ONCASPAR

5 WARNINGS AND PRECAUTIONS Anaphylaxis or serious hypersensitivity reactions : Observe patients for 1 hour after administration. Discontinue ONCASPAR in patients with serious hypersensitivity reactions. ( 5.1 ) Thrombosis : Discontinue ONCASPAR in patients with serious thrombotic events. ( 5.2 ) Pancreatitis : Evaluate patients with abdominal pain for pancreatitis. Discontinue ONCASPAR in patients with pancreatitis. ( 5.3 ) Glucose intolerance : Monitor serum glucose. ( 5.4 ) Hemorrhage : Discontinue ONCASPAR for severe or life-threatening hemorrhage. Evaluate for etiology and treat. ( 5.5 ) Hepatotoxicity, including hepatic veno-occlusive disease (VOD) : Monitor for toxicity through recovery from cycle. Discontinue ONCASPAR for severe liver toxicity. ( 5.6 ) 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 [see Adverse Reactions (6.1) ] . Premedicate patients 30-60 minutes prior to administration of ONCASPAR. [see Dosage and Administration (2.2) ] . 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) [see Dosage and Administration (2.4) ] . Discontinue ONCASPAR in patients with serious hypersensitivity reactions. 5.2 Thrombosis Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving ONCASPAR [see Adverse Reactions (6.1) ] . Discontinue ONCASPAR in patients with serious thrombotic events [see Dosage and Administration (2.3) ] . 5.3 Pancreatitis Pancreatitis can occur in patients receiving ONCASPAR. Hemorrhagic or necrotizing pancreatitis with fatal outcomes have been reported [see Adverse Reactions (6.1) ] . 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 (2.3) ] . 5.4 Glucose Intolerance Glucose intolerance can occur in patients receiving ONCASPAR [see Adverse Reactions (6.1) ] . In some cases, glucose intolerance is irreversible. Monitor serum glucose [see Dosage and Administration (2.3) ] . 5.5 Hemorrhage Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving ONCASPAR [see Adverse Reactions (6.1) ] . 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. Discontinue ONCASPAR for severe or life-threatening hemorrhage [see Dosage and Administration (2.3) ] . 5.6 Hepatotoxicity, Including Hepatic Veno-Occlusive Disease Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of hepatic veno-occlusive disease (VOD), have been observed in patients treated with ONCASPAR in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy [see Adverse Reactions (6) ]. Do not administer ONCASPAR to patients with severe hepatic impairment [see Contraindications (4) ] . Evaluate bilirubin and transaminases prior to each dose of ONCASPAR and at least weekly, during cycles of treatment that include ONCASPAR, through 6 weeks after the last dose of ONCASPAR. Monitor frequently for signs and symptoms of hepatic VOD, which may include rapid weight gain, fluid retention with ascites, hepatomegaly (which may be painful), and rapid increase of bilirubin. For patients who develop abnormal liver tests after ONCASPAR, more frequent monitoring for liver test abnormalities and clinical signs and symptoms of VOD is recommended. In the event of serious liver toxicity, including VOD, discontinue treatment with ONCASPAR and provide supportive care [see Dosage and Administration (2.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Anaphylaxis and serious hypersensitivity reactions [see Warnings and Precautions (5.1) ] Thrombosis [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.3) ] Glucose intolerance [see Warnings and Precautions (5.4) ] Hemorrhage [see Warnings and Precautions (5.5) ] Hepatotoxicity, including VOD [see Warnings and Precautions (5.6) ] The most common (>5%) grade > 3 adverse reactions with ONCASPAR are hypoalbuminemia, elevated transaminase, febrile neutropenia, hypertriglyceridemia, hyperglycemia, bilirubin increased, pancreatitis, abnormal clotting studies, embolic and thrombotic events, hypersensitivity, sepsis, and infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals, at 1-800-807-6124 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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, hypersensitivity, sepsis, and infections. First-Line Treatment of Acute Lymphoblastic Leukemia (ALL) Study CCG-1962 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 race. 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. In Study CCG-1962, detailed safety information was collected for pre-specified adverse reactions identified as asparaginase induced adverse reactions and for grade 3 and 4 nonhematologic 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 2: Table 2. Incidence of Selected Grades 3 and 4 Adverse Reactions in Study CCG-1962 ONCASPAR (n=58) Native E. coli L-Asparaginase (n=59) Infection 3 (5%) 3 (5%) Abnormal Liver Tests 3 (5%) 5 (8%) Elevated Transaminases Aspartate aminotransferase, alanine aminotransferase. 2 (3%) 4 (7%) Hyperbilirubinemia 1 (2%) 1 (2%) Hyperglycemia 3 (5%) 2 (3%) Central Nervous System Thrombosis 2 (3%) 2 (3%) Coagulopathy Prolonged prothrombin time or partial thromboplastin time; or hypofibrinogenemia. 1 (2%) 3 (5%) Pancreatitis 1 (2%) 1 (2%) Allergic Reactions to Asparaginase 1 (2%) 0 The safety of ONCASPAR was investigated in Study DFCI 11-001, an open label, randomized, active-controlled multicenter clinical trial that included 119 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma treated with ONCASPAR in combination with the Dana Farber Cancer Institute (DFCI) ALL Consortium backbone therapy. The median age on enrollment was 4 years (range, 1-18 years). The majority of patients were male (60%) and white (75%). Most patients were considered standard risk ALL (59%) and had B-cell lineage ALL (87%). The median number of doses of ONCASPAR during the study was 16 doses (one dose during induction therapy then administered every two weeks during post induction therapy). The median duration of exposure to ONCASPAR was 8 months. Table 3 summarizes the incidence of selected Grades ≥3 adverse reactions that occurred in 2 or more patients receiving ONCASPAR. Because not all grade 1 and 2 adverse reactions were collected prospectively, only grade 3 and 4 adverse reactions are presented in Table 3. Table 3. Incidence of Selected Grades ≥3 Adverse Reactions in Patients Receiving ONCASPAR With Multi-Agent Chemotherapy in Study DFCI 11-001 Adverse Reaction Grouped terms: Elevated transaminase : Alanine aminotransferase increased, Aspartate aminotransferase increased; Pancreatitis : Amylase increased, Lipase increased, Pancreatic necrosis, Pancreatitis, Pancreatitis relapsing; Bilirubin increased : Bilirubin conjugated increased, Blood bilirubin increased; Abnormal clotting studies : Activated partial thromboplastin time prolonged, Blood fibrinogen decreased; Febrile neutropenia : Febrile neutropenia; Embolic and thrombotic events : Embolism, Pulmonary embolism, Thrombosis in device, Venous thrombosis, Venous thrombosis limb; Hypersensitivity : Hypersensitivity, Anaphylactic reaction, Drug hypersensitivity; Pneumonia: Lung infection, Pneumonia, Pneumonitis; Sepsis: Bacterial sepsis, Sepsis; Diarrhea : Colitis, Diarrhea, Enterocolitis, Neutropenic colitis; Hemorrhages SMQ (excludes laboratory terms): Disseminated intravascular coagulation, Epistaxis, Hematoma, Hemorrhage intracranial, Melena, Esophageal ulcer hemorrhage, Small intestinal hemorrhage, Upper gastrointestinal hemorrhage; Fungal infection: Fungal infection, Hepatic infection fungal, Respiratory tract infection fungal, Splenic infection fungal, Systemic candida. ONCASPAR 2500 IU/m 2 N=119 Grade ≥3 Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. n (%) Elevated transaminase 79 (66) Febrile neutropenia 48 (40) Hypertriglyceridemia 36 (30) Hypoalbuminemia 33 (28) Bilirubin increased 30 (25) Hyperglycemia 29 (24) Pancreatitis 29 (24) Abnormal clotting studies 25 (21) Embolic and thrombotic events 10 (8) Hypersensitivity 8 (7) Pneumonia 8 (7) Sepsis 7 (6) Diarrhea 6 (5) Hemorrhages 5 (4) Fungal Infection 3 (3) 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 [see Clinical Studies (14.2) ] . 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 3 ). 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 CCG-1962, 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 4 ). 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 4 ). Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to ONCASPAR (see Table 4 ). Table 4. Incidence of Clinical Allergic Reactions, Overall and by Severity Grade Patient Status Toxicity Grade, n (%) Total 1 2 3 4 Previously Hypersensitive Patients (n=62) 7 (11) 8 (13) 4 (6) 1 (2) 20 (32) Non-Hypersensitive Patients (n=112) 5 (4) 4 (4) 1 (1) 1 (1) 11 (10) First Line (n=58) 1 (2) 0 1 (2) 0 2 (3) 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 in the studies described below with the incidence of antibodies in other studies or to other asparaginase 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). In study CCG-1962, 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). In Study DFCI 11-001, of the 100 evaluable patients treated with ONCASPAR, 19 (19%) patients developed anti-drug antibodies (ADA) during treatment; 18 of these 19 patients were positive for anti-PEG antibodies. The presence of ADA correlated with the occurrence of hypersensitivity reactions. There is insufficient information to determine whether the development of antibodies is associated with 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. Hepatic: Veno-occlusive disease. Immune system disorders: Anaphylactic shock, hypersensitivity reaction. Investigations: Blood cholesterol increased. Metabolism and nutrition disorders: Hyperglycemia, hyperammonemia. Musculoskeletal and connective tissue disorders: Osteonecrosis. Vascular disorders: Hemorrhage including central nervous system hemorrhage, thrombosis including superior sagittal sinus thrombosis.

<table width="75%" ID="Table2"><caption>Table 2. Incidence of Selected Grades 3 and 4 Adverse Reactions in Study CCG-1962</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule" valign="bottom">ONCASPAR (n=58)</th><th styleCode="Rrule" valign="bottom">Native <content styleCode="italics">E. coli</content> L-Asparaginase (n=59)</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">Infection</td><td styleCode="Rrule">3 (5%)</td><td styleCode="Rrule">3 (5%)</td></tr><tr><td styleCode="Lrule Rrule">Abnormal Liver Tests</td><td styleCode="Rrule">3 (5%)</td><td styleCode="Rrule">5 (8%)</td></tr><tr><td styleCode="Lrule Rrule"> Elevated Transaminases<footnote>Aspartate aminotransferase, alanine aminotransferase.</footnote></td><td styleCode="Rrule">2 (3%)</td><td styleCode="Rrule">4 (7%)</td></tr><tr><td styleCode="Lrule Rrule"> Hyperbilirubinemia</td><td styleCode="Rrule">1 (2%)</td><td styleCode="Rrule">1 (2%)</td></tr><tr><td styleCode="Lrule Rrule">Hyperglycemia</td><td styleCode="Rrule">3 (5%)</td><td styleCode="Rrule">2 (3%)</td></tr><tr><td styleCode="Lrule Rrule">Central Nervous System Thrombosis</td><td styleCode="Rrule">2 (3%)</td><td styleCode="Rrule">2 (3%)</td></tr><tr><td styleCode="Lrule Rrule">Coagulopathy<footnote>Prolonged prothrombin time or partial thromboplastin time; or hypofibrinogenemia.</footnote></td><td styleCode="Rrule">1 (2%)</td><td styleCode="Rrule">3 (5%)</td></tr><tr><td styleCode="Lrule Rrule">Pancreatitis</td><td styleCode="Rrule">1 (2%)</td><td styleCode="Rrule">1 (2%)</td></tr><tr><td styleCode="Lrule Rrule">Allergic Reactions to Asparaginase</td><td styleCode="Rrule">1 (2%)</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="75%" ID="Table3"><caption>Table 3. Incidence of Selected Grades &#x2265;3 Adverse Reactions in Patients Receiving ONCASPAR With Multi-Agent Chemotherapy in Study DFCI 11-001</caption><col width="50%" align="left" valign="middle"/><col width="50%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction<footnote ID="t3f1">Grouped terms: <content styleCode="bold">Elevated transaminase</content>: Alanine aminotransferase increased, Aspartate aminotransferase increased; <content styleCode="bold">Pancreatitis</content>: Amylase increased, Lipase increased, Pancreatic necrosis, Pancreatitis, Pancreatitis relapsing; <content styleCode="bold">Bilirubin increased</content>: Bilirubin conjugated increased, Blood bilirubin increased; <content styleCode="bold">Abnormal clotting studies</content>: Activated partial thromboplastin time prolonged, Blood fibrinogen decreased; <content styleCode="bold">Febrile neutropenia</content>: Febrile neutropenia; <content styleCode="bold">Embolic and thrombotic events</content>: Embolism, Pulmonary embolism, Thrombosis in device, Venous thrombosis, Venous thrombosis limb; <content styleCode="bold">Hypersensitivity</content>: Hypersensitivity, Anaphylactic reaction, Drug hypersensitivity; <content styleCode="bold">Pneumonia:</content> Lung infection, Pneumonia, Pneumonitis; <content styleCode="bold">Sepsis:</content> Bacterial sepsis, Sepsis; <content styleCode="bold">Diarrhea</content>: Colitis, Diarrhea, Enterocolitis, Neutropenic colitis; <content styleCode="bold">Hemorrhages SMQ</content> (excludes laboratory terms): Disseminated intravascular coagulation, Epistaxis, Hematoma, Hemorrhage intracranial, Melena, Esophageal ulcer hemorrhage, Small intestinal hemorrhage, Upper gastrointestinal hemorrhage; <content styleCode="bold">Fungal infection:</content> Fungal infection, Hepatic infection fungal, Respiratory tract infection fungal, Splenic infection fungal, Systemic candida.</footnote></th><th styleCode="Rrule">ONCASPAR 2500 IU/m² N=119 Grade &#x2265;3<footnote>Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.</footnote> n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Elevated transaminase<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">79 (66)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Febrile neutropenia</td><td styleCode="Rrule">48 (40)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertriglyceridemia</td><td styleCode="Rrule">36 (30)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypoalbuminemia</td><td styleCode="Rrule">33 (28)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bilirubin increased<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">30 (25)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperglycemia</td><td styleCode="Rrule">29 (24)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pancreatitis<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">29 (24)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abnormal clotting studies<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">25 (21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Embolic and thrombotic events<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">10 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypersensitivity<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">8 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">8 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sepsis<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">7 (6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">6 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemorrhages<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">5 (4)</td></tr><tr><td styleCode="Lrule Rrule">Fungal Infection<footnoteRef IDREF="t3f1"/></td><td styleCode="Rrule">3 (3)</td></tr></tbody></table>

<table width="75%" ID="Table4"><caption>Table 4. Incidence of Clinical Allergic Reactions, Overall and by Severity Grade</caption><col width="20%" align="left" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" valign="bottom">Patient Status</th><th styleCode="Rrule Botrule" colspan="4">Toxicity Grade, n (%)</th><th styleCode="Lrule Rrule" rowspan="2" valign="bottom">Total</th></tr><tr><th styleCode="Lrule Rrule" align="center">1</th><th styleCode="Rrule">2</th><th styleCode="Rrule">3</th><th styleCode="Rrule">4</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Previously Hypersensitive Patients (n=62)</td><td styleCode="Rrule">7 (11)</td><td styleCode="Rrule">8 (13)</td><td styleCode="Rrule">4 (6)</td><td styleCode="Rrule">1 (2)</td><td styleCode="Rrule">20 (32)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Non-Hypersensitive Patients (n=112)</td><td styleCode="Rrule">5 (4)</td><td styleCode="Rrule">4 (4)</td><td styleCode="Rrule">1 (1)</td><td styleCode="Rrule">1 (1)</td><td styleCode="Rrule">11 (10)</td></tr><tr><td styleCode="Lrule Rrule">First Line (n=58)</td><td styleCode="Rrule">1 (2)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1 (2)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2 (3)</td></tr></tbody></table>