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.

2.1 Recommended Dosage

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.

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.

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)].

6.1 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.

8.1 Pregnancy

8.2 Lactation

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.

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 or 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.

14.1 First-Line Treatment of ALL

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.

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.

Anaphylaxis and Serious Hypersensitivity Reactions

Inform 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)].

Thrombosis

Instruct 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)].

Pancreatitis

Instruct 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 Intolerance

Instruct 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)].

Hemorrhage

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

Hepatotoxicity

Advise 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 Lactation

Advise 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)].