CALASPARGASE PEGOL: 125 Adverse Event Reports & Safety Profile

Calaspargase pegol-mknl contains an asparagine specific enzyme derived from Escherichia coli , as a conjugate of L-asparaginase (L-asparagine amidohydrolase) and monomethoxypolyethylene glycol (mPEG) with a succinimidyl carbonate (SC) linker. The SC linker is a chemically stable carbamate bond between the mPEG moiety and the lysine groups of L-asparaginase. L-asparaginase is a tetrameric enzyme that is produced endogenously by E. coli and consists of identical 34.5 kDa subunits.

Approximately

31 to 39 molecules of SC-PEG are linked to L-asparaginase; the molecular weight of each SC-PEG molecule is about 5 kDa. The activity of ASPARLAS is expressed in units (U). ASPARLAS injection is supplied as a clear, colorless, preservative-free, isotonic sterile solution in phosphate-buffered saline, pH 7.3 that requires dilution prior to intravenous infusion. Each vial of ASPARLAS contains 3,750 units in 5 mL of solution. Each milliliter contains 750 units of calaspargase pegol-mknl; dibasic sodium phosphate, USP (5.58 mg); monobasic sodium phosphate, USP (1.20 mg); and sodium chloride, USP (8.50 mg) in water for injection, USP.

AND USAGE ASPARLAS is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years. ( 1.1 )

1.1 Acute Lymphoblastic Leukemia ASPARLAS is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years.

AND ADMINISTRATION Recommended Dosage: 2,500 units/m 2 intravenously no more frequently than every 21 days. ( 2.1 )

See Full Prescribing

Information for important details regarding dosing modifications and preparation and administration. ( 2.2 , 2.3 , 2.4 )

2.1 Recommended Dosage The recommended dose of ASPARLAS is 2,500 units/m 2 given intravenously no more frequently than every 21 days.

2.2 Recommended Premedication Premedicate patients with acetaminophen, an H-1 receptor blocker (such as diphenhydramine), and an H-2 receptor blocker (such as famotidine) 30-60 minutes prior to administration of ASPARLAS to decrease the risk and severity of both infusion and hypersensitivity reactions <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

2.3 Recommended Monitoring and Dosage Modifications for Adverse Reactions 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.

Table

1: Dosage Modifications Adverse Reaction Severity Grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening.

Action Infusion

Reaction/ Hypersensitivity Reaction [see Warnings and Precautions (5.1) ]

Grade

1 Reduce the infusion rate by 50% Grade 2 Interrupt the infusion of ASPARLAS Treat the symptoms When symptoms resolve, resume the infusion and reduce the infusion rate by 50% Grade 3 to 4 Discontinue ASPARLAS permanently Pancreatitis [see Warnings and Precautions (5.2) ]

Grades

3 to 4 Hold ASPARLAS for elevations in lipase or amylase >3 × upper limit of normal (ULN) until enzyme levels stabilize or are declining Discontinue ASPARLAS permanently if clinical pancreatitis is confirmed Thrombosis [see Warnings and Precautions (5.3) ] Uncomplicated deep vein thrombosis Hold ASPARLAS Treat with appropriate antithrombotic therapy Upon resolution of symptoms consider resuming ASPARLAS, while continuing antithrombotic therapy Severe or life-threatening thrombosis Discontinue ASPARLAS permanently Treat with appropriate antithrombotic therapy Hemorrhage [see Warnings and Precautions (5.4) ]

Grade

3 to 4 Hold ASPARLAS Evaluate for coagulopathy and consider clotting factor replacement as needed Resume ASPARLAS with the next scheduled dose if bleeding is controlled Hepatotoxicity [see Warnings and Precautions (5.5) ] Total bilirubin more than 3 times to no more than 10 times the ULN Hold ASPARLAS until total bilirubin is ≤1.5 times the ULN Total bilirubin more than 10 times the ULN Discontinue ASPARLAS and do not make up for missed doses

2.4 Preparation and Administration ASPARLAS 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. Do not administer if ASPARLAS has been shaken or vigorously agitated, frozen, or stored at room temperature for more than 48 hours. Dilute ASPARLAS in 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP using sterile/aseptic technique. Discard any unused portion left in a vial. After dilution, administer immediately into a running infusion of either 0.9% sodium chloride or 5% dextrose, respectively. Administer the dose over a period of 1 hour. Do not infuse other drugs through the same intravenous line during administration of ASPARLAS. The diluted solution may be stored for up to 4 hours at room temperature (15°C to 25°C [59°F to 77°F]) or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours. Protect from light. Do not shake or freeze.

ASPARLAS is contraindicated in patients with: History of serious hypersensitivity reactions, including anaphylaxis, to pegylated L-asparaginase therapy [see Warnings and Precautions (5.1) ] History of serious pancreatitis during previous L-asparaginase therapy [see Warnings and Precautions (5.2) ] History of serious thrombosis during previous L-asparaginase therapy [see Warnings and Precautions (5.3) ] History of serious hemorrhagic events during previous L-asparaginase therapy [see Warnings and Precautions (5.4) ] Severe hepatic impairment [see Warnings and Precautions (5.5) ] History of serious hypersensitivity reactions to pegylated L-asparaginase. ( 4 ) History of serious thrombosis during L-asparaginase therapy. ( 4 ) History of serious pancreatitis related to previous L-asparaginase treatment. ( 4 ) History of serious hemorrhagic events during previous L-asparaginase therapy. ( 4 ) Severe hepatic impairment. ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Pancreatitis [see Warnings and Precautions (5.2) ] Thrombosis [see Warnings and Precautions (5.3) ] Hemorrhage [see Warnings and Precautions (5.4) ] Hepatotoxicity, including VOD [see Warnings and Precautions (5.5) ] The most common (incidence ≥10%) grade ≥3 adverse reactions were elevated transaminase, bilirubin increased, pancreatitis, and abnormal clotting studies. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals LLC 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, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Study DFCI 11-001 The safety of ASPARLAS was investigated in Study DFCI 11-001, an open-label, randomized, active-controlled multicenter clinical trial that treated 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma, with ASPARLAS 2,500 U/m 2 (n=118) or pegaspargase 2,500 U/m 2 (n=119) as part of a Dana-Farber Cancer Institute (DFCI)

All

Consortium backbone therapy. The median age on enrollment was 5 years (range, 1-20 years). The majority of patients were male (62%) and white (70%). Most patients were considered standard risk (SR, 59%) and had B-cell lineage ALL (87%). The median number of doses during the study was 11 doses for ASPARLAS (administered every three weeks) and 16 doses for pegaspargase (administered every two weeks). The median duration of exposure was 8 months for both ASPARLAS and pegaspargase. There was 1 fatal adverse reaction (multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst).

Table

2 summarizes the incidence of selected grades ≥3 adverse reactions that occurred in 2 or more patients receiving ASPARLAS. Because not all grade 1 and 2 adverse reactions were collected prospectively, only grade 3 and 4 adverse events are presented in Table 2.

Table

2: Selected Grades ≥3 Adverse Reactions in Patients Receiving ASPARLAS with Multi-Agent Chemotherapy (Study DFCI 11-001) ASPARLAS or pegaspargase were administered as a component of multi-agent chemotherapy regimens.

Adverse Reaction

Grouped terms: Elevated transaminase : Alanine aminotransferase increased, Aspartate aminotransferase increased, Transaminases increased; Bilirubin increased : Bilirubin conjugated increased, Blood bilirubin increased; Pancreatitis : Amylase increased, Lipase increased, Pancreatic necrosis, Pancreatitis, Pancreatitis relapsing; Abnormal clotting studies : Activated partial thromboplastin time prolonged, Blood fibrinogen decreased; Diarrhea : Colitis, Diarrhea, Enterocolitis, Neutropenic colitis; Hypersensitivity : Anaphylactic reaction, Drug hypersensitivity, Hypersensitivity; Embolic and thrombotic events SMQ : Device related thrombosis, Disseminated intravascular coagulation, Embolism, Intracardiac thrombus, Intracranial venous sinus thrombosis, Pulmonary embolism, Superior sagittal sinus thrombosis, Thrombosis in device, Venous thrombosis, Venous thrombosis limb; Sepsis : Bacterial sepsis, Sepsis; Dyspnea : Hypoxia, Respiratory failure; 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; Pneumonia : Lung infection, Pneumonia, Pneumonitis; Arrhythmia : Atrioventricular block complete, Sinus tachycardia, Ventricular arrhythmia; Cardiac failure : Ejection fraction decreased, Left ventricular dysfunction. ASPARLAS 2,500 U/m 2 N=118 Pegaspargase 2,500 U/m 2 N=119 Grades ≥3 n (%) Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grades ≥3 n (%) Elevated transaminase 61 (52) 79 (66) Bilirubin increased 24 (20) 30 (25)

Pancreatitis

21 (18) 29 (24) Abnormal clotting studies 17 (14) 25 (21)

Diarrhea

10 (9) 6 (5)

Hypersensitivity

9 (8) 8 (7) Embolic and thrombotic events 9 (8) 10 (8)

Sepsis

6 (5) 7 (6)

Dyspnea

5 (4) 1 (1)

Hemorrhages

5 (4) 5 (4) Fungal infection 4 (3) 3 (3)

Pneumonia

4 (3) 8 (7)

Arrhythmia

2 (2) 1 (1) Cardiac failure 2 (2) 1 (1) In the subgroup of patients with B-cell lineage ALL, the complete remission rate in the ASPARLAS arm was 98% (95/97), compared to 99% in the pegaspargase arm; the Kaplan-Meier estimates of overall survival of the treatment arms were comparable. Study AALL07P4 The safety of ASPARLAS was also evaluated in Study AALL07P4, an open-label, randomized, active-controlled, multicenter clinical trial that treated patients with newly diagnosed high-risk B-precursor ALL using ASPARLAS 2,500 U/m 2 (n=43) or 2,100 U/m 2 (n=68), or pegaspargase 2,500 U/m 2 (n=52), as a component of an augmented Berlin-Frankfurt-Münster (BFM) therapy regimen. The median age was 11 years (range, 1-26 years); the median duration of exposure was 7 months for both ASPARLAS and pegaspargase. In this study, the induction mortality of patients treated with ASPARLAS was 2.8% (3 out of 111); there were no induction deaths among 52 patients treated with pegaspargase. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions In Study DFCI 11-001, hypersensitivity reactions occurred in 80% of ASPARLAS-treated patients with new or an increased titer of anti-drug antibodies (ADA) and in 6% of those without ADA [see Clinical Pharmacology (12.6) ] . Two patients with ADA experienced anaphylaxis [see Warnings and Precautions (5.1) ] .

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ASPARLAS. 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. Hepatic: Veno-occlusive disease

AND PRECAUTIONS Hypersensitivity : Observe patients for one hour after administration. Discontinue ASPARLAS in patients with serious hypersensitivity reactions. ( 5.1 ) Pancreatitis : Discontinue ASPARLAS in patients with pancreatitis. Monitor blood glucose. ( 5.2 ) Thrombosis : Discontinue ASPARLAS for severe or life-threatening thrombosis. ( 5.3 ) Hemorrhage : Discontinue ASPARLAS for severe or life-threatening hemorrhage. Evaluate for etiology and treat. ( 5.4 ) Hepatotoxicity, including hepatic veno-occlusive disease (VOD) : Monitor for toxicity through recovery from cycle. Discontinue ASPARLAS for severe liver toxicity. ( 5.5 )

5.1 Hypersensitivity Grade 3 and 4 hypersensitivity reactions, including anaphylaxis, have been reported in clinical trials with ASPARLAS with an incidence between 7 and 21% <span class="opacity-50 text-xs">[see Contraindications (4) , Adverse Reactions (6.1) ]</span> . Hypersensitivity reactions observed with other asparaginases include angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnea, pruritus, and rash <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Premedicate patients 30-60 minutes prior to administration of ASPARLAS <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer ASPARLAS in a clinical setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines) <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> and observe patients for 1 hour after administration. Discontinue ASPARLAS in patients with serious hypersensitivity reactions.

5.2 Pancreatitis Cases of pancreatitis have been reported in clinical trials with ASPARLAS with an incidence between 12 and 16% <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Hemorrhagic or necrotizing pancreatitis have been reported with other asparaginases. Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Assess serum amylase and/or lipase levels to identify early signs of pancreatic inflammation. Discontinue ASPARLAS if pancreatitis is suspected; if pancreatitis is confirmed, do not resume ASPARLAS <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.3 Thrombosis Serious thrombotic events, including sagittal sinus thrombosis, have been reported in clinical trials with ASPARLAS with an incidence of 9 to 12%. Discontinue ASPARLAS in patients experiencing serious thrombotic events <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) , Adverse Reactions (6.1) ]</span> .

5.4 Hemorrhage Hemorrhage associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia have been reported in patients receiving ASPARLAS <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.5 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 ASPARLAS in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . Do not administer ASPARLAS to patients with severe hepatic impairment <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Evaluate bilirubin and transaminases prior to each dose of ASPARLAS and at least weekly, during cycles of treatment that include ASPARLAS, through 6 weeks after the last dose of ASPARLAS. 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 ASPARLAS, 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 ASPARLAS and provide supportive care <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .