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 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 patients with ALL and hypersensitivity to native forms of L-asparaginase.

2.1 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.

2.2 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.

2.3 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/Storage and Handling (16)]

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.

5.1 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.

5.2 Thrombosis

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

5.3 Pancreatitis

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

5.4 Glucose Intolerance

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

5.5 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.

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.

6.2 Clinical Allergic Reactions

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

6.3 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.

8.1 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.

8.3 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.

8.4 Pediatric Use

[see Clinical Studies (14.1)]

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.

12.1 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.

12.2 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 [seeClinical Studies (14)].

12.3 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 IU/mL/day in the previously hypersensitive patients and 9.8 ± 6.0 IU/mL/day in the non-hypersensitive patients.

13.1 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.

14.1 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.

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.

14.2 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.

Storage and Handling

Keep refrigerated at +2°C to +8ºC (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.

17.1 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.

17.2 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.

17.3 Pancreatitis

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

17.4 Glucose Intolerance

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

U.S. License No. 1171