Three patients received 10,000 International Units/m² of Lyophilized Pegaspargase® 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.
The following serious adverse reactions are described in greater detail in other sections of the label:
The most common adverse reactions with Lyophilized Pegaspargase® are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, hepatotoxicity and elevated transaminases.
Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) has been reported in patients exposed to Lyophilized Pegaspargase.
Clinical Trials ExperienceBecause 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.
First-Line ALLThe data presented below are derived from 2 studies in patients with standard-risk ALL who received Lyophilized Pegaspargase® as a component of first-line multi-agent chemotherapy. Study 1 was a randomized (1:1), active-controlled study that enrolled 118 patients, with a median age of 4.7 years (1.1-9.9 years), of whom 54% were males and 65% White, 14% Hispanic, 8% Black, 8% Asian, and 6% other. Of the 59 patients in Study 1 who were randomized to Lyophilized Pegaspargase® , 48 patients (81%) received all 3 planned doses of Lyophilized Pegaspargase®, 6 (10%) received 2 doses, 4 (7%) received 1 dose, and 1 patient (2%) did not receive the assigned treatment. Study 2 is an ongoing, multi-factorial design study in which all patients received Lyophilized Pegaspargase® as a component of various multi-agent chemotherapy regimens; interim safety data are available for 2,770 patients. Study participants had a median age of 4 years (1-10 years), and were 55% male, 68% White, 18% Hispanic, 4% Black, 3% Asian, and 7% other. Per protocol, the schedule of Lyophilized Pegaspargase® varied by treatment arm, with intermittent doses of Lyophilized Pegaspargase® for up to 10 months.
In Study 1, detailed safety information was collected for pre-specified adverse reactions identified as asparaginase-induced adverse reactions and for grade 3 and 4 non-hematologic adverse reactions according to the Children's Cancer Group (CCG) Toxicity and Complication Criteria. The per-patient incidence, by treatment arm, for these selected adverse reactions occurring at a severity of grade 3 or 4 are presented in Table 1 below:
TABLE 1 : STUDY 1: PER-PATIENT INCIDENCE OF SELECTED GRADE 3 AND 4 ADVERSE REACTIONS
| Lyophilized Pegaspargase® (n=58) | Native E. coli L-Asparaginase (n=59) | |
| Abnormal Liver Tests | 3 (5%) | 5 (8%) |
| Elevated Transaminases1 | 2 (3%) | 4 (7%) |
| Hyperbilirubinemia | 1 (2%) | 1 (2%) |
| Hyperglycemia | 3 (5%) | 2 (3%) |
| Central Nervous System Thrombosis | 2 (3%) | 2 (3%) |
| Coagulopathy2 | 1 (2%) | 3 (5%) |
| Pancreatitis | 1 (2%) | 1 (2%) |
| Clinical Allergic Reactions to Asparaginase | 1 (2%) | 0 |
| 1Aspartate aminotransferase, alanine aminotransferase. 2Prolonged prothrombin time or partial thromboplastin time; or hypofibrinogenemia. |
Safety data were collected in Study 2 only for National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0, grade 3 and 4 non-hematologic toxicities. In this study, the per-patient incidence for the following adverse reactions occurring during treatment courses in which patients received Lyophilized Pegaspargase® were: elevated transaminases, 11%; coagulopathy, 7%; hyperglycemia, 5%; CNS thrombosis/hemorrhage, 2%; pancreatitis, 2%; clinical allergic reaction, 1%; and hyperbilirubinemia, 1%. There were 3 deaths due to pancreatitis.
Previously Treated ALLAdverse reaction information was obtained from 5 clinical trials that enrolled a total of 174 patients with relapsed ALL who received Lyophilized Pegaspargase® as a single agent or in combination with multi-agent chemotherapy. The toxicity profile of Lyophilized Pegaspargase® in patients with previously treated relapsed ALL is similar to that reported above with the exception of clinical allergic reactions (see Table 2). The most common adverse reactions of Lyophilized Pegaspargase® were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to Lyophilized Pegaspargase® treatment were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).
Allergic ReactionsAllergic reactions include the following: bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, and urticaria.
First-Line ALLAmong 58 Lyophilized Pegaspargase®-treated patients enrolled in Study 1, 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 2).
Previously Treated ALLAmong 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 Lyophilized Pegaspargase® (see Table 2).
Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to Lyophilized Pegaspargase® (see Table 2).
TABLE 2 : INCIDENCE OF CLINICAL ALLERGIC REACTIONS, OVERALL AND BY SEVERITY GRADE
| Patient Status | Toxicity Grade, n (%) | Total | |||
| 1 | 2 | 3 | 4 | ||
| Previously Hypersensitive Patients (n=62) | 7 (11) | 8 (13) | 4 (6) | 1 (2) | 20 (32) |
| Non-Hypersensitive Patients (n=112) | 5 (4) | 4 (4) | 1 (1) | 1 (1) | 11 (10) |
| First Line (n=58) | 1 (2) | 0 | 1 (2) | 0 | 2 (3) |
As with all therapeutic proteins, there is a potential for immunogenicity, defined as development of binding and/or neutralizing antibodies to the product.
In Study 1, Lyophilized Pegaspargase®-treated patients were assessed for evidence of binding antibodies using an enzyme-linked immunosorbent assay (ELISA) method. The incidence of protocol-specified “high-titer” antibody formation was 2% in Induction (n=48), 10% in Delayed Intensification 1 (n=50), and 11% in Delayed Intensification 2 (n=44). There is insufficient information to determine whether the development of antibodies is associated with an increased risk of clinical allergic reactions, altered pharmacokinetics, or loss of anti-leukemic efficacy.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Lyophilized Pegaspargase® with the incidence of antibodies to other products may be misleading.
Lyophilized Pegaspargase® is indicated as a component of a multi-agent chemotherapeutic regimen for the first line treatment of patients with ALL.
Acute Lymphoblastic Leukemia And Hypersensitivity To AsparaginaseLyophilized Pegaspargase® is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with ALL and hypersensitivity to native forms of L-asparaginase.
In Study 1, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three intramuscular doses of Lyophilized Pegaspargase® (2,500 International Units/m²), one each during induction and two delayed intensification treatment phases. Pharmacodynamic activity was assessed through serial measurements of asparagine in sera (n=57) and cerebrospinal fluid (CSF) (n=50). The data for asparagine depletion are presented in CLINICAL STUDIES.
Pharmacokinetic assessments were based on an enzymatic assay measuring asparaginase activity. Serum pharmacokinetics were assessed in 34 newly diagnosed pediatric patients with standard-risk ALL in Study 1 following intramuscular administration of 2,500 International Units/m². The elimination half-life of Lyophilized Pegaspargase® was approximately 5.8 days during the induction phase. Similar elimination half-lives were observed during Delayed Intensification 1 and Delayed Intensification 2. Concentrations greater than 0.1 International Units/mL were observed in over 90% of the samples from patients treated with Lyophilized Pegaspargase® during induction, Delayed Intensification 1, and Delayed Intensification 2 for approximately 20 days.
In 3 pharmacokinetic studies, 37 patients with relapsed ALL received Lyophilized Pegaspargase® at 2,500 International Units/m² intramuscularly every 2 weeks. The plasma half-life of Lyophilized Pegaspargase® was 3.2 ± 1.8 days in 9 patients who were previously hypersensitive to native E. coli L-asparaginase and 5.7 ± 3.2 days in 28 non-hypersensitive patients. The area under the plasma concentration-time curve (AUC) was 9.5 ± 4.0 International Units/mL/day in the previously hypersensitive patients and 9.8 ± 6.0 International Units/mL/day in the non-hypersensitive patients.
Included as part of the PRECAUTIONS section.
PRECAUTIONS Anaphylaxis And Serious Allergic ReactionsAnaphylaxis and serious allergic reactions can occur in patients receiving Lyophilized Pegaspargase®. The risk of serious allergic reactions is higher in patients with known hypersensitivity to other forms of L-asparaginase. Observe patients for 1 hour after administration of Lyophilized Pegaspargase® in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue Lyophilized Pegaspargase® in patients with serious allergic reactions.
ThrombosisSerious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving Lyophilized Pegaspargase®. Discontinue Lyophilized Pegaspargase® in patients with serious thrombotic events.
PancreatitisPancreatitis can occur in patients receiving Lyophilized Pegaspargase®. Evaluate patients with abdominal pain for evidence of pancreatitis. Discontinue Lyophilized Pegaspargase® in patients with pancreatitis.
Glucose IntoleranceGlucose intolerance can occur in patients receiving Lyophilized Pegaspargase®. In some cases, glucose intolerance is irreversible.
CoagulopathyIncreased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving Lyophilized Pegaspargase®. Monitor coagulation parameters at baseline and periodically during and after treatment. Initiate treatment with fresh-frozen plasma to replace coagulation factors in patients with severe or symptomatic coagulopathy.
Hepatotoxicity And Abnormal Liver FunctionHepatotoxicity and abnormal liver function, including elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin (direct and indirect), and depression of serum albumin, and plasma fibrinogen can occur. Perform appropriate monitoring.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityAnimal reproduction studies have not been conducted with Lyophilized Pegaspargase®. It is also not known whether Lyophilized Pegaspargase® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lyophilized Pegaspargase® should be given to a pregnant woman only if clearly needed.
Nursing MothersIt is not known whether Lyophilized Pegaspargase® is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Lyophilized Pegaspargase®, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use Geriatric UseClinical studies of Lyophilized Pegaspargase® did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects.
The recommended dose of Lyophilized Pegaspargase® is 2,500 International Units/m² intramuscularly or intravenously. Lyophilized Pegaspargase® should be administered no more frequently than every 14 days.
Instructions For AdministrationWhen Lyophilized Pegaspargase® is administered intramuscularly, the volume at a single injection site should be limited to 2 mL. If the volume to be administered is greater than 2 mL, multiple injection sites should be used. Lyophilized Pegaspargase® does not contain a preservative. Use only one dose per vial; discard unused product.
When administered intravenously, Lyophilized Pegaspargase® should be given over a period of 1 to 2 hours in 100 mL of sodium chloride or dextrose injection 5%, through an infusion that is already running. After the solution is diluted for intravenous use, the 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). Storage after dilution should not exceed 48 hours from the time of preparation to completion of administration. Protect infusion bags from direct sunlight.
Preparation And Handling PrecautionsDo not administer Lyophilized Pegaspargase® if drug has been:
Parenteral drug products should be inspected visually for particulate matter, cloudiness, or discoloration prior to administration, whenever solution and container permit. If any of these are present, discard the vial.
