Oncaspar® (pegaspargase) is a modified version of the enzyme L-asparaginase. To produce Oncaspar®, L-asparaginase is modified by covalently conjugating units of monomethoxypolyethylene glycol (PEG), molecular weight of 5,000, to the enzyme, forming the active ingredient PEG-L-asparaginase. The L-asparaginase (L-asparagine amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of Oncaspar® is derived from E coli and supplied by Ovation Pharmaceuticals (U.S. License No. 1688) under a shared manufacturing arrangement. Oncaspar® activity is expressed in International Units (IU) according to the recommendation of the International Union of Biochemistry. One IU of L-asparaginase is defined as that amount of enzyme required to generate 1 umol of ammonia per minute at pH 7.3 and 37°C.

Oncaspar® is supplied as a clear, colorless, preservative-free, isotonic sterile solution in phosphate-buffered saline, pH 7.3. Each milliliter contains Oncaspar® 750 IU ± 20% (based on specific activity of at least 85 IU per milligram protein), 1.20 mg monobasic sodium phosphate, USP, 5.58 mg dibasic sodium phosphate, USP, and 8.50 mg sodium chloride, USP, in water for injection, USP.

Last updated on RxList: 3/2/2009

First Line Acute Lymphoblastic Leukemia (ALL)

Oncaspar® 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 Asparaginase

Oncaspar® 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.

Recommended Dose

The recommended dose of Oncaspar® is 2,500 IU/m² intramuscularly (IM) or intravenously (IV). Oncaspar® should be administered no more frequently than every 14 days.

Instructions for Administration

When Oncaspar® is administered IM, 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.

When administered IV, Oncaspar® 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.

Preparation and Handling Precautions

Do not administer Oncaspar® if drug has been:

• frozen
• stored at room temperature (+15°C to +25°C; 59°F to 77°F) for more than 48 hours
• shaken or vigorously agitated [see HOW SUPPLIED]

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.

Dosage Forms And Strengths

3,750 IU/5 mL single-use vial

Dosage Form

NDC 57665-002-02

3,750 IU/5 mL single-use vial individually packaged in a carton

Storage and Handling

Keep refrigerated at +2°C to +8°C (36°F to 46°F).

Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.

Do not administer Oncaspar® if the drug:

• has been frozen
• has been stored at room temperature (+15°C to +25°C: 59°F to 77°F) for more than 48 hours
• has been shaken or vigorously agitated
• is cloudy, discolored, and precipitate is present.

Enzon Pharmaceuticals, Inc. Bridgewater NJ 08807.

Last updated on RxList: 3/2/2009

The following serious adverse reactions occur with Oncaspar® treatment [see WARNINGS AND PRECAUTIONS]:

• Anaphylaxis and serious allergic reactions
• Serious thrombosis
• Pancreatitis
• Glucose intolerance
• Coagulopathy

The most common adverse reactions with Oncaspar® are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases.

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.

First-Line ALL

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.

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 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%).

Clinical Allergic Reactions

Clinical allergic reactions include the following: bronchospasm. hypotension, laryngeal edema, local erythema or swelling, systemic rash, and urticaria.

First-Line ALL

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).

Previously Treated ALL

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 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.

No formal drug interaction studies, between Oncaspar® and other drugs, have been performed.

Last updated on RxList: 3/2/2009

Included as part of the PRECAUTIONS section.

Anaphylaxis and Serious Allergic Reactions

Serious allergic reactions can occur in patients receiving Oncaspar®. 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 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 allergic reactions.

Thrombosis

Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving Oncaspar®. Discontinue Oncaspar® in patients with serious thrombotic events.

Pancreatitis

Pancreatitis can occur in patients receiving Oncaspar®. Evaluate patients with abdominal pain for evidence of pancreatitis. Discontinue Oncaspar® in patients with pancreatitis.

Glucose Intolerance

Glucose intolerance can occur in patients receiving Oncaspar®. In some cases, glucose intolerance is irreversible.

Coagulopathy

Increased prothrombin time, increased partial thromboplastin time. and hypofibrinogenemia can occur in patients receiving Oncaspar®. 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• No long-term carcinogenicity studies in animals have been performed with Oncaspar®.
• No relevant studies addressing mutagenic potential have been conducted. Oncaspar® did not exhibit a mutagenic effect when tested against Salmonella typhimurium strains in the Ames assay.
• No studies have been performed on impairment of fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C Animal reproduction studies have not been conducted with Oncaspar®. It is also not known whether Oncaspar® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Oncaspar® should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Oncaspar® 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 Oncaspar®, 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

[see Clinical Studies]

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.

Last updated on RxList: 3/2/2009

Three patients received 10,000 IU/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.

• History of serious allergic reactions to Oncaspar®
• History of serious thrombosis with prior L-asparaginase I therapy
• History of pancreatitis with prior L-asparaginase therapy
• History of serious hemorrhagic events with prior L-asparaginase therapy

Last updated on RxList: 3/2/2009

Mechanism of Action

The mechanism of action of Oncaspar® is thought to be based on selective killing of leukemic cells due to depletion of plasma asparagine. Some leukemic cells are unable to synthesize asparagine due to a lack of asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. Normal cells, however, are less affected by the depletion due to their ability to synthesize asparagine.

Pharmacodynamics

In Study 1, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three IM doses of Oncaspar® (2,500 IU/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 [see Clinical Studies].

Pharmacokinetics

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 IM administration of 2,500 IU/m². The elimination half-life of Oncaspar® 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 IU/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.

In 3 pharmacokinetic studies, 37 patients with relapsed ALL received Oncaspar® at 2,500 IU/m² IM every 2 weeks. The plasma half-life of Oncaspar® 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 lU/mL/day in the previously hypersensitive patients and 9.8 ± 6.0 lU/mL/day in the non-hypersensitive patients.

Clinical Studies

First-Line ALL

The safety and effectiveness of Oncaspar® was evaluated in an open-label, multicenter, randomized, active-controlled study (Study 1). 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 IM at a dose of 2,500 IU/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 IM at a dose of 6,000 IU/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.

FIGURE 1: MEAN (± STANDARD ERROR) SERUM ASPARAGINE CONCENTRATIONS DURING STUDY 1 INDUCTION PHASE

Note: Oncaspar® (2,500 IU/m² IM) was administered on Day 3 of the 4-week induction phase. Native E coli L-asparaginase (6,000 IU/m² IM) was administered 3 times weekly for 9 doses during induction.

CSF asparagine concentrations were determined in 50 patients during the induction phase. CSF asparagine decreased from a mean pretreatment concentration of 3.1 µM to 1.7 µM on Day 4 ± 1 and 1.5 µM 25 ± 1 days after administration of Oncaspar®. These findings were similar to those observed in the native E coli L-asparaginase treatment arm.

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 1 was not designed to evaluate for differences in EFS rates.

ALL Patients 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 IU/m² administered IM or IV 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.

Last updated on RxList: 3/2/2009

Serious Allergic Reactions

Patients should be informed of the possibility of serious allergic reactions. including anaphylaxis, and to immediately report any swellings or difficulty breathing.

Thrombosis

Patients should be advised to immediately report any severe headache. Arm or leg swelling, acute shortness of breath, and chest pain also should be reported immediately.

Pancreatitis

Patients should be advised to immediately report any severe abdominal pain.

Glucose Intolerance

Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

Last updated on RxList: 3/2/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PEGASPARGASE - INJECTION

(peg-ASP-are-gace)

COMMON BRAND NAME(S): Oncaspar

USES: This medication is usually used with other anti-cancer (chemotherapy) drugs to treat acute lymphocytic leukemia (ALL), especially in patients who are allergic to L-asparaginase. It works by starving tumor cells of a certain amino acid (asparagine), causing the tumor cells to die.

HOW TO USE: This medication is given by injection into a vein or a muscle by a health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Do not shake the liquid, and do not use this medication if it has been shaken. If injecting this medication into a muscle, do not inject more than 2 milliliters into a single injection site. Use 2 or more injection sites instead. If injecting this medication in the vein, follow all instructions for proper mixing with the correct IV fluids, and give the medication over 1 to 2 hours. If you have any questions about the use or preparation of this medication, consult your pharmacist.

Dosage is based on your body size and response to treatment. This medication should not be given more often than every 14 days.

Use care when preparing and giving this medication. Avoid getting the medication on the skin or in the eyes, mouth, or nose. If you do get the medication in those areas, flush with plenty of water and tell your doctor immediately.

SIDE EFFECTS: Nausea, vomiting, weakness, loss of appetite, diarrhea, dizziness, or pain/swelling/redness at injection site may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: severe stomach/abdominal pain, signs of an infection (e.g., fever), increased thirst/urination, easy bruising/bleeding, dark urine, yellowing eyes/skin, pain/redness/swelling/numbness/tingling of the arms or legs, change in the amount of urine.

Seek immediate medical attention if any of these rare but very serious side effects occur: sudden shortness of breath, chest pain, severe headache, seizures, slurred speech, confusion, vision changes, weakness on one side of the body.

A very serious allergic reaction to this drug can occur. Seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using pegaspargase, tell your doctor or pharmacist if you are allergic to it; or to L-asparaginase; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: history of a serious reaction to L-asparaginase (e.g., bleeding, blood clots, pancreatitis).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes, clotting/bleeding disorders, liver disease, pancreatitis.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

Wash your hands well to prevent the spread of infections.

This drug may make you dizzy. Use caution while driving, using machinery, or taking part in any other activity that requires alertness. Avoid alcoholic beverages because they may make you dizzy and increase the risk of liver disease.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

This drug may infrequently make your blood sugar level rise, causing or worsening diabetes. Tell your doctor immediately if you develop symptoms of high blood sugar such as increased thirst and urination. If you already have diabetes, be sure to check your blood sugar level regularly as directed by your doctor.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other drugs that can cause bleeding/bruising (e.g., "blood thinners" such as warfarin/heparin, anti-platelet drugs including NSAIDs such as ibuprofen), other medications that can affect the liver (e.g., ketoconazole).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., prothrombin time, complete blood counts, liver function tests, amylase levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store in the refrigerator between 36-46 degrees F (2 to 8 degrees C). Brief storage at room temperature between 59-77 degrees F (15-25 degrees C) is permitted for up to 48 hours. Discard this medication if it has been stored at room temperature for longer than 48 hours. Do not freeze. Do not use this medication if it has been frozen. The medication in the vial should be used only once. Throw away any unused portion. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.