravenously no more frequently than every 21 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 ASPARLAS 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. Action Infusion Reaction/ Hypersensitivity Reaction

Preparation and Administration ASPARLAS 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.

Do not administer if ASPARLAS has been shaken or vigorously agitated, frozen, or stored at room temperature for more than 48 hours. Dilute ASPARLAS in 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP using sterile/aseptic technique. Discard any unused portion left in a vial.

After dilution, administer immediately into a running infusion of either 0.9% sodium chloride or 5% dextrose, respectively. Administer the dose over a period of 1 hour. Do not infuse other drugs through the same intravenous line during administration of ASPARLAS.

The diluted solution may be stored for up to 4 hours at room temperature (15°C to 25°C ) or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours. Protect from light. Do not shake or freeze.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The median age on enrollment was 5 years (range, 1-20 years). The majority of patients were male (62%) and white (70%).

Most patients were considered standard risk (SR, 59%) and had B-cell lineage ALL (87%). The median number of doses during the study was 11 doses for ASPARLAS (administered every three weeks) and 16 doses for pegaspargase (administered every two weeks). The median duration of exposure was 8 months for both ASPARLAS and pegaspargase.

There was 1 fatal adverse reaction (multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst). Table 2 summarizes the incidence of selected grades ≥3 adverse reactions that occurred in 2 or more patients receiving ASPARLAS. Table 2: Selected Grades ≥3 Adverse Reactions in Patients Receiving ASPARLAS with Multi-Agent Chemotherapy (Study DFCI 11-001) ASPARLAS or pegaspargase were administered as a component of multi-agent chemotherapy regimens. 2 1 In the subgroup of patients with B-cell lineage ALL, the complete remission rate in the ASPARLAS arm was 98% (95/97), compared to 99% in the pegaspargase arm; the Kaplan-Meier estimates of overall survival of the treatment arms were comparable.

Study AALL07P4 The safety of ASPARLAS was also evaluated in Study AALL07P4, an open-label, randomized, active-controlled, multicenter clinical trial that treated patients with newly diagnosed high-risk B-precursor ALL using ASPARLAS 2,500 U/m 2 (n=43) or 2,100 U/m 2 (n=68), or pegaspargase 2,500 U/m 2 (n=52), as a component of an augmented Berlin-Frankfurt-Münster (BFM) therapy regimen. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions In Study DFCI 11-001, hypersensitivity reactions occurred in 80% of ASPARLAS-treated patients with new or an increased titer of anti-drug antibodies (ADA) and in 6% of those without ADA. Two patients with ADA experienced anaphylaxis.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of ASPARLAS. 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. Hepatic: Veno-occlusive disease

Pregnancy Risk Summary Based on published literature studies with L-asparaginase in pregnant animals, ASPARLAS can cause fetal harm when administered to a pregnant woman. There are no available data on ASPARLAS use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of calaspargase pegol-mknl to pregnant rats during organogenesis at doses 0.2 to 1 times the maximum recommended human doses did not result in adverse developmental outcomes.

Published literature studies in pregnant rabbits, however, 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 risk of major birth defects and miscarriage in clinically recognized pregnancies are respectively.

Data Animal Data In an embryo-fetal development study, calaspargase pegol-mknl was administered intravenously at doses of times the maximum recommended human dose, respectively, based on AUC to pregnant rats during the period of organogenesis. Maternal toxicity of decreased body weight and food consumption was seen at all dose levels resulting in reductions in gravid uterine and placental weights, and slight reductions in fetal body weights. No evidence of structural abnormalities or embryo-fetal mortality were observed in this study at any of the doses tested.

Published literature studies in which pregnant rabbits were administered L-asparaginase suggested harm to the animal offspring.

Pediatric Use The safety and effectiveness of ASPARLAS in the treatment of ALL have been established in pediatric patients 1 month to <17 years (no data for the age group <1 month old). Use of ASPARLAS in these age groups is supported by evidence from an adequate and well-controlled trial with additional safety from a second trial. There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups.

ASPARLAS is contraindicated in patients with: History of serious hypersensitivity reactions, including anaphylaxis, to pegylated L-asparaginase therapy History of serious pancreatitis during previous L-asparaginase therapy History of serious thrombosis during previous L-asparaginase therapy History of serious hemorrhagic events during previous L-asparaginase therapy Severe hepatic impairment History of serious hypersensitivity reactions to pegylated L-asparaginase. History of serious pancreatitis related to previous L-asparaginase treatment. Severe hepatic impairment.