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Stability: IV admixture: 48 hours room temperature.
CLINICAL PHARMACOLOGY
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 (14)].
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.
INDICATIONS AND USAGE
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. DOSAGE AND ADMINISTRATION
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.
3. DOSAGE FORMS AND STRENGTHS
3,750 IU/5 mL single-use vial
4. CONTRAINDICATIONS
History of serious allergic reactions to Oncaspar®
History of serious thrombosis with prior L-asparaginase therapy
History of pancreatitis with prior L-asparaginase therapy
History of serious hemorrhagic events with prior L-asparaginase therapy
5. WARNINGS AND PRECAUTIONS
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.
HOW SUPPLIED/STORAGE AND HANDLING
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 +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
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