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crisantaspase recombinant
Crisantaspase recombinant hydrolyzes extracellular L-asparagine, an amino acid that is essential for protein synthesis by leukemic cells, which are unable to synthesize asparagine and depend on an exogenous source, and results in cytotoxicity.
Crisantaspase recombinant is a recombinant form of Erwinia asparaginase. It is expressed in Pseudomonas fluorescens with an identical amino acid sequence to native Erwinia asparaginase. This is antigenically distinct from E. coli-derived asparaginase and therefore can be used as an alternative in patients who have a documented hypersensitivity (reaction and/or silent inactivation) to E. coli-derived asparaginase products.
Exposure increases proportionally over a dosing range from 12.5 to 50 mg/m2.
| Bioavailability |
37% (IM) |
| T max |
13.7 hours |
Crisantaspase recombinant is expected to be metabolized by catabolic pathways into small peptides.
| Half-life |
19.1 hours (IM) |
- Acute lymphoblastic leukemia (ALL)*
- Lymphoblastic lymphoma (LBL)*
Refer to the product monograph for a full list of approved indications.
Other Uses:
- Mixed/biphenotypic leukemia*
*For use in patients who have a documented hypersensitivity (reaction and/or silent inactivation) to E. coli-derived asparaginase products
Emetogenic Potential:
The following adverse effects were reported (≥5% incidence) in a small Phase II/III open-label trial of pediatric and adult patients with ALL or LBL, who had developed hypersensitivity to E. coli-derived asparaginase (pegaspargase), in combination with other chemotherapy. Severe and life-threatening adverse effects from post-marketing or other sources may also be included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial/venous thromboembolism (4%) (2% severe) | E | |||
| Hypertension (14%) | E | ||||
| Hypotension (8%) | E | ||||
| Tachycardia (16%) | E | ||||
| Dermatological | Rash, pruritus (8%) | E | |||
| Gastrointestinal | Abdominal pain (26%) | E | |||
| Anorexia, weight loss (28%) | E | ||||
| Constipation (14%) | E | ||||
| Dehydration (12%) | E | ||||
| Diarrhea (24%) | E | ||||
| Gastroesophageal reflux disease (6%) | E | ||||
| Mucositis (28%) | E | ||||
| Nausea, vomiting (35%) (6% severe) | I E | ||||
| General | Fatigue (22%) | E | |||
| Hematological | Hemorrhage (2%) (severe) | E | |||
| Other - Prolonged PT/aPTT, ↓ antithrombin III, hypofibrinogenemia (6%) | E | ||||
| Hepatobiliary | ↑ Bilirubin (8%) | E | |||
| ↑ LFTs (22%) (8% severe) | E | ||||
| Pancreatitis (12%) (8% severe) | E | ||||
| Hypersensitivity | Hypersensitivity (29%) (2% anaphylaxis) | I E D | |||
| Injection site | Injection site reaction (8%) | I | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (22%) (↓ K, Ca, Na) | E | |||
| Hyperglycemia (12%) | E | ||||
| ↑ Triglycerides (12%) | E | ||||
| Musculoskeletal | Musculoskeletal pain (16%) | E | |||
| Nervous System | Dizziness (8%) | E | |||
| Headache (22%) | E | ||||
| Paresthesia (8%) | E | ||||
| Renal | Creatinine increased (6%) | E | |||
| Respiratory | Cough (14%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
When given in combination with chemotherapy, the most common side effects for crisantaspase recombinant include nausea, vomiting, hypersensitivity, anorexia, weight loss, mucositis, abdominal pain, diarrhea, fatigue, headache, ↑ LFTs and abnormal electrolyte(s).
In clinical trials, the onset of hypersensitivity occurred after a median of 12 crisantaspase recombinant IM doses (range 1-64 doses). The most common reaction was rash (including maculopapular rash). Severe reactions were reported in 6% of patients, including anaphylaxis (2%). Hypersensitivity reactions were higher in patients who received IV crisantaspase recombinant than IM; thus, the IV route of administration is not recommended.
Bleeding was reported in trials (26%) but the most commonly observed reactions were bruising and nose bleeds. Hemorrhage, in patients treated with L-asparaginase-class of products, may be associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT) and hypofibrinogenemia. Patients should be evaluated for coagulopathy and receive appropriate treatment as needed.
Pancreatitis, including acute pancreatitis, was observed in clinical trials and may be severe. Hemorrhagic or necrotizing pancreatitis has been reported with asparaginase class products.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Premedications (prophylaxis for administration-related reactions)
To be given 30-60 minutes prior to crisantaspase recombinant administration:
- acetaminophen
- H1 receptor blocker (e.g. diphenhydramine)
- H2 receptor blocker (e.g. famotidine)
Risk of medication error: Different asparaginase formulations are not interchangeable and dosing schedules are different. Confirm the formulation carefully against the regimen used before prescribing, dispensing and administration.
Intramuscular: 25 mg/m2 on Monday and Wednesday, and 50 mg/m2 on Friday*
*for a total of 6 doses to replace each planned dose of pegaspargase
Refer to protocol by which patient is being treated for cycle frequency. Usually used in combination with other cytotoxic drugs.
Discontinue in patients who experience silent inactivation, high grade toxicities, or evidence of disease progression.
| Toxicity | Severity | Action |
| Hypersensitivity | Grade 3 to 4 | Discontinue. |
| Amylase or lipase |
> 2 x ULN |
Hold. Restart when amylase and lipase < 1.5 x ULN and symptoms resolve. Discontinue if clinical necrotizing or hemorrhagic pancreatitis is confirmed. |
| Thrombosis | Uncomplicated |
Hold. Treat with appropriate antithrombotic therapy. Consider restart if symptoms resolve, while continuing antithrombotic therapy. |
| Severe or life-threatening |
Discontinue. Treat with appropriate antithrombotic therapy. |
|
| Hemorrhage | Grade 3 to 4 |
Hold. Evaluate for coagulopathy and consider clotting factor replacement as needed. If clinically appropriate, resume with the next scheduled dose. |
| Hepatotoxicity | Total bilirubin > 3 to ≤10 x ULN | Hold. Restart when total bilirubin ≤1.5 x ULN. |
| Total bilirubin > 10 x ULN | Discontinue. |
Crisantaspase recombinant has not been studied in patients with hepatic impairment.
Crisantaspase recombinant has not been studied in patients with renal impairment.
There was insufficient data in patients ≥ 65 years of age to determine if there are differences in response compared to younger patients.
There were no clinically significant differences in the pharmacokinetics of crisantaspase recombinant based on gender.
Black patients had 29% lower clearance which may increase exposure compared to White and Asian patients.
Safety and efficacy of crisantaspase recombinant has been established in patients ≥ 1 year of age. There were no clinically significant differences in safety or asparaginase activity based on age (1.4 to 25 years).
Risk of medication error: Different asparaginase formulations are not Interchangeable and dosing schedules are different. Confirm the formulation carefully against the regimen used before prescribing, dispensing and administration.
- Crisantaspase recombinant should be is administered by intramuscular injection only.
- Do not shake the vial.
- No reconstitution or dilution is required. Withdraw the indicated injection volume into the syringe(s) for injection.
- The maximum volume for injection at a single injection site is 2 mL. Use multiple injection sites if the volume to be administered is > 2 mL.
- Do not inject crisantaspase recombinant into scar tissue or areas that are reddened, inflamed, or swollen.
- Store unopened vials at 2°C to 8°C in the original carton, protected from light.
- Patients who are hypersensitive to this drug or any of its components, or have had serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis
- Patients who have a history of serious pancreatitis, thrombosis or hemorrhagic events during previous asparaginase therapy
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
Crisantaspase recombinant is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for 3 months after the last dose.
A method of contraception other than oral contraceptives should be used in people who can become pregnant, since an indirect interaction between oral contraception and crisantaspase recombinant cannot be excluded.
-
Breastfeeding:
Breastfeeding is not recommended during treatment and for 2 weeks after the last dose.
-
Fertility effects:
Unknown
No formal drug interaction studies have been conducted with crisantaspase recombinant.
The following interactions were reported with other formulations of asparaginase:
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Hepatotoxic drugs | ↑ hepatotoxicity | Additive | Monitor liver function; use with caution |
| Drugs requiring hepatic enzyme metabolism | May ↑ toxicity of these agents | Asparaginase may interfere with enzymatic detoxification | Caution |
| Methotrexate | ↓ effect of both drugs when asparaginase given immediately before or concurrently with methotrexate; Enhanced effect of both drugs when asparaginase given after methotrexate | Suppression of asparagine concentrations or cell replication | Refer to protocol by which patient is treated |
| Cytarabine | ↓ effect of asparaginase when asparaginase given immediately before or concurrently with cytarabine; Enhanced effect of asparaginase when asparaginase given after cytarabine | Suppression of asparagine concentrations or cell replication | Refer to protocol by which patient is treated |
| Immunosuppressants (i.e., cyclosporine, tacrolimus, sirolimus) | ↑immunosuppression, risk of lymphoproliferation | Additive | Caution |
| Phenytoin | ↑ risk of seizures | ↓ phenytoin uptake; risk of ↑ toxicity or ↓ efficacy of cytotoxics due to metabolism induction | Use other anticonvulsant alternatives |
| Prednisone | ↑hyperglycemia | Additive | Monitor |
| Vincristine and/or prednisone | ↑ vincristine toxicity when vincristine given concurrently or immediately after asparaginase | Unknown | Refer to protocol by which patient is treated |
| Anticoagulants, including NSAIDs, ASA | ↑ risk of bleeding | Changes in coagulation by asparaginase | Use with caution |
| Serum thyroxine-binding globulin | ↓ total serum thyroxine-binding globulin concentration | ↓ synthesis of thyroxine-binding globulin in liver | Delay measurement until 4 weeks after end of asparaginase therapy |
| Live and attenuated live vaccines | ↑ risk of severe infections | Immunosuppressive activity of asparaginase | Avoid. Vaccinations with live vaccines should be given at least 3 months after the end of the entire treatment protocol |
| Oral contraceptives | May ↓ efficacy of oral contraceptives (reported with pegaspargase) | May impair hepatic clearance of oral contraceptives due to asparaginase's hepatotoxic effects | Use alternative contraception method |
| Glucocorticoids | ↑ effects on fibrinogen and ATIII decreases (reported with pegaspargase) | Unknown | Refer to protocol by which patient is treated |
| Highly protein-bound drugs | ↑ toxicity of these drugs (reported with pegaspargase) | Decreased serum proteins | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
LFTs, bilirubin |
Baseline, before each cycle, and as clinically indicated |
Amylase and lipase |
Baseline, before each cycle, and as clinically indicated |
Clotting profile (PT, aPTT, fibrinogen, AT III) |
Baseline, and as clinically indicated; more frequent in patients at risk of coagulopathies |
Blood glucose |
Baseline, as clinically indicated and more frequently if patients have diabetes |
Trough serum asparaginase level |
Refer to local protocol |
Clinical toxicity assessment for tumour lysis syndrome, pancreatitis, GI effects, infection, hypersensitivity reactions, thromboembolism/bleeding |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and as clinically indicated |
Cholesterol and triglycerides |
As clinically indicated |
Urinary glucose |
As clinically indicated |
Albumin levels |
As clinically indicated |
New Drug Funding Program (NDFP Website )
- Crisantaspase Recombinant - Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma Mixed or Biphenotypic Leukemia
CADTH reimbursement review: Crisantaspase recombinant (Rylaze). Canadian Journal of Health Technologies, July 2023 (published online).
Maese L, Loh ML, Choi MR, et al. Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study. Blood 2023; 141 (7): 704-12.
NCI Drug Dictionary: Asparaginase Erwinia chrysanthemi (recombinant)-rywn. Accessed July 17, 2023.
Prescribing information: asparaginase Erwinia chrysanthemi (recombinant)-rywn. Jazz Pharmaceuticals Inc. (USA), November 2022.
Product monograph: crisantaspase recombinant (Rylaze™). Jazz Pharmaceuticals Canada Inc., September 2, 2022.
Recombinant Erwinia asparaginase: Lexicomp drug information. Accessed August 29, 2023.
December 2023 New drug monograph
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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