NDC 72694-954 Oncaspar

Pegaspargase

NDC Product Code 72694-954

NDC 72694-954-01

Package Description: 1 VIAL, SINGLE-USE in 1 CARTON > 5 mL in 1 VIAL, SINGLE-USE

NDC Product Information

Oncaspar with NDC 72694-954 is a a human prescription drug product labeled by Servier Pharmaceuticals Llc. The generic name of Oncaspar is pegaspargase. The product's dosage form is injection, solution and is administered via intramuscular; intravenous form.

Labeler Name: Servier Pharmaceuticals Llc

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Oncaspar Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • PEGASPARGASE 750 [iU]/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM PHOSPHATE, MONOBASIC, DIHYDRATE (UNII: 5QWK665956)
  • SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM (UNII: GR686LBA74)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intramuscular - Administration within a muscle.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Asparaginase - [CS]
  • Asparagine-specific Enzyme - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Servier Pharmaceuticals Llc
Labeler Code: 72694
FDA Application Number: BLA103411 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-02-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Pegaspargase Injection

Pegaspargase Injection is pronounced as (peg as' par jase)

Why is pegaspargase injection medication prescribed?
Pegaspargase is used with other chemotherapy drugs to treat a certain type of acute lymphocytic leukemia (ALL; a type of cancer of the white blood cells). Pegaspargase is...
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* Please review the disclaimer below.

Oncaspar Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 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.

1.2 Acute Lymphoblastic Leukemia And Hypersensitivity To Asparaginase

ONCASPAR is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of pediatric and adult patients with ALL and hypersensitivity to native forms of L-asparaginase.

Other

Patients ≤21 years of ageThe recommended dose of ONCASPAR for patients up to and including 21 years of age is 2,500 International Units/m2 intramuscularly or intravenously no more frequently than every 14 days.

Patients >21 years of ageThe recommended dose for adult patients more than 21 years of age is 2000 International Units/m2 intramuscularly or intravenously no more frequently than every 14 days.

First-Line Treatment of Acute Lymphoblastic Leukemia (ALL)Study CCG-1962 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 race. Of the 59 patients in Study 1 who were randomized to ONCASPAR, 48 patients (81%) received all 3 planned doses of ONCASPAR, 6 (10%) received 2 doses, 4 (7%) received 1 dose, and 1 patient (2%) did not receive the assigned treatment.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. 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 2 below:Table 2. Incidence of Selected Grades 3 and 4 Adverse Reactions in Study CCG-1962ONCASPAR(n=58)Native E. coli L-Asparaginase(n=59)Abnormal Liver Tests3 (5%)5 (8%)  Elevated TransaminasesAspartate aminotransferase, alanine aminotransferase.2 (3%)4 (7%)  Hyperbilirubinemia1 (2%)1 (2%)Hyperglycemia3 (5%)2 (3%)Central Nervous System Thrombosis2 (3%)2 (3%)CoagulopathyProlonged prothrombin time or partial thromboplastin time; or hypofibrinogenemia.1 (2%)3 (5%)Pancreatitis1 (2%)1 (2%)Allergic Reactions to Asparaginase1 (2%)0The 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 8 or more patients receiving ONCASPAR. Because not all grade 1 and 2 adverse reactions were collected prospectively, only grade 3 and 4 adverse reactions are presented in Table 3.Table 3: Incidence of Selected Grades ≥ 3 Adverse Reactions in Patients Receiving ONCASPAR With Multi-Agent Chemotherapy in Study DFCI 11-001Adverse ReactionGrouped terms: Elevated transaminase: Alanine aminotransferase increased, Aspartate aminotransferase increased; Pancreatitis: Amylase increased, Lipase increased, Pancreatitis, Pancreatitis relapsing; Bilirubin increased: Bilirubin conjugated increased, Blood bilirubin increased; Abnormal clotting studies: Activated partial thromboplastin time prolonged, Blood fibrinogen decreased; Febrile neutropenia: Febrile neutropenia; Embolic and thrombotic events: Embolism, Pulmonary embolism, Thrombosis in device, Venous thrombosis, Venous thrombosis limb; Hypersensitivity: Hypersensitivity, Anaphylactic reaction, Drug hypersensitivity.ONCASPAR 2500 IU/m2N=119Grade ≥ 3Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.n (%)Elevated transaminase79 (66)Febrile neutropenia48 (40)Hypertriglyceridemia36 (30)Hypoalbuminemia33 (28)Bilirubin increased30 (25)Hyperglycemia29 (24)Pancreatitis29 (24)Abnormal clotting studies25 (21)Embolic and thrombotic events10 (8)Hypersensitivity8 (7)

Previously Treated ALLAdverse 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 [see Clinical Studies (14.2)]. 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 ReactionsAllergic 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 E. coli L-asparaginase, and 27 patients (44%) had a history of clinical allergic reactions to both native Escherichia (E.) coli and native Erwinia L-asparaginase. Twenty (32%) of these 62 patients experienced clinical allergic reactions to ONCASPAR (see Table 4).Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to ONCASPAR (see Table 4).Table 4. Incidence of Clinical Allergic Reactions, Overall and by Severity GradePatient StatusToxicity Grade, n (%)Total1234Previously 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)01 (2)02 (3)

Risk summaryThere are no available data on the use of ONCASPAR in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Published literature studies in pregnant animals suggest asparagine depletion may cause harm to the animal offspring (see Data). Advise patients of the potential risk to a fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2%-4% and 15%-20%, respectively.

Data

Animal DataAnimal 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.

Risk summaryThere are no data on the presence of pegaspargase in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child, advise lactating women not to breastfeed while receiving ONCASPAR and for 3 months after the last dose.

Pregnancy TestingConduct pregnancy testing in females of reproductive potential prior to starting treatment with ONCASPAR.

ContraceptionAdvise females of reproductive potential to avoid becoming pregnant while receiving ONCASPAR. Females should use effective contraceptive methods, including a barrier method, during treatment and for at least 3 months after the last dose of ONCASPAR. Since there is a potential for an indirect interaction between ONCASPAR and oral contraceptives, the concomitant use of ONCASPAR and oral contraceptives is not recommended. Another, non-oral contraceptive method should be used in women of childbearing potential.

AbsorptionThe mean maximum asparaginase activity (Cmax) was reached at approximately 1 IU/mL (n=45-52) on Day 5 after a single IM injection. The mean half-life of absorption from the IM site was 1.7 days. The relative bioavailability was 82% following the first IM dose and 98% following repeat dosing.The mean Cmax and the area under the curve (AUC0-inf) was 1.6 IU/mL and 16.6 IU/mL*day, respectively, after a single IV infusion (n=47) during the induction phase.

DistributionThe mean volume of distribution at steady state was estimated to be 1.86 L/m2 after a single IM injection and approximately 2 L after a single IV infusion based on non-compartmental analysis.

EliminationThe mean elimination half-life was approximately 5.8 days following a single IM injection and 5.3 days following a single IV infusion. The clearance was 0.17 L/m2/day and 0.2 L/day, respectively, for a single IM and IV dose.

Specific PopulationsThe impact of renal and hepatic impairment on the pharmacokinetics of ONCASPAR is unknown.

Study CCG-1962The safety and effectiveness of ONCASPAR was evaluated in an open-label, multicenter, randomized, active-controlled study (Study CCG-1962). In this study, 118 pediatric patients aged 1 to 9 years with previously untreated standard-risk ALL were randomized 1:1 to ONCASPAR or native E. coli L-asparaginase as part of combination therapy. ONCASPAR was administered intramuscularly at a dose of 2,500 International Units/m2 on Day 3 of the 4-week induction phase and on Day 3 of each of two 8-week delayed intensification phases. Native E. coli L-asparaginase was administered intramuscularly at a dose of 6,000 International Units/m2 three times weekly for 9 doses during induction and for 6 doses during each delayed intensification phase.The primary determination of effectiveness was based on demonstration of similar asparagine depletion (magnitude and duration) in the ONCASPAR and native E. coli L-asparaginase arms. The protocol-specified goal was achievement of asparagine depletion to a serum concentration of ≤1 μM. The proportion of patients with this level of depletion was similar between the 2 study arms during all 3 phases of treatment at the protocol-specified time points.In all phases of treatment, serum asparagine concentrations decreased within 4 days of the first dose of asparaginase in the treatment phase and remained low for approximately 3 weeks for both ONCASPAR and native E. coli L-asparaginase arms. Serum asparagine concentrations during the induction phase are shown in Figure 1. The patterns of serum asparagine depletion in the 2 delayed intensification phases are similar to the pattern of serum asparagine depletion in the induction phase.Note: ONCASPAR (2,500 International Units/m2 intramuscular) was administered on Day 3 of the 4-week induction phase. Native E. coli L-asparaginase (6,000 International Units/m2 intramuscular) was administered 3 times weekly for 9 doses during induction.Figure 1. Mean (± Standard Error) Serum Asparagine Concentrations During Study CCG-1962 Induction PhaseCSF asparagine concentrations were determined in 50 patients during the induction phase. CSF asparagine decreased from a mean pre-treatment concentration of 3.1 µM to 1.7 µM on Day 4±1 and 1.5 µM at 25±1 days after administration of ONCASPAR. These findings were similar to those observed in the native E. coli L-asparaginase treatment arm.Concentrations of asparaginase activities greater than 0.1 International Units/mL were observed in over 90% of the samples from patients treated with ONCASPAR during Induction, Delayed Intensification 1, and Delayed Intensification 2 for approximately 20 days.While the 3-year Event-Free Survival (EFS) for the ONCASPAR and native E. coli L-asparaginase study arms were similar and in the range of 80%, Study CCG-1962 was not designed to evaluate for differences in EFS rates.

Anaphylaxis and Serious Hypersensitivity ReactionsInform patients of the possibility of serious allergic reactions, including anaphylaxis, and to seek immediate medical care for any swellings or difficulty breathing [see Warnings and Precautions (5.1)].

ThrombosisInstruct patients on the risk of thrombosis and hemorrhage and to seek immediate medical attention if they experience severe headache, arm or leg swelling, shortness of breath, or chest pain [see Warnings and Precautions (5.2)].

PancreatitisInstruct patients on the signs and symptoms of pancreatitis and to seek immediate medical attention if they experience severe abdominal pain [see Warnings and Precautions (5.3)].

Glucose IntoleranceInstruct patients on the risk of hyperglycemia and glucose intolerance. Advise patients to immediately report excessive thirst or increase in the volume or frequency of urination [see Warnings and Precautions (5.4)].

HemorrhageAdvise patients to report any unusual bleeding or bruising to their physician [see Warnings and Precautions (5.5)].

HepatotoxicityAdvise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.6)].

Pregnancy and LactationAdvise female patients of reproductive potential to use effective contraceptive methods while receiving ONCASPAR and for at least 3 months after the last dose. Advise patients to notify their healthcare provider immediately in the event of a pregnancy, or if pregnancy is suspected during ONCASPAR treatment. Since there is a potential for an indirect interaction between ONCASPAR and oral contraceptives, the concomitant use of ONCASPAR and oral contraceptives is not recommended [see Use in Specific Populations (8.3)].Advise lactating women not to breastfeed during treatment with ONCASPAR and for at least 3 months after the last dose [see Use in Specific Populations (8.2)].

ONCASPAR® is a registered trademark of Servier IP UK LTD, a wholly owned, indirect subsidiary of Les Laboratoires Servier.Servier and the Servier logo are trademarks of Les Laboratoires Servier.I-301-21-US-GManufactured by: Servier Pharmaceuticals LLC, Boston, MA 02210U.S. License No. 2125

2.2 Dose Modifications

  • 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. Dose ModificationsAdverse ReactionSeverityGrade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threateningActionInfusion Reaction/ Hypersensitivity ReactionGrade 1Reduce the infusion rate by 50%Grade 2Interrupt the infusion of ONCASPARTreat the symptomsWhen symptoms resolve, resume the infusion and reduce the infusion rate by 50%Grade 3 to 4Discontinue ONCASPAR permanentlyHemorrhageGrade 3 to 4Hold ONCASPAR.Evaluate for coagulopathy and consider clotting factor replacement as needed.Resume ONCASPAR with the next scheduled dose if bleeding is controlled.PancreatitisGrades 3 to 4Hold ONCASPAR for elevations in lipase or amylase >3 × ULN until enzyme levels stabilize or are decliningDiscontinue ONCASPAR permanently if clinical pancreatitis is confirmed.ThromboembolismUncomplicated deep vein thrombosisHold ONCASPAR.Treat with appropriate antithrombotic therapyUpon resolution of symptoms consider resuming ONCASPAR, while continuing antithrombotic therapy.Severe or life-threatening thrombosisDiscontinue ONCASPAR permanently.Treat with appropriate antithrombotic therapy.HepatotoxicityTotal bilirubin more than 3 times to no more than 10 times the upper limit of normalHold ONCASPAR until total bilirubin is ≤ 1.5 times the upper limit of normalTotal bilirubin more than 10 times the upper limit of normalDiscontinue ONCASPAR and do not make up for missed doses

2.3 Preparation And Administration

  • Administer ONCASPAR in a healthcare setting with appropriate medical support and resuscitation equipment to manage hypersensitivity reactions, should they occur [see Warnings and Precautions (5.1)].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.

3 Dosage Forms And Strengths

Injection: 3,750 International Units/5 mL (750 International Units/mL) clear, colorless solution in a single-dose vial.

4 Contraindications

  • ONCASPAR is contraindicated in patients with a:History of serious hypersensitivity reactions, including anaphylaxis, to ONCASPAR or to any of the excipients [see Warnings and Precautions (5.1)].History of serious thrombosis with prior L-asparaginase therapy [see Warnings and Precautions (5.2)].History of pancreatitis, including pancreatitis related to prior L-asparaginase therapy [see Warnings and Precautions (5.3)].History of serious hemorrhagic events with prior L-asparaginase therapy [see Warnings and Precautions (5.5)].Severe hepatic impairment [see Warnings and Precautions (5.6)].

5.1 Anaphylaxis And Serious Hypersensitivity Reactions

Anaphylaxis and serious hypersensitivity reactions can occur in patients receiving ONCASPAR. The risk of serious hypersensitivity reactions is higher in patients with known hypersensitivity to (E.) coli derived L-asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnea, pruritus, and rash.Observe patients for 1 hour after administration of ONCASPAR in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue ONCASPAR in patients with serious hypersensitivity reactions [see Dosage and Administration (2.2)].

5.2 Thrombosis

Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving ONCASPAR. Discontinue ONCASPAR in patients with serious thrombotic events [see Dosage and Administration (2.2)].

5.3 Pancreatitis

Pancreatitis can occur in patients receiving ONCASPAR. Hemorrhagic or necrotizing pancreatitis with fatal outcomes have been reported.Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Assess serum amylase and/or lipase levels to confirm early signs of pancreatic inflammation. Discontinue ONCASPAR in patients where pancreatitis is suspected. If pancreatitis is confirmed, do not resume ONCASPAR [see Dosage and Administration (2.2)].

5.4 Glucose Intolerance

Glucose intolerance can occur in patients receiving ONCASPAR. In some cases, glucose intolerance is irreversible. Monitor serum glucose.

5.5 Hemorrhage

Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving ONCASPAR. Evaluate patients with signs and symptoms of hemorrhage with coagulation parameters including PT, PTT, fibrinogen. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy [see Dosage and Administration (2.2)].

5.6 Hepatotoxicity

Hepatotoxicity and abnormal liver function, including elevations of transaminase, bilirubin (direct and indirect), reduced serum albumin, and plasma fibrinogen can occur. Evaluate bilirubin and transaminases at least weekly during cycles of treatment that include ONCASPAR through at least 6 weeks after the last dose of ONCASPAR. In the event of serious liver toxicity, discontinue treatment with ONCASPAR and provide supportive care [see Dosage and Administration (2.2)].

6 Adverse Reactions

  • The following serious adverse reactions are described in greater detail in other sections of the labeling:Anaphylaxis and serious hypersensitivity reactions [see Warnings and Precautions (5.1)]Thrombosis [see Warnings and Precautions (5.2)]Pancreatitis [see Warnings and Precautions (5.3)]Glucose intolerance [see Warnings and Precautions (5.4)]Hemorrhage [see Warnings and Precautions (5.5)]Hepatotoxicity [see Warnings and Precautions (5.6)]

6.1 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, and hypersensitivity.

6.2 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 to pegaspargase with the incidence of antibodies in other studies or to other 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. 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 or altered pharmacokinetics (i.e., loss of asparaginase activity).

6.3 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.Immune system disorders: Anaphylactic shock, hypersensitivity reaction.Investigations: Blood cholesterol increased.Metabolism and nutrition disorders: Hyperglycemia, hyperammonemia.Vascular disorders: Hemorrhage including central nervous system hemorrhage, thrombosis including superior sagittal sinus thrombosis.

8.3 Females And Males Of Reproductive Potential

Based on published literature studies in pregnant animals, ONCASPAR can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 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 [see Clinical Studies (14.1)], and safety data from 7 total trials. The pediatric patients treated with ONCASPAR 2,500 International Units/m2 on these trials included 26 infants (1 month to <2 years old), 165 children (2 years to <12 years old), and 39 adolescents (12 to 17 years old).

8.5 Geriatric Use

Clinical studies of ONCASPAR did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects.

10 Overdosage

Three patients received 10,000 International Units/m2 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.

11 Description

Pegaspargase is a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase (L-asparagine amidohydrolase), an asparagine specific enzyme. L-asparaginase is a tetrameric enzyme that is produced endogenously by E. coli and consists of identical 34.5 kDa subunits. Approximately 69 to 82 molecules of mPEG are linked to L-asparaginase; the molecular weight of each mPEG molecule is about 5 kDa. ONCASPAR activity is expressed in International Units.ONCASPAR (pegaspargase) injection is supplied as a clear, colorless, preservative-free, isotonic sterile solution in phosphate-buffered saline, pH 7.3, for intramuscular use or for dilution prior to intravenous infusion. Each vial of ONCASPAR contains 3,750 International Units of pegaspargase in 5 mL of solution. Each milliliter contains 750 International Units of pegaspargase, dibasic sodium phosphate, USP (5.58 mg), monobasic sodium phosphate, USP (1.20 mg), and Sodium Chloride, USP (8.50 mg) in Water for Injection, USP.

12.1 Mechanism Of Action

L-asparaginase is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacological effect of ONCASPAR is thought to be based on selective killing of leukemic cells due to depletion of plasma L-asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize L-asparagine and therefore depend on an exogenous source of L-asparagine for survival.

12.2 Pharmacodynamics

Pharmacodynamic activity was assessed through serial measurements of asparagine in sera and cerebrospinal fluid (CSF).In Study CCG-1962, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three intramuscular doses of ONCASPAR (2,500 International Units/m2), one each during induction and two delayed intensification treatment phases [see Clinical Studies (14.1)].In Study AALL07P4, the pharmacodynamic response of pegaspargase was assessed in 47 evaluable patients with newly diagnosed high risk B-precursor ALL. Asparagine concentrations in plasma (N=42) were maintained below the assay limit of quantification for at least 11 days following a single dose of ONCASPAR 2,500 International Units/m2 during the induction phase. CSF asparagine concentration was decreased from a mean pretreatment concentration of 0.6 µg/mL (N=20) to 0.2 µg/mL on Day 4 (N=41) and remained decreased at 0.2 µg/mL (N=39) 25 days after the administration of a single dose of ONCASPAR in the induction phase.

12.3 Pharmacokinetics

Pharmacokinetic assessments were based on an enzymatic assay measuring asparaginase activity after intramuscular (IM, CCG-1962) and intravenous (IV, AALL07P4) administration of 2,500 International Units/m2 in patients with ALL.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity, mutagenicity and impairment of fertility studies have not been conducted with pegaspargase.

14.2 Patients With All Hypersensitive To Asparaginase

The safety and effectiveness of ONCASPAR was evaluated in 4 open-label studies enrolling a total of 42 patients with multiply-relapsed, acute leukemia [39 (93%) with ALL] with a history of prior clinical allergic reaction to asparaginase. Hypersensitivity to asparaginase was defined by a history of systemic rash, urticaria, bronchospasm, laryngeal edema, hypotension, or local erythema, urticaria, or swelling, greater than 2 centimeters, for at least 10 minutes following administration of any form of native E. coli L-asparaginase. All patients received ONCASPAR at a dose of 2,000 or 2,500 International Units/m2 administered intramuscularly or intravenously every 14 days. Patients received ONCASPAR as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50% (95% confidence interval: 35%, 65%), based upon 36% complete remissions and 14% partial remissions. These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E. coli L-asparaginase-containing re-induction chemotherapy. Anti-tumor activity was also observed with single-agent ONCASPAR. Three responses (1 complete remission and 2 partial remissions) were observed in 9 adult and pediatric patients with relapsed ALL and hypersensitivity to native E. coli L-asparaginase.

16 How Supplied/Storage And Handling

ONCASPAR (pegaspargase) Injection is supplied as a sterile, clear, colorless, preservative-free solution in Type I single-dose vials containing 3,750 International Units of pegaspargase per 5 mL (750 International Units per mL) solution (NDC 72694-954-01).

Storage And Handling

Store ONCASPAR refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not shake or freeze product. Unopened vials may be stored at room temperature (15°C to 25°C [59°F to 77°F]) for no more than 48 hours.

17 Patient Counseling Information

Advise Patients/Caregivers of the following risks of ONCASPAR:

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