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Manufacturing RYLAZE

Learn about the recombinant manufacturing process.

My name is Austin Power and I’m the senior director for the biologics development team at Jazz Pharmaceuticals. I’ve had the honor to work with my team to shape the RYLAZE manufacturing process. What you need to know about RYLAZE is that it is recombinant Erwinia asparaginase that will help meet the supply needs of the ALL/LBL community. RYLAZE is derived from a novel Pseudomonas fluorescens expression platform that produces an enzyme with no immunological crossreactivity to E. coli-derived asparaginases.

In my experience, manufacturing biologics can be a complex process. The living systems used to produce biologics can be sensitive to very minor changes in the manufacturing process. With this in mind, we wanted to achieve a consistent and reliable process while producing RYLAZE, which is why we partnered with trusted manufacturers who make use of state of the art facilities, innovative modern manufacturing technology, and the highest standard of production and quality control.

Our modern manufacturing of RYLAZE utilizes Pfenex technology, which is a novel approach to recombinant protein production. To produce RYLAZE, recombinant Erwinia asparaginase is extracted from a common and nonpathogenic microbe. Our partner, AGC Biologics in Denmark efficiently manufactures RYLAZE with technology developed at Pfenex. That helps to produce high yields of purified product in as little as 3 weeks. RYLAZE is then filled and finished in the United States at Patheon Thermo Fisher in North Carolina, in a sterile environment. This results in a ready-to-use, high-concentration formulation.

We’ve developed an efficient and modern drug manufacturing process from start to finish, resulting in rapid and reliable supply. Our partnerships with Pfenex, AGC, and Patheon help to ensure the high-quality product, and I can speak from experience that at Jazz Pharmaceuticals, we remain committed to redefining the possibilities for patients with ALL/LBL as we have been for 10 years. By choosing RYLAZE, you can rely on the supply you need for your patients when you need it.

Thanks for taking the time to watch this video about the RYLAZE manufacturing process.

OK Michael, I think that’s a wrap.

That was fantastic, Austin.

Indication

RYLAZE is indicated as a component of a multi-agent chemotherapeutic regimen given by intramuscular injection 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.

IMPORTANT SAFETY INFORMATION

Contraindications

RYLAZE is contraindicated in patients with a history of:

  • Serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis
  • Serious pancreatitis during previous asparaginase therapy
  • Serious thrombosis during previous asparaginase therapy
  • Serious hemorrhagic events during previous asparaginase therapy

Warnings and Precautions

Hypersensitivity Reactions

Hypersensitivity reactions after the use of RYLAZE occurred in 25% of patients in clinical trials, and it was severe in 2% of patients. The median time from the first dose of RYLAZE to the onset of the first hypersensitivity event was 27 days (range 1-171 days). The most commonly observed reaction was rash (17%), and no patient experienced a severe rash. The median time from the first dose to the first onset of rash was 33.5 days (range 1-127 days).

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.

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). Discontinue RYLAZE in patients with serious hypersensitivity reactions.

Pancreatitis

Pancreatitis was reported in 14% of patients in clinical trials of RYLAZE and was severe in 6%. Clinical pancreatitis occurred in 5% of patients, and it was severe in 4% of patients. Elevated amylase or lipase without clinical diagnosis of pancreatitis was observed in 9% of patients, and it was severe in 2% 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. After resolution of mild pancreatitis, treatment with RYLAZE may be resumed.

Thrombosis

Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported following treatment with L-asparaginase class products. 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.

Hemorrhage

Bleeding was reported in 17% of patients treated with RYLAZE, and it was severe in 1%. Most commonly observed reactions were bruising (8%) (contusion, increased tendency to bruise and injection site bruising) and nose bleeding (6%), which was severe in 1% of patients. Other observed bleeding reactions included hematuria (2%), disseminated intravascular coagulopathy (1%), rectal bleeding (1%) and gingival bleeding (1%).

In patients treated with 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.

Hepatotoxicity

Elevated bilirubin and/or transaminases occurred in 62% of patients treated with RYLAZE in clinical trials, and 12% had Grade ≥3 elevations.

Inform patients of the signs and symptoms of hepatotoxicity. Evaluate bilirubin and transaminases prior to treatment every 2-3 weeks and as indicated clinically during treatment with RYLAZE. In the event of serious liver toxicity, discontinue treatment with RYLAZE and provide supportive care.

Adverse Reactions

Serious adverse reactions occurred in 55% of patients who received RYLAZE. The most frequent serious adverse reactions (in ≥5% of patients) were febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea, and viral infection.

The most common adverse reactions (incidence >20%) with RYLAZE are abnormal liver test (70%), nausea (46%), musculoskeletal pain (39%), fatigue (36%), infection (30%), headache (30%), pyrexia (27%), drug hypersensitivity (24%), febrile neutropenia (24%), decreased appetite (21%), stomatitis (21%), bleeding (21%), and hyperglycemia (21%).

Use in Specific Populations

Pregnancy and Lactation

RYLAZE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with RYLAZE and for 3 months after the last dose. Advise women not to breastfeed during treatment with RYLAZE and for 1 week after the last dose.

Please see full Prescribing Information.

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Indication

RYLAZE is indicated as a component of a multi-agent chemotherapeutic regimen given by intramuscular injection 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.

IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY 
INFORMATION AND INDICATION

Contraindications

RYLAZE is contraindicated in patients with a history of:

  • Serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis
  • Serious pancreatitis during previous asparaginase therapy
  • Serious thrombosis during previous asparaginase therapy
  • Serious hemorrhagic events during previous asparaginase therapy