Oncaspar

Pegaspargase is injected into a muscle or into a vein through an IV. A healthcare provider will give you this injection.

You will be watched closely for at least 1 hour after receiving pegaspargase, to make sure you do not have an allergic reaction to the medication.

Pegaspargase can lower blood cells that help your blood to clot. Your blood will need to be tested often to be sure this medication is not causing harmful effects. You may also need liver function tests.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Contact your doctor if you miss an appointment for your pegaspargase injection.

The following serious adverse reactions are described in greater detail in other sections of the label:

• Anaphylaxis and serious allergic reactions [see WARNINGS AND PRECAUTIONS]
• Serious thrombosis [see WARNINGS AND PRECAUTIONS]
• Pancreatitis [see WARNINGS AND PRECAUTIONS]
• Glucose intolerance [see WARNINGS AND PRECAUTIONS]
• Coagulopathy [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity and abnormal liver function [see WARNINGS AND PRECAUTIONS]

The most common adverse reactions with Oncaspar® 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 Oncaspar.

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 data presented below are derived from 2 studies in patients with standard-risk ALL who received Oncaspar® 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 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. Study 2 is an ongoing, multi-factorial design study in which all patients received Oncaspar® 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 Oncaspar® varied by treatment arm, with intermittent doses of Oncaspar® 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

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 Oncaspar® 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.

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 2). 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 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).

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 2).

Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to Oncaspar® (see Table 2).

TABLE 2 : INCIDENCE OF CLINICAL ALLERGIC REACTIONS, OVERALL AND BY SEVERITY GRADE

Immunogenicity

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, 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, 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 Oncaspar® with the incidence of antibodies to other products may be misleading.

Included as part of the PRECAUTIONS section.

Serious Allergic Reactions

Inform patients of the possibility of serious allergic reactions, including anaphylaxis, and to seek immediate medical care for any swellings or difficulty breathing.

Thrombosis

Inform patients to seek immediate medical attention for severe headache, arm or leg swelling, acute shortness of breath, or chest pain.

Pancreatitis

Advise patients to seek immediate medical attention for severe abdominal pain.

Glucose Intolerance

Advise patients to immediately report excessive thirst or increase in the volume or frequency of urination.

• Aventis Pharmaceuticals, Inc.

• Enzon Pharmaceuticals, Inc.

• Sigma-Tau Pharmaceuticals, Inc.

No drug interactions have been studied. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category C. There are no well-controlled studies that have been done in pregnant women. Oncaspar should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

Pegaspargase is injected into a muscle or into a vein through an IV. A healthcare provider will give you this injection.

You will be watched closely for at least 1 hour after receiving pegaspargase, to make sure you do not have an allergic reaction to the medication.

Pegaspargase can lower blood cells that help your blood to clot. Your blood will need to be tested often to be sure this medication is not causing harmful effects. You may also need liver function tests.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;

• dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• high blood sugar (increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pegaspargase belongs to the general group of medicines known as antineoplastics. It is used with other cancer medicines as a first-line treatment to a certain type of blood cancer called acute lymphoblastic leukemia (ALL). This medicine also treats ALL in patients who have had serious allergic reactions to L-asparaginase .

Pegaspargase seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells also may be affected by pegaspargase, other effects also occur. Some of these effects may be serious and must be reported to your doctor.

Before you begin treatment with pegaspargase, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

Pegaspargase is to be administered only by or under the immediate supervision of your doctor.

This medicine is available only with your doctor's prescription .

• If you need to store Oncaspar at home, talk with your doctor, nurse, or pharmacist about how to store it.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Oncaspar (pegaspargase) is supplied as a sterile solution in Type I single-use vials containing 3,750 International Units of L-asparaginase per 5 mL solution (NDC 0944-3810-01).

Store Oncaspar under refrigeration at 2°C to 8ºC (36°F to 46°F). Do not shake or freeze product. Protect from light. Do not use Oncaspar after the expiration date on the vial.