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/m2 administered intramuscularly every 48 hours;

     When administered on a Monday/Wednesday/Friday schedule:

•

25 mg/m2 intramuscularly on Monday morning and Wednesday morning, and 50 mg/m2 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.

*See bullet above for timing of 25/25/50 mg/m2 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 [see Warnings and Precautions (5.1)].

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.

* 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 [see Warnings and Precautions (5.1)].

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.

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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.2)]. 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) [see Dosage and Administration (2.3)]. Discontinue RYLAZE in patients with serious hypersensitivity reactions [see Dosage and Administration (2.3)].

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% [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.3)]. 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 [see Dosage and Administration (2.3)].

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%) [see Adverse Reactions (6.1)].

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 [see Dosage and Administration (2.3)].

5.5 Hepatotoxicity

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 [see Adverse Reactions (6.1)].

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 [see Dosage and Administration (2.3)].

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 [see Clinical Studies (14)]. 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/m2 on Monday, Wednesday, and Friday or 25 mg/m2 on Monday and Wednesday, and 50 mg/m2 on Friday, for 6 doses as a replacement for a single dose of pegaspargase as a component of multi-agent chemotherapy [see Clinical Studies (14)]. 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/m2 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 > 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.

* 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

8.1 Pregnancy

Risk Summary
Based on findings from animal reproduction studies, RYLAZE can cause fetal harm when administered to a pregnant woman. There are no available data on RYLAZE use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive and developmental toxicity studies, intramuscular administration of asparaginase Erwinia chrysanthemi to pregnant rats and rabbits during organogenesis resulted in structural abnormalities and embryo-fetal mortality (see Data) at exposures below those in patients at the recommended human dose. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Data
Animal Data
Animal reproductive and developmental toxicity studies have not been conducted with RYLAZE.

In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 3, 6, or 12 mg/m2) and rabbits (at 0.12, 0.30, or 0.48 mg/m2). In rats given 12 mg/m2 (approximately 0.48 times the maximum recommended human dose), maternal toxicity of decreased body weight gain was observed, as was a fetal finding of increased incidence of partially undescended thymic tissue. In rabbits, maternal toxicity consisting of decreased body weight was observed at 0.48 mg/m2 (approximately 0.02 times the maximum recommended human dose). Increased post-implantation loss, a decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of ≥ 0.12 mg/m2 (approximately 0.005 times the maximum recommended human dose).

8.2 Lactation

Risk Summary
There are no data on the presence of asparaginase erwinia chrysanthemi (recombinant)-rywn in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with RYLAZE and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

RYLAZE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing
Pregnancy testing is recommended in females of reproductive potential prior to initiating RYLAZE.

Contraception
Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with RYLAZE and for 3 months after the last dose.

8.4 Pediatric Use

The safety and effectiveness of RYLAZE in the treatment of ALL and LBL have been established in pediatric patients 1 month to < 17 years who have developed hypersensitivity to a long-acting E. coli-derived asparaginase. Use of RYLAZE in these age groups is supported by evidence from an adequate and well-controlled study in adults and pediatric patients. The trial included 139 pediatric patients, including 2 infants (1 month to < 2 years), 99 children (2 years to < 12 years old), and 38 adolescents (12 years to < 17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups. The safety and effectiveness of RYLAZE have not been established in pediatric patients younger than 1 month of age.

8.5 Geriatric Use

Clinical studies of RYLAZE did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

12.1 Mechanism of Action

Asparaginase erwinia chrysanthemi (recombinant)-rywn is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacological effect of RYLAZE is based on the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.

12.2 Pharmacodynamics

Asparaginase erwinia chrysanthemi (recombinant)-rywn exposure-response relationships and the time course of pharmacodynamic response are unknown.

12.3 Pharmacokinetics

The pharmacokinetic parameters of asparaginase erwinia chrysanthemi (recombinant)-rywn are presented based on serum asparaginase activity (SAA) after administration of RYLAZE in pediatric and young adult patients with ALL or LBL, unless otherwise specified. Asparaginase erwinia chrysanthemi (recombinant)-rywn maximum SAA (Cmax) and area under the SAA-time curve (AUC) increase proportionally over a dosage range from 12.5 to 50 mg/m2 (0.25 to 1 times the maximum approved recommended dose of 50 mg/m2). The simulated exposures for asparaginase erwinia chrysanthemi (recombinant)-rywn after administration of the approved recommended dosages in a virtual population are summarized in Table 4.

a Ctrough at maximum interval of 58 hours after the last 25 mg/m2 Wednesday morning dose.
b Ctrough at maximum interval of 67 hours after the last 50 mg/m2 Friday afternoon dose.

Absorption
The median (min, max) Tmax of asparaginase erwinia chrysanthemi (recombinant)-rywn after intramuscular administration is 12 (8, 24) hours. The mean absolute bioavailability after intramuscular administration is 37% in healthy subjects.

Distribution
The geometric mean (%CV) volume of distribution of asparaginase erwinia chrysanthemi (recombinant)-rywn is 1.37 L/m2 (47%).

Elimination
The geometric mean (%CV) clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn is 0.17 L/hour/m2 (42%) and the apparent half-life is 15.9 (11%) hours.

Metabolism
Asparaginase erwinia chrysanthemi (recombinant)-rywn is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations
There were no clinically significant differences in the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn based on age (1.4 to 25 years), weight (9 to 131 kg), or sex after the dose was adjusted by body surface area (BSA). The effect of renal and hepatic impairment on the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn has not been studied.

Body Surface Area
The volume of distribution and clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn increase with increasing BSA (0.44 to 2.53 m2).

Racial and Ethnic Groups
Black or African American patients had 29% lower clearance which may increase SAA exposure compared to White and Asian patients. There were no clinically significant differences in clearance between Hispanic and Non-Hispanic patients.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti‑drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of RYLAZE or of other asparaginase erwinia chrysanthemi (recombinant) products.

During treatment in Study JZP458-201 (range 1 to 15 courses), 78/166 (47%) of patients treated with RYLAZE intramuscularly developed anti-asparaginase erwinia chrysanthemi (recombinant)-rywn antibodies. The effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, and effectiveness have not been adequately characterized.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and impairment of fertility studies have not been conducted with asparaginase erwinia chrysanthemi (recombinant)-rywn.

In a fertility and early embryonic development study in rats, asparaginase Erwinia chrysanthemi had no effect on male or female fertility when administered intramuscularly at doses of up to 12 mg/m2 (approximately 0.48 times the maximum recommended human dose) every other day for a total of 35 doses. In males, decreased sperm count was observed at all doses but did not impact fertility.