ASPARAGINASE: 4,990 Adverse Event Reports & Safety Profile

Asparaginase erwinia chrysanthemi (recombinant)-rywn contains an asparagine specific bacterial enzyme (L-asparaginase). L-asparaginase is a tetrameric enzyme that consists of four identical 35 kDa subunits with a combined molecular weight of 140 kDa. The amino acid sequence is identical to native asparaginase Erwinia chrysanthemi (also known as crisantaspase). The activity of asparaginase erwinia chrysanthemi (recombinant)-rywn is expressed in units, defined as the amount of enzyme that catalyzes the conversion of 1μmol of L-asparagine per reaction minute, per mg of protein. Asparaginase erwinia chrysanthemi (recombinant)-rywn is produced by fermentation of a genetically engineered Pseudomonas fluorescens bacterium containing the DNA which encodes for asparaginase Erwinia chrysanthemi . RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn) injection is supplied as a sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution for intramuscular injection.

Each

0.5 mL contains 10 mg asparaginase erwinia chrysanthemi (recombinant)-rywn and the inactive ingredients: polysorbate 80 (0.1 mg), sodium chloride (1.5 mg), sodium phosphate dibasic anhydrous (0.8 mg), sodium phosphate monobasic monohydrate (0.6 mg), and trehalose dihydrate (32.1 mg). Sodium hydroxide may be added during manufacture to adjust the pH. The pH is approximately 7.

AND USAGE RYLAZE is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli -derived asparaginase. RYLAZE is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli -derived asparaginase. ( 1 )

AND ADMINISTRATION There are two RYLAZE regimens that can be used to replace a long-acting asparaginase product. The recommended dosages of RYLAZE are: When administered every 48 hours

• 25 mg/m 2 intramuscularly every 48 hours; When administered Monday/Wednesday/Friday
• 25 mg/m 2 intramuscularly on Monday morning and Wednesday morning and 50 mg/m 2 intramuscularly on Friday afternoon. ( 2.1 )

2.1 Recommended Dosage There are two RYLAZE regimens that can be used to replace a long-acting asparaginase product. The recommended dosages of RYLAZE are: When administered every 48 hours:

• 25 mg/m 2 administered intramuscularly every 48 hours; When administered on a Monday/Wednesday/Friday schedule:
• 25 mg/m 2 intramuscularly on Monday morning and Wednesday morning, and 50 mg/m 2 intramuscularly on Friday afternoon. Administer the Friday afternoon dose 53 to 58 hours after the Wednesday morning dose (e.g., 8:00 am on Monday and Wednesday, and 1:00 pm to 6:00 pm on Friday) [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] .

Table

1 shows the number of RYLAZE dosages recommended for the intended duration of treatment for replacement of one dose of calaspargase pegol products (3 weeks of asparaginase coverage) or one dose of pegaspargase products (2 weeks of asparaginase coverage). See the full prescribing information for the long-acting asparaginase product to determine the total duration of administration of RYLAZE as replacement therapy.

Table

1: Recommended Duration of RYLAZE Dosing to Replace One Long-Acting Asparaginase Dose When RYLAZE is Administered: Recommended Duration of RYLAZE to Replace Calaspargase Pegol Products Recommended Duration of RYLAZE to Replace Pegaspargase Products 25 mg/m 2 intramuscular every 48 hours Replace one dose of calaspargase pegol products with 11 doses of RYLAZE Replace one dose of pegaspargase products with 7 doses of RYLAZE 25 mg/m 2 intramuscular on Monday morning and Wednesday morning, and 50 mg/m 2 intramuscular on Friday afternoon* Replace one dose of calaspargase pegol products with 9 doses of RYLAZE Replace one dose of pegaspargase products with 6 doses of RYLAZE *See bullet above for timing of 25/25/50 mg/m 2 dosing of RYLAZE.

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 RYLAZE to decrease the risk and severity of 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 patient’s bilirubin, transaminases, glucose, and clinical examinations prior to treatment every 2-3 weeks and as indicated clinically. If results are abnormal, monitor patients until recovery from the cycle of therapy. If an adverse reaction occurs, modify treatment according to Table 2.

Table

2: Dosage Modifications Adverse Reaction Severity* Action Hypersensitivity Reaction [see Warnings and Precautions ( 5.1 )]

Grade

2

• Treat the symptoms.

Grade

3 to 4

• Discontinue RYLAZE permanently. Pancreatitis [see Warnings and Precautions ( 5.2 )]

Grade

2 to 4

• Hold RYLAZE for elevations in lipase or amylase > 2 times the ULN**, or for symptomatic pancreatitis.
• Resume treatment when lipase and amylase are < 1.5 times the ULN and symptoms are resolved.
• Discontinue RYLAZE permanently if clinical necrotizing or hemorrhagic pancreatitis is confirmed. Thrombosis [see Warnings and Precautions ( 5.3 )] Uncomplicated thrombosis
• Hold RYLAZE.
• Treat with appropriate antithrombotic therapy.
• Upon resolution of symptoms, consider resuming RYLAZE, while continuing antithrombotic therapy. Severe or life-threatening thrombosis
• Discontinue RYLAZE permanently.
• Treat with appropriate antithrombotic therapy. Hemorrhage [see Warnings and Precautions ( 5.4 )]

Grade

3 to 4

• Hold RYLAZE.
• Evaluate for coagulopathy and consider clotting factor replacement as needed.
• Resume RYLAZE with the next scheduled dose if bleeding is controlled. Hepatotoxicity [see Warnings and Precautions ( 5.5 )] Total bilirubin > 3 times to ≤ 10 times the ULN
• Hold RYLAZE until total bilirubin levels decrease to ≤ 1.5 times the ULN. Total bilirubin > 10 times the ULN
• Discontinue RYLAZE and do not make up missed doses. * Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. ** Upper limit of normal

2.4 Preparation and Administration Instructions Ensure that medical support is available to appropriately manage anaphylactic reactions when administering RYLAZE <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter, cloudiness, or discoloration are present, discard the vial.

• Use aseptic technique.
• Determine the dose, total volume of RYLAZE solution required, and the number of RYLAZE vials needed based on the individual patient’s BSA. More than one vial may be needed for a full dose.
• Withdraw the indicated injection volume of RYLAZE into the syringe for injection. o Do not shake the vial. o Limit the volume of RYLAZE at a single injection site to 2 mL. o If the volume to be administered is greater than 2 mL, divide the doses equally into multiple syringes, one for each injection site. o Discard the remaining unused RYLAZE in the single-dose vial.
• Administer RYLAZE by intramuscular injection. o Rotate injection sites. o Do not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen.
• If the prepared dose is not used immediately, store the syringe(s) at room temperature 15°C to 25°C (59°F to 77°F) for up to 8 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours. The syringe does not need to be protected from light during storage.

RYLAZE is contraindicated in patients with:

• History of serious hypersensitivity reactions to Erwinia asparaginase , including anaphylaxis [see Warnings and Precautions ( 5.1 )] ;
• History of serious pancreatitis during previous asparaginase therapy [see Warnings and Precautions ( 5.2 )] ;
• History of serious thrombosis during previous asparaginase therapy [see Warnings and Precautions ( 5.3 )] ;
• History of serious hemorrhagic events during previous asparaginase therapy [see Warnings and Precautions ( 5.4 )] ;
• Severe hepatic impairment [ see Warnings and Precautions ( 5.5 ) ]. RYLAZE is contraindicated in patients with:
• History of serious hypersensitivity reactions to RYLAZE, including anaphylaxis. ( 4 )
• History of serious pancreatitis during previous L-asparaginase therapy. ( 4 )
• History of serious thrombosis during previous L-asparaginase therapy. ( 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 in greater detail in other sections of the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )]
• Pancreatic Toxicity [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 )] Most common adverse reactions (incidence > 20%) are abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals Ireland Limited at 1-800-520-5568 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. The safety of RYLAZE described in the WARNINGS AND PRECAUTIONS reflect exposure in 167 patients administered RYLAZE intramuscularly at various dosages when used in combination with chemotherapy in study JZP458-201 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . These patients received a median of 4 courses of RYLAZE (range: 1-15 courses); 65% of patients received at least four courses. The safety of RYLAZE described below and in Table 3 was evaluated in study JZP458-201, a multi-cohort study. Patients received RYLAZE administered intramuscularly at dosages of 25 mg/m 2 on Monday, Wednesday, and Friday or 25 mg/m 2 on Monday and Wednesday, and 50 mg/m 2 on Friday, for 6 doses as a replacement for a single dose of pegaspargase as a component of multi-agent chemotherapy <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . The patients had a median age of 11 years (range: 1‑25 years); the majority of patients were male (57%) and White (68%). The patients received a median of 4 courses of RYLAZE (range: 1-14 courses); 65% of patients received at least four courses. A fatal adverse reaction (infection) occurred in 1 patient treated with the RYLAZE 25/25/25 mg/m 2 dosage. Serious adverse reactions occurred in 60% of patients who received the recommended dosages of RYLAZE. The most frequent nonhematological serious adverse reactions (in ≥ 5% of patients) were febrile neutropenia, infection, drug hypersensitivity, pyrexia, nausea, dehydration, stomatitis, acute kidney injury, pancreatitis, diarrhea, and viral infection. Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RYLAZE intramuscularly at the recommended dosages. Adverse reactions resulting in permanent discontinuation included pancreatitis (5%), drug hypersensitivity (4%), and infection (1%). All patients treated with the recommended dosages of RYLAZE as a component of multi-agent chemotherapy experienced neutropenia, anemia, or thrombocytopenia. The most common nonhematological adverse reactions (incidence &gt; 20%) in patients were abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia.

Table

3 shows the common adverse reactions occurring in at least 15% of the patients.

Table

3: Adverse Reactions (≥ 15% Incidence) in Patients Receiving RYLAZE as a Component of Multi-Agent Chemotherapy in Study JZP458-201 Adverse Reaction RYLAZE 25/25/25 mg/m 2 Intramuscular Dosage a (N = 33) RYLAZE 25/25/50 mg/m 2 Intramuscular Dosage a (N = 51)

All

Grades (%)

Grades

3-4 (%)

All

Grades (%)

Grades

3-4 (%) Abnormal liver test* # 70 18 75 27 Musculoskeletal pain* 45 6 35 4 Nausea* 45 9 47 8 Fatigue* 36 18 22 18 Headache 36 0 22 0 Infection* b 36 15 27 17 Febrile neutropenia 30 30 27 27 Pyrexia 30 6 20 0 Hemorrhage* 24 0 27 6 Stomatitis 24 12 27 4 Abdominal pain* 21 0 25 2 Decreased appetite 21 6 27 6 Drug hypersensitivity* 21 6 24 2 Hyperglycemia 21 3 12 4 Diarrhea* 18 6 25 4 Tachycardia* 18 0 16 2 Cough 15 0 14 0 Dehydration 15 9 12 6 Insomnia 15 0 4 0 Peripheral neuropathy* 15 0 6 0 Pancreatitis* # 12 0 22 10 Hypokalemia 9 3 22 8 * Includes grouped terms: Abnormal liver test : alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased; Musculoskeletal pain : arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, pain in extremity; Nausea : nausea, vomiting; Fatigue : fatigue, asthenia; Infection : sepsis, upper respiratory tract infection, enterocolitis infectious, skin infection, bacteremia, paronychia, pneumonia, otitis externa, soft tissue infection, abdominal infection, conjunctivitis, device related infection, folliculitis, lymph gland infection, necrotizing fasciitis, perirectal abscess, peritonsillar abscess, sinusitis, subcutaneous abscess, wound infection; Drug hypersensitivity : drug hypersensitivity, rash, infusion related reaction, lip swelling, periorbital edema, throat irritation, urticaria, dry skin, eczema, erythema, hand dermatitis, rash maculo-papular, rash papular; Hemorrhage : contusion, epistaxis, catheter site hemorrhage, petechiae, hematochezia, menorrhagia, mouth hemorrhage, increased tendency to bruise, rectal hemorrhage; Abdominal pain : abdominal pain, abdominal pain upper; Diarrhea : diarrhea, colitis; Tachycardia : sinus tachycardia, tachycardia; Peripheral neuropathy : peripheral motor neuropathy, neuropathy peripheral, peripheral sensory neuropathy; Pancreatitis : pancreatitis, pancreatitis acute, amylase increased, lipase increased. *Includes adverse event terms and laboratory abnormalities Grading is based on Common Terminology Criteria for Adverse Events version 5.0. a RYLAZE was administered as a component of multi-agent chemotherapy regimens on a Monday, Wednesday, and Friday schedule. b Does not include the following fatal adverse reactions: infection (N=1). Clinically relevant adverse reactions in < 15% of patients who received RYLAZE in combination with chemotherapy included: Gastrointestinal disorders : Abdominal discomfort, abdominal distension, constipation, gastritis General disorders and administration site conditions : Infusion site reaction, injection site reaction, pain Infections and infestations : Viral infection, bacterial infection, fungal infection Investigations : Antithrombin III decreased, blood cholesterol increased, blood fibrinogen decreased, activated partial thromboplastin time prolonged Metabolism and nutrition disorders : Acidosis, hyperammonemia, hyperphosphatemia, hypertriglyceridemia, hypoglycemia Musculoskeletal and connective tissue disorders : Bone pain, muscular weakness, muscle spasms Nervous system disorders : Paresthesia, dizziness, gait disturbance, hyperammonemic encephalopathy Psychiatric disorders : Agitation, anxiety, irritability Respiratory, thoracic, and mediastinal disorders: Acute respiratory distress syndrome, pulmonary edema Renal and urinary disorders : Acute kidney injury Skin and subcutaneous disorders : Pruritus Vascular disorders : Hypertension, hypotension, thrombosis

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of RYLAZE. 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 (VOD)

AND PRECAUTIONS

• Hypersensitivity: Monitor for signs or symptoms. Discontinue RYLAZE for serious reaction. ( 5.1 )
• Pancreatitis: Monitor for symptoms. Discontinue if pancreatitis occurs. ( 5.2 )
• Thrombosis: Discontinue RYLAZE for severe or life-threatening thrombosis. Provide anticoagulation therapy as indicated. ( 5.3 )
• Hemorrhage: Discontinue RYLAZE for severe or life-threatening hemorrhage. ( 5.4 )
• Hepatotoxicity, including hepatic veno-occlusive disease: Discontinue RYLAZE for grade 4 increases of bilirubin. ( 5.5 )

5.1 Hypersensitivity Reactions Hypersensitivity reactions after the use of RYLAZE occurred in 29% of patients in clinical trials, and it was severe in 6% of patients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Anaphylaxis was observed in 2% of patients after intramuscular administration. Discontinuation of RYLAZE due to hypersensitivity reactions occurred in 5% of patients. Hypersensitivity reactions were higher in patients who received intravenous asparaginase erwinia chrysanthemi (recombinant)-rywn. The intravenous route of administration is not approved. In patients administered RYLAZE intramuscularly in clinical trials, the median number of doses of RYLAZE that patients received prior to the onset of the first hypersensitivity reaction was 12 doses (range: 1-64 doses). The most commonly observed reaction was rash (19%), and 1 patient (1%) experienced a severe rash. Hypersensitivity reactions observed with L-asparaginase class products include angioedema, urticaria, lip swelling, eye swelling, rash or erythema, blood pressure decreased, bronchospasm, dyspnea, and pruritus. Premedicate patients prior to administration of RYLAZE as recommended <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 RYLAZE in a 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 ( 2.3 )]</span> . Discontinue RYLAZE in patients with serious hypersensitivity reactions <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

5.2 Pancreatitis Pancreatitis, including elevated amylase or lipase, was reported in 20% of patients in clinical trials of RYLAZE and was severe in 8% <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Symptomatic pancreatitis occurred in 7% of patients, and it was severe in 6% of patients. Elevated amylase or lipase without symptomatic pancreatitis was observed in 13% of patients treated with RYLAZE. Hemorrhagic or necrotizing pancreatitis have been reported with L-asparaginase class products. Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Assess serum amylase and lipase levels in patients with any signs or symptoms of pancreatitis. Discontinue RYLAZE in patients with severe or hemorrhagic pancreatitis. In the case of mild pancreatitis, withhold RYLAZE until the signs and symptoms subside and amylase and/or lipase levels return to 1.5 times the ULN <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . After resolution of mild pancreatitis, treatment with RYLAZE may be resumed.

5.3 Thrombosis Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported in 1% of patients following treatment with RYLAZE. Discontinue RYLAZE for a thrombotic event, and administer appropriate antithrombotic therapy. Consider resumption of treatment with RYLAZE only if the patient had an uncomplicated thrombosis <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

5.4 Hemorrhage Bleeding was reported in 25% of patients treated with RYLAZE, and it was severe in 2%. Most commonly observed reactions were bruising (12%) and nose bleed (9%) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In patients treated with L-asparaginase class products, hemorrhage may be associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia. 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 Elevated bilirubin and/or transaminases occurred in 75% of patients treated with RYLAZE in clinical trials, and 26% had Grade ≥ 3 elevations. Elevated bilirubin occurred in 28% of patients treated with RYLAZE in clinical trials, and 2% had Grade ≥ 3 elevations. Elevated transaminases occurred in 73% of patients treated with RYLAZE in clinical trials, and 25% had Grade ≥ 3 elevations <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Hepatotoxicity, including severe, life-threatening, and potential fatal cases of hepatic veno-occlusive disease (VOD), have been observed in patients treated with asparaginase class products 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 RYLAZE to patients with severe hepatic impairment <span class="opacity-50 text-xs">[see Contraindication ( 4 )]</span>. Inform patients of the signs and symptoms of hepatotoxicity. Evaluate bilirubin and transaminases prior to each cycle of RYLAZE and at least weekly during cycles of treatment that include RYLAZE, through four weeks after the last dose of RYLAZE. 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 RYLAZE, 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 RYLAZE and provide supportive care <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span>.