ASPARAGINASE

ASPARAGINASE
Evaluaciones de DRUGDEX
Overview
1) Class
a) This drug is a member of the following class(es):
Antineoplastic Agent
Asparaginase (class)
2) Dosing Information
a) Asparaginase
1) Adult
a) Acute lymphoid leukemia, In combination with other chemotherapeutic agents
1) 6000 International Units/m(2) IM or IV 3 times/wk; observe for 1 hour following administration in a setting
enabled with resuscitation equipment, oxygen, and medications required to treat anaphylaxis
[1]
2) Pediatric
a) premedication and desensitization: dexamethasone 2 mg/kg (MAX, 16 mg) IV and pheniramine hydrogen
maleate 1 mg/kg (MAX, 40 mg) IV 1 hour prior to each infusion, followed by asparaginase 0.1% of the total dose
(prepared in 240 mL of 0.9% saline solution) IV at a rate of 60 mL/hr, then 1% of the total dose and 10% of the
total dose (each also prepared in 240 mL of 0.9% saline solution) sequentially given IV at a rate of 60 mL/hr, then
the remaining amount of the total dose prepared and administered the same way; total infusion time, 16 hours; each
dose administered according to protocol each time
[12]
b) premedication and desensitization: methylprednisolone 2 mg/kg/dose (MAX, 60 mg) given 13, 7, and 1 hours
before, hydroxyzine 1 mg/kg (MAX, 25 mg) and ranitidine 1 mg/kg 1 hour before, then asparaginase 1 International
Unit IV, doubled every 10 minutes until the total dose is administered
[13]
1) Acute lymphoid leukemia, In combination with other chemotherapeutic agents
a) 6000 International Units/m(2) IM or IV 3 times/wk; observe for 1 hour following administration in a setting
enabled with resuscitation equipment, oxygen, and medications required to treat anaphylaxis
[1]
[1]
b) 6000 International Units/m(2) IM 3 times/wk for 9 doses (starting on day 3) plus prednisone 40 mg/m(2)/day
ORALLY for 28 days plus vincristine 1.5 mg/m(2) IV weekly (maximum, 2 mg/wk) for 4 weeks (days 0, 7, 14, and
21)
[2]
b) Asparaginase Erwinia Chrysanthemi
1) Adult
a) Acute lymphoid leukemia, In combination with other chemotherapeutic agents in patients with hypersensitivity to
E coli-derived asparaginase
1) substitute for pegaspargase, 25,000 International Units/m(2) IM 3 times weekly (Monday/Wednesday/Friday) for
6 doses for each planned dose of pegaspargase
[15]
2) substitute for E coli-derived asparaginase, 25,000 International Units/m(2) IM for each scheduled dose of E coli-
derived asparaginase
[15]
2) Pediatric
1) substitute for pegaspargase, 25,000 International Units/m(2) IM 3 times weekly (Monday/Wednesday/Friday) for
6 doses for each planned dose of pegaspargase
[15]
2) substitute for E coli-derived asparaginase, 25,000 International Units/m(2) IM for each scheduled dose of E coli-
derived asparaginase
[15]
3) Contraindications
a) Asparaginase
1) allergic reactions, serious, to asparaginase or other forms of L-asparaginase

[1]
2) hemorrhagic events, serious, with prior L-asparaginase therapy

[1]
3) pancreatitis with prior L-asparaginase therapy

[1]
4) thrombosis, serious, with prior L-asparaginase therapy

[1]

[15]
2) hypersensitivity reactions to asparaginase Erwinia chrysanthemi therapy, serious, including anaphylaxis; history
[15]
3) pancreatitis, serious, with prior L-asparaginase therapy

[15]

[15]
4) Serious Adverse Effects
a) Asparaginase
1) Acute hemorrhagic pancreatitis

2) Anaphylaxis
3) Blood coagulation disorder
4) Coma
5) Diabetic ketoacidosis
6) Hepatotoxicity
7) Intracranial hemorrhage
8) Myocardial infarction
9) Pancreatitis
10) Pseudocyst of pancreas
11) Seizure
12) Thrombosis
1) Disseminated intravascular coagulation

2) Immune hypersensitivity reaction
3) Pancreatitis
4) Transient ischemic attack
5) Clinical Applications
a) Asparaginase
1) FDA Approved Indications
a) Acute lymphoid leukemia, In combination with other chemotherapeutic agents

1) FDA Approved Indications
Dosing Information
Drug Properties
A) Information on specific products and dosage forms can be obtained by referring to the Tradename List
(Product Index)
B) Synonyms
Asparaginase
Asparaginase Erwinia
Asparaginase Erwinia Chrysanthemi
Colaspase
Crisantaspase
L-Asparaginase
C) Physicochemical Properties
1) Asparaginase Erwinia Chrysanthemi
a) Molecular Weight
1) Approximately 35 kiloDaltons
[15]
Storage and Stability
A) Asparaginase
1) Preparation
a) General Information
1) Administration
a) The reconstituted solution should be clear but may develop a small number of gelatinous fiber-like
particles if left standing. A 5-micron filter may be used during administration to remove these particles
[1]
.
b) After administration, patients should be observed for 1 hour in a setting enabled with resuscitation
equipment, oxygen, and medications required to treat anaphylaxis
[1]
.
b) Intramuscular route
1) Preparation
a) For intramuscular use, reconstitute asparaginase with Sodium Chloride Injection to a concentration of
5000 international units/mL. The reconstituted solution should be stored at 2 to 8 degrees Celsius (36 to 46
degrees Farenheit) and used within 8 hours
[1]
.
2) Administration
a) When administered intramuscularly, the volume at a single injection site should be limited to 2 mL. If a
volume greater than 2 mL is necessary, use 2 injection sites
[1]
.
c) Intravenous route
1) Preparation
a) For intravenous use, reconstitute asparaginase with Sterile Water for Injection or Sodium Chloride
Injection to a concentration of 2000 international units/mL. The reconstituted solution should be stored at 2
to 8 degrees Celsius (36 to 46 degrees Farenheit) and used within 8 hours
[1]
.
2) Administration
a) Reconstituted asparaginase should be administered over at least 30 minutes through the side arm of a
running IV infusion of Sodium Chloride Injection or D5W
[1]
.
B) Asparaginase Erwinia Chrysanthemi
1) Preparation
a) Intramuscular route
1) Preparation
a) Reconstitute by slowly injecting 1 or 2 mL of NS against inner vial wall. Gently mix or swirl; do not
shake or invert vial. Withdraw volume of calculated dose into a polypropylene syringe within 15 minutes of
reconstitution. Do not refrigerate or freeze reconstituted solution. Administer within 4 hours of
reconstitution
[15]
.
2) Administration
a) Administer by IM injection. Do not inject a single injection site with a volume of more than 2 mL. If the
volume of the reconstituted dose is greater than 2 mL, use multiple injection sites. Discard unused portions
of a vial
[15]
.
C) Asparaginase
1) Parenteral route
a) Powder for Solution
1) Store vials in the refrigerator between 2 and 8 degrees C (36 and 46 degrees F)
[1]
.
2) Store unused, reconstituted solution in the refrigerator between 2 and 8 degrees C (36 and 46 degrees F).
Discard after 8 hours or sooner if the solution becomes cloudy
[1]
.
3) Asparaginase vials are stable for up to 48 hours at room temperature (15 to 30 degrees C). If returned to
the refrigerator, the stability of the product is as originally labeled by the manufacturer (Merck)
[108]
.
D) Asparaginase Erwinia Chrysanthemi
1) Intramuscular route
a) Powder for Solution
1) Store between 2 and 8 degrees C (36 and 46 degrees F); protect from light
[15]
.
2) Once reconstituted, solution may be stored at room temperature up to 4 hours. Do not freeze or refrigerate
[15]
.
Adult Dosage
Normal Dosage
Asparaginase
Intramuscular route
Acute lymphoid leukemia, In combination with other chemotherapeutic agents
1) The recommended dosage of asparaginase is 6000 International Units/m(2)
IM 3 times/wk, as a component of a multiagent chemotherapeutic regimen for
the treatment of acute lymphoblastic leukemia. After administration, patients
should be observed for 1 hour in a setting enabled with resuscitation
[1]
.
Intravenous route
IV 3 times/wk, as a component of a multiagent chemotherapeutic regimen for
[1]
.
Acute lymphoid leukemia, Induction therapy failure
1) A frequently used remission induction protocol for acute lymphocytic
leukemia (ALL) is DAUNORUBICIN 45 milligrams/square meter
(mg/m(2))/day intravenously on days 1, 2, and 3 and VINCRISTINE 2 mg
intravenously on days 1, 8, and 15. On days 1 through 22, PREDNISONE 40
mg/m(2)/day orally is administered, then tapered between days 22 to 29. L-
ASPARAGINASE 500 International Units/kilogram/day intravenously is
given on days 22 to 32
[171]
[172]
.
Intramuscular route
Acute lymphoid leukemia, In combination with other chemotherapeutic agents in
patients with hypersensitivity to E coli-derived asparaginase
1) Substitution for Pegaspargase
a) The recommended dose of asparaginase Erwinia chrysanthemi to substitute

for a dose of pegaspargase in patients with acute lymphoblastic leukemia is
25,000 International Units/m(2) IM 3 times weekly
(Monday/Wednesday/Friday) for 6 doses for each planned dose of
pegaspargase
[15]
.
2) Substitution for E coli-derived Asparaginase

for a dose of E coli-derived asparaginase in patients with acute lymphoblastic
leukemia is 25,000 International Units/m(2) IM for each scheduled dose of E.
coli-derived asparaginase within a treatment
[15]
.
Dosage in Other Disease States
A) Asparaginase
1) Obesity
a) The American Society of Clinical Oncology guidelines on appropriate chemotherapy dosing for
obese adult patients with cancer include the following highlights
[14]
:
1). Chemotherapy doses should be calculated using actual body weight in overweight, obese, and
morbidly obese adult patients (BMI greater than 25). Toxicity is no greater for obese patients with
appropriate dosing; however, comorbidities must be considered.
2). Full weight-based dosing (IV or oral) should be administered to obese patients, especially when
the goal of treatment is cure.
3). BSA can be calculated using any of the standard formulas such as Mosteller, Dubois and Dubois,
Haycock, Gehan and George, or Boyd.
4). Depending on the type and severity of a toxicity, comorbid conditions, and the intent of the
treatment (ie, curative or palliative), the same guidelines for dose reductions, regardless of obesity,
should be followed. If a dose reduction is needed, consider returning to the appropriate weight-based
dose upon resolution, and closely monitor.
5). Fixed dosing is only recommended for select cytotoxic agents which can safely be dosed
independently of weight or body surface area (eg, carboplatin and bleomycin, or when vincristine is
capped at a maximum dose of 2 mg when used in the CHOP and CVP regimens).
1) Obesity
a) The American Society of Clinical Oncology guidelines on appropriate chemotherapy dosing for
obese adult patients with cancer include the following highlights
[14]
:
1). Chemotherapy doses should be calculated using actual body weight in overweight, obese, and
morbidly obese adult patients (BMI greater than 25). Toxicity is no greater for obese patients with
appropriate dosing; however, comorbidities must be considered.
2). Full weight-based dosing (IV or oral) should be administered to obese patients, especially when
the goal of treatment is cure.
3). BSA can be calculated using any of the standard formulas such as Mosteller, Dubois and Dubois,
Haycock, Gehan and George, or Boyd.
4). Depending on the type and severity of a toxicity, comorbid conditions, and the intent of the
treatment (ie, curative or palliative), the same guidelines for dose reductions, regardless of obesity,
should be followed. If a dose reduction is needed, consider returning to the appropriate weight-based
dose upon resolution, and closely monitor.
5). Fixed dosing is only recommended for select cytotoxic agents which can safely be dosed
independently of weight or body surface area (eg, carboplatin and bleomycin, or when vincristine is
capped at a maximum dose of 2 mg when used in the CHOP and CVP regimens).
Pediatric Dosage
Normal Dosage
Asparaginase
Intramuscular route
IM 3 times/wk, as a component of a multiagent chemotherapeutic regimen for
[1]
.
2) In the Children's Cancer Group 101/143 trial in previously untreated
children with acute lymphocytic or undifferentiated leukemia (n=815), the
treatment regimen consisted of prednisone 40 mg/m(2)/day orally for 28 days,
vincristine 1.5 mg/m(2) IV weekly (maximum, 2 mg/wk) for 4 weeks (days 0,
7, 14, and 21), and L-asparaginase 6000 International Units/m(2) IM 3
times/wk for 9 doses (starting on day 3). If complete remission, requiring
marrow remission (defined as less than 5% blasts), was not achieved by day
28, prednisone and vincristine were continued until day 42
[2]
.
Intravenous route
IV 3 times/wk, as a component of a multiagent chemotherapeutic regimen for
[1]
.
Acute lymphoid leukemia, Induction therapy failure
1) The following regimen has been used for the treatment of acute
lymphocytic leukemia in children
[173]
:
a) Prednisone 40 milligrams/square meter of body surface area per day orally

in 3 divided doses for 15 days, followed by tapering of the dosage as follows:
20 milligrams/square meter for 2 days, 10 milligrams/square meter for 2 days,
5 milligrams/square meter for 2 days, 2.5 milligrams/square meter for 2 days
and then discontinue.
b) Vincristine 2 milligrams/square meter of body surface area intravenously
once weekly on Days 1, 8 and 15 of the treatment period. The maximum single
dose should not exceed 2 milligrams.
c) Asparaginase 1000 units/kilogram/day intravenously for 10 successive days
beginning on Day 22 of the treatment period.
2) The following combined induction regimen has been used in children with
acute lymphocytic leukemia
[173]
:
a) Prednisone 40 milligrams/square meter of body surface area per day orally

in 3 divided doses for 28 days (the total daily dose should be to the nearest 2.5
milligrams), following which the dosage of prednisone should be discontinued
gradually over a 14-day period.
b) Vincristine 1.5 milligrams/square meter of body surface area intravenously
weekly for 4 doses on Days 1, 8, 15, and 22 of the treatment period. The
maximum single dose should not exceed 2 milligrams.
c) Asparaginase 6000 units/square meter of body surface area intramuscularly
on Days 4, 7, 10, 13, 16, 19, 22, 25, and 28 of the treatment period. When a
remission is obtained with either of the above regimens, appropriate
maintenance therapy must be instituted. Asparaginase should not be used as
part of a maintenance regimen.
Desensitization
a) A premedication and desensitization protocol for IV L-asparaginase was successfully used

in 9 male pediatric patients (range, 2 to 17 years) who had previously developed severe (n=4)
or mild/moderate (n=5) systemic hypersensitivity reactions after receiving IV L-asparaginase
for acute lymphocytic leukemia (n=8) or Langerhans cell histiocytosis (n=1). The protocol
consisted of premedication with dexamethasone 2 mg/kg (maximum, 16 mg) IV and
pheniramine hydrogen maleate 1 mg/kg (maximum, 40 mg) IV given 1 hour prior to each L-
asparaginase infusion. L-asparaginase was given over 16 hours, starting with 0.1% of the total
dose of 10,000 International Units/m(2) (prepared in 240 mL of 0.9% saline solution)
administered IV at a rate of 60 mL/hr. Preparations of 1% of the total dose and 10% of the
total dose, each also prepared in 240 mL of 0.9% saline solution) were sequentially given IV
at a rate of 60 mL/hr. The remaining amount of the total dose was then prepared and
administered the same way. The 9 patients received 2 to 15 doses of L-asparaginase (median,
6 doses/patient) administered according to this protocol each time, without any additional
hypersensitivity reactions
[12]
.
b) Twelve of 16 pediatric patients with previous systemic hypersensitivity reactions to
intramuscular (IM) E coli-asparaginase successfully received it following premedication with
or without desensitization. Of 19 pediatric patients (range, 1.3 to 17 years) with acute
lymphoblastic leukemia who experienced systemic hypersensitivity reactions to IM E coli-
asparaginase, 3 were able to obtain polyethylene glycol-asparaginase, 8 who had previously
experienced anaphylaxis were treated with premedication and desensitization to E coli-
asparaginase, and 8 who had previous acute allergic reactions confined to the skin or mucosa
were only premedicated before receiving a full dose of IM E coli-asparaginase (10,000
International Units/m(2)) without desensitization. Premedication consisted of
methylprednisolone 2 mg/kg/dose (maximum, 60 mg) given 13, 7, and 1 hours prior to E coli-
asparaginase, and hydroxyzine 1 mg/kg (maximum, 25 mg) and ranitidine 1 mg/kg given 1
hour prior to E coli-asparaginase. Desensitization started with 1 International Unit of E coli-
asparaginase given IV and then doubled every 10 minutes until the total dose was
administered. Premedication and desensitization prevented hypersensitivity reactions in 7 of
the 8 patients with previous anaphylaxis to E coli-asparaginase, while 1 experienced
anaphylaxis again. Premedication alone was successful in 5 of the 8 patients with previous
acute allergic reactions while anaphylaxis occurred in 3 patients. These 3 patients again
experienced anaphylaxis after both premedication and desensitization were attempted
[13]
.
Intramuscular route
Acute lymphoid leukemia, In combination with other chemotherapeutic agents in
patients with hypersensitivity to E coli-derived asparaginase
1) Substitution for Pegaspargase

for a dose of pegaspargase in patients with acute lymphoblastic leukemia is
25,000 International Units/m(2) IM 3 times weekly
(Monday/Wednesday/Friday) for 6 doses for each planned dose of
pegaspargase
[15]
.
2) Substitution for E coli-derived Asparaginase

for a dose of E coli-derived asparaginase in patients with acute lymphoblastic
leukemia is 25,000 International Units/m(2) IM for each scheduled dose of E
coli-derived asparaginase within a treatment
[15]
.
Pharmacokinetics
Onset and Duration
A) Onset
1) Initial Response
a) Acute leukemia, 14 to 21 days

[84]
[85]
[86]
B) Duration
1) Asparaginase
a) Multiple Dose
1) Acute leukemia, intravenous: 6 to 21 weeks

[87]
.
a) Response durations in children with acute leukemia have ranged from a mean of 15 weeks with 1 to 4
cycles of 1,000 IU/kg/day for 4 days
[88]
to only 67 days with 4 doses of 5,000 IU/m(2) three times daily
[89]
. At lower doses (200 IU/kg/day to 750 IU/kg), remissions have lasted at least 1 month
[90]
.
a) Single Dose
1) Asparaginase activity: 7 to 15 days

[107]
a) In a pharmacokinetic study of children (n=37) newly diagnosed with acute lymphoblastic leukemia (ALL)
randomized to receive 1 of 3 preparations of asparaginase as a single IM injection (asparaginase Erwinia
chrysanthemi 25,000 International Units/m(2), n=10; asparaginase E coli 25,000 International Units/m(2),
n=17; or pegaspargase glycol 2500 International Units/m(2), n=10), the duration of asparagine depletion was
significantly different (p less than 0.01) between groups. Asparaginase activity (greater than 0.01
International Units/mL) was present for 7 to 15 days, 14 to 23 days, and 26 to 34 days and in the serum of
patients treated with Erwinia chrysanthemi asparaginase, asparaginase E coli, and pegaspargase glycol,
respectively
[107]
.
Drug Concentration Levels
A) Asparaginase
1) Time to Peak Concentration

a) Intramuscular: 14 to 24 hours
[92]
.
1) Therapeutic Drug Concentration
a) Acute lymphoblastic leukemia: 0.1 International Units/mL or greater

[15]
1) Serum trough asparaginase concentrations of 0.1 International Units/mL or greater were achieved in a
clinical study of 48 evaluable acute lymphoblastic leukemia (ALL) patients, aged 2 to 18 years, either at 48
or 72 hours following the third dose of asparaginase Erwinia chrysanthemi 25,000 International Units/m(2)
IM on Monday, Wednesday, and Friday. Twenty-eight of the 35 patients (80%) evaluated at 48 hours and 5
of the 13 patients (38%) evaluated at 72 hours had serum asparaginase activity levels of 0.4 International
Units/mL or greater. Serum trough asparaginase activity of 0.1 International Units/mL or greater has been
demonstrated to correlate with serum levels that predict clinical efficacy in ALL patients
[15]
.
ADME
Absorption
A) Bioavailability
1) Intramuscular: Fair
[93]
[94]
a) Intramuscular asparaginase reaches plasma levels one-half those following intravenous

administration
[94]
.
b) Following a single intramuscular dose of asparaginase (10,000 U/m(2)), the enzyme appeared in
plasma at 1 hour; plateau levels were not attained until 14 to 24 hours after administration
[93]
.
Distribution
A) Distribution Sites
1) OTHER DISTRIBUTION SITES
a) CEREBROSPINAL FLUID, less than 1% to 10% of plasma levels at equilibrium

[92]
[95]
.
b) LYMPH FLUID, 20% of plasma levels at 3 hours
[96]
1) LEUKEMIC CELLS
a) Asparaginase readily enters leukemic cells, particularly lymphoblasts, and depletes asparagine by
catalyzing its hydrolysis to aspartic acid and ammonia
[97]
.
B) Distribution Kinetics
1) Volume of Distribution
a) 4.8 L to 7 L
[98]
1) Volume of distribution is approximately 70 to 80% of estimated asparaginase plasma volume

[92]
[99]
, but has exceeded plasma volume by 20 to 30%, indicating some movement of the drug out of the
intravascular compartment
[96]
.
Excretion
A) Kidney
1) Neither the total enzyme nor fragments were detectable in the urine of children within 8 hours
after L-asparaginase infusion. L-asparaginase is not cleared by proteases in humans and is cleared by
the reticuloendothelial system
[100]
.
Elimination Half-life
A) Parent Compound
1) Asparaginase
a) ELIMINATION HALF-LIFE
1) 8 to 49 hours
[92]
[96]
[101]
[99]
a) 0.65 days (+/- 0.13)

[107]
1) In a pharmacokinetic study of children (n=37) newly diagnosed with acute lymphoblastic

leukemia (ALL) randomized to receive 1 of 3 preparations of asparaginase as a single IM injection
(asparaginase Erwinia chrysanthemi 25,000 International Units/m(2), n=10; asparaginase E coli
25,000 International Units/m(2), n=17; or pegaspargase glycol 2500 International Units/m(2), n=10),
the mean elimination half-life was 0.65 (+/- 0.13), 1.28 (+/- 0.35), and 5.73 days (+/-3.24),
respectively. Statistically significant differences between groups were seen (asparaginase E coli vs
asparaginase Erwinia chrysanthemi, p less than 0.001; pegaspargase glycol vs asparaginase E coli; p
less than 0.0001)
[107]
.
Cautions
Contraindications
A) Asparaginase
1) allergic reactions, serious, to asparaginase or other forms of L-asparaginase

[1]

[1]
3) pancreatitis with prior L-asparaginase therapy

[1]

[1]

[15]
2) hypersensitivity reactions to asparaginase Erwinia chrysanthemi therapy, serious, including anaphylaxis;

history
[15]
3) pancreatitis, serious, with prior L-asparaginase therapy

[15]
[15]
Precautions
A) Asparaginase
1) allergic reactions, serious, including anaphylaxis, have been reported; risk increased with prior exposure;
monitoring recommended; discontinue therapy if a serious reaction develops
[1]
2) CNS hemorrhages have been reported

[1]
3) coagulopathy, including increased prothrombin time, partial thromboplastin time, and

hypofibrinogenemia, has been reported; monitoring recommended
[1]
4) glucose intolerance has been reported; monitoring recommended

[1]
5) hepatotoxicity (including fulminant hepatic failure) and abnormal liver function (ie, elevations of AST,
ALT, alkaline phosphatase, and bilirubin (direct and indirect) and decreases of serum albumin and plasma
fibrinogen) have been reported; monitoring recommended
[1]
6) pancreatitis, fulminant or fatal, has been reported; discontinue therapy if pancreatitis develops
[1]
7) thrombotic events, serious, including sagittal sinus thrombosis, have been reported; discontinue therapy if
serious thrombotic events develop
[1]
1) glucose intolerance, irreversible in some cases, has been reported; monitoring recommended
[15]
2) hemorrhagic events have been reported; temporarily discontinue therapy until symptoms resolve
[15]
3) hypersensitivity reactions, serious, including anaphylaxis have occurred

[15]
4) pancreatitis has been reported; discontinuation of therapy may be necessary, only resume therapy in mild
cases
[15]
5) thrombotic events, serious, including sagittal sinus thrombosis, have occurred; temporarily discontinue
therapy until symptoms resolve
[15]
Adverse Reactions
Cardiovascular Effects
Electrocardiogram abnormal
1) A 55-year-old woman experienced ECG disturbances and hyperkalemia while receiving
asparaginase for acute lymphatic leukemia. The patient received doses of 100 to 200
international units/kg/day for 4 of 5 days in combination with dexamethasone and allopurinol.
On the fifth day, the patient developed diffuse muscular tremors, hypotension, dyspnea, and
hyperkalemia (up to 9.5 mEq/L). Hyperuricemia increased from 8.4 to 12 mg%, and ECG
revealed a disappearance of atrial activity and prolongation of the QRS interval (0.2 msec)
with increases in T-wave amplitude and voltage. Asparaginase was discontinued resulting in
normalization of ECG and potassium levels
[30]
.
Myocardial infarction
1) Asparaginase-induced occlusive coronary thrombosis was suspected in a 21-year-old man
receiving combination chemotherapy for acute lymphoblastic leukemia (ALL). On day 14 of
antineoplastic therapy, the patient received his daily dose of asparaginase 9000 international
units, and 12 hours later developed an acute myocardial infarction. Following resolution of
infarction, the patient continued chemotherapy without asparaginase and without further
sequel
[31]
.
Dermatologic Effects
Asparaginase
Urticaria
a) Urticaria has been reported with asparaginase use and may occur in the absence of
a positive skin test or during continued maintenance therapy
[29]
[57]
.
Injection site reaction
a) Incidence: less than 1%
[15]
b) In a single-arm, multicenter, open-label study (n=58; median age, 10 years; range,

2 to 18 years) and expanded access program (n=572; median age, 9 years; range, 1 to
66 years), local injection-site reactions were reported in less than 1% (3 of 630) of
patients with acute lymphoblastic leukemia or lymphoblastic lymphoma who received
3 to 48 doses of asparaginase Erwinia chrysanthemi 20,000 to 25,000 international
units/m(2)
[15]
.
Endocrine/Metabolic Effects
Asparaginase
Diabetic ketoacidosis
a) Summary
1) Hyperglycemia is one of most common adverse effects following use of

asparaginase. Glucose intolerance, irreversible in some cases, has occurred with
asparaginase therapy
[1]
. Several cases of diabetes mellitus have been induced during asparaginase therapy,
including severe diabetic ketoacidosis with insulin dependence
[37]
[38]
[39]
[40]
[41]
[42]
[43]
. Hyperglycemia due to decreased serum insulin usually responds to discontinuation
of the drug, IV fluids, and insulin, but death has occurred
[40]
[36]
.
b) Several cases of complications due to glucose intolerance, including diabetic
ketoacidosis, have been reported following L-asparaginase therapy. Diabetic
ketoacidosis developed in 2 children with acute lymphoblastic leukemia after
induction treatment with vincristine (1.5 mg/m(2) IV weekly), L-asparaginase (10,000
international units/m(2) IV biweekly), prednisolone (60 mg/m(2) orally daily),
doxorubicin (25 mg/m(2) weekly for 4 doses), and methotrexate (12 mg intrathecal
weekly). The induction period lasted 6 weeks, after which both children achieved
remission and started maintenance therapy. In the first case, an 11-year-old boy
developed diabetic ketoacidosis 7 days after the last dose of L-asparaginase. The
patient experienced abdominal pain and unexplained dehydration following 1 week of
maintenance therapy. Laboratory results revealed hyperglycemia (blood glucose 646
mg/dL), serum amylase of 1024 units/L, and serum lipase of 840 units/L, with
ketonuria and acidosis (pH of 7.1); ultrasound revealed a swollen pancreas. The
patient was treated with IV fluids, an infusion of insulin, and parenteral broad-
spectrum antibiotics for the diabetic ketoacidosis, but he died due to the event 3 days
later. The second case was a 12-year-old boy who developed pancreatic pseudocyst
and diabetic ketoacidosis at 2 and 3 months, respectively, after the last dose of L-
asparaginase. The patient experienced unexplained weight loss with persistent
abdominal pain and fever following 3 months of maintenance therapy. Laboratory
results revealed hyperglycemia (blood glucose 486 mg/dL), ketonuria, and acidosis.
The patient was treated for the diabetic ketoacidosis with fluid correction, an infusion
of insulin, insulin injections, and supportive management that included parenteral
antibiotics. Insulin glargine 5 units subQ twice daily was added to the insulin therapy
due to inadequate glycemic control. The patient's blood sugar normalized with the
insulin injections and glargine therapy and was maintained at the follow-up visit a few
weeks later
[37]
.
c) Diabetes mellitus with ketoacidosis was described in a 10-year-old girl following
asparaginase 6600 international units IV daily (200 international units/kg/day)
following 2 courses of 3 to 5 days each. The patient was receiving prednisone,
vincristine, and antibiotics concurrently with asparaginase. Following the second
course of therapy, the patient became lethargic, irritable, with increasing polydipsia
and polyuria, and developed a semicomatose state. Average urine output was 300
mL/hr with acetonuria and glycosuria. Maximum blood glucose levels were 560
mg%. The patient received 180 units of regular insulin over 12 hours with rapid
clinical improvement and subsidence of glycosuria
[42]
.
Hyperglycemia
a) Summary
1) Hyperglycemia is one of most common adverse effects following use of

asparaginase. Glucose intolerance, irreversible in some cases, has occurred with
[1]
. Several cases of diabetes mellitus have been induced during asparaginase therapy,
including severe diabetic ketoacidosis with insulin dependence
[37]
[38]
[39]
[40]
[41]
[42]
[43]
. Hyperglycemia due to decreased serum insulin usually responds to discontinuation
of the drug, IV fluids, and insulin, but death has occurred
[40]
[36]
.
b) The exact mechanism of asparaginase-induced diabetes mellitus is unclear, but is
likely related to interference with insulin production caused by protein synthesis
inhibition
[39]
[44]
. It has been suggested that L-asparaginase induces nonketotic hyperglycemia with
hypoinsulinemia and hyperglucagonemia from a combined effect on alpha and beta
cell function
[45]
.
c) Several cases of complications due to glucose intolerance, including diabetic
ketoacidosis, have been reported following L-asparaginase therapy. Diabetic
ketoacidosis developed in 2 children with acute lymphoblastic leukemia after
induction treatment with vincristine (1.5 mg/m(2) IV weekly), L-asparaginase (10,000
international units/m(2) IV biweekly), prednisolone (60 mg/m(2) orally daily),
doxorubicin (25 mg/m(2) weekly for 4 doses), and methotrexate (12 mg intrathecal
weekly). The induction period lasted 6 weeks, after which both children achieved
remission and started maintenance therapy. In the first case, an 11-year-old boy
developed diabetic ketoacidosis 7 days after the last dose of L-asparaginase. The
patient experienced abdominal pain and unexplained dehydration following 1 week of
maintenance therapy. Laboratory results revealed hyperglycemia (blood glucose 646
mg/dL), serum amylase of 1024 units/L, and serum lipase of 840 units/L, with
ketonuria and acidosis (pH of 7.1); ultrasound revealed a swollen pancreas. The
patient was treated with IV fluids, an infusion of insulin, and parenteral broad-
spectrum antibiotics for the diabetic ketoacidosis, but he died due to the event 3 days
later. The second case was a 12-year-old boy who developed pancreatic pseudocyst
and diabetic ketoacidosis at 2 and 3 months, respectively, after the last dose of L-
asparaginase. The patient experienced unexplained weight loss with persistent
abdominal pain and fever following 3 months of maintenance therapy. Laboratory
results revealed hyperglycemia (blood glucose 486 mg/dL), ketonuria, and acidosis.
The patient was treated for the diabetic ketoacidosis with fluid correction, an infusion
of insulin, insulin injections, and supportive management that included parenteral
antibiotics. Insulin glargine 5 units subQ twice daily was added to the insulin therapy
due to inadequate glycemic control. The patient's blood sugar normalized with the
insulin injections and glargine therapy and was maintained at the follow-up visit a few
weeks later
[37]
.
d) Diabetes mellitus with ketoacidosis was described in a 10-year-old girl following
asparaginase 6600 international units IV daily (200 international units/kg/day)
following 2 courses of 3 to 5 days each. The patient was receiving prednisone,
vincristine, and antibiotics concurrently with asparaginase. Following the second
course of therapy, the patient became lethargic, irritable, with increasing polydipsia
and polyuria, and developed a semicomatose state. Average urine output was 300
mL/hr with acetonuria and glycosuria. Maximum blood glucose levels were 560
mg%. The patient received 180 units of regular insulin over 12 hours with rapid
clinical improvement and subsidence of glycosuria
[42]
.
e) Nonketotic hyperglycemia was secondary to prednisone following the development
of ketotic hyperglycemia from the combination of asparaginase with prednisone in a
13-year-old boy with acute leukemia. The patient developed glucosuria (5%) and
hyperglycemia (600 mg%) 5 days after asparaginase therapy 2000 international
units/m(2) daily in combination with prednisone, vincristine and antibiotics. The
patient was given regular insulin 30 units subQ on day 1 and 60 units over the next
week. Diuresis increased during insulin therapy and small to moderate amounts of
acetone were detected in the urine on days 2 and 3. Remission was induced with
vincristine and prednisone with no recurrence of ketosis or hyperglycemia. However,
subsequent therapy with prednisone resulted in nonketotic hyperglycemia which
responded to regular insulin. The authors stress that the patient who develops a
transient hyperglycemia secondary to combination asparaginase and prednisone may
subsequently develop a diabetic state secondary to prednisone in the absence of
asparaginase
[43]
.
f) Researchers determined retrospectively the frequency and risk of hyperglycemia in
421 children with leukemia who had L-asparaginase and prednisone as part of their
remission induction therapy. Of these patients, 9.7% developed this complication (41
of 421) with 39 within 1 week after the first dose. Age, obesity, and Down syndrome
each had a significant bearing on the frequency of hyperglycemia with children older
than 10 years more likely to develop the complication
[46]
.
g) Ten children with acute lymphocytic leukemia developed transient diabetes
mellitus during treatment with L-asparaginase and prednisone. They had relative
hyperglucagonemia similar to other patients with diabetes mellitus
[47]
.
Hyperkalemia
a) A 55-year-old woman experienced ECG disturbances and hyperkalemia while
being treated with asparaginase for acute lymphatic leukemia. The patient received
doses of 100 to 200 international units/kg/day for 4 of 5 days in combination with
dexamethasone and allopurinol. On the fifth day, the patient developed diffuse
muscular tremors, hypotension, dyspnea, and hyperkalemia (up to 9.5 mEq/L).
Hyperuricemia increased from 8.4 to 12 mg% and ECG revealed a disappearance of
atrial activity and prolongation of the QRS interval (0.2 msec) with increases in T-
wave amplitude and voltage. Asparaginase was discontinued resulting in
normalization of ECG and potassium levels
[30]
.
Hyperlipidemia
a) Hyperlipidemia, including hypertriglyceridemia and hypercholesterolemia, has
occurred with asparaginase therapy
[1]
.
b) Hypertriglyceridemia with acute pancreatitis occurred in an 18-year-old man with
acute lymphoblastic leukemia treated with asparaginase as part of a multidrug
chemotherapeutic regimen including daunorubicin, vincristine, prednisone, teniposide,
and cytarabine. Two weeks after his third exposure to asparaginase, the patient
presented with acute abdominal pain, a serum triglyceride of 1742 mg/dL, serum
amylase of 284 international units/L, and serum lipase of 3256 international units/L.
The patient was treated conservatively and discharged 2 weeks later with a serum
triglyceride level of 243 mg/dL
[48]
.
c) Hyperlipidemia has occurred with asparaginase (with or without prednisone) in
patients undergoing induction therapy for acute lymphoblastic leukemia (ALL). A 10-
year-old girl developed peak plasma triglyceride and cholesterol levels of 20,600
mg/dL and 1640 mg/dL, respectively, following asparaginase plus prednisone
induction therapy. On a review of patients receiving New York II protocol
(asparaginase plus prednisone pulses for ALL induction), 5 of 60 patients experienced
transient, marked, benign hyperlipidemia
[49]
.
Hyperammonemia
a) Incidence: 1%
[15]

66 years), hyperammonemia was reported in 1% (4 of 630) of patients with acute
lymphoblastic leukemia or lymphoblastic lymphoma who received 3 to 48 doses of
asparaginase Erwinia chrysanthemi 20,000 to 25,000 international units/m(2)
[15]
.
Hyperglycemia
a) Incidence: all grades, 2%; grade 3 and 4, 2%
[15]
b) Hyperglycemia reported with asparaginase Erwinia chrysanthemi may not be

reversible upon drug discontinuation. Baseline and periodic monitoring of glucose
levels is recommended during therapy, along with administration of insulin as
indicated
[15]
.
c) In a single-arm, multicenter, open-label study (n=58; median age, 10 years; range, 2
to 18 years) and expanded access program (n=572; median age, 9 years; range, 1 to 66
years), hyperglycemia was reported in 2% (15 of 630) of patients with acute
[15]
.
d) Among acute lymphoblastic leukemia/lymphoblastic lymphoma patients who
received asparaginase Erwinia chrysanthemi, Grade 3 and 4 hyperglycemia was
reported in 0% of patients in a single-arm, multicenter, open-label study (n=58) and in
2% (11 of 572) of patients in an expanded access program
[15]
.
Gastrointestinal Effects
Asparaginase
Acute hemorrhagic pancreatitis
a) Asparaginase induction therapy of acute lymphocytic leukemia in a 5-year-old girl
led to the development of acute, hemorrhagic pancreatitis that progressed to systemic
inflammatory response syndrome (SIRS), and hypovolemic shock. Supportive care,
including aggressive volume replacement, imipenem, narcotic analgesia, histamine-2
antagonist therapy, and total parenteral nutrition, brought about a full recovery
[52]
.
Pancreatitis
a) Pancreatitis, sometimes fulminant and fatal, has been reported as one of the most
common side effects with the use of asparaginase
[1]
[52]
[53]
[54]
[35]
[29]
[55]
; (Shaw et al, 1970; Ohnuma et al, 1969). Acute pancreatitis may occur during therapy
or after discontinuation. In 1 case series, 58% of patients were able to receive
subsequent Erwinia asparaginase without further complications
[53]
.
b) Hypertriglyceridemia with acute pancreatitis occurred in an 18-year-old man with
acute lymphoblastic leukemia treated with asparaginase as part of a multidrug
chemotherapeutic regimen, including daunorubicin, vincristine, prednisone,
teniposide, and cytarabine. Two weeks after his third exposure to asparaginase, the
patient presented with acute abdominal pain, a serum triglyceride of 1742 mg/dL,
serum amylase of 284 international units/L, and serum lipase of 3256 international
units/L. The patient was treated conservatively and discharged 2 weeks later with a
serum triglyceride level of 243 mg/dL
[48]
.
c) Acute pancreatitis was observed in 19 pediatric patients (median age, 5.5 years)
receiving L-asparaginase (dose unspecified) to treat acute lymphoblastic leukemia. In
the majority of these cases (63%), onset of pancreatitis occurred during the induction
phase. Clinical presentation was characterized by anorexia, nausea and vomiting,
fever, icterus, increased urination, and abdominal pain, distention, or tenderness. Eight
patients had gastrointestinal bleeding. Signs and symptoms lasted for a median of 4
weeks, while the median durations of elevated amylase and lipase were 3 weeks and
2.5 weeks, respectively. On average, biochemical changes were evident 2 days after
the onset of symptoms. Five patients developed pseudopancreatic cysts, which were
managed conservatively. Among the remaining 14 patients, 4 eventually died as a
result of pancreatitis. Eleven patients were switched to Erwinia asparaginase without
any further pancreatic complication. Surviving patients suffered no long-term adverse
sequelae
[53]
.
d) A 15-year-old boy treated for non-Hodgkin lymphoma developed acute pancreatitis
5 weeks after the last dose of IM asparaginase 2500 units/m(2) every 2 weeks for 4
doses. The patient had also received daily 6-mercaptopurine and weekly methotrexate
as maintenance therapy. He presented with diffuse abdominal pain, nausea, and
vomiting and was diagnosed on CT scan to have an enlarged pancreas. The patient
received parenteral nutrition and nasogastric decompression, but the nausea and
vomiting continued. A large pancreatic pseudocyst and pancreatic necrosis were
identified on repeat CT scan. The cyst was drained percutaneously and the patient
recovered completely
[54]
.
Parotitis
a) Bilateral parotitis was reported in a 17-year-old boy following administration of
asparaginase 10,000 units/m(2) and concomitant dexamethasone. The patient, who
was previously diagnosed with stage 4 non-Hodgkin lymphoma, developed bilateral
parotitis after receiving 4 doses of asparaginase (onset period, 18 days).
Ultrasonography confirmed the bilateral parotitis diagnosis and the patient's mumps
titer was negative. The patient had an elevated serum amylase level of 1914 units/L.
Information was not provided with regard to ruling out viral or bacterial etiologies.
The Naranjo adverse reaction probability scale score of 4 indicated a possible
relationship between asparaginase and parotitis. The bilateral parotitis resolved within
8 days of asparaginase discontinuation
[50]
.
b) Acute parotitis was reported in 4 out of 117 pediatric patients (96 children
diagnosed with acute lymphoblastic leukemia and 21 diagnosed with non-Hodgkin
lymphoma) who received either the modified Berlin Frankfurt-Munster Study (BFM-
95) protocol or the Hong Kong Paediatric Hematology and Oncology Study Group
Acute Lymphoblastic Leukaemia (HKPHOSG-ALL-97) protocol
[50]
[51]
. Three of the 4 cases occurred at the end of the 2b phase of protocol B (total
asparaginase dose of 80,000 international units/m(2) divided into 8 doses of 5000
international units/m(2) and 4 doses of 10,000 international units/m(2)). One case of
acute parotitis was reported during the consolidation phase of protocol C (total
asparaginase dose of 65,000 international units/m(2) divided into 8 doses of 5000
international units/m(2) and 1 dose of 25,000 international units/m(2)). Each patient
also received dexamethasone, vincristine, and doxorubicin together with asparaginase.
Three of the 4 patients had marked hyper-amylasemia. The patients' mumps titers
were not elevated but oral swabs for herpes simplex virus and cytomegalovirus were
negative and acute bacterial infections were ruled out
[51]
. The Naranjo adverse reaction probability scale score of 4 indicated a possible
relationship between asparaginase and the occurrence of parotitis. It is theorized that a
common mechanism exists between asparaginase-related parotid gland and pancreas
toxicity. The authors also suggested asparaginase-induced acute parotitis may be dose
related (but this is not supported in other reports) or due to individual genetic
variations
[50]
. Type of asparaginase preparation did not appear to contribute to parotitis
development, as the 4 patients were administered 2 different asparaginase
preparations (1 received Elspar(R) while the other 3 received Leunase(R))
[51]
.
Pseudocyst of pancreas
a) A 5-year-old boy with lymphocytic leukemia received 9 doses of IM asparaginase
6000 units/m(2) 3 times weekly, in addition to vincristine, prednisone, and intrathecal
methotrexate. On day 21 of treatment, the patient had vomiting, abdominal distension,
epigastric tenderness, decreased oral intake, and a serum amylase of 1524 Somogyi
units/100 mL. Within 24 hours, the patient was under intensive care, requiring
intubation and fluid resuscitation, and he was started on ceftazidime and ticarcillin
disodium. Serial CT scans revealed pancreatic necrosis and a large pseudocyst. The
cyst was drained on laparotomy. The patient later died of bleeding complications
involving his endotracheal tube
[54]
.
b) Acute pancreatitis was observed in 19 pediatric patients (median age, 5.5 years)
receiving L-asparaginase (dose unspecified) to treat acute lymphoblastic leukemia. In
the majority of these cases (63%), onset of pancreatitis occurred during the induction
phase. Clinical presentation was characterized by anorexia, nausea and vomiting,
fever, icterus, increased urination, and abdominal pain, distention, or tenderness. Eight
patients had gastrointestinal bleeding. Signs and symptoms lasted for a median of 4
weeks, while the median durations of elevated amylase and lipase were 3 weeks and
2.5 weeks, respectively. On average, biochemical changes were evident 2 days after
the onset of symptoms. Five patients developed pseudopancreatic cysts, which were
managed conservatively. Among the remaining 14 patients, 4 eventually died as a
result of pancreatitis. Eleven patients were switched to Erwinia asparaginase without
any further pancreatic complication. Surviving patients suffered no long-term adverse
sequelae
[53]
.
c) A 15-year-old boy treated for non-Hodgkin lymphoma developed acute pancreatitis
5 weeks after the last dose of IM asparaginase 2500 units/m(2) every 2 weeks for 4
doses. The patient had also received daily 6-mercaptopurine and weekly methotrexate
as maintenance therapy. He presented with diffuse abdominal pain, nausea, and
vomiting and was diagnosed on CT scan to have an enlarged pancreas. The patient
received parenteral nutrition and nasogastric decompression, but the nausea and
vomiting continued. A large pancreatic pseudocyst and pancreatic necrosis were
identified on repeat CT scan. The cyst was drained percutaneously and the patient
recovered completely
[54]
.
Abdominal pain
a) Incidence: 1%
[15]

66 years), abdominal pain was reported in 1% (6 of 630) of patients with acute
[15]
.
Diarrhea
a) Incidence: 1%
[15]

66 years), diarrhea was reported in 1% (5 of 630) of patients with acute lymphoblastic
leukemia or lymphoblastic lymphoma who received 3 to 48 doses of asparaginase
Erwinia chrysanthemi 20,000 to 25,000 international units/m(2)
[15]
.
Nausea
a) Incidence: 2%
[15]

66 years), nausea was reported in 2% (10 of 630) of patients with acute lymphoblastic
[15]
.
Pancreatitis
[15]
b) If pancreatitis is diagnosed during asparaginase Erwinia chrysanthemi therapy,

discontinue treatment for severe or hemorrhagic pancreatitis (abdominal pain greater
than 72 hours and amylase elevation of 2 x ULN or greater) and interrupt treatment
for mild pancreatitis until signs/symptoms resolve and amylase levels return to
normal. Treatment may be resumed after resolution of mild pancreatitis. Do not
resume treatment in patients who develop severe pancreatitis
[15]
.
years), pancreatitis was reported in 4% (24 of 630) of patients with acute
[15]
.
received asparaginase Erwinia chrysanthemi, Grade 3 and 4 pancreatitis was reported
in 0% of patients in a single-arm, multicenter, open-label study (n=58) and in 1% (4
of 572) of patients in an expanded access program
[15]
.
Vomiting
a) Incidence: 2%
[15]

66 years), vomiting was reported in 2% (15 of 630) of patients with acute
[15]
.
Hematologic Effects
Asparaginase
Blood coagulation disorder
a) Summary
1) Coagulopathy, including increased prothrombin time, increased partial

thromboplastin time, and decreased fibrinogen, protein C, protein S and antithrombin
III, has occurred with asparaginase therapy
[1]
[17]
. Bleeding has been associated with only a small number of those identified to have
coexisting coagulopathy. Due to the ability of asparaginase to inhibit the synthesis of
clotting factors, administration most likely results in the depletion of vitamin-K-
dependent factors such as protein C and its cofactor protein S, antithrombin III, and
factors II, VII, IX, and X
[17]
. A significant decrease in protein C may occur within 2 days following the beginning
of the infusion. Low levels of protein C have been implicated in early thrombotic
events.
b) The asparaginase component of a combination chemotherapeutic regimen for acute
lymphocytic leukemia was implicated as the probable cause of hemostatic
complications in a retrospective review of 1100 pediatric patients. The overall
incidence was 2.8%, of which 19 cases (61% of total) involved thrombosis and 12
cases (39% of total) involved hemorrhage. Three cases were fatal. The most
frequently affected sites were the CNS (42%) and subclavian vein (29%). Almost all
episodes occurred during the induction period when concomitant asparaginase and
glucocorticoids were administered
[18]
.
c) The effect of asparaginase on coagulation factors was studied during initiation of
chemotherapy in 26 patients with acute lymphoblastic leukemia. Fibrinogen levels
decreased to less than 0.2 g in all patients with prolongation of partial thromboplastin
time (PTT) to greater than 45 seconds at 2 to 12 days of therapy in 23 patients.
Coagulation factors IX and XI were decreased to less than 70% in 9 and 14 patients,
respectively. Factor VIII was elevated in 13 patients. Coagulation factors returned to
normal within 3 to 11 days after discontinuation of asparaginase
[19]
.
d) Several cases of complications due to clotting abnormalities have been reported
following L-asparaginase therapy. Dural sinus thrombosis developed in 2 children
with acute lymphoblastic leukemia (ALL) during induction treatment with vincristine,
prednisone, and asparaginase
[20]
; 2 patients developed clinical features of intracranial bleeding during induction for
ALL
[21]
; and 2 children developed intracranial hemorrhagic infarcts with focal seizures and
hemiparesis following induction therapy for ALL
[22]
.
e) Hemostatic changes were reported in children with acute lymphoblastic leukemia
(ALL) according to 2 different L-asparaginase schedules
[23]
. L-asparaginase-induced coagulopathy is most commonly associated with vincristine
and prednisone. Thus, the risk/benefit ratio for the use of L-asparaginase early in the
induction of children with low risk ALL needs to be further evaluated.
Leukopenia
a) Leukopenia has been reported during asparaginase therapy
[24]
[25]
[26]
[27]
[28]
; (Mayer & Holton, 1971).
b) Profound leukopenia was reported in a 25-year-old man who received IV
asparaginase 12,500 international units daily for 4 days for acute lymphoblastic
leukemia. After 2 days of therapy, the patient developed nausea, vomiting, and high
fever in addition to chest pain and left-sided pleural effusion. Leukocytes decreased to
550/mm(3). Asparaginase was discontinued, and the patient was given penicillin G
with cephaloridine for development of infection and nystatin for Candida infection.
However, the patient remained thrombocytopenic and leukopenic and died 15 days
later in cardiac failure. Autopsy revealed a decrease in bulk of leukemia tissue and
depressed normal cellular elements of bone marrow
[25]
.
Thrombocytopenia
a) Thrombocytopenia has been reported during asparaginase therapy
[24]
[29]
.
Thrombosis
a) Serious thrombosis, including sagittal sinus thrombosis, has occurred with
[1]
.
Disseminated intravascular coagulation
[15]

66 years), disseminated intravascular coagulation was reported in less than 1% (1 of
630) of patients with acute lymphoblastic leukemia or lymphoblastic lymphoma who
received 3 to 48 doses of asparaginase Erwinia chrysanthemi 20,000 to 25,000
international units/m(2)
[15]
.
Hemorrhage
a) Incidence: all grades, 1%; grade 3 and 4, less than 1%
[15]
b) Decreased coagulation proteins (ie, fibrinogen, protein C activity, protein S

activity, and anti-thrombin III) were reported in the majority of patients who received
a 2-week course of asparaginase Erwinia chrysanthemi. If a thrombotic or
hemorrhagic event occurs during asparaginase Erwinia chrysanthemi therapy,
discontinue until resolution of symptoms. Treatment may be resumed after resolution
[15]
.
years), hemorrhagic abnormalities were reported in 1% (5 of 630) of patients with
acute lymphoblastic leukemia or lymphoblastic lymphoma who received 3 to 48 doses
of asparaginase Erwinia chrysanthemi 20,000 to 25,000 international units/m(2)
[15]
.
received asparaginase Erwinia chrysanthemi, Grade 3 and 4 hemorrhage was reported
in 0% of patients in a single-arm, multicenter, open-label study (n=58) and in less
than 1% (1 of 572) of patients in an expanded access program
[15]
.
Thrombosis
[15]
b) Decreased coagulation proteins (ie, fibrinogen, protein C activity, protein S

activity, and anti-thrombin III) were reported in the majority of patients who received
a 2-week course of asparaginase Erwinia chrysanthemi. If a thrombotic or
hemorrhagic event occurs during asparaginase Erwinia chrysanthemi therapy,
discontinue until resolution of symptoms. Treatment may be resumed after resolution
[15]
.
years), thrombotic abnormalities were reported in 2% (10 of 630) of patients with
[15]
.
received asparaginase Erwinia chrysanthemi, Grade 3 and 4 thrombosis was reported
in 0% of patients in a single-arm, multicenter, open-label study (n=58) and in 1% (6
of 572) of patients in an expanded access program
[15]
.
Hepatic Effects
Asparaginase
Abnormal liver function
a) Liver function abnormalities, including hyperbilirubinemia and elevated
transaminase levels, have been reported commonly with asparaginase therapy
[1]
.
Hepatotoxicity
a) Hepatotoxicity, in some cases fatal, has been reported with asparaginase therapy
[1]
.
b) Hepatotoxicity of asparaginase has been reported in children with advanced
leukemia. In 105 children receiving asparaginase 200 international units/kg/day IV
intermittently over a period of 26 days or 200 international units/kg every other day
for 15 days, abnormal liver function tests were reported in 76, bilirubin increases in
16, and icterus in 3. Fatty changes in the liver were noted upon autopsy in 18 children.
There was no significant correlation between dosage regimen and hepatotoxic effects
[35]
.
c) Fatty metamorphosis of the liver was described in 31 children upon necropsy
[56]
.
Hyperbilirubinemia
a) Incidence: 1%
[15]

66 years), hyperbilirubinemia was reported in 1% (8 of 630) of patients with acute
[15]
.
Liver enzymes abnormal
a) Incidence: all grades, 3%; grade 3 and 4, up to 2%
[15]

66 years), abnormal transaminase was reported in 3% (22 of 630) of patients with
[15]
.
c) Among acute lymphoblastic leukemia/lymphoblastic lymphoma patients who
received asparaginase Erwinia chrysanthemi, Grade 3 and 4 elevated transaminases
were reported in 2% (1 of 58) of patients in a single-arm, multicenter, open-label
study and in less than 1% (2 of 572) of patients in an expanded access program
[15]
.
Immunologic Effects
Asparaginase
Anaphylaxis
a) Serious allergic reactions, including anaphylaxis, have occurred commonly during
asparaginase therapy. There is a higher risk in patients with previous exposure to
asparaginase or other E coli L-asparaginase products, but serious allergic reactions
have also occurred with the first dose. Treatment should be discontinued in patients
with serious allergic reactions
[1]
.
b) The incidence and clinical characteristics of anaphylactoid reactions to IV
asparaginase were assessed in 196 patients given E coli asparaginase and 49 patients
given Erwinia asparaginase. Twenty-nine of 196 patients (14.8%) given E coli
asparaginase had an anaphylactoid reaction, occurring after their first through 12th
doses. The risk of an anaphylactoid reaction to E coli asparaginase was significantly
greater in patients who were not receiving concomitant prednisone-vincristine therapy
and patients who had a hiatus of at least 1 month between courses. Seven of 49
patients (14%) treated with Erwinia asparaginase had an anaphylactoid reaction; all
had been treated with E coli asparaginase earlier
[59]
.
Immune hypersensitivity reaction
a) Hypersensitivity reactions, including serious allergic reactions, have occurred
commonly during asparaginase therapy. There is a higher risk of serious allergic
reactions in patients with previous exposure to asparaginase or other E coli L-
asparaginase products, but serious reactions have also occurred with the first dose.
Treatment should be discontinued in patients with serious allergic reactions
[1]
.
b) Intermittent analysis of antibodies in patients receiving asparaginase may be useful
in predicting hypersensitivity. In a clinical study of 35 children receiving asparaginase
to treat acute lymphoblastic leukemia, anti-asparaginase antibody levels were higher
at all comparable time points in patients with hypersensitivity reactions (n=22) than in
control patients (n=13) receiving an identical treatment regimen. Initial reactions
occurred after a median of 11.5 doses of E. coli asparaginase, and half of the reacting
patients were switched to Erwinia asparaginase. Reactions occurring after Erwinia
asparaginase developed after a median of 4 doses. In reacting patients, the median
anti-asparaginase antibody levels increased from 0.039 (optical density, 1 to 3200
dilution ratio) at baseline to 0.506 after hypersensitivity reactions (p=0.0002). In
nonreacting control patients, these levels increased from 0.011 to 0.032 after 25 doses
of asparaginase (p=0.02). After induction, 59% of reacting patients had anti-
asparaginase antibody levels that were 3 times greater than background levels in blood
samples from human volunteers, and 91% exhibited these increases after reinduction.
Postinduction antibody levels among nonreacting patients did not differ significantly
from those of normal control volunteers
[58]
.
Immune hypersensitivity reaction
a) Incidence: all grades, 17%; grade 3 and 4, 5% to 9%
[15]

66 years), systemic allergic reactions (ie, anaphylaxis, hypersensitivity, urticaria) were
reported in 17% (108 of 630) of patients with acute lymphoblastic leukemia or
lymphoblastic lymphoma who received 3 to 48 doses of asparaginase Erwinia
chrysanthemi 20,000 to 25,000 international units/m(2)
[15]
.
c) Among acute lymphoblastic leukemia/lymphoblastic lymphoma patients who
received asparaginase Erwinia chrysanthemi, Grade 3 and 4 allergic
reaction/hypersensitivity was reported in 9% (5 of 58) of patients in a single-arm,
multicenter, open-label study and in 5% (27 of 572) of patients in an expanded access
program
[15]
.
Neurologic Effects
Asparaginase
Aseptic meningitis
a) Allergic meningitis occurred in a 19-year-old man following intrathecal
asparaginase therapy (total of 35,000 international units) for acute lymphoblastic
leukemia. The patient was also receiving cytarabine. Ten minutes following the last
injection of asparaginase, the patient developed intense headache, vomiting,
photophobia, stiffness of the neck, and a fever of 39.5 degrees C. Within a few hours,
the patient developed psychomotor agitation and confusion. Symptoms subsided
within 1 day. Six days later the patient received a single IV infusion of 1000
international units/kg and developed fever, malaise, and arterial hypotension. The
symptoms subsided upon discontinuation of the infusion. This is apparently the first
report of an allergic meningitis secondary to intrathecal asparaginase (Goudmand et
al, 1972).
Coma
a) Coma has been reported with asparaginase therapy
[1]
[35]
.
b) The cerebral dysfunction manifested by confusion, stupor, or coma may occur in
up to 25% of those receiving the drug
[36]
.
Electroencephalogram abnormal
a) Asparaginase administration has been associated with abnormal EEG changes, such
as decreased alpha activity and increased theta and delta activity
[32]
. EEG abnormalities were described in 3 patients following total doses of asparaginase
of 190,000 to 300,000 international units over a period of 6 to 19 days. Abnormalities
consisted of slowing of basal rhythm, predominance of theta and delta waves with and
without paroxysmal appearance. These effects were coexistent with hyperammonemia
in 2 patients receiving higher doses (240,000 units and 300,000 units total for 6 days
and 15 days, respectively)
[33]
.
b) Asparaginase increases blood ammonia levels secondary to conversion of
asparagine to aspartic acid and ammonia. Moderate to marked EEG abnormalities
(decreased alpha activity or increased theta and delta activity) were observed in 6 of 7
patients with blood ammonia levels from 600 to greater than 800 mcg/100 mL and 10
of 14 patients with blood ammonia levels of 200 to 600 mcg/100 mL
[32]
.
Intracranial hemorrhage
a) CNS hemorrhages have been reported with asparaginase therapy
[1]
.
Seizure
a) Seizures have been reported with asparaginase therapy
[1]
[29]
[34]
.
Somnolence
a) Asparaginase has been associated with CNS symptoms including somnolence
[29]
[34]
.
Headache
a) Incidence: 1%
[15]

66 years), headache was reported in 1% (5 of 630) of patients with acute
[15]
.
Seizure
a) Incidence: 1%
[15]

66 years), seizure was reported in 1% (4 of 630) of patients with acute lymphoblastic
[15]
.
Transient ischemic attack
[15]

66 years), transient ischemic attack was reported in less than 1% (1 of 630) of patients
with acute lymphoblastic leukemia or lymphoblastic lymphoma who received 3 to 48
doses of asparaginase Erwinia chrysanthemi 20,000 to 25,000 international units/m(2)
[15]
.
Psychiatric Effects
Agitation
1) Mild to severe agitation has been reported with asparaginase therapy
[29]
[34]
.
Depression
1) Mild to severe depression has been reported with asparaginase therapy
[29]
[34]
.
Hallucinations
1) Hallucinations have been reported with asparaginase therapy
[1]
[29]
[34]
.
Renal Effects
Azotemia
1) Azotemia has been commonly reported with asparaginase therapy
[1]
.
Other
Asparaginase
Angioedema
a) Asparaginase use has been associated with angioneurotic edema
[29]
[57]
.
Fatigue
a) Mild to severe fatigue has been reported with asparaginase therapy
[29]
[34]
.
Fever
a) Incidence: 3%
[15]

66 years), fever was reported in 3% (16 of 630) of patients with acute lymphoblastic
[15]
.
Teratogenicity/Effects in Pregnancy/Breastfeeding
A) Teratogenicity/Effects in Pregnancy
1) Asparaginase
a) U.S. Food and Drug Administration's Pregnancy Category: Category C (All Trimesters)
1) Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other)
and there are no controlled studies in women or studies in women and animals are not available. Drugs
should be given only if the potential benefit justifies the potential risk to the fetus.
See Drug Consult reference:
PREGNANCY RISK CATEGORIES
b) Crosses Placenta: Unknown

c) Clinical Management
1) Teratogenic effects have been reported in animals and in case reports using combination chemotherapy
with asparaginase use in pregnancy. In general, antineoplastic agents when given during the first trimester
are believed to cause increases in the risk of congenital malformations, but when given during the second or
third trimesters are believed to only increase the risk of growth retardation
[77]
[78]
. Depending upon the nature of the malignancy, the progression of the disease, and how advanced the
gestation, chemotherapy can in some cases be deferred allowing fetal maturation to occur, and in some cases
earlier-than-term delivery provides an acceptable compromise between maternal and fetal risk
[79]
[78]
. Because apparently normal infants have been born despite having been exposed to virtually any
antineoplastic agent or combination of agents, it should not be assumed that termination of pregnancy is
necessary (unless it is in the best interest of the health of the mother), and the decision of the parents must
take into account their desire to have children (Mitchell, 1995).
d) Literature Reports
1) There have been no studies on the use of asparaginase during pregnancy. However, asparaginase is
teratogenic in animals
[73]
, and until additional data are available, the drug should be considered potentially teratogenic in humans.
2) There are no case reports available of asparaginase exposure during pregnancy in which asparaginase was
used exclusively. Combination chemotherapy that included asparaginase has been reported in 6 cases. Of the
7 infants born (one set of twins), no congenital malformations were observed; however, 2 infants had
transient bone marrow hypoplasia
[74]
[75]
, and one infant had chromosomal gaps and a ring chromosome
[76]
.
3) The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small
number of reports, variation in dosages, routes of administration, timing of administration with respect to
gestational age, and the variety of combinations of drugs administered. Although fetal exposure to
chemotherapy throughout all trimesters of pregnancy has been reported to not induce abnormalities, there is
no assurance that deleterious fetal effects will not occur. Exposure during the first trimester is still
considered by the majority of practitioners as the most critical for abnormal fetal development
[77]
.
a) U.S. Food and Drug Administration's Pregnancy Category: Category C (All Trimesters)
1) Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other)
and there are no controlled studies in women or studies in women and animals are not available. Drugs
should be given only if the potential benefit justifies the potential risk to the fetus.
PREGNANCY RISK CATEGORIES
b) Crosses Placenta: Unknown

1) There are no adequate and well-controlled studies of asparaginase Erwinia chrysanthemi use in pregnant
women or in animals. As it is unknown if asparaginase Erwinia chrysanthemi can cause fetal harm when
administered to a pregnant woman, it should be used during pregnancy only if clearly needed
[15]
.
1) There are no adequate and well-controlled studies of asparaginase Erwinia chrysanthemi use in pregnant
women or in animals
[15]
.
B) Breastfeeding
1) Asparaginase
a) World Health Organization Rating: Avoid breastfeeding.

b) Micromedex Lactation Rating: Infant risk cannot be ruled out.
1) Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk
when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks before
prescribing this drug during breastfeeding.
1) No reports describing the use of asparaginase during human lactation are available and the effects on the
nursing infant from exposure to the drug in milk are unknown. The manufacturer recommends that a
decision be made whether to discontinue asparaginase or discontinue nursing, taking into account the
importance of the drug to the mother
[81]
.
1) No reports describing the use of asparaginase during human lactation or measuring the amount, if any, of
the drug excreted into milk have been located.
a) Micromedex Lactation Rating: Infant risk cannot be ruled out.
1) Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk
when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks before
prescribing this drug during breastfeeding.
b) Clinical Management
1) No reports describing the use of asparaginase Erwinia chrysanthemi during human lactation are available
and the effects on the nursing infant from exposure to the drug in milk are unknown. The manufacturer
recommends that a decision be made whether to discontinue asparaginase Erwinia chrysanthemi or
discontinue nursing, taking into account the importance of the drug to the mother
[15]
.
Drug Interactions
Drug-Drug Combinations
Adenovirus Vaccine Type 4, Live
1) Interaction Effect: an increased risk of infection by the live vaccine
2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a
chemotherapeutic agent has resulted in severe and fatal infections
[61]
[62]
. One patient experienced disseminated vaccinia infection after receiving a smallpox vaccine
while on concomitant methotrexate therapy
[63]
. Live virus and bacterial vaccines should not be administered to a patient receiving an
immunosuppressive chemotherapeutic agent. At least 3 months should elapse between the
discontinuation of chemotherapy and vaccination with a live vaccine
[60]
.
3) Severity: major
4) Onset: delayed
5) Substantiation: established
6) Clinical Management: Patients receiving chemotherapy for leukemia and other
hematopoietic malignancies, for solid tumors, or after solid organ transplant should be
assumed to have altered immunocompetence and should not be vaccinated with a live
vaccine. Patients with leukemia, lymphoma, or other malignancies whose disease is in
remission, who have restored immunocompetence, and whose chemotherapy has been
discontinued for at least 3 months can receive a live vaccine
[60]
.
7) Probable Mechanism: decreased immune response allows live vaccine to produce infection
Adenovirus Vaccine Type 7, Live
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Bacillus of Calmette and Guerin Vaccine, Live
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Influenza Virus Vaccine, Live
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Measles Virus Vaccine, Live
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Methotrexate
1) Interaction Effect: decreased methotrexate antineoplastic activity
2) Summary: Tissue culture and animal studies have demonstrated that the administration of
asparaginase immediately prior to or concurrently with methotrexate can diminish or abolish
methotrexate antineoplastic activity. This effect persists as long as plasma asparagine levels
are suppressed
[64]
.
3) Severity: major
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Administer asparaginase nine to ten days before methotrexate
therapy or shortly after methotrexate therapy.
7) Probable Mechanism: asparaginase prohibits the cell replication necessary for
methotrexate antineoplastic activity
Mumps Virus Vaccine, Live
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Prednisolone
1) Interaction Effect: an increased risk of asparaginase toxicity
2) Summary: The liver reduces the 11-oxo group of prednisone to form the biologically active
steroid, prednisolone
[67]
. The administration of asparaginase concurrently with or before prednisone therapy may
result in increased toxicity. Administer asparaginase after prednisone to avoid this effect
[68]
. The same effects would be expected from the administration of prednisolone.
3) Severity: major
4) Onset: delayed
6) Clinical Management: Administer asparaginase after prednisolone rather than before or
concurrently to avoid an increased risk of toxicity.
7) Probable Mechanism: unknown
Prednisone
1) Interaction Effect: an increased risk of toxicity
2) Summary: The administration of asparaginase concurrently with or before prednisone
therapy may result in increased toxicity. Administer asparaginase after prednisone to avoid
this effect
[66]
.
3) Severity: major
4) Onset: delayed
6) Clinical Management: Administer asparaginase after prednisone rather than before or
7) Probable Mechanism: unknown
Rotavirus Vaccine, Live
[69]
[70]
[71]
. The administration of the rotavirus vaccine is contraindicated in patients who are
immunosuppressed due to chemotherapeutic agents
[72]
.
3) Severity: contraindicated
4) Onset: delayed
6) Clinical Management: Vaccination with rotavirus vaccine is contraindicated in patients
receiving immunosuppressive chemotherapy.
Rubella Virus Vaccine, Live
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Smallpox Vaccine
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Typhoid Vaccine
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Varicella Virus Vaccine
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Vincristine
2) Summary: The administration of asparaginase concurrently with or before vincristine
therapy may result in increased toxicity. Administer asparaginase after vincristine to avoid
this effect
[65]
.
3) Severity: major
4) Onset: delayed
6) Clinical Management: Administer asparaginase after vincristine rather than before or
7) Probable Mechanism: decreased vincristine metabolism due to effects of asparaginase on
hepatic function
Vincristine Sulfate Liposome
2) Summary: The administration of asparaginase concurrently with or before vincristine
therapy may result in increased toxicity. Administer asparaginase after vincristine to avoid
this effect
[65]
.
3) Severity: major
4) Onset: delayed
6) Clinical Management: Administer asparaginase after vincristine rather than before or
7) Probable Mechanism: decreased vincristine metabolism due to effects of asparaginase on
hepatic function
Yellow Fever Vaccine
[61]
[62]
[63]
[60]
.
3) Severity: major
4) Onset: delayed
[60]
.
Intravenous Admixtures
Solutions
Dextrose 5% in water
1) Compatible
a) Dextrose 5% in water (recommended as a diluent for reconstituted asparaginase;

solutions should be infused within 8 hours and only if clear)
[173]
Sodium chloride 0.9%

1) Compatible
a) Sodium chloride 0.9% (may be used to reconstitute asparaginase to a recommended

concentration of 10,000 U/5 mL; recommended as a diluent for reconstituted
asparaginase; solutions should be infused within 8 hours and only if clear)
[173]
Sterile water for injection

1) Compatible
a) Sterile water for injection (may be used to reconstitute asparaginase to a

recommended concentration of 10,000 U/5 mL; solution should be administered
within 8 hours and only if clear)
[173]
Clinical Applications
Monitoring Parameters
A) Asparaginase
1) Therapeutic
a) Physical Findings
1) Clinical remission of leukemia is indicative of efficacy.

2) Toxic
a) Laboratory Parameters
1) Monitor coagulation parameters at baseline and periodically during and after asparaginase therapy
[1]
.
2) Monitor hepatic function tests at baseline and periodically thereafter
[1]
.
3) Monitor serum glucose during therapy
[1]
.
b) Physical Findings
1) Observe patients for anaphylaxis for one hour following asparaginase administration
[1]
.
1) Therapeutic
a) Physical Findings
1) Clinical remission of leukemia is indicative of efficacy.

2) Toxic
a) Laboratory Parameters
1) Monitor serum glucose at baseline and periodically during therapy

[15]
.
Patient Instructions
A) Asparaginase (Injection)
Asparaginase
Treats certain kinds of leukemia and other cancers.
When This Medicine Should Not Be Used:

You should not receive this medicine if you have pancreatitis (inflammation of the pancreas) or had an
allergic reaction to asparaginase.
How to Use This Medicine:

Injectable
This medicine, like all medicines used to treat cancer, is very strong. Make sure you understand why you are
getting it and what the risks and benefits of treatment are. It is important for you to work closely with your
doctor.
Your doctor will prescribe your exact dose and tell you how often it will be given.
You may get your medicine through a tube that is put in your vein, usually in your arm, wrist, or hand and
sometimes in your chest. This is called intravenous (in-tra-VEEN-us), or IV.
Or you may get the medicine in a shot given in a muscle, usually in your buttock, upper arm, or thigh. This
is called intramuscular (in-tra-MUSS-cue-lar), or IM.
A nurse or other caregiver trained to give cancer drugs will give your treatment.
You probably will get your medicine at a hospital or clinic so the results of your treatment can be watched
closely.
If a Dose is Missed:
This medicine needs to be given on a regular schedule. If you miss a dose, call your doctor, home health
caregiver, or the clinic where you get your treatments for instructions.
How to Store and Dispose of This Medicine:
If you have your treatments at home, you may need to store the medicine. Keep the medicine in the
refrigerator. Do not freeze. Keep all medicine out of the reach of children.
If you get your treatments at home, you should be given a special container for the used needles, medicine
bag or bottles, and tubes. Keep it where children or pets cannot reach it.
Drugs and Foods to Avoid:

Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines,
vitamins, and herbal products.
You should not use aspirin or any product that has aspirin in it (such as some cold medicines) unless you
have talked to your doctor.
Talk to your doctor before getting any vaccines (such as flu shots).
Warnings While Using This Medicine:
Do not breastfeed while you are being treated with this medicine.
Asparaginase can increase the level of sugar in your blood. Make sure your doctor knows if you have
diabetes or high blood sugar.
You may have a test before you start your treatments to see if you are allergic to the medicine.
Do not get pregnant while you or your sexual partner are receiving asparaginase. Use an effective form of
birth control while you are getting this medicine.
If you are pregnant, talk to your doctor before you start your treatments.
Possible Side Effects While Using This Medicine:

Call your doctor right away if you notice any of these side effects:
Trouble breathing, rash or hives

Swelling of the face, mouth, or tongue
Yellowing of the skin or eyes
Fever, chills, or sore throat
Unusual bleeding and bruising
Having to go to the bathroom (urinate) often
Swollen feet and ankles
If you notice these less serious side effects, talk with your doctor:
Weakness, tired feeling

Loss of appetite, mild upset stomach or vomiting
If you notice other side effects that you think are caused by this medicine, tell your doctor.
B) Asparaginase Erwinia Chrysanthemi (Injection)
Treats acute lymphoblastic leukemia (ALL) in patients who have had an allergic reaction to E. coli-derived
asparaginase.
When This Medicine Should Not Be Used:

You should not receive this medicine if you have had an allergic reaction to asparaginase Erwinia
chrysanthemi or if you have a history of bleeding problems, blood clotting problems, or pancreas problems
caused by L-asparaginase (Elspar) treatment.
How to Use This Medicine:

Injectable
Your doctor will prescribe your exact dose and tell you how often it should be given. This medicine is given
as a shot into one of your muscles.
You will receive this medicine while you are in a hospital or cancer treatment center. A nurse or other
trained health professional will give you this medicine.
Erwinaze is sometimes given together with other medicines. It is important that you receive each
medicine at the proper time. If you take some of these medicines by the mouth, ask your doctor to help you
plan a way to take them at the right times.
If a Dose is Missed:
This medicine needs to be given on a fixed schedule. If you miss a dose, call your doctor, home health
caregiver, or treatment clinic for instructions.
Drugs and Foods to Avoid:

Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines,
vitamins, and herbal products.
Warnings While Using This Medicine:
Make sure your doctor knows if you are pregnant or breastfeeding or if you have diabetes.
Tell your doctor right away if you have sudden and severe stomach pain, chills, constipation, nausea,
vomiting, fever, or lightheadedness. These may be symptoms of pancreatitis.
Check with your doctor right away if you have increased thirst or hunger, increased urination, pale skin,
nausea, sweating, or faintness. These may be signs of problems with your blood sugar level.
Tell your doctor right away if you develop confusion, headache, nausea and vomiting, numbness or tingling
in the arms or legs, shortness of breath, or chest pain. These may be symptoms of a serious bleeding or blood
clotting problem.
Your doctor will need to check your blood at regular visits while you are using this medicine. Be sure to
keep all appointments.
Possible Side Effects While Using This Medicine:

Call your doctor right away if you notice any of these side effects:
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or
throat, chest tightness, trouble breathing
Chest pain, shortness of breath, or coughing up blood
Increase in how much or how often you urinate
Increased hunger or thirst
Numbness or weakness in your arm or leg, or on one side of your body
Pain or swelling in your lower leg (calf)
Sudden and severe stomach pain, nausea, vomiting, fever, and lightheadedness
Sudden or severe headache, or problems with vision, speech, or walking
Unusual bleeding
If you notice these less serious side effects, talk with your doctor:
If you notice other side effects that you think are caused by this medicine, tell your doctor.
Place In Therapy
A) Asparaginase
1) Asparaginase is often used in combination with vincristine and prednisone for the induction of remission
in patients with childhood acute lymphocytic leukemia. Asparaginase is seldom used as a sole induction
agent, unless combination therapy is not appropriate; the drug is not recommended for maintenance therapy.
2) Asparaginase is also useful as an alternative to cyclophosphamide, chlorambucil, vincristine/prednisone,
and etoposide for treating non-Hodgkin's lymphoma (Anon, 1989).
3) Pegaspargase was significantly less costly to payers compared to asparaginase in a pharmacoeconomic
assessment study based on 3 common adult ALL protocols. Cost savings parameters of pegaspargase
therapy included decreased hospital stay or decreased number of office visits, less frequent dosing (drug
administration costs), and decreased nurse, physician and pharmacist time
[109]
.
1) Asparaginase Erwinia chrysanthemi is indicated in combination with other chemotherapeutic agents for
patients with acute lymphoblastic leukemia who have developed hypersensitivity to E coli-derived
asparaginase. In a single-arm, multicenter, open-label, safety and pharmacokinetic study (n=58),
asparaginase Erwinia chrysanthemi provided an acceptable trough asparaginase activity level in pediatric
patients with ALL who were unable to continue pegaspargase therapy because of hypersensitivity reactions
[15]
.
Mechanism of Action / Pharmacology
A) Asparaginase
1) MECHANISM OF ACTION
a) Asparaginase contains the enzyme L-asparagine amidohydrolase type EC-2, which is derived from
Escherichia coli. Asparaginase is a unique chemotherapeutic agent that removes asparagine from leukemic
cells (especially lymphoblasts) by hydrolysis to aspartic acid and ammonia. These cells depend upon an
exogenous source of asparagine for survival. Normal cells, however, are able to synthesize asparagine and
are less affected by the effects of asparaginase
[97]
[92]
[104]
.
2) ANTIBODIES AND HYPERSENSITIVITY
a) In a study of 154 children with newly diagnosed acute lymphoblastic leukemia (ALL), the probability of
event-free survival (EFS) was not significantly different in patients with asparaginase antibodies than in
those without antibodies (p = 0.54), and EFS was not significantly different in patients who experienced
hypersensitivity reactions than in those who did not (p = 0.68). Antibodies measured on day 29 of induction
therapy (10 days after 9 doses of E coli asparaginase) were present in 35.5% of patients (54 of 152). Patients
with asparaginase antibodies were more likely to experience a hypersensitivity reaction (p less than .001).
Fifty patients (32.5%) had one or more hypersensitivity reactions to Escherichia coli asparaginase and were
premedicated if continued on this preparation (n=13), switched to Erwinia asparaginase (n=36), or switched
to pegaspargase (n=1). An asparaginase dose of 10,000 International Units/square meter was administered
intramuscularly 3 times weekly for 9 doses during induction and reinduction phases, as part of a multiagent
regimen also including methotrexate, vincristine, daunomycin, etoposide, cytarabine, mercaptopurine, and
cyclophosphamide.
[105]
.
3) REVIEW ARTICLES
a) Ettinger et al provide a review of the pharmacokinetics, mechanism of action, and the use of asparaginase
in childhood acute lymphoblastic leukemia
[97]
.
b) The Medical Letter consultants provide a review of drugs commonly used for various cancer types
[106]
.
1) Mechanism of Action
a) Asparaginase Erwinia chrysanthemi administration causes a reduction in circulating asparagine levels by

catalyzing the deamidation of asparagine to aspartic acid and ammonia. Leukemic cells are not able to
synthesize asparagine due to lack of asparagine synthetase activity, therefore a reduction in asparagine levels
results in a cytotoxicity specific for leukemic cells, which depend on an exogenous source of asparagine for
protein metabolism and survival
[15]
.
Therapeutic Uses
Asparaginase
FDA Labeled Indication
a) Overview
FDA Approval: Adult, yes; Pediatric, yes

Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Asparaginase is indicated in combination with other chemotherapeutic agents for the

treatment of acute lymphoblastic leukemia (ALL)
[1]
.
The addition of daunorubicin to the vincristine/prednisone/asparaginase regimen improved

remission rate but not response duration in 53 adult patients with previously untreated ALL
[3]
.
Vindesine, daunorubicin, asparaginase, and prednisone, followed by cytarabine and etoposide

as a 2-phase regimen produced a 64% response rate in 66 adults with relapsed or refractory
ALL
[4]
.
Treatment with the combination of prednisone, vincristine, and L-asparaginase led to a 93%
remission induction rate in 815 children with ALL in the single-arm Children's Cancer Group
101/143 trial
[2]
.
A 93% response rate was achieved with cytarabine, cyclophosphamide, prednisone,

daunorubicin, methotrexate, asparaginase, and vincristine in 27 infants younger than a year
old
[5]
.
c) Adult:
1) The addition of daunorubicin to vincristine, prednisone and asparaginase in adult patients
with previously untreated acute lymphocytic leukemia increased the number of complete
remissions (83% versus 47%), but did not improve median response duration. Fifty-three
patients received vincristine 2 milligrams (mg) on days 1, 8, and 15 and prednisone 40
mg/square meter (m(2)) on days 1 through 22 (dose reduced on days 22 through 29).
Asparaginase 500 units/kilogram/day was administered on days 22 to 32. Forty-six other
patients received the above regimen plus daunorubicin 45 mg/m(2) on days 1, 2, and 3.
Patients then received central nervous system prophylaxis consisting of irradiation and
intrathecal methotrexate, and maintenance therapy (mercaptopurine and methotrexate) with
reinforcement (vincristine and prednisone)
[3]
.
2) Complete remission was achieved in 64% of 66 adult patients with relapsed or refractory
acute lymphocytic leukemia receiving the following 2-phase regimen:
FIRST PHASE
vindesine 3 milligrams (mg) per square meter (m(2))
daunorubicin 45 mg/m(2)
erwinia-asparaginase 10,000 units/m(2)
prednisone 60 mg/m(2)
SECOND PHASE
cytarabine 3000 mg/m(2)
etoposide 100 mg/m(2)
Median overall survival for the study was 6.6 months and toxicity was tolerable
[4]
.
d) Pediatric:
1) Treatment with the combination of prednisone, vincristine, and L-asparaginase led to a

high remission induction rate in children with acute lymphocytic leukemia (ALL) in the large,
single-arm Children's Cancer Group (CCG) 101/143 trial. Patients (n=815) younger than 16
years with previously untreated ALL or acute undifferentiated leukemia were treated with
prednisone 40 mg/m(2)/day orally for 28 days, vincristine 1.5 mg/m(2) IV weekly
(maximum, 2 mg/wk) for 4 weeks (days 0, 7, 14, and 21), and L-asparaginase 6000
International Units/m(2) IM 3 times/wk for 9 doses (starting on day 3). If complete remission
(CR), requiring marrow remission (defined as less than 5% blasts), was not achieved by day
28, prednisone and vincristine were continued until day 42. The overall CR induction rate
was 93% (n=758), with 635 achieving remission on day 28 and 123 by day 42. Of 9 patients
with CNS leukemia, 8 achieved CR. Hyperglycemia occurred in 20 patients, leading to L-
asparaginase discontinuation in all 20 and prednisone dose reduction in 6. Severe
hypersensitivity reactions occurred in 2 patients (hypotension, n=1; brief respiratory distress,
n=1), and were presumed to be due to L-asparaginase. Six additional patients had minor
allergic reactions, consisting primarily of skin rash, and occurring after at least 5 doses of L-
asparaginase in 5 patients. Acute pancreatitis occurred in 4 patients, including 2 severe cases.
Of 26 deaths during the induction phase, 21 were due to infection, 3 due to hemorrhage
associated with thrombocytopenia, 1 due to massive hemorrhagic pancreatitis, and 1 due to
superior mediastinal syndrome associated with a large anterior mediastinal mass. In an
historical comparison to treatment of 499 children with vincristine and prednisone in the
CCG 903 trial, the addition of L-asparaginase in the CCG 101/143 trial improved the
remission induction rate from 86% to 93% (p less than 0.05)
[2]
.
2) The Children's Cancer Study Group reported improved results following induction with
intensive multiagent chemotherapy (cytarabine, cyclophosphamide, prednisone,
daunorubicin, methotrexate, asparaginase, and vincristine) in 27 infants younger than 1 year
with acute lymphoblastic leukemia. This aggressive protocol achieved a complete response
rate of 93%, with a median response duration of 17 months. Historically, early relapse had
limited the duration of remission to a median of only 8 months, with only 21% of patients
experiencing event-free survival at 4 years. These children had an event-free survival of 36%
at 4 years
[5]
.
Acute myeloid leukemia
a) Overview
FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence favors efficacy; Pediatric, Evidence favors efficacy
Recommendation: Adult, Class IIb; Pediatric, Class IIb
b) Summary:
Response rates have ranged from 37% to 74% in adults with acute nonlymphocytic leukemia
receiving combination chemotherapy with asparaginase and high-dose cytarabine
[6]
[7]
[8]
.
In pediatric patients with acute nonlymphocytic leukemia, complete remission occurred in

19.5% of those who received asparaginase and methotrexate (n=41)
[9]
and 42% of those who received asparaginase and high-dose cytarabine (n=41)
[10]
.
c) Adult:
1) A 42% clinical response rate was reported in 138 patients with relapsed and refractory
acute myelogenous leukemia following high-dose cytarabine plus asparaginase. Therapy
consisted of cytarabine 3 grams/square meter (m(2)) every 12 hours for 2 days and
intramuscular asparaginase 6000 units/m(2) at hour 42. This regimen was repeated on day 8
[6]
.
2) A 74% complete response rate was reported with post-remission chemotherapy in 100
adults with nonlymphocytic leukemia using high-dose cytarabine with asparaginase following
conventional induction therapy. The therapy consisted of 4 doses of cytarabine 3
grams/square meter every 12 hours with a single intramuscular dose of asparaginase 10,000
units at hour 42
[7]
.
3) The overall complete remission rate was 37% among 41 patients with "poor risk" acute
nonlymphocytic leukemia receiving high-dose cytarabine plus asparaginase
[8]
.
d) Pediatric:
1) Eight of 41 children with acute nonlymphocytic leukemia (ANLL) had a complete

response and 6 had a partial response to methotrexate plus asparaginase. This combination
has antileukemic activity and is relatively nontoxic in childhood ANLL
[9]
.
2) Sequential high-dose cytarabine plus asparaginase produced significant clinical responses
in 41 children with advanced acute lymphocytic or acute nonlymphocytic (45% and 42%
complete remission, respectively)
[10]
.
Chronic myeloid leukemia
a) Overview

Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category C
b) Summary:
In lymphoid blast crisis treatment, the regimen of choice is vincristine plus prednisone plus
L-asparaginase with or without doxorubicin or daunorubicin plus intrathecal methotrexate
(Anon, 1997)
Optional maintenance with methotrexate 6-mercaptopurine may be considered

Malignant lymphoma
a) Overview

Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category C
b) Summary:
Complete remission was achieved in 1 patient with positive Epstein-Barr virus, multidrug
resistant, cutaneous T-cell lymphoma
[11]
.
c) Adult:
1) Asparaginase may be an important treatment in relatively young lymphoma patients

resistant to usual chemotherapy who exhibit some of the characteristics of high fever,
hepatosplenomegaly, involvement of skin or paranasal region, and association with Epstein-
Barr virus. Asparaginase induced complete remission in a 30 year-old Asian man with diffuse
malignant lymphoma who presented with high fever, severe hepatosplenomegaly, and
subcutaneous tumors on the limbs and shoulder. Epstein-Barr virus-encoded small RNAs
were observed in the nuclei of the lymphoma cells. Previous unsuccessful treatment included
two trials of adriamycin, cyclophosphamide, vincristine, and prednisolone (CHOP) followed
by a trial of carboplatin, ifosfamide and etoposide. Asparaginase was administered
intravenously over 3 hours at a dose of 8000 Units/day for 4 days; tumor and fever
disappeared after several days. Mild nausea was the only side effect. One course of
asparaginase was given each month; good progress was noted over 3 months
[11]
.
Acute lymphoid leukemia, In combination with other chemotherapeutic agents in patients with
hypersensitivity to E coli-derived asparaginase
FDA Labeled Indication
a) Overview
FDA Approval: Adult, yes; Pediatric, yes

Efficacy: Adult, Evidence favors efficacy; Pediatric, Evidence favors efficacy
Recommendation: Adult, Class IIb; Pediatric, Class IIb
b) Summary:
Asparaginase Erwinia chrysanthemi is indicated in combination with other chemotherapeutic

agents for patients with acute lymphoblastic leukemia who have developed hypersensitivity
to E coli-derived asparaginase
[15]
.
In a single-arm, multicenter, open-label, safety and pharmacokinetic study (n=58),

asparaginase Erwinia chrysanthemi provided an acceptable trough asparaginase activity level
in pediatric patients with ALL who were unable to continue pegaspargase therapy because of
hypersensitivity reactions
[15]
.
c) Adult:
1) The Erwinaze master treatment protocol (EMPT), an expanded access study, enrolled 843
patients with ALL (97%) or lymphoblastic lymphoma (3%) who received asparaginase
Erwinia chrysanthemi after developing systemic hypersensitivity to E coli-derived
asparaginase. Safety data for patients (n=574; median age, 9 years; range, 1 to 66 years) who
received asparaginase Erwinia chrysanthemi at several dosing schedules (doses ranged from
20,000 to 25,000 International Units/m(2)) were combined with data from a single-arm,
multi-center, open-label, safety and clinical pharmacology trial. The most common adverse
events were systemic allergic reactions (17%), pancreatitis (4%), liver abnormalities (4%),
and coagulation abnormalities (3%)
[15]
.
2) In a single-arm, multicenter, open-label, safety and pharmacokinetic study (n=58),
in pediatric patients with acute lymphoblastic leukemia (ALL) who were unable to continue
pegaspargase therapy because of hypersensitivity reactions. Patients (median age, 10 years;
range, 2 to 18 years) who were treated on National Cancer Institute-sponsored cooperative
group ALL protocols and who had hypersensitivity reactions to pegaspargase received
asparaginase Erwinia chrysanthemi 25,000 International Units/m(2) IM 3 times weekly for 2
weeks to replace scheduled doses of pegaspargase remaining on their original treatment
protocol. Among evaluable patients (n=48), a prespecified trough asparaginase activity level
of 0.1 International Units/mL (primary outcome) was achieved by 100% of patients at 48
hours after the third dose (35 of 35 patients; 95% confidence interval (CI), 90% to 100%) and
by 100% of patients at 72 hours after the third dose (13 of 13 patients; 95% CI, 77% to
100%). In an exploratory analysis, a trough asparaginase activity level of 0.4 International
Units/mL was achieved by 80% of patients at 48 hours (95% CI, 64% to 90%) and by 38% of
patients at 72 hours (95% CI, 18% to 65%). In a compilation of adverse effects (n=630) from
this trial and the Erwinaze(TM) Master Treatment Protocol (EMTP), an expanded access
program for patients with ALL or lymphoblastic lymphoma who developed systemic
hypersensitivity to E coli-derived asparaginase, the most common adverse effects were
systemic allergic reactions (17%), pancreatitis (4%), liver abnormalities (4%), and
coagulation abnormalities (3%)
[15]
.
d) Pediatric:
1) In a single-arm, multicenter, open-label, safety and pharmacokinetic study (n=58),

in pediatric patients with acute lymphoblastic leukemia (ALL) who were unable to continue
pegaspargase therapy because of hypersensitivity reactions. Patients (median age, 10 years;
range, 2 to 18 years) who were treated on National Cancer Institute-sponsored cooperative
group ALL protocols and who had hypersensitivity reactions to pegaspargase received
asparaginase Erwinia chrysanthemi 25,000 International Units/m(2) IM 3 times weekly for 2
weeks to replace scheduled doses of pegaspargase remaining on their original treatment
protocol. Among evaluable patients (n=48), a prespecified trough asparaginase activity level
of 0.1 International Units/mL (primary outcome) was achieved by 100% of patients at 48
hours after the third dose (35 of 35 patients; 95% confidence interval (CI), 90% to 100%) and
by 100% of patients at 72 hours after the third dose (13 of 13 patients; 95% CI, 77% to
100%). In an exploratory analysis, a trough asparaginase activity level of 0.4 International
Units/mL was achieved by 80% of patients at 48 hours (95% CI, 64% to 90%) and by 38% of
patients at 72 hours (95% CI, 18% to 65%). In a compilation of adverse effects (n=630) from
this trial and the Erwinaze(TM) Master Treatment Protocol (EMTP), an expanded access
program for patients with ALL or lymphoblastic lymphoma who developed systemic
hypersensitivity to E coli-derived asparaginase, the most common adverse effects were
systemic allergic reactions (17%), pancreatitis (4%), liver abnormalities (4%), and
coagulation abnormalities (3%)
[15]
.
Comparative Efficacy / Evaluation With Other Therapies
Carmustine
Non-Hodgkin's lymphoma
a) Following initial complete response to standard induction, consolidative sequential
chemotherapy with ifosfamide plus etoposide, followed by asparaginase, then cytarabine was
inferior to high-dose therapy with cyclophosphamide, carmustine and etoposide plus stem-
cell transplantation in high/intermediate and high-risk patients (n=236). Eight-year overall
survival (64% and 49%, p=0.04) and disease-free survival (55% and 39%, p=0.02) favored
the high-dose/transplant regimen over sequential chemotherapy, respectively (Haioun et al,
2000).
Cyclophosphamide
2000).
Cytarabine
2000).
Doxorubicin
Acute lymphoid leukemia
a) When added to a standard vincristine-prednisolone induction regimen, an E. coli-derived
L-asparaginase preparation (Leunase) was less efficacious than epidoxorubicin (doxorubicin)
in a randomized study of pediatric patients with standard-risk acute lymphocytic leukemia
(n=201, median age 4 years). The dose of L-asparaginase was 10,000 international
units/square meter, given intramuscularly 3 times weekly for 9 doses. Doxorubicin was
administered intravenously as 20 milligrams/square meter weekly for 2 doses. Patients also
received etoposide, cytarabine and triple intrathecal therapy to complete the induction
regimen. L-asparaginase was associated with an increased mortality rate during induction as
compared to doxorubicin (6% versus 0%, p = 0.009), with higher incidences of severe
infection (20% versus 7%, p = 0.01), hyperglycemia and hypoalbuminemia (6% versus 1%
for each, p = 0.05). Corresponding complete remission rates were 94% and 99%, respectively
(p = 0.05). These results may not be applicable to other L-asparaginase products because of
differing biological activities and clinical effects
[110]
.
Etoposide
2000).
Hemopoietic stem cell transplant
2000).
Ifosfamide
2000).
Pegaspargase
1) Pharmacoeconomics
a) Pegaspargase was significantly less costly to payers compared to asparaginase in a

pharmacoeconomic assessment study based on 3 common adult ALL protocols. Cost savings
parameters of pegaspargase therapy included decreased hospital stay or decreased number of office
visits, less frequent dosing (drug administration costs), and decreased nurse, physician and
pharmacist time
[111]
.
Prednisone
a) The clinical response in children (41%) is superior to that observed in adults (26%). One
study randomized 179 children who were in relapse from acute lymphoblastic leukemia to
receive reinduction therapy with either vindesine or vincristine in combination with
prednisone and L-asparaginase (Anderson et al, 1981). Complete remission rates were 57%
for both regimens and were significantly greater for first relapses (69%) than for subsequent
relapses (43%) suggesting that there is no advantage to using vindesine instead of vincristine
in standard reinduction therapy (Cersosimo et al, 1983).
Vincristine
Vindesine
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Last Modified: March 14, 2013
Truven Health Analytics Inc.

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ASPARAGINASE

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ASPARAGINASE

a) This drug is a member of the following class(es):

a) Acute lymphoid leukemia, In combination with other chemotherapeutic agents

1) Acute lymphoid leukemia, In combination with other chemotherapeutic agents

b) Asparaginase Erwinia Chrysanthemi

1) allergic reactions, serious, to asparaginase or other forms of L-asparaginase

2) hemorrhagic events, serious, with prior L-asparaginase therapy

3) pancreatitis with prior L-asparaginase therapy

4) thrombosis, serious, with prior L-asparaginase therapy

b) Asparaginase Erwinia Chrysanthemi

1) hemorrhagic events, serious, with prior L-asparaginase therapy

3) pancreatitis, serious, with prior L-asparaginase therapy

4) thrombosis, serious, with prior L-asparaginase therapy

4) Serious Adverse Effects

1) Acute hemorrhagic pancreatitis

1) Disseminated intravascular coagulation

1) FDA Approved Indications

a) Acute lymphoid leukemia, In combination with other chemotherapeutic agents

1) Asparaginase Erwinia Chrysanthemi

Storage and Stability

a) Powder for Solution

a) Powder for Solution

a) The recommended dose of asparaginase Erwinia chrysanthemi to substitute

a) The recommended dose of asparaginase Erwinia chrysanthemi to substitute

B) Asparaginase Erwinia Chrysanthemi

a) Prednisone 40 milligrams/square meter of body surface area per day orally

a) Prednisone 40 milligrams/square meter of body surface area per day orally

a) A premedication and desensitization protocol for IV L-asparaginase was successfully used

a) The recommended dose of asparaginase Erwinia chrysanthemi to substitute

a) The recommended dose of asparaginase Erwinia chrysanthemi to substitute

Onset and Duration

a) Acute leukemia, 14 to 21 days

1) Acute leukemia, intravenous: 6 to 21 weeks

1) Asparaginase activity: 7 to 15 days

Drug Concentration Levels

1) Time to Peak Concentration

1) Therapeutic Drug Concentration

a) Acute lymphoblastic leukemia: 0.1 International Units/mL or greater

a) Intramuscular asparaginase reaches plasma levels one-half those following intravenous

1) OTHER DISTRIBUTION SITES

a) CEREBROSPINAL FLUID, less than 1% to 10% of plasma levels at equilibrium

1) Volume of distribution is approximately 70 to 80% of estimated asparaginase plasma volume

a) 0.65 days (+/- 0.13)

1) In a pharmacokinetic study of children (n=37) newly diagnosed with acute lymphoblastic

1) allergic reactions, serious, to asparaginase or other forms of L-asparaginase

2) hemorrhagic events, serious, with prior L-asparaginase therapy

3) pancreatitis with prior L-asparaginase therapy

4) thrombosis, serious, with prior L-asparaginase therapy

B) Asparaginase Erwinia Chrysanthemi

1) hemorrhagic events, serious, with prior L-asparaginase therapy

2) hypersensitivity reactions to asparaginase Erwinia chrysanthemi therapy, serious, including anaphylaxis;

3) pancreatitis, serious, with prior L-asparaginase therapy

2) CNS hemorrhages have been reported

3) coagulopathy, including increased prothrombin time, partial thromboplastin time, and

4) glucose intolerance has been reported; monitoring recommended

B) Asparaginase Erwinia Chrysanthemi

3) hypersensitivity reactions, serious, including anaphylaxis have occurred

b) In a single-arm, multicenter, open-label study (n=58; median age, 10 years; range,

1) Hyperglycemia is one of most common adverse effects following use of

1) Hyperglycemia is one of most common adverse effects following use of

b) In a single-arm, multicenter, open-label study (n=58; median age, 10 years; range,

b) Hyperglycemia reported with asparaginase Erwinia chrysanthemi may not be

b) In a single-arm, multicenter, open-label study (n=58; median age, 10 years; range,