HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RYLAZE safely and effectively. See full prescribing information
for RYLAZE.
RYLAZETM (asparaginase erwinia chrysanthemi (recombinant)- rywn) injection, for intramuscular use
Initial U.S. Approval: 2021
-----------------------------INDICATIONS AND USAGE---------------------------
RYLAZE is an asparagine specific
enzyme indicated as a component of a multi-agent chemotherapeutic
regimen for the treatment of acute
lymphoblastic
leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity toE. coli-derived asparaginase.
(1)
------------------------DOSAGE AND ADMINISTRATION-----------------------
When replacing
a long-acting asparaginase product, the recommended dosage of RYLAZE is 25 mg/m2 administered intramuscularly every
48 hours. (2.1)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Injection: 10 mg/0.5
mL solution in a single-dose vial.
(3)
-------------------------------CONTRAINDICATIONS-------------------------------
RYLAZE is contraindicated in patients with a history of:
• Serious hypersensitivity reactions
to RYLAZE, including anaphylaxis. (4)
•
Serious pancreatitis during previous L-asparaginase therapy. (4)
•
Serious thrombosis during previous L-asparaginase therapy. (4)
• Serious hemorrhagic events during previous L-asparaginase therapy. (4)
------------------------WARNINGS AND PRECAUTIONS-----------------------
• Hypersensitivity: Monitor
for signs or symptoms. Discontinue RYLAZE for serious reaction. (5.1)
• Pancreatitis: Monitor
for symptoms. Discontinue if pancreatitis occurs. (5.2)
• Thrombosis: Discontinue RYLAZE for severe or life-threatening thrombosis.
Provide anticoagulation therapy as indicated.
(5.3)
• Hemorrhage: Discontinue RYLAZE for severe or life-threatening hemorrhage. (5.4)
• Hepatotoxicity: Discontinue RYLAZE for grade 4 increases of bilirubin.
(5.5)
-------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions
(incidence > 20%) are abnormal liver test, nausea,
musculoskeletal pain, fatigue, infection, headache,
pyrexia, drug hypersensitivity, febrile neutropenia,
decreased appetite, stomatitis, bleeding, and hyperglycemia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals Ireland Limited at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
--------------------------USE
IN SPECIFIC POPULATIONS---------------------
•
Lactation: Advise
not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 6/2021
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
2.2 Recommended Monitoring and Dosage
Modifications for Adverse Reactions
2.3
Preparation
and Administration Instructions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
5.2
Pancreatitis
5.3
Thrombosis
5.4
Hemorrhage
5.5
Hepatotoxicity
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Immunogenicity
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive
Potential
8.4
Pediatric Use
8.5 
Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted
from the full prescribing information
are not listed.
FUL
L PRESCRIBING INFORMATION
1 INDICATIONS
AND USAGE
RYLAZE is indicated
as a component of a multi-agent chemotherapeutic
regimen for the
treatment of acute lymphoblastic
leukemia (ALL) and
lymphoblastic
lymphoma (LBL) in adult
and pediatric patients 1 month
or
older who have
developed hypersensitivity
to E. coli-derived
asparaginase.
2
D
OSAGE AND
ADMINISTRATION
2.1 Recommended Dosage
When replacing
a long-acting asparaginase
product, the recommended
dosage of RYLAZE
is 25 mg/m2 administered intramuscularly every 48
hours.
See the full prescribing
information
for the long-acting asparaginase product to
determine
the duration of administration of
RYLAZE as replacement
therapy.
2.2
Reco
mmended Monitoring and
Dosage
Modifications for Adverse Reactions
Monitor patient’s bilirubin, transaminases, glucose, and
clinical examinations prior
to treatment every
2-3 weeks and as indicated
clinically. If results are
abnormal, monitor patients until
recovery
from the cycle of
therapy. If an adverse reaction occurs, modify
treatment according
to Table 1.
Table 1: Dosage Modifications
|
Adverse Reaction
|
Severity*
|
Action
|
|
Hypersensitivity Reaction[see Warnings and
Precautions (5.1)]
|
Grade 2
|
• Treat
the symptoms.
|
|
Grade 3 to 4
|
• Discontinue RYLAZE permanently.
|
|
Pancreatitis[see Warnings and
Precautions (5.2)]
|
Grade 2 to 4
|
• Hold RYLAZE for elevations in lipase or amylase > 2times the ULN, or
for symptomatic pancreatitis.
• Resume
treatment when lipase and amylase are
< 1.5
times the ULN and symptoms are resolved.
• Discontinue RYLAZE permanently if clinical
necrotizing or hemorrhagic pancreatitis is confirmed.
|
|
Thrombosis[see Warnings and Precautions (5.3)]
|
Uncomplicated thrombosis
|
• Hold RYLAZE.
• Treat with appropriate antithrombotic therapy
• Upon resolution of
symptoms, consider resuming
RYLAZE, while
continuing antithrombotic therapy.
|
|
Severe or life- threatening thrombosis
|
• Discontinue RYLAZE permanently.
• Treat with appropriate antithrombotic therapy.
|
|
Hemorrhage[see Warnings and Precautions (5.4)]
|
Grade 3 to 4
|
• Hold RYLAZE.
• Evaluate
for coagulopathy and consider clotting
factor replacement as needed.
• Resume
RYLAZE with the next scheduled dose if bleeding is controlled.
|
|
Hepatotoxicity[see Warnings and Precautions (5.5)]
|
Total bilirubin >3 times
to ≤ 10 times the ULN
|
• Hold RYLAZE until total bilirubin
levels decrease to ≤
1.5 times the ULN.
|
|
Total bilirubin
>10 times the ULN
|
• Discontinue RYLAZE and do not make up missed doses.
|
* Common Terminology Criteria for
Adverse Events (CTCAE)
version 5.0.
2.3
P
reparation
and
Administration Instructions
Ensure that
medical support is available
to appropriately manage
anaphylactic reactions
when administering RYLAZE[see
Warnings and Precautions
(5.1)].
Visually
inspect parenteral drug products for particulate matter, cloudiness,
or discoloration prior to administration. If
any of these are present,
discard the vial. RYLAZE
does not contain a preservative.
Use aseptic technique.
• Determine
the dose, total
volume of RYLAZE solution required, and
the number of RYLAZE
vials needed. More than one
vial may be needed for a full dose.
• Withdraw
the indicated
injection volume of RYLAZE into
the syringe for
injection.
– Do not shake
the vial.
– Limit the
volume of RYLAZE at a single
injection site to
2 mL.
– If the volume
to be administered
is greater than
2 mL, divide the doses equally
into multiple syringes, one
for each injection site.
– Discard the
remaining
unused RYLAZE in the
single-dose vial.
• Administer
RYLAZE by intramuscular
injection within 4 hours after drawing the
dose into the syringe(s).
– Rotate injection sites.
– Do not inject
RYLAZE into scar tissue or
areas that
are
reddened, inflamed, or swollen
– If needed, store
the syringe(s) at room temperature (15°C to 25°C
[59°F to 77°F]) or refrigerated at
2°C to 8°C (36°F to 46°F) for up
to 4 hours. The syringe does
not need to be protected from
light during storage.
3
D
OSAGE FORMS AND
STRENGTHS
Injection: 10
mg/0.5 mL clear
to opalescent, colorless to slightly yellow solution in a single-dose
vial.
4
C
ONTRAINDICATIONS
RYLAZE is contraindicated in
patients
with a history of:
•
Serious
hypersensitivity
reactions toErwinia
asparaginase,
including anaphylaxis[see Warnings and Precautions (5.1)];
•
Serious
pancreatitis during previous
asparaginase therapy[see
Warnings
and Precautions (5.2)];
•
Serious
thrombosis
during
previous
asparaginase
therapy[see
Warnings
and
Precautions (5.3)];
•
Serious
hemorrhagic events during previous
asparaginase
therapy[see Warnings and
Precautions (5.4)].
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Hypersensitivity reactions after the use
of RYLAZE
occurred in
25% of patients in
clinical trials, and
it was
severe
in 2%
of patients [see Adverse Reactions
(6.1)]. The median
time from the first
dose of RYLAZE to the onset of
the
first hypersensitivity event was
27 days (range
1-171 days). The most
commonly observed
reaction was rash (17%), and
no
patient experienced
a severe rash. The
median time from the first
dose
to the first onset of rash was
33.5 days (Range 1-127
days).
Hypersensitivity
reactions observed
with L-asparaginase class
products
include angioedema, urticaria,
lip
swelling, eye swelling, rash
or
erythema, blood
pressure
decreased, bronchospasm,
dyspnea, and
pruritus.
Because of the
risk of serious
allergic reactions (e.g., life-threatening
anaphylaxis), administer
RYLAZE in a
setting with resuscitation equipment and
other
agents necessary to treat anaphylaxis
(e.g., epinephrine, oxygen, intravenous
steroids, antihistamines) [see Dosage and Administration (2.3)]. Discontinue
RYLAZE in patients with
serious
hypersensitivity reactions.
5.2
Panc
reatitis
Pancreatitis
was reported in 14%
of patients
in clinical
trials of RYLAZE and was severe in
6% [see Adverse Reactions (6.1)]. Clinical
pancreatitis occurred in
5% of
patients,
and it was severe
in 4%
of patients. Elevated
amylase
or lipase without clinical diagnosis
of pancreatitis was
observed in
9% of
patients, and it
was severe in 2%
of patients treated with RYLAZE. Hemorrhagic
or necrotizing pancreatitis have
been reported with L-asparaginase
class products.
Inform patients
of
the signs and symptoms of
pancreatitis, which,
if left
untreated, could be fatal. Evaluate patients with
symptoms compatible with pancreatitis
to establish a diagnosis. Assess serum amylase
and lipase levels
in patients
with any signs or symptoms
of pancreatitis.
Discontinue RYLAZE in patients with
severe
or hemorrhagic
pancreatitis. In
the case of mild
pancreatitis, withhold
RYLAZE until the
signs and symptoms subside and
amylase
and/or lipase levels
return
to 1.5
times
the ULN [see Dosage and Administration (2.2)].After resolution
of mild pancreatitis,
treatment with
RYLAZE may be resumed.
5.3
Thrombosis
Serious thrombotic events, including
sagittal sinus thrombosis and pulmonary embolism,
have been reported
following treatment with
L-asparaginase class
products.
Discontinue RYLAZE for
a thrombotic event, and
administer appropriate antithrombotic
therapy. Consider
resumption
of treatment with
RYLAZE only if the patient had
an uncomplicated thrombosis [see Dosage and Administration
(2.2)].
5.4
He
morrhage
Bleeding was reported in
17% of patients treated
with RYLAZE, and it
was severe in 1%. Most
commonly observed
reactions were bruising (8%) (contusion, increased tendency
to bruise and injection site bruising) and
nose bleeding (6%),
which was severe in
1% of patients.
Other
observed bleeding
reactions included hematuria
(2%), disseminated intravascular coagulopathy (1%),
rectal bleeding (1%) and gingival bleeding (1%) [see Adverse Reactions (6.1)].
In patients treated with
asparaginase
class products, hemorrhage may
be associated with increased prothrombin
time (PT), increased
partial thromboplastin time (PTT), and hypofibrinogenemia.
Consider appropriate
replacement therapy
in
patients with severe or
symptomatic coagulopathy [see Dosage and
Administration
(2.2)].
5.5
Hepa
totoxicity
Elevated bilirubin and/or transaminases
occurred in 62% of
patients treated with
RYLAZE in clinical trials, and
12% had Grade ≥ 3 elevations [see Adverse Reactions
(6.1)].
Inform patients
of
the signs and symptoms of
hepatotoxicity.
Evaluate bilirubin and
transaminases prior
to treatment every
2-3 weeks and as indicated
clinically during treatment with
RYLAZE. In the event of
serious
liver
toxicity, discontinue
treatment with RYLAZE
and provide supportive
care [see Dosage
and Administration
(2.2)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are
described in greater
detail in
other
sections of the labeling:
•
Hypersensitivity Reactions[Warnings
and Precautions
(5.1)]
•
Pancreatic Toxicity[see
Warnings
and Precautions
(5.2)]
•
Thrombosis[see Warnings
and
Precautions (5.3)]
•
Hemorrhage[see Warnings
and
Precautions (5.4)]
•
Hepatotoxicity
[seeWarnings and Precautions (5.5)]
6.1
C
linical Trials
Experience
Because clinical trials are
conducted under widely varying conditions, adverse
reaction rates observed in the
clinical trials of
a drug cannot be directly
compared to rates in
the clinical trials
of another drug and
may
not reflect
the rates observed
in practice.
The safety of RYLAZE described in the
WARNINGS AND PRECAUTIONS
reflect
exposure to RYLAZE at various dosages, including dosage
other
than
the recommended,
used in combination with chemotherapy
in 102
patients in
JZP458-201 [see Clinical Studies (14)]. These
patients received a
median of 3 courses of
RYLAZE (range: 1-14 courses); 38%
of
patients received at
least
four courses.
The safety of
RYLAZE described below
was evaluated in a cohort of 33
patients
from JZP458-201 who
received RYLAZE
25 mg/m2 intramuscularly
on Monday, Wednesday, and
Friday
for 6 doses as
a replacement for
a single
dose of pegaspargase as
a component of multi-agent
chemotherapy [see Clinical Studies (14)]. The
patients had
a median
age of 11 years
(range: 1 to 24 years); the majority of
patients were male
(51%) and white (73%). The
patients
received a median of
4 courses of RYLAZE
(range: 1-14 cycles); 48%
of patients received
at least
four
courses.
A fatal
adverse
reaction (infection)
occurred in
1 patient treated
with the RYLAZE 25 mg/m2 dosage.
Serious adverse
reactions occurred
in 55%
of patients
who received the
RYLAZE 25
mg/m2 dosage. The most frequent serious
adverse
reactions (in ≥ 5% of patients) were
febrile neutropenia,
dehydration, pyrexia, stomatitis,
diarrhea, drug
hypersensitivity,
infection, nausea, and viral infection.
Permanent discontinuation
due to an adverse reaction occurred
in 9%
of patients
who received the
RYLAZE 25 mg/m2 dosage.
Adverse reactions resulting in
permanent discontinuation included
hypersensitivity (6%)
and
infection (3%).
All patients
treated with the RYLAZE 25
mg/m2 dosage
as a component of multi-agent
chemotherapy developed neutropenia, anemia, or
thrombocytopenia. The
most common nonhematological
adverse
reactions in patients were
abnormal liver test, nausea,
musculoskeletal pain,
fatigue,
infection, headache, pyrexia,
drug
hypersensitivity,
febrile neutropenia, decreased appetite, stomatitis,
bleeding, and hyperglycemia. Table
2 shows the common adverse reactions occurring
in at
least 15% of the patients.
Table 2:
Adverse Reactions (≥
15% incidence) in Patients Receiving RYLAZE
25 mg/m2 a
s a Component
of
Multi-Agent Chemotherapy in Study JZP458-201
|
Adverse Reaction
|
RYLAZE 25 mg/m2 Dosage a
N=33
|
|
All Grades (%)
|
Grades 3-4 (%)
|
|
Abnormal liver test*
|
70
|
12
|
|
Nausea*
|
46
|
9
|
|
Musculoskeletal pain*
|
39
|
6
|
|
Fatigue*
|
36
|
3
|
|
Infection*b
|
30
|
12
|
|
Headache
|
30
|
0
|
|
Pyrexia
|
27
|
6
|
|
Drug hypersensitivity*
|
24
|
6
|
|
Febrile neutropenia
|
24
|
24
|
|
Decreased appetite
|
21
|
6
|
|
Stomatitis
|
21
|
9
|
|
Bleeding*
|
21
|
0
|
|
Hyperglycemia
|
21
|
3
|
|
Abdominal pain*
|
18
|
0
|
|
Tachycardia*
|
18
|
0
|
|
Diarrhea*
|
18
|
6
|
|
Constipation
|
15
|
0
|
|
Dehydration
|
15
|
9
|
|
Neuropathy peripheral*
|
15
|
0
|
|
Cough
|
15
|
0
|
|
Insomnia
|
15
|
0
|
*Includes grouped terms
Grading is based on Common Terminology Criteria for
Adverse Events
version 5.0
a RYLAZE was administered
as
a component of multi-agent
chemotherapy regimens.
b Does not
include the following fatal adverse reactions: infection
(N=1).
Safety data for
patients treated
on a Monday, Wednesday and Friday schedule.
Clinically relevant adverse reactions in
<15% of patients
who received
RYLAZE in combination with chemotherapy
included:
Gastrointestinal disorders: Abdominal discomfort, abdominal
distension, pancreatitisGeneral
disorders
and administration
site conditions: Infusion site
reaction, painInfections and
infestations:
Viral
infection, bacterial
infection, fungal infection
Investigations: Blood fibrinogen
decreased, activated
partial thromboplastin time prolonged
Metabolism and nutrition
disorders: Acidosis
Musculoskeletal
and connective tissue
disorders: bone pain, muscular weakness,
muscle spasms
Nervous
system disorders: paresthesiaPsychiatric
disorders: Agitation, anxiety, irritabilityRenal
and urinary disorders:
Acute
kidney injurySkin and
subcutaneous disorders: PruritusVascular disorders: Hypotension
6.2
Immunogenicity
The incidence of
ADA
and subsequent effects
on pharmacokinetics, pharmacodynamics, safety, or
effectiveness
have not been established.
8 USE
IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on
findings from animal reproduction
studies, RYLAZE can
cause fetal harm
when administered to a pregnant
woman.
There are no available data
on RYLAZE use in pregnant women to evaluate for
a drug-associated risk
of major birth defects, miscarriage, or
adverse
maternal or
fetal
outcomes. In animal reproductive and developmental toxicity studies, intramuscular administration of asparaginase Erwinia chrysanthemito pregnant rats and rabbits during organogenesis resulted in
structural abnormalities and embryo-fetal mortality (see Data)at exposures below those in patients at the recommended human dose. Advise pregnant women of the potential risk to a fetus.
In the
U.S. general population, the
estimated
background risks
of
major birth defects and
miscarriage in clinically
recognized pregnancies are
2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Animal reproductive and
developmental
toxicity studies
have not been conducted
with RYLAZE.
In embryofetal development studies,
asparaginase Erwinia chrysanthemiwas administered
intramuscularly
every other
day during the period of
organogenesis to pregnant rats (at
3,
6, or 12 mg/m2) and
rabbits (at 0.12, 0.30, or
0.48 mg/m2). In rats given
12 mg/m2 (approximately
0.48 times the
maximum
recommended human dose), maternal toxicity
of decreased
body weight gain was observed, as
was a fetal finding of increased
incidence of
partially undescended thymic tissue. In
rabbits, maternal toxicity consisting
of decreased
body weight was observed at 0.48
mg/m2 (approximately 0.02 times the
maximum recommended
human
dose).
Increased post-implantation
loss, a decrease in the
number
of
live fetuses,
and gross abnormalities (e.g., absent
kidney, absent accessory lung
lobe, additional subclavian
artery,
and delayed ossification)
were observed at doses of ≥ 0.12 mg/m2 (approximately 0.005 times the maximum recommended human dose).
8.2
Lac
tation
Risk Summary
There are no
data on the presence of
asparaginase erwinia
chrysanthemi (recombinant)-rywn in human milk, the
effects on
the breastfed child,
or
the effects on milk
production. Because of the potential for
adverse
reactions in the
breastfed child, advise women
not to breastfeed
during
treatment with RYLAZE and
for
1 week after
the last dose.
8.3
Fe
males and Males of
Reproductive Potential
RYLAZE can cause
fetal
harm when administered to a
pregnant woman[see Use
in Specific Populations
(8.1)].
Pregnancy Testing
Pregnancy testing is
recommended in
females
of reproductive potential
prior
to initiating RYLAZE.
Contraception
Advise females of
reproductive potential
to use effective
non-hormonal contraceptive methods during treatment with RYLAZE and
for
3 months after the last dose.
8.4
Ped
iatric Use
The safety and effectiveness of
RYLAZE in the treatment of
ALL and LBL have been
established
in pediatric patients 1 month
to < 17 years who have developed hypersensitivity
to a long-acting E. coli- derived
asparaginase. Use
of RYLAZE
in these age groups
is supported by
evidence
from an adequate and well-controlled
study in adults and pediatric
patients.
The trial included 84 pediatric patients, including
2 infants (1 month
to < 2 years), 62 children
(2 years to < 12 years
old), and
20 adolescents (12
years
to < 17 years old).
There were no clinically meaningful differences in
safety
or nadir
serum asparaginase activity across age
groups. The
safety
and effectiveness of
RYLAZE have not been
established in
pediatric patients
younger than 1 month
of age.
8.5
Geriatric Use
Clinical
studies of RYLAZE did
not include sufficient
numbers
of patients
65 years of age and
older to determine whether they
respond differently from younger patients.
1
1 DESCRIPTION
Asparaginase erwinia chrysanthemi (recombinant)-rywn
contains an asparagine
specific bacterial enzyme (L-asparaginase).
L-asparaginase is a tetrameric enzyme
that consists of four identical
35 kDa subunits with
a combined molecular weight of
140
kDa. The amino acid
sequence is identical to
native
asparaginase Erwinia chrystanthemi(also known as
crisantaspase). The activity of
asparaginase erwinia chrysanthemi (recombinant)-rywn
is expressed in
units, defined as the
amount of enzyme
that catalyzes the
conversion of 1μmol of L-asparagine per
reaction minute, per mg of
protein.
Asparaginase erwinia chrysanthemi (recombinant)-rywn
is produced
by fermentation of
a genetically engineeredPseudomonas
fluorescensbacterium containing the
DNA which encodes
for asparaginaseErwinia chrysanthemi.
RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn)
injection is supplied as a sterile, clear
to opalescent, colorless to slightly yellow, preservative-free solution for
intramuscular
injection. Each 0.5 mL contains 10
mg asparaginase erwinia chrysanthemi
(recombinant)-rywn and the
inactive ingredients:
polysorbate 80 (0.1 mg),
sodium chloride (1.5 mg),
sodium
phosphate dibasic
anhydrous
(0.8 mg),
sodium
phosphate monobasic monohydrate (0.6
mg), and trehalose (32.1
mg).
Sodium hydroxide may be
added to adjust the pH. The pH
is approximately 7.
12 CL
INICAL
PHARMACOLOGY
12.1 Mechanism of Action
Asparaginase erwinia chrysanthemi (recombinant)-rywn
is an
enzyme that catalyzes
the conversion of the
amino acid L-asparagine into aspartic acid and
ammonia. The pharmacological
effect of
RYLAZE is based
on the killing of leukemic
cells due to depletion of plasma
asparagine. Leukemic
cells with low expression
of asparagine
synthetase
have a reduced ability
to synthesize asparagine, and therefore depend
on an
exogenous source of
asparagine
for survival.
12.2 Pha
rmacodynamics
Asparaginase erwinia chrysanthemi (recombinant)-rywn
exposure-response
relationships and
the time course of
pharmacodynamic response are
unknown.
12.3 Pha
rmacokinetics
The pharmacokinetic parameters of asparaginase
erwinia chrysanthemi
(recombinant)-rywn
are presented
based
on serum asparaginase activity
(SAA) following administration
of the approved recommended dosage in
pediatric and young adult
patients
(1 to 24 years), unless
otherwise specified.
The exposures for
asparaginase
erwinia
chrysanthemi (recombinant)-rywn are summarized in Table 3. Asparaginase erwinia chrysanthemi (recombinant)-rywn
maximum SAA (Cmax) and area under the
SAA-time curve (AUC) increase proportionally
over
a dosage range from 12.5
to 50 mg/m2
(0.5 to 2 times
the approved recommended dose
of 25
mg/m2).
Table 3: RYLAZE
Pharmacokinetic
Parameters
Based on SAA
|
Parameter
|
Dose in Course
|
Geometric Mean
(%CV)
|
|
Cmax (U/mL)
|
1
|
1.80
(40%)
|
|
7
|
2.24
(42%)
|
|
C48ha (U/mL)
|
1
|
0.33
(88%)
|
|
7
|
0.40
(93%)
|
|
AUC0-48h (h·U/mL)
|
1
|
37.9 (39%)
|
|
7
|
48.5 (41%)
|
a SAA 48 hours
after the most recent dose
Absorption
The median tmax of asparaginase erwinia chrysanthemi
(recombinant)-rywn is 10
hours. The mean absolute bioavailability for IM administration is 37%
in healthy subjects.
Distribution
The geometric
mean (%CV) apparent
volume of distribution
of asparaginase erwinia
chrysanthemi
(recombinant)-rywn is 1.48
L/m2 (49%).
Elimination
The geometric
mean (%CV) apparent
clearance of asparaginase
erwinia chrysanthemi
(recombinant)-rywn is 0.31
L/hour/m2 (36%)
and the apparent
half-life is 18.2 hours
(16%).
Metabolism
Asparaginase erwinia chrysanthemi (recombinant)-rywn
is expected
to be metabolized into small
peptides by catabolic pathways.
Specific
Populations
There were no
clinically significant
differences in
the pharmacokinetics
of asparaginase erwinia chrysanthemi
(recombinant)-rywn
based
on age
(1 to 52 years), weight (9 to 131 kg), or sex after the dose
was adjusted by
body surface area
(BSA). The effect of renal
and hepatic impairment
on the pharmacokinetics of
asparaginase
erwinia
chrysanthemi
(recombinant)-rywn
has not been studied.
Body Surface
Area
The apparent volume
of distribution
and apparent clearance of
asparaginase erwinia chrysanthemi (recombinant)-rywn increase
with increasing BSA (0.44 to 2.53 m2).
Race and Ethnicity
Black (n=10)
and Asian (n=5) patients
had 29% lower clearance
which may increase SAA
exposure compared
to White (n=61) patients. There
were
no clinically significant differences
in clearance between Hispanic
(n=28)
and Non-Hispanic
(n=53)
patients.
13 N
ONCLINICAL TOXICOLOGY
13.1 Carcinogenesis,
Mutagenesis, Impairment of
Fertility
Carcinogenicity, mutagenicity,
and
impairment of fertility
studies have not been
conducted with asparaginase erwinia chrysanthemi (recombinant)-rywn.
In a fertility and
early
embryonic development
study in rats, asparaginase Erwinia chrysanthemihad no effect on
male or female fertility when
administered
intramuscularly
at doses of
up to 12 mg/m2 (approximately 0.48 times the
maximum recommended
human
dose)
every other
day for a total of
35 doses. In males, decreased
sperm count was observed at
all doses but did
not
impact fertility.
14 CL
INICAL
STUDIES
The efficacy of
RYLAZE for the treatment of patients
with acute lymphoblastic
leukemia (ALL) or
lymphoblastic lymphoma (LBL)
who
have developed hypersensitivity
to E.coli-derived asparaginase as
a component of a multi-agent
chemotherapeutic regimen
was evaluated in Study JZP458-201
(NCT04145531),
an open-label,
multi-cohort, multicenter trial.
A treatment course
consisted of RYLAZE
at
various dosages administered intramuscularly
every
Monday,
Wednesday, and Friday
for a total of 6 doses
to replace each dose
of pegaspargase.
For the 102
patients
treated, the median
age was 10 years (range,
1 - 24 years); 57% were male
and 43% were female; 73%
were white, 12% were Black/African American, 5%
were Asian, and 10%
were of other or
unknown
race.
Ninety-seven (94%)
patients had
experienced a hypersensitivity
reaction to pegaspargase, and
6 patients (7%) had reported silent
inactivation.
The determination of
efficacy was
based
on a demonstration
of the achievement and
maintenance of nadir serum
asparaginase activity
(NSAA) above the level of
0.1 U/mL. The results
of modeling and
simulations showed that
for
a dosage of 25 mg/m2 administered
intramuscularly
every
48 hours,
the proportion of patients maintaining NSAA ≥ 0.1
U/mL at 48 hours after a dose of RYLAZE was
93.6% (95% CI: 92.6%,
94.6%) [see Clinical Pharmacology
(12.3)].
16 H
OW SUPPLIED/STORAGE AND HANDLING
RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn) injection
is supplied as a sterile, clear
to opalescent, colorless to slightly yellow, preservative-free solution in single-dose vials.
Each single-dose vial (NDC 68727-900-01) contains
10 mg/0.5 mL asparaginase erwinia
chrysanthemi (recombinant)-rywn. Each carton of RYLAZE (NDC
68727-900-03)
contains 3 single-dose vials.
Store RYLAZE
vials
refrigerated at
2°C to 8°C (36°F to 46°F)
in the original carton to protect from
light. Do not shake
or
freeze.
17 P
ATIENT COUNSELING
INFORMATION
• Hypersensitivity
Inform patients of the
risk of allergic reactions, including anaphylaxis. Instruct the patient on
the symptoms of allergic reactions and
to seek medical advice immediately
if they experience such
symptoms [see Warnings and
Precautions
(5.1)].
• Pancreatitis
Instruct patients on signs
and symptoms of pancreatitis and
to seek medical attention if
they experience severe abdominal pain[see
Warnings and Precautions
(5.2)].
• Thrombosis
Instruct patients on the risk of thrombosis
and to seek medical
advice
immediately if
they experience headache, arm or leg swelling, shortness
of
breath, and chest pain [see Warnings and Precautions (5.3)].
• Hemorrhage
Advise patients to report any
unusual bleeding
or bruising
to their healthcare provider[see Warnings and
Precautions
(5.4)].
• Hepatoxicity
Advise patients to report any
jaundice, severe nausea
or
vomiting, or easy
bleeding or
bruising to their
healthcare provider[see
Warnings
and
Precautions (5.5)].
• Pregnancy
Advise pregnant women of the potential risk to a fetus. Advise females of
reproductive potential
to inform their healthcare provider of a known
or suspected pregnancy [see Use in Specific Populations (8.1)].
Advise females of
reproductive potential
to use effective non-hormonal
contraception during treatment with RYLAZE and
for
3 months after the last dose[see Use
in Specific
Populations (8.3)].
• Lactation
Advise women
not to breastfeed during treatment with RYLAZE
and for 1 week
after the
last dose[see Use
in Specific
Populations (8.2)].
Manufactured by:
Jazz Pharmaceuticals Ireland Limited
Leinster, Ireland
U.S. License No. 2167
Distributed by:
Jazz Pharmaceuticals, Inc.
3170 Porter Drive, Palo Alto,
CA 94304
Protected by U.S. Patent nos. 8,288,127 and 10,787,671
RYLAZETM is a trademark
of Jazz Pharmaceuticals plc
or its subsidiaries.
©2021 Jazz Pharmaceuticals
