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DRUGS & SUPPLEMENTS
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L-Asp
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L-Asp uses
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
1 INDICATIONS AND USAGE
L-Asp (asparaginase Erwinia chrysanthemi) is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived L-Asp.
L-Asp (asparaginase Erwinia chrysanthemi) is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived asparaginase. (1)
2 DOSAGE AND ADMINISTRATION
- To substitute for a dose of pegaspargase: The recommended dose for each planned dose of pegaspargase is 25,000 International Units/m2 administered intramuscularly or intravenously 3 times a week for 6 doses. (2.1)
- To substitute for a dose of native E. coli L-Asp: The recommended dose is 25,000 International Units/m2 administered intramuscularly or intravenously for each scheduled dose of native E. coli L-Asp. (2.1)
2.1 Recommended Dose
To substitute for a dose of pegaspargase:
The recommended dose for each planned dose of pegaspargase is 25,000 International Units/m2 administered intramuscularly or intravenously three times a week (Monday/Wednesday/Friday) for six doses.
To substitute for a dose of native E. coli L-Asp:
The recommended dose is 25,000 International Units/m2 administered intramuscularly or intravenously for each scheduled dose of native E. coli L-Asp within a treatment.
When administering L-Asp intravenously, consider monitoring nadir (pre-dose) serum L-Asp activity (NSAA) levels and switching to intramuscular administration if desired NSAA levels are not achieved [see Clinical Pharmacology (12.3)].
2.2 Preparation and Handling Instructions
1. Visually inspect the L-Asp powder for foreign particulate matter and discoloration prior to reconstitution. Discard vial if present.
2. Reconstitute the contents of each vial by slowly injecting 1 or 2 mL of preservative free sterile sodium chloride injection (USP) against the inner vial wall.
3. Do not forcefully inject solution for reconstitution directly onto or into the powder. When reconstituted with 1 mL the resultant concentration is 10,000 International Units per mL. When reconstituted with 2 mL the resultant concentration is 5,000 International Units per mL.
4. Dissolve contents by gentle mixing or swirling. Do not shake or invert vial.
5. When reconstituted, L-Asp should be a clear, colorless solution. Inspect the solution after reconstitution and discard if any visible particles or protein aggregates are present.
6. Calculate the dose needed and the volume needed to obtain the calculated dose.
7. Withdraw the volume containing the calculated dose from the vial into a polypropylene syringe within 15 minutes of reconstitution. For intravenous use, slowly inject the reconstituted L-Asp into an IV infusion bag containing 100 mL of normal saline acclimatized to room temperature. Do not shake or squeeze the IV bag.
8. If partial vial is used, do not save or reuse the unused drug for later administration. Discard unused portions.
9. Do not freeze or refrigerate reconstituted solution and administer within 4 hours or discard [see How Supplied/Storage and Handling (16)].
2.3 Administration Instructions
L-Asp solution can be administered by intramuscular injection or by intravenous infusion.
- For intramuscular use, limit the volume of reconstituted L-Asp at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 2 mL, use multiple injection sites.
- For intravenous use, infuse L-Asp in 100 mL of normal saline over 1 to 2 hours. Do not infuse other intravenous drugs through the same intravenous line while infusing L-Asp.
3 DOSAGE FORMS AND STRENGTHS
Lyophilized powder 10,000 International Units per vial
- 10,000 International Units lyophilized powder per vial.
4 CONTRAINDICATIONS
- History of serious hypersensitivity reactions to L-Asp, including anaphylaxis
- History of serious pancreatitis with prior L-asparaginase therapy
- History of serious thrombosis with prior L-asparaginase therapy
- History of serious hemorrhagic events with prior L-asparaginase therapy
- History of serious hypersensitivity reactions to L-Asp, including anaphylaxis (4)
- History of serious pancreatitis with prior L-asparaginase therapy (4)
- History of serious thrombosis with prior L-asparaginase therapy (4)
- History of serious hemorrhagic events with prior L-asparaginase therapy (4)
5 WARNINGS AND PRECAUTIONS
- If the following occur, discontinue L-Asp:
Serious hypersensitivity reactions, including anaphylaxis
Severe or hemorrhagic pancreatitis (5.2)
- Glucose intolerance can occur and, in some cases, may be irreversible. Perform appropriate monitoring and treat hyperglycemia with insulin, as necessary (5.3)
- Thrombosis, hemorrhage: discontinue L-Asp until resolved (5.4)
5.1 Hypersensitivity Reactions
Grade 3 and 4 hypersensitivity reactions after the use of L-Asp have occurred in 5% of patients in clinical trials [see Adverse Reactions (6.1)].
Administer this product in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. If a serious hypersensitivity reaction occurs, discontinue L-Asp and initiate appropriate therapy.
5.2 Pancreatitis
Pancreatitis has been reported in 4% of patients in clinical trials [see Adverse Reactions ].
Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Discontinue L-Asp for severe or hemorrhagic pancreatitis manifested by abdominal pain > 72 hours and amylase elevation ≥ 2.0 x ULN. Severe pancreatitis is a contraindication to additional L-Asp administration. In the case of mild pancreatitis, hold L-Asp until the signs and symptoms subside and amylase levels return to normal. After resolution, treatment with L-Asp may be resumed.
5.3 Glucose Intolerance
Glucose intolerance has been reported in 5% of patients receiving L-Asp in clinical trials [see Adverse Reactions (6.1)]. In some cases glucose intolerance may be irreversible. Monitor glucose levels in patients at baseline and periodically during treatment. Administer insulin therapy as necessary in patients with hyperglycemia.
5.4 Thrombosis and Hemorrhage
Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism have been reported with both E. coli and Erwinia-derived L-asparaginase therapy. The following coagulation proteins were decreased in the majority of patients after a 2-week course of L-Asp by intramuscular administration: fibrinogen, protein C activity, protein S activity, and anti-thrombin III. Discontinue L-Asp for a thrombotic or hemorrhagic event until symptoms resolve; after resolution, treatment with L-Asp may be resumed.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Hypersensitivity reactions [see Warnings and Precautions ]
- Pancreatitis [see Warnings and Precautions (5.2)]
- Glucose intolerance [see Warnings and Precautions (5.3)]
- Thrombosis and hemorrhage [see Warnings and Precautions (5.4)]
The most common adverse reactions (incidence 1% or greater) with L-Asp treatment are systemic hypersensitivity, hyperglycemia, transaminases abnormal, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.
Most common adverse reactions (incidence 1% or greater) are: systemic hypersensitivity, hyperglycemia, transaminases abnormal, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.
To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Studies
Because clinical trials are conducted under controlled, but widely varying conditions, adverse reaction rates observed in clinical trials of L-Asp cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.
The data presented below are based on information collected from Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial (intramuscular administration), the L-Asp Master Treatment Protocol (EMTP), an expanded access program (both intramuscular, intravenous, and other or unknown administration), and Study 2, a single-arm, multi-center, open-label, pharmacokinetic (PK) study trial of intravenous administration of L-Asp.
Study 1 enrolled 58 patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. Patients received 6 doses of L-Asp 25,000 International Units/m2 intramuscularly on a Monday, Wednesday, and Friday schedule as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. The Study 1 population included patients with a median age of 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino. In Study 1, the number of L-Asp courses ranged from 1 to 9. In this study, 76% (44 of 58) completed all planned therapy. Fourteen (24%) patients stopped therapy prior to completion; seven due to allergic reactions, five due to physician or patient choice, one due to disease progression, and one due to discontinuation during frontline protocol. All other chemotherapy was continued according to the patient’s prescribed treatment regimen [see Clinical Studies ( 14 )].
Study 2 enrolled 30 patients [29 were being treated for ALL and one for lymphoblastic lymphoma (LBL)] following allergy to native E. coli L-Asp or pegaspargase. Patients received L-Asp 25,000 International Unit/m2/dose, administered by intravenous infusion on a Monday, Wednesday, and Friday schedule (6 doses) as a replacement for doses remaining on their original treatment plan. The Study 2 population included patients with a median age of 7 years (1 to 17 years); 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native or Indian) [see Clinical Studies (14)].
The EMTP trial enrolled 1368 patients with ALL or lymphoblastic lymphoma who received L-Asp after developing systemic hypersensitivity to an E. coli-derived L-Asp. Of these 1368 patients, safety data were received for 940 patients with a median age of 9 years (0 to 76 years), 63% were male, 91% with leukemia, 3% with lymphoma, and 6% with unknown disease information. Patients received L-Asp according to several schedules, and treatment center specifications with doses that ranged from 20,000 to 25,000 International Units/m2. The route of administration was intramuscular n=852, intravenous n=29, other or unknown n=59. In the EMTP trial, the planned number of doses of L-Asp ranged from 3 to 48 doses. Seventy-eight percent of patients (693 of 893) were able to receive all planned doses to complete their prescribed treatment regimen.
In Study 1 and Study 2, safety information was prospectively and systematically collected. In Study 1, all Grades of adverse events were reported for the following adverse events of special interest: allergy, pancreatitis, coagulopathy (hemorrhage, thrombosis or infarct), hyperbilirubinemia, hyperglycemia, hyperlipidemia, ketoacidosis, and CNS events (hemorrhage, thrombosis or infarction, and cerebral venous thrombosis) and only Grade 3 and 4 events were reported for other adverse events. In Study 2 all adverse events of all Grades were prospectively collected. In the EMTP trial, safety data were derived from case report forms that collected adverse event information. The forms specifically requested information on occurrence of allergic reactions, thrombotic events, hemorrhagic events, hepatobiliary disorders, pancreatic disorders, and hyperglycemia.
The incidence of non-hematologic, non-infectious, adverse events (all Grades) in Study 1, Study 2, and the EMTP trial is provided in Table 1.
The incidence of Grade 3 or greater non-hematologic, non-infectious adverse reactions occurring with L-Asp in Study 1, Study 2 and EMTP trial is provided in Table 2.
Table 1 Table 2
6.2 Immunogenicity
As with most therapeutic proteins, patients may develop anti-drug antibodies (ADA) to L-Asp.
In a study with L-Asp treatment by intramuscular administration (Study 1), 6 of 56 (11%) patients treated with L-Asp developed antibodies to L-Asp. Of these 6 ADA positive patients, one experienced a hypersensitivity reaction during Study 1 (2%, 1 of 56). None of these 6 patients had neutralizing antibodies.
In a study with L-Asp treatment by intravenous administration (Study 2), 4 of 30 (13.3%) patients treated with L-Asp developed anti-ERWINAZE antibodies. Of these 4 patients who developed anti-ERWINAZE antibodies, 3 experienced hypersensitivity reactions (10%, 3 of 30) during the study. None of these 4 patients had neutralizing antibodies.
The presence of ADA to L-Asp is associated with a higher risk of hypersensitivity reactions in patients who received L-Asp through intravenous infusion compared to intramuscular administration of L-Asp.
Immunogenicity assay are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to L-Asp with the incidence of antibodies to other products may be misleading.
7 DRUG INTERACTIONS
No formal drug interaction studies between L-Asp and other drugs have been performed.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies of L-Asp in pregnant women. In embryofetal development studies in rats and rabbits, L-Asp Erwinia chrysanthemi produced embryofetal toxicities and fetal abnormalities. L-Asp should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
In embryofetal development studies, L-Asp Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats and rabbits (at 10, 25, and 40 IU/kg). In rats given 2000 IU/kg (approximately 50% of the recommended human dose, adjusted for body surface area), maternal toxicity of decreased body weight gain was observed, as well as a fetal finding of increased incidence of partially undescended thymic tissue.
In rabbits, maternal toxicity consisting of decreased body weight was observed at 40 IU/kg (approximately 2% of the recommended human dose, adjusted for body surface area). 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 ≥10 IU/kg (approximately 0.5% of the recommended human dose, adjusted for body surface area).
8.3 Nursing Mothers
It is not known whether L-Asp is secreted in human milk. Because many drugs are secreted in human milk, and because of the potential for serious adverse reactions in nursing infants from L-Asp, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
[see Clinical Studies ].
8.5 Geriatric Use
The safety and efficacy of L-Asp has not been studied in geriatric patients.
10 OVERDOSAGE
There are no known cases of overdose with L-Asp.
11 DESCRIPTION
L-Asp (asparaginase Erwinia chrysanthemi) contains an asparagine specific enzyme derived from Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme consisting of four identical subunits, each having a molecular weight of about 35 kDa. The activity of L-Asp is expressed in terms of International Units.
L-Asp is supplied as a sterile, lyophilized, white powder in vials. Each vial contains 10,000 International Units of L-Asp Erwinia chrysanthemi, and the following inactive ingredients: glucose monohydrate (5.0 mg), sodium chloride (0.5 mg).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
L-Asp Erwinia chrysanthemi catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of asparagine. The mechanism of action of L-Asp is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous source of amino acid asparagine for their protein metabolism and survival.
12.3 Pharmacokinetics
Based on a population PK model, the mean (%CV) half-life of intravenous L-Asp was 7.51 (23.9%) hours in contrast to a mean (%CV) half-life of 15.6 (20%) hours reported for intramuscular L-Asp. These differences in PK between intravenous and intramuscular L-Asp are reflected in the proportion of patients with 2-day and 3-day nadir serum L-Asp activity (NSAA) levels of L-Asp Erwinia chrysanthemi ≥ 0.1 or 0.4 IU/mL [see Clinical Studies (14)].
Following administration of L-Asp 25,000 International Units/m2 intramuscularly to 48 ALL patients aged ≥ 2 years to ≤ 18 years in Study 1 on a Monday, Wednesday, and Friday schedule for 6 doses, 100% of patients who completed Course 1 achieved NSAA levels ≥ 0.1 International Units/mL at either 48 hours (n=35) or 72 hours (n=13) post dose 3. Eighty percent (28/35) of those evaluated at 48 hours and 38% (5/13) evaluated at 72 hours had nadir serum L-Asp activity levels ≥ 0.4 International Units/mL [see Clinical Studies (14)].
Following intravenous administration of L-Asp 25,000 International Units/m2 to 24 evaluable patients (aged ≥ 1 year to ≤ 17 years) in Study 2 on a Monday, Wednesday, and Friday schedule, 83% (20/24) and 43% (9/21) of patients who completed Course 1 achieved NSAA levels ≥ 0.1 International Units/mL at 48 hours post-dose 5 and 72 hours post dose 6, respectively. Twenty-nine percent (7/24) of those evaluated at 48 hours and no patients (0/21) evaluated at 72 hours had nadir serum L-Asp activity levels ≥ 0.4 International Units/mL [see Clinical Studies (14)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term carcinogenicity studies in animals have been performed with L-Asp Erwinia chrysanthemi. No studies that assess the mutagenic potential of L-Asp Erwinia chrysanthemi have been conducted.
In a fertility and early embryonic development study in rats, L-Asp Erwinia chrysanthemi had no effect on male or female fertility when administered intramuscularly at doses of up to 2000 IU/kg (approximately 50% of the recommended human dose, when adjusted for total body surface area) every other day for a total of 35 doses. Findings in males included decreased sperm count at doses of more than 500 IU/kg (approximately 12% of the recommended human dose).
14 CLINICAL STUDIES
The safety and efficacy of L-Asp was established in Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial. Additional safety data were obtained in the L-Asp Master Treatment Protocol (EMTP), an expanded access program [see Adverse Reactions (6)]. Study 1 enrolled patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The main outcome measure was determination of the proportion of patients who achieved a serum trough L-Asp level greater than or equal to 0.1 International Units/mL. Serum trough L-Asp activity ≥ 0.1 International Units/mL has been demonstrated to correlate with asparagine depletion (asparagine < 0.4 mcg/mL or 3 µM) and to serum levels that predict clinical efficacy. Patients received L-Asp 25,000 International Units/m2 intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol.
Fifty-eight patients were enrolled in Study 1, of these 48 were evaluable for the main outcome measure based on availability of pharmacokinetic samples in Course 1. The median age was 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino.
Study 1 met its main outcome measure of demonstrating that greater than 50% of the patients achieved the pre-specified trough L-Asp activity level of ≥ 0.1 International Units/mL at 48 or 72 hours following the third dose. Results for the main outcome measure and for an exploratory analysis using a higher cut-off (trough serum L-Asp activity levels ≥ 0.4 International Units/mL are presented in Table 3 [see Clinical Pharmacology (12.3)].
The safety and efficacy of intravenous administration were determined in Study 2 by characterizing the PK of a 25,000 International Units/m2 L-Asp dose given 3 days per week on a Monday, Wednesday, and Friday schedule for up to 30 weeks. This open-label, single-arm, multicenter PK study enrolled 30 patients. The main outcome measure was determination of the proportion of patients with 2-day NSAA levels (48-hour levels taken after the fifth dose) ≥ 0.1 International Unit/mL in the first 2 weeks of L-Asp treatment.
Of the thirty patients enrolled, 24 were evaluable for the main outcome measure based on the pharmacokinetic samples in Course 1. The median age was 7 years (1-17 years), 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native, or Indian).
In Study 2, serum L-Asp activity of L-Asp Erwinia chrysanthemi was determined in 24 evaluable patients (aged ≥ 1 year to ≤17 years) following intravenous administration of L-Asp 25,000 International Units/m2. Five minutes after the 60-minute infusion in Course 1, the mean L-Asp activity level was 12.65 ± 3.16 International Unit/mL post-dose 1 and 12.11 ± 3.11 International Unit/mL post dose 4. The main study objective was met with an L-Asp activity level of ≥ 0.1 International Units/mL 48 hours after the fifth dose observed in 83% of patients. The 72-hour post dose 6 L-Asp activity level of ≥ 0.1 International Unit/mL was the secondary endpoint, with 43% of patients achieving this endpoint. Results are presented in Table 3 [see Clinical Pharmacology (12.3)].
16 HOW SUPPLIED/STORAGE AND HANDLING
L-Asp is a sterile, white lyophilized powder supplied in a clear 3 mL glass vial. Each carton of L-Asp (NDC 57902-249-05) contains 5 vials. Each single vial (NDC 57902-249-01) contains 10,000 International Units L-Asp Erwinia chrysanthemi.
Store unused or unopened vials and cartons at 36°F to 46°F (2°C to 8°C). Protect from light. Do not use L-Asp after the expiration date on the vial.
17 PATIENT COUNSELING INFORMATION
- Instruct patients on the risk of allergic reactions, including anaphylaxis. Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical advice immediately if they experience such symptoms.
- Instruct patients on the risk of pancreatitis and to seek medical advice immediately if they experience abdominal pain.
- Instruct patients on the risk of hyperglycemia and glucose intolerance. Advise patients to seek medical advice if they experience excessive thirst or any increase in the volume or frequency of urination.
- Instruct patients on the risk of thrombosis and hemorrhage and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain.
Manufactured by:
Jazz Pharmaceuticals, Inc.
Palo Alto, CA 94304
U.S. License No. 1901
L-Asp® is a registered trademark of Porton Biopharma Limited used under license by Jazz Pharmaceuticals.
L-Asp pharmaceutical active ingredients containing related brand and generic drugs:
L-Asp available forms, composition, doses:
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.