An Exploratory Study of the Safety and Efficacy of Immune Tolerance Induction (ITI) in Patients With Pompe Disease Who Have Previously Received Myozyme
Phase: PHASE4
Conditions: Pompe Disease, Glycogen Storage Disease Type II (GSD-II), Glycogenesis 2 Acid Maltase Deficiency
Sponsor: Genzyme, a Sanofi Company

Genzyme Corporation 
500 Kendall Street 
Cambridge, MA 02142 
USA 
(617) 252-7500
 PHASE 4 CLINICAL STUDY PROTOCOL 
An Exploratory Study of the Safety and Efficacy of Immune Tolerance Induction (ITI) in 
Patients with Pompe Disease Who Have Previously Received Myozyme 
Protocol Number: AGLU03707 
IND Number: 10780 
Final:  28 August 2007 
Amendment 1:  21 August 2008 
Amendment 2:  19 March 2009 
Amendment 3:  01 October 2009 
Study Manager: 
 
 
Statistician: 
 
 
Safety Officer: 
 
 
Medical Monitor: 
 
Medical Monitor Signature 
Date 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
principles of Good Clinical Practice (GCP) guidelines.  These guidelines are stated in United States (US) 
federal regulations as well as “Guidance for Good Clinical Practice,” International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
I have read and agree to abide by the requirements of this protocol. 
Investigator Signature   
  Date 
Page 1
NCT00701701

Myozyme® (alglucosidase alfa) 
2 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
1. 
SYNOPSIS 
NAME OF COMPANY 
Genzyme Corporation 
500 Kendall St. 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme®
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE: An Exploratory Study of the Safety and Efficacy of Immune Tolerance Induction (ITI) in 
Patients with Pompe Disease Who Have Previously Received Myozyme 
PROTOCOL NO.:  AGLU03707 
INVESTIGATOR STUDY CENTERS:  Up to 9 centers may participate in this study.  Investigators 
overseeing this protocol and administering the agents in this regimen should be familiar with the 
medications administered, and preferably be an infectious disease expert and/or other specialist (such as 
an oncologist, immunologist, rheumatologist, or transplant specialist). 
OBJECTIVES: 
The objectives of the study are as follows: 
1. To evaluate the efficacy of ITI regimens, as assessed by anti-recombinant human acid 
α-glucosidase (anti-rhGAA) antibody titers, and antibodies that inhibit the enzymatic activity 
and/or uptake of Myozyme; 
2. To evaluate Pompe disease activity in patients receiving these regimens, as measured by overall 
survival, respiratory function, left ventricular mass index (LVMI), motor function, and 
disability index; and 
3. To evaluate the safety of these regimens, as assessed by the incidence of adverse events (AEs), 
serious adverse events (SAEs), and clinical laboratory abnormalities. 
METHODOLOGY: 
This is an exploratory, open-label study of patients of any age with Pompe disease to evaluate the 
efficacy, safety, and clinical benefit of 2 ITI regimens in combination with Myozyme in patients 
receiving Myozyme treatment.  The patient (and/or the patient’s legal guardian[s] if the patient is 
<18 years of age) must provide written informed consent prior to any protocol-related procedure being 
performed.  Eligible patients who are currently receiving Myozyme therapy will be enrolled into the 
study, and will be followed for a minimum of 18 months on-study (a 6-month ITI treatment module and 
a 12-month follow-up module on Myozyme alone).  Eligible cross-reacting immunologic material 
(CRIM)-negative patients will be followed for a minimum of 18 months on treatment or, if a patient is 
<6 months of age at the time of enrollment, until the patient is 2 years of age. 
Two ITI regimens will be evaluated in this protocol:   
• 
Regimen A:  Patients will be assigned to Regimen A if they exhibit clinical decline since 
starting Myozyme therapy and have inhibitory antibodies and/or a sustained high anti-rhGAA 
antibody titer (defined as at least 2 titers ≥25,600 obtained at least 1 month apart), regardless of 
their CRIM status.  This regimen consists of a 6-month regimen of monthly cyclophosphamide.  
• 
Regimen B:  Only CRIM-negative patients are eligible to enroll in Regimen B.  CRIM-negative 
patients will be assigned to Regimen B if they either (1) exhibit clinical decline since starting 
Myozyme therapy and do not have inhibitory antibodies or a sustained high anti-rhGAA 
antibody titer (defined as at least 2 titers ≥25,600 obtained at least 1 month apart), or (2) do not 
exhibit clinical decline since starting Myozyme therapy, regardless of their anti-rhGAA or 
GENZYME CORPORATION 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
Page 2
 

M y oz y me
®  (al gl uc osi dase alfa)
 3
Cli nical Pr ot oc ol N u m ber A G L U 0 3 7 0 7, A me n d me nt 3 
 
 
 
N A M E O F C O M P A N Y  
Ge nz y me C or p orati o n 
5 0 0 Ke n dall St. 
Ca m bri d ge, M A  0 2 1 4 2 
N A M E O F FI NI S H E D P R O D U C T 
M y oz y me
®
N A M E O F A C TI V E I N G R E DI E N T 
al gl uc osi dase alfa 
S U M M A R Y T A B L E  
Referri n g t o Part … … 
of t he D ossier: 
V ol u me:                       
Pa ge:                            
Refere nce:                   
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
i n hi bit or y a nti b o d y stat us.  Re gi me n B c o nsists of a 4- wee k c ycle of wee kl y rit u xi ma b i n 
c o m bi nati o n wit h a 6- m o nt h re gi me n of bi wee kl y met h otre xate.  A n o pti o nal, a d diti o nal 
4- wee k c ycle of rit u xi ma b ( u p t o 4 a d diti o nal d oses) ma y be a d mi nistere d wit hi n t he first 
6 m o nt hs of t he st u d y, as descri be d u n der D ose/ R o ute/ Re gi me n . 
Patie nts o n b ot h re gi me ns will r ecei ve i n trave n o us (I V) i nf usi o ns of M y oz y me ( 2 0 m g/ k g e ver y ot her 
wee k ( q o w) f or a mi ni m u m of 1 8 m o nt hs or, if t he patie nt is < 6 m o nt hs of a ge at t he ti me of e nr oll me nt, 
u ntil t he patie nt is 2 years of a ge.   
T he treat me nt re gi me ns are prese nte d sc he maticall y u n der D ose/ R o ute/ Re gi me n . 
Cli nical decli ne f or patie nts re gar dless of C RI M stat us will be defi ne d as decli ne i n at least 1 of t he 
f oll o wi n g para meters as c o m pare d t o t he c o n diti o n of t he patie nt pri or t o be gi n ni n g M y oz y me treat me nt:
C ar di ac 
Persiste nce of Left Ve ntric ular Mass ( L V M) Z-sc ore ≥6 after a mi ni m u m of 6 m o nt hs of treat me nt 
wit h M y oz y me, O R 
Res pir at ory 
Ne w de vel o p me nt of res pirat or y fail ure re q uiri n g t he use of ve ntilat or y assista nce (i n vasi ve or 
n o n-i n vasi ve) after a mi ni m u m of 6 m o nt hs of treat me nt wit h M y oz y me.  Ve ntilat or y assista nce 
m ust ha ve bee n re q uire d f or at least 4 wee ks pri or t o st u d y e nr oll me nt, O R 
M ot or Skills 
F or patie nts ≤2 years of a ge  at st u d y e ntr y, fail ure t o ac q uire at least 2 ne w gr oss m ot or milest o nes 
or l oss of at least 2 pre vi o usl y ac q uire d gr oss m o t or milest o nes ( or a c o m bi nati o n t here of) after a 
mi ni m u m of 6 m o nt hs of treat me nt wit h M y oz y me, e. g.: 
1.  T ur ni n g hea d si de t o si de (s u pi ne); 
2.  Gras pi n g s mall o bjects wit h ha n ds; 
3.  Tra nsferri n g o bjects fr o m ha n d t o ha n d; 
4.  H ol di n g hea d u pri g ht wit h b o d y s u p p orte d; 
5.  R olli n g (s u pi ne t o pr o ne or pr o ne t o s u pi ne); 
6.  Sitti n g (s u p p orte d or u ns u p p orte d); 
7.  Wal ki n g ( wit h s u p p ort, i.e., cr uisi n g, or i n de pe n de ntl y); 
8.  Wal ki n g u p stairs ( wit h assista nce or i n de pe n de ntl y); O R 
W orse n i n g of pr o xi mal u p per e xtre mit y m uscle wea k ness as deter mi ne d b y t he I n vesti gat or t hr o u g h 
l oss of f u ncti o nal use of t he u p per e xtre mities after a mi ni m u m of 6 m o nt hs of treat me nt wit h 
M y oz y me; O R 
Pr o gressi o n t o use of a n assisti ve de vice f or a m b ulati o n d ue t o w orse ni n g of pr o xi mal l o wer 
e xtre mit y m uscle wea k ness after a mi ni m u m of 6 m o nt hs of treat me nt wit h M y oz y me. 
Safet y, efficac y, a n d e x pl orat or y e val uati o ns will be  perf or me d at sc he d ule d visits t hr o u g h o ut t he st u d y 
as s pecifie d i n t he Sc he d ule of Assess me nts.  Ve ntila t or use, A Es, gra de d acc or di n g t o Nati o nal Ca ncer 
I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI/ C T C A E), Versi o n 3. 0 ( date d 
0 9 A u g ust 2 0 0 6), a n d c o nc o mita nt a n d pre-i nf usi o n me dicati o ns/t hera pies will be m o nit ore d 
c o nti n u o usl y t hr o u g h o ut t he st u d y.   
A n I m m u ne T olera nce I n d ucti o n Re vi e w B o ar d (I TI R B) will e val uate t he safet y a n d efficac y of eac h of 
t he I TI re gi me ns after eac h patie nt c o m pletes 1 m o nt h of treat me nt o n a gi ve n re gi me n, after eac h patie nt 
G E N Z Y M E C O R P O R A TI O N  
FI N A L: 0 1  O C T O B E R 2 0 0 9  
P R O P RI E T A R Y A N D C O N FI D E N TI A L
Pa ge 3
 
 

Myozyme® (alglucosidase alfa) 
4 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
NAME OF COMPANY 
Genzyme Corporation 
500 Kendall St. 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme®
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
completes 6 months of treatment on a given regimen, and, if applicable, after the patient completes an 
optional, additional cycle of rituximab, as well as on an expedited ad hoc basis, as outlined in the ITIRB 
Charter (which is maintained separately from the protocol).  The ITIRB will also provide 
recommendations about the risk/benefit profile of the ITI regimens.  Should any safety concern arise, the 
final decision regarding the continuation of any or all patients in the study will be made by the Genzyme 
Global Patient Safety and Risk Management (GPS-RM) Safety Officer, or designee, and the ITIRB.  If 
there are no major safety concerns, patients will continue to receive treatment in the study. 
An independent Allergic Reaction Review Board (ARRB) will be consulted on an ad hoc basis, as 
outlined in the ARRB Charter (which is also maintained separately from the protocol).  Should any 
major safety issues arise, the final decisions regarding the study will be made by the Genzyme GPS-RM 
Safety Officer, or designee, and the ARRB. 
For consistency, a central cardiologist will review all electrocardiograms (ECGs) and echocardiograms 
(ECHOs). 
Following study completion, patients may receive commercial Myozyme treatment as prescribed by 
their treating physicians.  To facilitate long-term data collection, patients will be encouraged to enroll in 
the Pompe Disease Registry after study completion. 
NUMBER OF SUBJECTS:  It is planned that a total of 9 patients will initially be enrolled in the study.  
Patients will be assigned to either Regimen A or Regimen B based on their qualifications for a given 
regimen.  Regimens will enroll as patients present until a total of 9 patients are treated.  An attempt will 
be made to enroll a similar number of CRIM-positive and CRIM-negative patients on Regimen A, 
provided that sufficient number of qualified CRIM-negative patients can be identified within a 
reasonable study recruitment period.  Enrollment will proceed in a sequential manner within each 
treatment regimen such that ITIRB review of data from the first patient within a regimen (for the first 
month of treatment) is completed prior to enrollment of any further patients on that regimen.  If the 
regimen appears to have an acceptable risk/benefit profile after the first 3 patients in a given regimen 
have completed 1 month of treatment, additional patients may be enrolled as they present, or as 
necessary, to further evaluate the ITI regimen. 
DIAGNOSIS/INCLUSION CRITERIA: 
Inclusion Criteria: 
1. The patient (and/or the patient’s legal guardian(s) if the patient is <18 years of age) must 
provide written informed consent prior to any study-related procedures being performed; 
2. The patient must have a clinical diagnosis of Pompe disease as defined by documented acid 
α-glucosidase (GAA) deficiency (deficient endogenous GAA activity) in skin fibroblasts, 
muscle, or blood, or presence of 2 GAA mutations.  Consent will also be sought from the 
biological parent(s) for parental GAA mutational analysis, but is not a requirement for study 
eligibility; 
3. The patient (and/or the patient’s legal guardian(s) if the patient is <18 years of age) must have 
the ability to comply with the clinical protocol. 
4. If the patient is CRIM-positive, he/she must have received Myozyme therapy (20 mg/kg qow) 
for at least 6 consecutive months immediately prior to enrollment in the study.  
5. If the patient is CRIM-negative, he/she must have received at least 1 Myozyme infusion prior to 
GENZYME CORPORATION 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
Page 4
 

Myozyme® (alglucosidase alfa) 
5 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
NAME OF COMPANY 
Genzyme Corporation 
500 Kendall St. 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme®
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
enrollment in the study. 
6. Regimen A only:  
• 
The patient exhibits clinical decline (as defined under Methodology); 
• 
The patient has persistent high anti-rhGAA antibody titers (defined as at least 2 titers 
≥25,600 obtained at least 1 month apart) and/or has tested positive for antibodies that 
inhibit enzymatic activity and/or uptake of Myozyme.  
7. Regimen B only:  
• 
The patient is CRIM-negative via Western blot analysis of skin fibroblasts; AND 
• 
The patient does NOT exhibit clinical decline (as defined under Methodology).  
OR 
• 
The patient is CRIM-negative via Western blot analysis of skin fibroblasts; AND 
• 
The patient exhibits clinical decline (as defined under Methodology); AND 
• 
The patient does NOT have persistent high anti-rhGAA antibody titers (defined as at least 
2 titers ≥25,600 obtained at least 1 month apart) and has NOT tested positive for antibodies 
that inhibit enzymatic activity and/or uptake of Myozyme. 
Note that historical CRIM testing results by Western blot analysis (performed prior to enrollment) are 
acceptable, provided that written documentation of the laboratory results is available at the enrolling site. 
Exclusion Criteria: 
1. The patient has any medical condition that, in the opinion of the Investigator, could interfere 
with the study regimens (i.e., Myozyme, cyclophosphamide, rituximab, and/or methotrexate) or 
assessments; such conditions may include, but are not limited to, active human 
immunodeficiency virus infection, cancer, or tuberculosis; 
2. The patient is at risk of reactivation or is a carrier of Hepatitis B (e.g., Hepatitis B surface 
antigen is positive) or Hepatitis C (e.g., detectable Hepatitis C viral load by reverse 
transcriptase – polymerase chain reaction);   
3. The patient is at risk of reactivation or has positive serology suggestive of active infection for 
cytomegalovirus (CMV), Herpes simplex, JC virus (progressive multifocal 
leukoencephalopathy), Parvovirus, or Epstein Barr virus; 
4. The patient is at risk of reactivation of tuberculosis or has regular contact (e.g., in the 
household) with individuals who are being actively treated for tuberculosis; 
5. The patient has low serum albumin, relative to institutional age-appropriate range, that is 
uncorrected; 
6. The patient has a major congenital abnormality; 
7. The patient has used any investigational product (other than Myozyme in those regions where 
the product is not commercially available and is considered investigational) within 30 days 
prior to study enrollment; 
8. The patient is pregnant or lactating; 
GENZYME CORPORATION 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
Page 5
 

Myozyme® (alglucosidase alfa) 
6 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
NAME OF COMPANY 
Genzyme Corporation 
500 Kendall St. 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme®
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
9. The patient has had or is required to have any live vaccination within 1 month prior to 
enrollment. 
At the discretion of the Investigator, clinical laboratory test results that are deemed to be due to transient 
illness may be repeated for the purpose of determining study eligibility. 
DOSE/ROUTE/REGIMEN:   
The treatments to be administered in this study are summarized below: 
Patients on Regimen A 
• 
Myozyme:  20 mg/kg IV qow for a minimum of 18 months or, if the patient is <6 months of age at 
the time of enrollment, until the patient is 2 years of age.  
• 
Cyclophosphamide:  250 mg/ m2 IV every 4 weeks after Myozyme infusion for 6 months. 
The first 5 weeks of treatment for Regimen A are shown below. 
 
W1a
W2a
W3a
W4a
W5a
 
D0 
D7 
D14 
D21 
D28 
Myozyme 
X 
 
X 
 
X 
Cyclophosphamideb
X 
 
 
 
X 
a Weeks 2 to 5 will be repeated through Week 24 for Myozyme and cyclophosphamide AND from Week 
25 to Week 75 for Myozyme. 
b Refer to Table 9-1 of the study protocol for further guidance regarding the administration of 
cyclophosphamide. 
Note:  It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider 
intravenous immunoglobulin (IVIG) administration at a dose of 400 mg/kg, regardless of age, if indicated 
per the individual Investigator’s clinical discretion. 
Key:  W=Week; D=Day 
 
Patients on Regimen B 
• 
Myozyme:  20 mg/kg IV qow for a minimum of 18 months or, if the patient is <6 months of age at 
the time of enrollment, until the patient is 2 years of age. 
• 
Rituximab:  375 mg/m2 (or 12.5 mg/kg in those patients with a body surface area [BSA] ≤0.5 m2) 
IV weekly for 4 weeks, beginning the day after the first Myozyme infusion.  An optional, additional 
4-week cycle of rituximab (up to 4 additional doses) may be administered within the first 6 months 
of the study.  The administration of an additional cycle of rituximab must be discussed with and 
approved by the Genzyme GPS-RM Safety Officer, or designee, prior to implementation and may, 
at the discretion of Genzyme, also be reviewed with the ITIRB prior to implementation.  This 
additional cycle must be completed within the first 6 months of the study.  If the additional cycle is 
approved, these data will be included in the 6-month periodic ITIRB review.  The total number of 
rituximab doses will not exceed 8 doses. 
• 
Methotrexate:  15 mg/m2 subcutaneous (SC) qow on the day after Myozyme infusion for 6 months.  
Folinic acid may be given at the discretion of the Investigator beginning 24 hours after the dose of 
methotrexate. 
The first 6 weeks of treatment for Regimen B are shown below.   
 
W1 
W2 
W3 
W4 
W5a
W6a
GENZYME CORPORATION 
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PROPRIETARY AND CONFIDENTIAL 
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Myozyme® (alglucosidase alfa) 
7 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
NAME OF COMPANY 
Genzyme Corporation 
500 Kendall St. 
Cambridge, MA  02142 
NAME OF FINISHED PRODUCT 
Myozyme®
NAME OF ACTIVE INGREDIENT 
alglucosidase alfa 
SUMMARY TABLE 
Referring to Part …… 
of the Dossier: 
Volume:                       
Page:                            
Reference:                   
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
 
D0 
D1 
D8 
D14
D15
D22
D28
D29 
D35 
Myozyme 
X 
 
 
X 
 
 
X 
 
 
Rituximabb,c
 
X 
X 
 
X 
X 
 
 
 
Methotrexatec
 
X 
 
 
X 
 
 
X 
 
a Weeks 5 and 6 will be repeated through Week 24 for Myozyme and methotrexate AND from Week 25 to 
Week 75 for Myozyme.   
bAn optional, additional 4-week cycle of rituximab (up to 4 additional doses) may be administered as described 
above.  This additional cycle must be completed within the first 6 months of the study. 
c Refer to Table 9-2 of the study protocol for further guidance regarding the administration of rituximab and 
methotrexate. 
Note:  It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider IVIG 
administration at a dose of 400 mg/kg, regardless of age, if indicated per the individual Investigator’s clinical 
discretion. 
Key:  W=Week; D=Day 
 
REFERENCE TREATMENT:  Not applicable 
CRITERIA FOR EVALUATION:  
Efficacy: Efficacy will be assessed by anti-rhGAA antibody titers; the evaluation of inhibitory antibody 
formation (activity and uptake); overall survival; respiratory function as assessed by (a) the proportion of 
patients who were alive and ventilator-free over the course of treatment, time to overall invasive 
ventilator-dependence, and ventilator-free survival time for patients who were ventilator-free at the onset 
of the study, and (b) the overall duration of ventilator support and the number of hours of ventilator use 
in the 24 hours preceding each infusion visit for patients who required ventilator use at the onset of the 
study; LVMI as assessed by ECHO; and motor function and development as assessed by Gross Motor 
Function Measure-66, the Alberta Infantile Motor Scale, and the Pompe Pediatric Evaluation of 
Disability Inventory.   
Safety:  Safety will be evaluated in terms of AEs graded according to NCI/CTCAE, Version 3.0; vital 
sign parameters; physical examination findings; ECG parameters; routine laboratory measurements 
(hematology, chemistry, and urinalysis); lymphocyte subpopulations; an immunoglobulin panel; and 
pregnancy testing.  Additional immunology measurements will include anti-rhGAA immunoglobulin E 
(IgE), serum tryptase, complement activation, and skin testing, when clinically indicated following 
moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), or recurrent mild (Grade 1) infusion-
associated reactions (IARs) to Myozyme that are suggestive of hypersensitivity; and circulating immune 
complex detection when clinically indicated by symptoms suggestive of immune complex disease.   
Research immunophenotyping and functional T cell assays will also be performed as exploratory 
measures.   
STATISTICAL METHODS: 
Statistical analyses of all safety and efficacy measurements will be conducted on all patients who receive 
Myozyme under this protocol.  All data will be presented in by patient listings.  Graphical displays will 
be presented as appropriate.  Summary statistics will be produced as appropriate and meaningful.  
Continuous variables will be summarized using descriptive statistics (number [n], mean, median, 
standard deviation, minimum, and maximum).  Categorical variables will be summarized using 
frequencies and percentages.  No statistical testing will be conducted.  Missing data will not be imputed 
using statistical methods. 
GENZYME CORPORATION 
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PROPRIETARY AND CONFIDENTIAL 
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Myozyme® (alglucosidase alfa) 
8 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS.......................................................................................................................2 
2. 
TABLE OF CONTENTS ...............................................................................................8 
3. 
ABBREVIATIONS AND TERMS..............................................................................12 
4. 
INTRODUCTION.........................................................................................................14 
4.1 
Pompe Disease....................................................................................................14 
4.2 
Myozyme ............................................................................................................15 
4.2.1 
AGLU01602/AGLU02403...............................................................16 
4.2.2 
AGLU01702 .....................................................................................16 
4.2.3 
AGLU02804 .....................................................................................17 
4.3 
Immune Tolerance Induction..............................................................................17 
4.3.1 
Cyclophosphamide ...........................................................................20 
4.3.2 
Rituximab..........................................................................................21 
4.3.3 
Methotrexate.....................................................................................21 
4.3.4 
Intravenous Immunoglobulin............................................................22 
4.4 
Risks ...................................................................................................................22 
4.4.1 
Risks Associated With Myozyme (alglucosidase alfa).....................22 
4.4.1.1 
Anaphylaxis and Allergic Reactions ...........................22 
4.4.1.2 
Acute Cardiorespiratory Failure ..................................23 
4.4.1.3 
Cardiac Arrhythmia and Sudden Cardiac Death 
During General Anesthesia for Central Catheter 
Placement.....................................................................23 
4.4.1.4 
Infusion-Associated Reactions ....................................23 
4.4.1.5 
Immune-Mediated Reactions.......................................24 
4.4.1.6 
Adverse Events............................................................24 
4.4.1.7 
Immunogenicity...........................................................24 
4.4.2 
Risks Associated With Immune Tolerance Induction (ITI)..............25 
4.4.2.1 
Risks Associated With Cyclophosphamide.................26 
4.4.2.2 
Risks Associated With Rituximab...............................28 
4.4.2.3 
Risks Associated With Methotrexate...........................29 
4.4.2.4 
Risks Associated With Intravenous 
Immunoglobulin ..........................................................31 
5. 
STUDY OBJECTIVES.................................................................................................33 
6. 
INVESTIGATIONAL PLAN ......................................................................................34 
6.1 
Study Design.......................................................................................................34 
7. 
PATIENT POPULATION AND SELECTION.........................................................38 
7.1 
Inclusion Criteria ................................................................................................38 
7.2 
Exclusion Criteria ...............................................................................................39 
7.3 
Patient Withdrawal .............................................................................................40 
7.3.1 
Patient Withdrawal From the Study..................................................40 
7.3.2 
Patient Withdrawal From the Immune Tolerance Induction 
Regimen............................................................................................41 
7.3.3 
Patient Replacement .........................................................................42 
7.4 
Adjustments to Dose or Dosing Schedule ..........................................................42 
7.5 
Study or Site Termination...................................................................................43 
GENZYME CORPORATION 
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Myozyme® (alglucosidase alfa) 
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Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
8. 
TREATMENTS.............................................................................................................44 
8.1 
Treatments Administered....................................................................................44 
8.1.1 
Myozyme ..........................................................................................45 
8.1.2 
Cyclophosphamide ...........................................................................46 
8.1.3 
Rituximab..........................................................................................47 
8.1.4 
Methotrexate.....................................................................................47 
8.1.5 
Intravenous Immunoglobulin............................................................48 
8.2 
Investigational Products......................................................................................48 
8.2.1 
Receipt of Investigational Product....................................................49 
8.2.1.1 
Packaging and Labeling...............................................49 
8.2.1.2 
Treatment Preparation .................................................50 
8.3 
Supportive Measures...........................................................................................50 
8.3.1 
Gastrointestinal Toxicity...................................................................50 
8.3.2 
Nephrotoxicity ..................................................................................50 
8.3.3 
Hepatotoxicity...................................................................................51 
8.3.4 
Pulmonary Toxicity ..........................................................................51 
8.3.5 
Hydration ..........................................................................................51 
8.3.6 
Infection............................................................................................51 
8.3.7 
Anaphylactic/Allergic Reactions......................................................52 
8.4 
Concomitant Medication/Therapy......................................................................53 
8.5 
Study Drug Misdosing or Overdosing................................................................54 
8.6 
Dose Selection ....................................................................................................54 
8.7 
Blinding and Randomization ..............................................................................54 
9. 
EFFICACY AND SAFETY VARIABLES.................................................................55 
9.1 
Efficacy and Safety Measurements Assessed and Study Schedule of 
Assessments........................................................................................................55 
9.2 
Screening/Baseline Assessments........................................................................64 
9.2.1 
Informed Consent .............................................................................64 
9.2.2 
Medical History, Demographics, Eligibility Criteria........................64 
9.2.3 
Genotyping of the Human Acid Alpha-Glucosidase Gene...............65 
9.2.4 
Cross-Reacting Immunologic Material Status Testing.....................65 
9.2.5 
Optional Port-a-Catheter...................................................................65 
9.3 
Efficacy Measurements.......................................................................................66 
9.3.1 
Routine Recombinant Human Acid Alpha-Glucosidase 
Immunoglobulin G Antibody Testing...............................................66 
9.3.2 
Inhibitory Antibody Testing .............................................................66 
9.3.3 
Echocardiogram, Including Left Ventricular Mass Index ................66 
9.3.4 
Ventilator Use...................................................................................66 
9.3.5 
Motor Development and Functional Assessments............................67 
9.3.5.1 
Gross Motor Function Measure...................................67 
9.3.5.2 
Alberta Infantile Motor Scale......................................68 
9.3.5.3 
Pompe Pediatric Evaluation of Disability 
Inventory......................................................................68 
9.4 
Safety Measurements..........................................................................................69 
9.4.1 
Physical Examination .......................................................................69 
9.4.2 
Safety Laboratory Assessments........................................................69 
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9.4.3 
Electrocardiogram.............................................................................70 
9.4.4 
Vital Signs.........................................................................................70 
9.4.5 
Electrocardiogram Monitoring by Telemetry...................................71 
9.4.6 
Lymphocyte Subpopulation Counts .................................................71 
9.4.7 
Immunoglobulins Panel....................................................................72 
9.4.8 
Pregnancy Test and Use of Contraception........................................72 
9.5 
Other Assessments..............................................................................................73 
9.5.1 
Research Immunophenotyping .........................................................73 
9.5.2 
Functional T-Cell Assay...................................................................73 
9.5.3 
Testing for Moderate, Severe, or Recurrent Infusion-
Associated Reactions........................................................................73 
9.5.3.1 
Complement Activation Testing..................................74 
9.5.3.2 
Serum Tryptase Testing...............................................74 
9.5.3.3 
Serum Anti-Recombinant Human Acid Alpha-
Glucosidase Immunoglobulin E Antibody 
Testing .........................................................................74 
9.5.3.4 
Skin Testing.................................................................74 
9.5.3.5 
Circulating Immune Complexes..................................75 
9.5.4 
Concomitant Medications/Therapies................................................75 
9.6 
Adverse Events ...................................................................................................75 
9.6.1 
Adverse Event Definition .................................................................76 
9.6.2 
Serious Adverse Events ....................................................................77 
9.6.3 
Severity Scoring................................................................................77 
9.6.4 
Infusion-Associated Reactions .........................................................78 
9.6.5 
Adverse Experience and Serious Adverse Experience 
Reporting ..........................................................................................78 
9.7 
Study Drug Administration Stopping Rules.......................................................79 
10. DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT.........81 
10.1 
Recording of Data...............................................................................................81 
10.2 
Data Quality Assurance ......................................................................................81 
10.3 
Data Management...............................................................................................81 
11. STATISTICAL METHODS AND PLANNED ANALYSES....................................82 
12. SPECIAL REQUIREMENTS AND PROCEDURES...............................................84 
12.1 
Institutional and Ethical Review.........................................................................84 
12.2 
Changes to the Conduct of the Study or Protocol...............................................84 
12.3 
Immune Tolerance Induction Review Board......................................................84 
12.4 
Allergic Reaction Review Board........................................................................85 
12.5 
Investigator’s Responsibilities............................................................................86 
12.5.1 
Patient Informed Consent .................................................................86 
12.5.2 
Electronic Data Capture....................................................................86 
12.5.3 
Record Retention ..............................................................................86 
12.5.4 
Monitoring ........................................................................................87 
12.5.5 
Materials Control..............................................................................87 
12.5.5.1 
Receipt of Clinical Supplies ........................................87 
12.5.5.2 
Disposition of Unused Clinical Study Material...........88 
12.5.6 
Disclosure of Data ............................................................................88 
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12.5.7 
Clinical Study Report........................................................................88 
13. REFERENCES..............................................................................................................89 
14. APPENDICES...............................................................................................................91 
14.1 
Cyclophosphamide United States Prescribing Information................................92 
14.2 
Rituximab United States Prescribing Information..............................................95 
14.3 
Methotrexate United States Prescribing Information .......................................128
14.4 
Intravenous Immunoglobulin United States Prescribing Information..............131 
14.5 
National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 3.0 (09 August 2006)..............................................................148 
14.6 
Additional Study Visits: Weeks 77 Through 105............................................. 221 
 
 
LIST OF IN-TEXT TABLES 
Table 8-1 
Treatment Regimen A.................................................................................44 
Table 8-2 
Treatment Regimen B .................................................................................45 
Table 9-1 
Schedule of Assessments – Regimen A ITI Treatment Module 
(Months 1 Through 6).................................................................................56 
Table 9-2 
Schedule of Assessments – Regimen B ITI Treatment Module 
(Months 1 Through 6).................................................................................59 
Table 9-3 
Schedule of Assessments – Follow-up Module (Months 7 Through 
18) ...............................................................................................................62 
 
 
LIST OF IN-TEXT FIGURES 
Figure 6-1 
Schematic of Patient Enrollment.................................................................37 
 
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3. 
ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
6MWT 
6-Minute Walk Test 
°C 
Degrees Celsius 
AE 
Adverse event 
AIMS 
Alberta Infantile Motor Scale 
anti-rhGAA 
anti-recombinant human acid α-glucosidase 
ARRB 
Allergic Reaction Review Board 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CK-MB 
Creatine kinase-myocardial band  
CMV 
Cytomegalovirus 
CPRS 
Clinical Pharmacy Research Services 
CRIM 
Cross-reacting immunologic material 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELISPOT 
Enzyme-linked immunosorbent spot [assay] 
EOS 
End-of-Study 
ERT 
Enzyme replacement therapy 
EU 
European Union 
FVC 
Forced vital capacity 
GAA 
Acid α-glucosidase 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMAE 
Gross Motor Ability Estimator 
GMFM-66 
Gross Motor Function Measure-66 
GPS-RM 
Global Patient Safety and Risk Management (formally Genzyme 
Pharmacovigilance) 
HBV 
Hepatitis B virus 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IAR 
Infusion-associated reaction 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug [application] 
IRB 
Institutional Review Board 
ITI 
Immune tolerance induction 
ITIRB 
Immune Tolerance Induction Review Board 
IV 
Intravenous(ly) 
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Abbreviation 
Definition 
IVIG 
Intravenous immunoglobulin 
JRA 
Juvenile rheumatoid arthritis 
LSD 
Lysosomal storage disorder 
LVM 
Left ventricular mass 
LVMI 
Left ventricular mass index 
NCI/CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
PEDI 
Pediatric Evaluation and Disability Inventory 
PML 
Progressive multifocal leukoencephalopathy (also known as JC Virus) 
POR 
Proof of Receipt 
qow 
Every other week 
rhGAA 
Recombinant human acid α-glucosidase 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
SLE 
Systemic lupus erythematosus 
SOM 
Study Operations Manual 
US 
United States 
 
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4. 
INTRODUCTION 
4.1 
Pompe Disease 
Pompe disease is a rare, autosomal, recessive, metabolic muscle disease caused by the deficiency 
of acid α-glucosidase (GAA), an enzyme that degrades lysosomal glycogen.  As opposed to the 
exclusively cytoplasmic accumulation of glycogen that occurs in other glycogen storage 
disorders, Pompe disease is characterized by organelle-bound (lysosomal) accumulation of 
glycogen in many body tissues, ultimately leading to multisystemic pathology. 
Pompe disease is comprised of a broad spectrum of phenotypes ranging from a rapidly 
progressive form (infantile-onset) to a more slowly progressive form (late-onset), with 
considerable variability and overlap existing between these extremes (Chen, 2000, Mol Med 
Today; Hirschhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease; van den 
Hout, 2003, Pediatrics).  It is important to note that all presentations of Pompe disease share a 
common underlying pathology (i.e., deficiency of GAA with subsequent accumulation of 
glycogen). 
At the most rapidly progressive end of the disease spectrum, patients typically present with 
symptoms within the first 12 months of life.  A massive deposition of glycogen in the heart and 
skeletal muscle results in rapidly progressive cardiomyopathy and generalized muscle weakness 
and hypotonia.  Moreover, motor development is often completely arrested or, if motor 
milestones are achieved, they are subsequently lost.  Death from cardiac and/or respiratory 
failure generally occurs before most patients reach 1 year of age (Hirschhorn, 2001, The 
Metabolic and Molecular Bases of Inherited Disease).   
At the other end of the spectrum, symptoms can appear during childhood or as late as the sixth 
decade of life and progress less rapidly but relentlessly.  Patients present with progressive 
myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, and a 
variable progression of respiratory involvement.  Typically these patients develop minimal or no 
cardiomyopathy (Chen, 2000, Mol Med Today; Laforêt, 2000, Neurology; Hirschhorn, 2001, The 
Metabolic and Molecular Bases of Inherited Disease).  Pompe disease presenting in older 
children and adults is less predictable than in infants, with some patients experiencing a rapid 
deterioration in skeletal and respiratory muscle function leading to loss of ambulation and 
respiratory failure, others progressing less rapidly, and yet others with dissociation in the 
progression of skeletal and respiratory muscle involvement (Laforêt, 2000, Neurology).  
Eventually, most patients become wheelchair-bound, require ventilator support, and ultimately 
succumb to respiratory failure (Chen, 2000, Mol Med Today; Hirschhorn, 2001, The Metabolic 
and Molecular Bases of Inherited Disease). 
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4.2 
Myozyme 
Myozyme® (alglucosidase alfa) is indicated for use in patients with Pompe disease.  Myozyme 
has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease 
as compared to an untreated historical control, whereas use of Myozyme in patients with other 
forms of Pompe disease has not been adequately studied to assure safety and efficacy.  The 
recommended dosage regimen of Myozyme is 20 mg/kg body weight administered every other 
week (qow) as an intravenous (IV) infusion.  Genzyme Corporation has also successfully 
developed enzyme replacement therapy (ERT) for the treatment of 3 other lysosomal storage 
disorders (LSDs) – Gaucher disease, Fabry disease, and mucopolysaccharidosis type 1 – which, 
like Pompe disease, are characterized by accumulation of enzyme substrate in a variety of tissues 
resulting in multisystemic pathology (Barton, 1991, N Engl J Med; Eng, 2001, N Engl J Med; 
Kakkis, 2001, N Engl J Med). 
In this study, AGLU03707, Myozyme will be given at the recommended dose of 20 mg/kg qow 
as an approximately 4-hour infusion for a minimum of 18 months or until the patient is 2 years of 
age, whichever is longer.  The safety and efficacy of the recommended dose (and higher doses) 
of Myozyme has been evaluated in 3 clinical studies with patients naïve to ERT at initiation of 
treatment.  In addition, several other studies and expanded access programs were conducted 
which also evaluated safety and efficacy.  Key findings from the 3 aforementioned Good Clinical 
Practice (GCP) studies are detailed below; additional efficacy data from these and other studies 
may be found in the current Myozyme Investigator’s Brochure.  Specific information on the risks 
associated with Myozyme treatment is provided below in Section 4.4.1 and in the Myozyme 
Investigator’s Brochure. 
Two of these studies (AGLU01602/AGLU02403, AGLU01702) were conducted in patients with 
infantile-onset disease.  In these patients, Myozyme markedly extended survival and prevented 
or delayed time to ventilator dependence as compared with an untreated historical cohort.  
Myozyme also reversed indices of cardiomyopathy.  Moreover, consistent gains in motor 
function were observed, with a subset of patients achieving independent ambulation.  These 
findings contrast sharply with the severe and unremitting clinical deterioration observed in 
virtually all untreated patients with infantile-onset Pompe disease (van den Hout, 2003, 
Pediatrics).   
In older children with Pompe disease (AGLU02804), Myozyme was associated with 
maintenance or improvements in pulmonary function, muscle strength, gross motor function, and 
functional status/disability.  These results are in sharp contrast to the progressive nature of late-
onset Pompe disease in untreated patients (Laforêt, 2000, Neurology; Hagemans, 2005, 
Neurology; Hagemans, 2005, Brain; Winkel, 2005, J Neurol). 
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4.2.1 AGLU01602/AGLU02403 
The pivotal study, AGLU01602, was an international, multicenter, historically controlled clinical 
study of 18 patients presenting with Pompe disease as infants and who were age 7 months or less 
at first Myozyme infusion and were not ventilated.  Patients were randomized equally to receive 
either 20 mg/kg or 40 mg/kg Myozyme qow, with length of treatment ranging from 52 to 
106 weeks.  The primary endpoint was the proportion of patients alive and free of invasive 
ventilation at 18 months of age (time to event) with an untreated historical cohort derived from a 
retrospective natural history study (n=62) serving as a comparator group.  At the 18-month 
milestone age, 15 (83%) of the 18 patients were alive and free of invasive ventilation (3 patients 
were alive but invasively ventilated).  In contrast, only 2% of cases in the untreated historical 
cohort survived by age 18 months.  At the end of Study AGLU01602, 17 of the 18 treated 
patients were alive; 1 patient required invasive ventilation at 19.4 months and later died from 
desaturation and bradycardia (unrelated to Myozyme) at 19.8 months of age.  Sixteen of the 
17 surviving patients went on to receive Myozyme treatment in an approximately 12-month 
extension study (AGLU02403).  The remaining patient continued to receive treatment with 
Myozyme via the international expanded access program at a center near the patient's home and 
subsequently died of multi-organ failure secondary to septicemia (unrelated to Myozyme).  At 
the end of Study AGLU02403, 14 (77.8%) of the 18 patients initially treated in AGLU01602 
were alive.  The 2 patients who died in AGLU02403 were invasively ventilated at the time of 
death; cause of death in both patients was cardiorespiratory arrest assessed as unrelated to 
treatment with Myozyme. 
4.2.2 AGLU01702 
Study AGLU01702 was an international, multicenter, open-label clinical study of 21 patients 
presenting with Pompe disease as infants and who were >6 months to 3 years of age at first 
Myozyme treatment.  All patients received 20 mg/kg Myozyme qow.  Five of 21 patients were 
receiving invasive ventilator support at the time of first infusion.  The primary outcome measure 
was the proportion of patients alive at the conclusion of treatment.  At the 52-week interim 
analysis, 16 of 21 patients were alive, yielding a 52-week survival rate of 76%, as compared with 
a 52-week survival rate of 31.6% in an untreated historical reference subgroup.  In addition, 
treatment with Myozyme for 52 weeks under AGLU01702 prevented ventilator dependence in 
10 of the 16 patients who were invasive ventilator-free at Baseline.  As of the end of the study 
(up to approximately 39 months on treatment), 15 (71.4%) patients were alive.  The age range of 
the 15 surviving patients was from 34.7 to 80.3 months.  In the remaining 6 treated patients who 
died, cause of death was consistent with cardiac and respiratory complications of underlying 
Pompe disease; none of the deaths was assessed as related to treatment with Myozyme. 
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4.2.3 AGLU02804 
AGLU02804 was a single-center, open-label clinical study that assessed the efficacy of 
Myozyme in 5 patients with late-onset Pompe disease, who ranged in age from 5 to 15 years at 
initiation of treatment.  Patients received 20 mg/kg Myozyme qow for 26 weeks.  All patients 
were ambulatory at baseline and 4 of 5 patients did not require any form of ventilator support 
(1 patient required nocturnal non-invasive ventilation).  Of the 3 patients with significant 
pulmonary involvement at baseline (percentage predicted forced vital capacity [FVC] in the 
sitting position <80%), 2 demonstrated clinically meaningful improvements in FVC (>11%) in 
the sitting position by Week 26.  Evaluation of motor function was evaluated using the 6-Minute 
Walk Test (6MWT).  Three of the patients demonstrated a clinically meaningful improvement 
(>37 m difference) in the 6MWT at fast speed by Week 26. 
4.3 
Immune Tolerance Induction 
The majority of patients (approximately 90%) in clinical studies developed immunoglobulin G 
(IgG) antibodies to Myozyme, typically within 3 months of initiating Myozyme treatment (see 
Section 4.4.1.7, Immunogenicity, for further details).  Currently, the effect of antibody 
development on the long-term efficacy of Myozyme is not fully understood.  There is an 
observation that some patients who develop high and sustained anti-Myozyme antibody titers 
also exhibit a poorer clinical response to treatment.  The causes leading to the poor clinical 
response to Myozyme treatment in these and other patients are thought to be multi-factorial.  One 
strategy for potentially improving clinical outcome in patients receiving Myozyme may be to 
administer an immune tolerance induction (ITI) regimen, either before or after recombinant 
human acid α-glucosidase (rhGAA) antibodies and/or inhibitory antibodies have been detected.   
The timing of administration of such an ITI regimen will depend upon the risk:benefit ratio to the 
patient.  Patients with early onset of symptoms of Pompe disease (infantile-onset) may be at 
increased risk of developing anti-recombinant human acid α-glucosidase (anti-rhGAA) 
antibodies that affect efficacy due to the higher frequency of fully deleterious (null) mutations 
resulting in GAA protein absence (cross-reacting immunologic material [CRIM]-negative).  
Therefore, patients who are CRIM-negative may benefit most from prophylactic ITI treatment, 
i.e., an ITI regimen that is administered prior to the patient exhibiting any evidence of clinical 
decline.  In contrast, patients with less deleterious mutations (in at least 1 of 2 disease alleles) 
that result in defective but present endogenous GAA protein (CRIM-positive) may be at lower 
risk of antibody interference.  Therefore, given the potential risks of ITI treatment, for 
CRIM-positive patients it may be more prudent to begin an ITI regimen only if a patient exhibits 
evidence of clinical decline in association with the development of inhibitory antibodies or a 
sustained, high anti-rhGAA titer.  CRIM-negative patients who already exhibit clinical decline 
may also benefit from ITI treatment under these conditions, if the clinical decline is thought to be 
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the result of antibody interference.  In CRIM-negative patients who already present with clinical 
decline and inhibitory antibodies or high anti-rhGAA titer, a more aggressive ITI regimen may 
be warranted to achieve a significant reduction in antibody titer that may lead to clinical 
improvement.  Due to the increased risk for CRIM-negative patients to develop inhibitory 
antibodies or high anti-rhGAA titer, Genzyme is conducting a separate study (AGLU03807) to 
explore the effects of ITI in Myozyme-naïve CRIM-negative patients. 
There are few systematically collected data assessing ITI strategies for patients with LSDs in 
general, and in Pompe disease in particular.  Nevertheless, the potential serious consequence of 
antibody interference with the efficacy of Myozyme in patients with Pompe disease warrants 
consideration of therapeutic intervention with highly experimental ITI regimens.  It is 
hypothesized that prevention or significant reduction of antibody formation may minimize the 
clinical impact of antibodies on treatment outcomes while allowing continued treatment with 
Myozyme.   
The development of an ITI protocol for this Pompe patient population is challenging.  Relevant 
clinical precedent was primarily established in diseases such as hemophilia, which is not directly 
comparable to Pompe disease.  For example, hemophiliac patients are deficient in a secreted 
plasma protein while Pompe patients are deficient in an intracellular catabolic enzyme, which is 
mostly secluded in the lysosome.  Also, the presence of cardiac disease and respiratory 
insufficiency in the Pompe disease population adds a risk of potential cardiopulmonary 
complications due to immunotherapy that is usually not a concern for patients with hemophilia. 
Experience with the use of ITI regimens in other LSDs has shown that a total dose increase and 
change from biweekly to weekly infusions of ERT was successful for 2 patients with Gaucher 
disease who exhibited limited clinical benefit and inhibitory antibody development, as reported 
in the literature (Zhao, 2003, Blood Cells Mol Dis; Ponce, 1997, Blood).  A third patient with 
type 3 Gaucher disease successfully underwent ITI with a combination of increased dose of ERT 
and a 10-day cyclophosphamide regimen, including plasmapheresis on days 1, 3 and 5, and 
administration of intravenous immunoglobulin (IVIG) on days 5 to 10, as well as low-dose, oral 
cyclophosphamide for up to 30 days (Brady, 1997, Pediatrics).   
There also has been limited experience with the use of ITI regimens in Pompe disease.  Two 
CRIM-negative infants who received an earlier form of rhGAA (Synpac rhGAA under 
Investigational New Drug [IND] application 8324; different from Myozyme) developed high, 
sustained anti-rhGAA IgG titers and underwent unsuccessful experimental ITI on an ITI regimen 
similar to that described by Brady et al (Brady, 1997, Pediatrics).  In addition, 1 of these patients 
also received a total of 6 doses of Rituxan® (rituximab) in a subsequent, also unsuccessful, ITI 
regimen attempt (Genzyme Study GAA-CL-002).  In both patients, the ITI regimens proved 
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ineffective, as any reduction in anti-rhGAA antibody levels was transient.  Both patients 
experienced bacterial and viral infections during the ITI regimen; these infections were 
considered by the treating physicians to be possibly due to a weakened immune system.  One 
patient developed nephrotic syndrome secondary to immune complex formation while receiving 
high-dose Synpac rhGAA administered 5 times weekly; the onset of nephrotic syndrome 
occurred after the patient had discontinued the ITI regimen (Hunley, 2004, Pediatrics).   
Through a series of preclinical studies in GAA knockout mice, which exhibit an rhGAA-specific 
antibody response following treatment with rhGAA, a potential regimen for a short course of 
immunotherapy to induce long-term immune tolerance to Myozyme has been developed 
(Genzyme Study ITR-333-1106).  The regimen in GAA knockout mice involved prophylactic 
administration of three 3-day courses of intraperitoneal methotrexate, given around the first 3 or 
8 weekly infusions of Myozyme, and was based on previous experiments performed at Genzyme 
in a GAA knockout mouse model, in which the murine a-glucosidase gene has been disrupted 
through insertion of the neomycin phosphotransferase gene in exon 6 (6neo/6neo), as reported by 
Raben et al (Raben, 1998, J Biol Chem).  This regimen, when administered at doses of 0.5 mg/kg 
and 5.0 mg/kg, was found to consistently reduce the antibody levels in GAA knockout mice over 
at least 8 months, although variability was higher at the lower dose.  Notably, a number of 
unsuccessful therapeutic options were also tested in the GAA knockout mouse model, which 
included mycophenolate mofetil, cyclosporine A plus azathioprine, cytotoxic T-lymphocyte 
antigen 4-Ig fusion protein, and anti-thymocyte globulin.   
This exploratory clinical study (AGLU03707) will employ 2 clinical ITI regimens to determine 
whether this regimen can reduce the immunogenicity of Myozyme in patients with Pompe 
disease.  The first regimen (Regimen A) will involve administration of monthly 
IV cyclophosphamide for 6 months.  The second regimen (Regimen B) is similar to that used to 
induce immune tolerance in GAA knockout mice, and will consist of administration of biweekly 
subcutaneous (SC) methotrexate for 6 months, with the addition of a 4-week cycle of weekly IV 
rituximab to aid in decreasing long-term antibody production against Myozyme.  These 
immunosuppressant agents (cyclophosphamide, rituximab, and methotrexate) were considered 
because reports exist for use in children (and cyclophosphamide and methotrexate are both 
approved for specific indications in children), and these agents have been used successfully to 
treat diseases with an important immunologic component such as systemic lupus erythematosus 
(SLE) and juvenile rheumatoid arthritis (JRA), including cases where other therapies have failed, 
although the specific mechanism of action of these agents in the treatment of pediatric SLE and 
JRA are not known.  Cyclophosphamide is proposed for patients already demonstrating high 
antibody titers and/or in vitro inhibitory antibodies along with evidence of clinical decline, and 
was chosen primarily because of its rapid onset of action and potency based on limited 
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information in children with immune diseases (primarily SLE and JRA, as described above).  In 
CRIM-negative patients who do not yet demonstrate high antibody titers, inhibitory antibodies, 
or evidence of clinical decline, a regimen consisting of weekly rituximab and biweekly 
methotrexate is proposed because there may be less acute toxicity with this regimen, and it may 
therefore be more appropriate for a population where there is no immediate need to reduce 
antibody titer.  
It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider 
IVIG administration, regardless of age, if indicated per the individual Investigator’s clinical 
discretion. 
The development of antibody titers in patients treated with Myozyme points towards a role of the 
B cell compartment component in immunological response; however, the role of the T cell 
compartment in patients with Pompe disease has not been previously evaluated.  Therefore, in 
conjunction with administration of an ITI regimen in this study, laboratory assessments will be 
performed to study the contribution of the T cell compartment to the immune response against 
Myozyme.  Genzyme will also investigate the correlation among genotype, the level of 
α-glucosidase protein, and the presence of binding, anti-rhGAA IgG, and inhibitory antibodies 
over time, using validated assays. 
4.3.1 Cyclophosphamide 
In this study, cyclophosphamide will be given as an investigative, off-label agent at the dose of 
250 mg/m2 IV every 4 weeks for a total of 6 months, with each dose being administered after 
completion of a Myozyme infusion. 
Cyclophosphamide is an immunosuppressive agent that is biotransformed (principally in the 
liver) to active alkylating metabolites that interfere with the growth of susceptible rapidly 
proliferating malignant cells, presumably through a mechanism of action that involves cross-
linking of tumor cell deoxyribonucleic acid (DNA).  Cyclophosphamide is approved for the 
treatment of various malignancies and nephrotic syndrome in children.  Cyclophosphamide has 
also been used to treat autoimmune diseases such as pediatric SLE and JRA, with conventional 
therapy typically involving monthly IV doses of 500 to 1000 mg/m2. 
Further details on the potential risks of cyclophosphamide are provided in Section 4.4.2.1.  A full 
description of cyclophosphamide is available in the local prescribing information.  The United 
States (US) prescribing information is provided as an appendix to this protocol (Appendix 14.1); 
additional countries should refer to their local authorities’ approved prescribing information.  
Investigators should familiarize themselves with any relevant premedication requirements, 
contraindications, warnings, precautions for use, and the adverse event (AE) profile provided 
therein. 
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4.3.2 Rituximab 
In this study, rituximab will be given as an investigative, off-label agent at the recommended 
dose of 375 mg/m2 (or 12.5 mg/kg in those patients with a body surface area [BSA] ≤0.5 m2) IV 
infusion once weekly for 4 doses, with the first rituximab infusion occurring on the day after the 
first Myozyme infusion in this study.  A patient who completes the initial cycle of rituximab 
treatment may be considered for an optional, additional 4-week cycle of rituximab (up to 
4 additional doses) within the first 6 months of the study, as described in Section 8.1.  The total 
number of weekly 375 mg/m2 IV infusions of rituximab will not exceed 8 doses. 
Rituximab is a chimeric anti-CD20 monoclonal antibody designed to target the CD20 antigen, 
which is a transmembrane protein expressed on >90% of all B cell non-Hodgkin’s lymphomas.  
CD20 expression is restricted to B cell precursors and mature B cells, and is not found in plasma 
cells (or other normal tissues).  Rituximab is approved for the treatment of non-Hodgkin’s 
lymphoma and rheumatoid arthritis.  Rituximab is a liquid concentrate intended for IV 
administration via a dedicated line.   
In 14 patients given rituximab 375 mg/m2 as an IV infusion for 4 weekly doses, the mean serum 
half-life was 76.3 hours (range 31.5 to 152.6 hours) after the first infusion and 205.8 hours 
(range 83.9 to 407.0 hours) after the fourth infusion.  The wide range of half-lives may reflect the 
variable tumor burden among patients and changes in CD20-positive (normal and malignant) 
B-cell populations upon repeated administrations.   
Further details on the potential risks of rituximab are provided in Section 4.4.2.2.  A full 
description of rituximab is available in the local prescribing information.  The US prescribing 
information is provided as an appendix to this protocol (Appendix 14.2); additional countries 
should refer to their local authorities’ approved prescribing information.  Investigators should 
familiarize themselves with any relevant premedication requirements, contraindications, 
warnings, precautions for use, and the AE profile provided therein. 
4.3.3 Methotrexate 
In this study, methotrexate will be administered as an investigative off-label agent qow at a dose 
of 15 mg/m2, administered as an SC injection on the day after Myozyme infusion for the first 
6 months of treatment.  This dose of methotrexate is approximately 1.8-fold higher than the 
human equivalent of the lowest effective dose in the GAA knockout mouse studies, when 
accounting for species differences and frequency of methotrexate administration in AGLU03707 
and GAA knockout mouse studies.  Of note, this does not take into account the difference in 
route of administration between that proposed in AGLU03707 and that used in GAA knockout 
mouse studies. 
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Methotrexate is an anti-metabolite agent that acts by inhibiting dihydrofolate reductase (an 
enzyme required for cell division).  Methotrexate is approved for the treatment of cancer of the 
breast, head and neck, lung, stomach, and esophagus, as well as gestational trophoblastic cancer, 
sarcomas, non-Hodgkin’s lymphoma, psoriasis, rheumatoid arthritis, and Crohn’s disease.  To 
date, the safety and effectiveness of methotrexate for a pediatric population has been established 
for its use as therapy for cancer and polyarticular-course JRA.  
Methotrexate will be administered SC in this study, as experience in the treatment of 
polyarticular-course JRA suggests that children receiving 20 to 30 mg/m2/week may have better 
absorption and fewer gastrointestinal (GI) side effects if methotrexate is administered either 
intramuscularly or SC.  Folinic acid may be given at the discretion of the Investigator beginning 
24 hours after the dose of methotrexate. 
Further details on the potential risks of methotrexate are provided in Section 4.4.2.3.  A full 
description of methotrexate is available in the local prescribing information.  The US prescribing 
information is provided as an appendix to this protocol (Appendix 14.3); additional countries 
should refer to their local authorities’ approved prescribing information.  Investigators should 
familiarize themselves with any relevant premedication requirements, contraindications, 
warnings, precautions for use, and the AE profile provided therein. 
4.3.4 Intravenous Immunoglobulin 
It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider 
IVIG administration at a dose of 400 mg/kg, regardless of age, if indicated per the individual 
Investigator’s clinical discretion.  The US prescribing information is provided as an appendix to 
this protocol (Appendix 14.4). 
There are no published data regarding IVIG prophylaxis in this setting. 
4.4 
Risks 
4.4.1 Risks Associated With Myozyme (alglucosidase alfa) 
Refer to the current Investigator’s Brochure and local prescribing information for further details 
concerning clinical experience with Myozyme. 
4.4.1.1 Anaphylaxis and Allergic Reactions 
Life-threatening anaphylactic reactions, including anaphylactic shock, have been observed in 
patients during Myozyme infusions.  Because of the potential for severe infusion reactions, 
appropriate medical support measures should be available when Myozyme is administered.  
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If anaphylactic or other severe allergic reactions occur, immediate discontinuation of the 
administration of Myozyme should be considered, and appropriate medical treatment should be 
initiated.   
The risks and benefits of re-administering Myozyme following an anaphylactic or severe allergic 
reaction should be considered.  Some patients have been rechallenged and have continued to 
receive Myozyme under close clinical supervision.  Extreme care should be exercised, with 
appropriate resuscitation measures available, if the decision is made to re-administer the product.  
Refer to the local prescribing information and the Investigator’s Brochure for additional details 
on the risks of anaphylactic and allergic reactions. 
4.4.1.2 
Acute Cardiorespiratory Failure 
Acute cardiorespiratory failure requiring intubation and inotropic support has been observed up 
to 72 hours after infusion with Myozyme in infantile-onset Pompe disease patients with 
underlying cardiac hypertrophy, possibly associated with fluid overload with IV administration 
of Myozyme.  Patients with an acute illness at the time of Myozyme infusion may be at greater 
risk for experiencing acute cardiorespiratory failure.  Infants with cardiac dysfunction may 
require prolonged observation times that should be individualized based on the needs of the 
patient. 
4.4.1.3 
Cardiac Arrhythmia and Sudden Cardiac Death During General Anesthesia 
for Central Catheter Placement 
A central venous catheter may be inserted for this study, at the discretion of the Investigator.  
Caution should be used when administering general anesthesia for the placement of a central 
venous catheter or for other surgical procedures in infantile-onset Pompe disease patients with 
cardiac hypertrophy. 
Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia and bradycardia, 
resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been 
observed in infantile-onset Pompe disease patients with cardiac hypertrophy, associated with the 
use of general anesthesia for the placement of a central venous catheter intended for Myozyme 
infusion (Ing, 2004, Paediatr Anaesth). 
4.4.1.4 
Infusion-Associated Reactions 
An infusion-associated reaction (IAR) is a sub-category of AEs used only in relationship to 
Myozyme.  IARs were defined as AEs that occurred during either the Myozyme infusion or the 
observation period following the infusion which were deemed to be related (i.e., possibly, 
probably or definitely) to study drug.  At the discretion of the Investigator, AEs that occurred 
after completion of the post-infusion observation period that were assessed as related could also 
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be considered IARs.  IARs occurred in approximately 50% of patients treated for 52 weeks with 
Myozyme in 2 clinical studies of infantile-onset disease.  IARs occur at any time during, and 
mostly up to 2 hours after the infusion of Myozyme, and are more likely with higher infusion 
rates and have occurred in some patients after receiving antipyretics, antihistamines, or steroids.  
Patients with an acute illness at the time of Myozyme infusion may also be at greater risk for 
IARs.  The majority of IARs were assessed as mild to moderate; some reactions were severe.  
Refer to the current Investigator’s Brochure and local prescribing information for important 
safety information on IARs’ management. 
4.4.1.5 
Immune-Mediated Reactions 
Severe cutaneous and systemic immune mediated reactions have been reported in postmarketing 
safety experience with Myozyme in at least 2 patients, including ulcerative and necrotizing skin 
lesions, and possible type III immune complex-mediated reactions.  These reactions occurred 
several weeks to 3 years after initiation of Myozyme infusions.  Skin biopsy in 1 patient 
demonstrated deposition of anti-rhGAA antibodies in the lesion.  Another patient developed 
severe inflammatory arthropathy in association with fever and elevated erythrocyte 
sedimentation rate.  Patients should be monitored for the development of systemic immune 
complex-mediated reactions involving skin and other organs while receiving Myozyme. 
4.4.1.6 
Adverse Events 
While most patients experienced AEs, the majority of AEs were mild or moderate in severity and 
assessed as unrelated to treatment.  Most serious adverse events (SAEs) experienced by patients 
were also mild or moderate in severity and assessed as unrelated to treatment and were 
respiratory, cardiac, or infectious in nature.  The majority of SAEs and AEs were not unexpected 
given the multi-systemic nature or advanced stage of Pompe disease. 
4.4.1.7 
Immunogenicity 
The majority of patients (approximately 90%) in 2 clinical studies of infantile-onset disease 
tested positive for IgG antibodies to Myozyme.  The data reflect the percentage of patients whose 
test results were considered positive for antibodies to Myozyme using an enzyme-linked 
immunosorbent assay and radioimmunoprecipitation assay for Myozyme-specific IgG 
antibodies.  Most patients who develop antibodies do so within the first 3 months of exposure.   
Patients in clinical trials, expanded access programs, and on commercial therapy have undergone 
testing for Myozyme-specific immunoglobulin E (IgE) antibodies.  Testing was performed for 
IARs, especially moderate to severe or recurrent reactions, for which mast-cell activation was 
suspected.  A small number of these patients tested positive for Myozyme-specific IgE 
antibodies, some of whom experienced an anaphylactic reaction.  Some patients have been 
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successfully rechallenged and continued to receive treatment with Myozyme under close clinical 
supervision. 
It is therefore recommended that patients treated with Myozyme undergo antibody testing at least 
every 3 months and that those who experience a decrease in clinical benefit despite adhering to 
the recommended dosing regimen be tested for inhibition of enzyme uptake or activity by an in 
vitro assay.  In the current AGLU03707 study, more frequent monitoring of anti-rhGAA IgG 
titer will be performed to fully evaluate the antibody response during and following treatment 
with immunosuppressants. 
4.4.2 Risks Associated With Immune Tolerance Induction (ITI) 
ITI requires the use of agents that may cause additional complications (such as recurrent 
infections) that could be fatal for critically ill patients with Pompe disease.  For these reasons, 
Genzyme recommends that careful consideration of the risks and benefits for the individual 
patient be given and that investigators overseeing this protocol and administering the agents in 
this regimen should be familiar with the medications administered, and preferably be an 
infectious disease expert and/or other specialist (such as an oncologist, immunologist, 
rheumatologist, or transplant specialist).   
As discussed in detail in Section 4.4.2.1, Section 4.4.2.2 and Section 4.4.2.3, respectively, 
cyclophosphamide, rituximab, and methotrexate can have direct toxicities.  As there are no 
controlled studies using these agents in patients with Pompe disease or other patients <2 years of 
age who have diseases other than Pompe, the toxicities are unknown.  Furthermore, the proposed 
treatment combinations of Myozyme with cyclophosphamide, rituximab, and/or methotrexate 
have not been used, and the combination of agents could have broader side effects than those 
observed with the individual agents.  During this study, patients should be closely monitored for 
any signs of toxicity, including monitoring for any changes in serum creatinine, blood urea 
nitrogen (BUN), platelets, white cell count, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and bilirubin, the presence of red cells in the urine, as well as any 
clinical symptoms of renal, hepatic, bone marrow, or pulmonary toxicity.  Potentially 
confounding factors include the frequent elevation of ALT, AST, creatine kinase (CK), and 
creatine kinase-myocardial band (CK-MB) (secondary to muscle cell damage) and respiratory 
complications in patients with Pompe disease. 
Immunosuppression can also result in opportunistic infections such as Pneumocystis jiroveci 
(formerly known as Pneumocystis carinii) pneumonia as well as other common and opportunistic 
bacterial, fungal, and viral infections.  Patients with Pompe disease may be at increased risk of 
such infections due to the progressive effects of the disease on the respiratory muscles.  In the 
AGLU03707 study, precautions must be taken to prevent the transmission of infection, and 
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infection prophylaxis for P. jiroveci is recommended.  Patients should be monitored closely for 
any sign of infection during the study, with consequent aggressive treatment and management if 
this should occur.  In selecting an antibiotic to treat the infection, attention should be given to 
potential drug interactions among the investigative agents and certain antibiotics.  It is also 
recommended that an infectious disease specialist be consulted whenever any antimicrobial 
agent is to be administered for the treatment of active infection in patients receiving the ITI 
regimen.  Further detail on supportive measures for prophylaxis, monitoring, and treatment of 
infections are provided in Section 8.3, and in the Study Operations Manual (SOM). 
Vaccination with live virus is not recommended in immunosuppressed children.  Therefore, in 
the AGLU03707 study, vaccination with live virus will be prohibited within 1 month prior to 
enrollment in this study and until a patient’s B cell count returns to normal or at least 3 months 
following completion of the ITI regimen, whichever is longer.  The effectiveness of inactive 
virus given concomitantly with the immunosuppressant agents in this study is questionable.  
However, patients undergoing ITI regimens may benefit from specific immunizations directed at 
preventing infections by organisms to which they are particularly susceptible, e.g., 
pneumococcal, influenza, and/or meningococcal vaccines.  Further detail is provided in 
Section 8.3, and in the SOM. 
Adjustment to a patient’s ITI regimen may be made in consultation with Genzyme (and the 
Immune Tolerance Induction Review Board [ITIRB], as appropriate) if medically indicated, in 
an effort to allow the patient to safely continue in the study while maintaining the potential 
clinical benefit of the regimen.  If severe toxicity or infection should occur (see Section 7.3.2), 
the patient will be temporarily withdrawn from the ITI regimen until further evaluation, and the 
regimen may be permanently discontinued pending the outcome of that evaluation.  The 
Investigator may also withdraw the patient from the regimen at any time, if he/she considers this 
to be in the best interest of the patient.   
4.4.2.1 Risks Associated With Cyclophosphamide 
A full description of cyclophosphamide, any relevant premedication requirements, 
contraindications, warnings, precautions for use, and the AE profile, as well as preparation 
instructions, is in the local prescribing information (refer to Appendix 14.1).  Investigators are 
requested to adhere to recommendations provided therein.  A summary of boxed warnings and 
contraindications relevant to this patient population is provided directly below. 
Cyclophosphamide is contraindicated in patients who develop severely depressed bone marrow 
function. 
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Serious, sometimes fatal, infections may develop in severely immunosuppressed patients.  
Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, 
in patients who have or who develop viral, bacterial, fungal, protozoan, or helminthic infections. 
Secondary malignancies have developed in some patients treated with cyclophosphamide alone 
or in combination with other agents, and most frequently in patients treated for primary 
myeloproliferative or lymphoproliferative malignancies or nonmalignant disease in which 
immune processes are believed to be involved pathologically.   
Cyclophosphamide interferes with oogenesis and spermatogenesis, and may cause sterility in 
both sexes; sterility may be irreversible in some patients.  Amenorrhea associated with decreased 
estrogen and increased gonadotropin secretion develops in a significant proportion of women 
treated with cyclophosphamide; affected patients generally resume regular menses within a few 
months after cessation of therapy.  Men treated with cyclophosphamide may develop 
oligospermia or azoospermia associated with increased gonadotropin but normal testosterone 
secretion; azoospermia is reversible in some patients, though the reversibility may not occur for 
several years after cessation of therapy.  
Cyclophosphamide can also cause fetal harm when administered to a pregnant woman, with 
reported fetal abnormalities including ectrodactylia.  Women of childbearing potential should be 
advised to avoid becoming pregnant.  If a patient should become pregnant while taking 
cyclophosphamide, that patient should be appraised of the potential hazard to the fetus.   
Hemorrhagic cystitis may develop in patients treated with cyclophosphamide; in rare instances 
this can be severe and even fatal.  Fibrosis of the urinary bladder, sometimes extensive, also may 
develop with or without accompanying cystitis.  Atypical urinary bladder epithelial cells may 
appear in the urine.  These adverse effects appear to depend upon the dose of cyclophosphamide 
and the duration of therapy.  Such bladder injury is thought to be due to cyclophosphamide 
metabolites excreted in the urine.  Forced fluid intake helps to assure an ample output of urine, 
necessitates frequent voiding, and reduces the time the drug remains in the bladder.  Hematuria 
usually resolves in a few days after cyclophosphamide treatment is stopped, but it may persist.  
Medical and/or surgical supportive treatment may be required, rarely, to treat protracted cases of 
severe hemorrhagic cystitis.  It is usually necessary to discontinue cyclophosphamide therapy in 
instances of severe hemorrhagic cystitis.  In the current study, patients should be well hydrated 
prior to cyclophosphamide infusion (taking into account the proper hydration given the patient’s 
cardiac status) and monitored regularly for the presence of red cells in the urine, which may 
precede hemorrhagic cystitis. 
Although a few instances of cardiac dysfunction have been reported following use of 
recommended doses of cyclophosphamide, no causal relationship has been established.  Acute 
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cardiac toxicity has been reported with doses as low as 2.4 gram/m2 (usually as a portion of an 
intensive antineoplastic multidrug regimen or in conjunction with transplantation procedures) 
and, in a few instances, severe and sometimes fatal congestive heart failure has occurred after the 
first dose of a high-dose cyclophosphamide regimen.  
Anaphylactic reactions have been reported; death has also been reported in association with this 
event.  Possible cross-sensitivity with other alkylating agents has been reported. 
Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase 
activity, potentiates the effect of succinylcholine chloride.  If a patient has been treated with 
cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.  
4.4.2.2 Risks Associated With Rituximab 
A full description of rituximab, any relevant premedication requirements, contraindications, 
warnings, precautions for use, and the AE profile, as well as preparation instructions, is in the 
local prescribing information (refer to Appendix 14.2).  Investigators are requested to adhere to 
recommendations provided therein.  A summary of boxed warnings and contraindications 
relevant to this patient population is provided directly below. 
Deaths have been reported within 24 hours of infusion with rituximab.  These fatal infusion 
reactions followed an infusion reaction complex, which included hypoxia, pulmonary infiltrates, 
acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic 
shock.  Approximately 80% of fatal infusion reactions occurred with the first infusion.  
Therefore, in the current study, all rituximab infusions will be administered in a hospital setting 
with appropriate emergency care facilities.  
Severe mucocutaneous reactions, some fatal, have been reported with rituximab.  These include 
Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal 
necrolysis.  The onset of the reaction in the reported cases has varied from 1 to 13 weeks 
following rituximab exposure.  Patients experiencing a severe mucocutaneous reaction should 
not receive any further infusions and should receive prompt medical evaluation. 
Rituximab is contraindicated for patients with known anaphylaxis or IgE-mediated 
hypersensitivity to murine proteins or to any component of the product. 
Patients with pre-existing cardiac conditions have had recurrences of these events during 
rituximab therapy.  To manage these risks in the current study, continuous telemetry will be 
performed during all rituximab infusions, and infusions will be discontinued in the event of 
serious or life threatening cardiac arrhythmias, and may be adjusted or discontinued in response 
to any other clinically significant findings, at the discretion of the Investigator.  In addition, 
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patients who develop clinically significant arrhythmias may also undergo additional cardiac 
monitoring, also at the discretion of the Investigator. 
Hepatitis B virus (HBV) reactivation along with fulminant hepatitis, hepatic failure, and death 
has been reported in some patients with hematologic malignancies.  The rituximab prescribing 
information recommends that persons at high risk of HBV infection be screened before initiation 
of treatment, and that carriers of Hepatitis B should be closely monitored for clinical and 
laboratory signs of active HBV infection and for signs of hepatitis during and for up to several 
months following rituximab therapy.  Due to the combined risk of HBV reactivation with 
rituximab and methotrexate-induced hepatotoxicity, patients who are at risk of HBV reactivation 
or who are known carriers of Hepatitis B (i.e., Hepatitis B surface antigen is positive) will be 
excluded from the current study.   
The following additional serious viral infections, either new, reactivated or exacerbated, have 
been identified in clinical studies or postmarketing reports with rituximab, the majority of these 
in patients receiving rituximab in combination with chemotherapy or as part of a hematopoietic 
stem cell transplant: JC virus (progressive multifocal leukoencephalopathy [PML]), 
cytomegalovirus (CMV), herpes simplex virus, Parvovirus B19, varicella zoster virus, West Nile 
virus, and Hepatitis C.  JC virus (PML) is a very rare complication of rituximab and usually 
occurs only in conjunction with the use of other immunosuppressants over an extended period of 
time; the disease usually leads to life-threatening disability and death over weeks to months.  In 
some cases, viral infections occurred up to 1 year following discontinuation of rituximab and 
resulted in death. 
4.4.2.3 Risks Associated With Methotrexate 
A full description of methotrexate is in the local prescribing information (refer to Appendix 
14.3).  Investigators should familiarize themselves with any relevant premedication 
requirements, contraindications, warnings, precautions for use, and the AE profile provided 
therein.  A summary of boxed warnings and contraindications relevant to this patient population 
is provided directly below. 
Methotrexate should be administered only under the supervision of a physician experienced with 
antimetabolite treatments. 
Deaths have been reported with the use of methotrexate in the treatment of malignancy, 
psoriasis, and rheumatoid arthritis.  Patients should be closely monitored for bone marrow, liver, 
lung, and kidney toxicities. 
Delayed drug clearance has been identified as one of the major factors for methotrexate toxicity.  
Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural 
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effusions.  Such patients require especially careful monitoring for toxicity and require dose 
reduction or, in some cases, discontinuation of methotrexate administration. 
Unexpectedly severe, and sometimes fatal, bone marrow suppression, aplastic anemia, and GI 
toxicity have been reported with concomitant administration of methotrexate (usually in high 
dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).  With lower doses, 
NSAIDs and salicylates have been reported to reduce the tubular secretion of methotrexate in an 
animal model and may enhance its toxicity.  Therefore, concomitant administration of NSAIDs 
is strongly discouraged for patients receiving Regimen B in the current study. 
Methotrexate should be used with extreme caution in the presence of active infection.  Oral 
antibiotics, such as tetracycline, chloramphenicol, and non-absorbable broad spectrum antibiotics 
may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by 
inhibiting bowel flora and suppressing metabolism of the drug by bacteria.  Penicillins may 
reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with 
concomitant hematologic and GI toxicity have been observed with high- and low-dose 
methotrexate; use of methotrexate with penicillins should be carefully monitored.  Sulfonamides 
also may decrease renal clearance of methotrexate and increase the risk of hematologic toxicity.  
Therefore, penicillins and sulfonamides should be used with extreme caution for patients 
receiving Regimen B in the current study. 
Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged 
use.  Acute liver enzyme elevations are common; these are usually transient and asymptomatic, 
and do not appear predictive of later hepatic disease.  Liver biopsy after sustained use often 
shows histologic changes, and fibrosis and cirrhosis have been reported.  In rheumatoid arthritis 
patients persistent abnormalities in liver function tests may precede the appearance of fibrosis or 
cirrhosis, but in psoriasis patients these lesions are not necessarily preceded by symptoms or 
abnormal liver function tests.  Methotrexate will be administered for a short duration in the 
current study; however, the possibility of liver lesions cannot be ruled out, and it is unknown 
whether such lesions, if they were to occur, would be preceded by clinical symptoms or 
abnormal liver function tests in Pompe patients. 
Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a 
potentially dangerous lesion, which may occur acutely at any time during therapy and has been 
reported at low doses.  It is not always fully reversible and fatalities have been reported.  The 
prescribing information for methotrexate recommends interruption of treatment and careful 
investigation in the event of pulmonary symptoms, especially nonproductive dry cough.  In 
patients with Pompe disease, monitoring for pulmonary toxicity may be complicated by pre-
existing respiratory ailments due to disease progression.  Therefore, it is suggested that patients 
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have a chest X-ray obtained prior to beginning their methotrexate dosing so that it may be used 
at a later time for comparison should respiratory complications arise during the study.  In such 
patients, careful attention should be given to any worsening of symptoms and these should be 
thoroughly investigated prior to resuming the ITI regimen.  
Diarrhea and ulcerative stomatitis require interruption of treatment; otherwise, intestinal 
perforation may lead to hemorrhagic enteritis and death. 
Malignant lymphoma may occur with low-dose treatment and may regress when treatment is 
discontinued. 
Severe, occasionally fatal skin reactions may occur within days after single or multiple doses.  
Recovery has been reported with discontinuation of therapy. 
Potentially fatal opportunistic infections, especially P. jiroveci pneumonia, may occur with 
methotrexate therapy. 
Methotrexate has been reported to cause fetal death and/or congenital anomalies.  Therefore, it is 
not recommended for women of childbearing potential unless there is clear medical evidence that 
the benefits can be expected to outweigh the considered risks.  
Women of childbearing potential should not be started on methotrexate until pregnancy is 
excluded and should be fully counseled on the serious risk to the fetus should they become 
pregnant while undergoing treatment.  Pregnancy should be avoided if either partner is receiving 
methotrexate: during and for a minimum of 3 months after therapy for male patients, and during 
and for at least 1 ovulatory cycle after therapy for female patients.  Because of the potential for 
serious adverse reactions from methotrexate in breast-fed infants, it is contraindicated in nursing 
mothers. 
Limited experience in the treatment of polyarticular-course JRA shows a significant increase in 
the incidence and severity of serious toxic reactions, especially bone marrow suppression, at 
doses >20 mg/m2/week in adults.  Although there is experience with doses up to 30 mg/m2/week 
in children, there are too few published data to assess how doses over 20 mg/m2/week might 
affect the risk of serious toxicity in children.  Experience does suggest, however, that children 
receiving 20 to 30 mg/m2/week may have better absorption and fewer GI side effects if 
methotrexate is administered either intramuscularly or SC. 
4.4.2.4 Risks Associated With Intravenous Immunoglobulin 
A full description of IVIG is in the local prescribing information (refer to Appendix 14.4).  
Investigators should familiarize themselves with any relevant pre-medication requirements, 
contraindications, warnings, precautions for use, and the AE profile provided therein.  A 
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summary of warnings and contraindications relevant to this patient population is provided 
directly below. 
The most significant risks associated with IVIG therapy are acute renal dysfunction, renal 
failure, osmotic nephrosis, and death.  The IVIG local prescribing information contains a black 
box warning about risk of renal events.  Patients in this study who are pre-disposed to renal 
disease are particularly susceptible to these events. The risk is increased in IVIG products 
containing sucrose.  Per the local prescribing information, other risks associated with IVIG 
treatment include hemolysis, transfusion-related acute lung injury, thrombotic events, and aseptic 
meningitis syndrome. 
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5. 
STUDY OBJECTIVES 
The objectives of this study are as follows: 
1. To evaluate the efficacy of ITI regimens, as assessed by anti-rhGAA antibody titers, and 
antibodies that inhibit the enzymatic activity and/or uptake of Myozyme; 
2. To evaluate Pompe disease activity in patients receiving these regimens, as measured by 
overall survival, respiratory function, left ventricular mass index (LVMI), motor function, 
and disability index; and 
3. To evaluate the safety of these regimens, as assessed by the incidence of AEs, SAEs, and 
clinical laboratory abnormalities. 
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6. 
INVESTIGATIONAL PLAN 
6.1 
Study Design 
This is an exploratory, open-label study of patients of any age with Pompe disease to evaluate 
the efficacy, safety, and clinical benefit of 2 ITI regimens in combination with Myozyme in 
patients receiving Myozyme treatment.  The patient and/or the patient’s legal guardian(s) must 
provide written informed consent prior to any protocol-related procedure being performed.  
Eligible patients who are currently receiving Myozyme therapy will be enrolled into the study, 
and will be followed for a minimum of 18 months on-study (a 6-month ITI treatment module and 
a 12-month follow-up module on Myozyme alone).  Eligible CRIM-negative patients will be 
followed for a minimum of 18 months on treatment or, if a patient is <6 months of age at the 
time of enrollment, until the patient is 2 years of age.   
Two ITI regimens will be evaluated in this protocol (see schematic in Figure 6-1):  
• Regimen A:  Patients will be assigned to Regimen A if they exhibit clinical decline since 
starting Myozyme therapy and have inhibitory antibodies and/or a sustained high anti-
rhGAA antibody titer (defined as at least 2 titers ≥25,600 obtained at least 1 month 
apart), regardless of their CRIM status.  Regimen A consists of a 6-month regimen of 
monthly cyclophosphamide.  All cyclophosphamide infusions to patients with 
cardiomegaly or hypertrophic cardiomyopathy will be administered in a hospital and 
patients will be observed for a minimum of 24 hours post-infusion. 
• Regimen B:  Only CRIM-negative patients are eligible to enroll in Regimen B.  CRIM-
negative patients will be assigned to Regimen B if they either (1) exhibit clinical decline 
since starting Myozyme therapy and do not have inhibitory antibodies or a sustained high 
anti-rhGAA antibody titer (defined as at least 2 titers ≥25,600 obtained at least 1 month 
apart), or (2) do not exhibit clinical decline since starting Myozyme therapy, regardless of 
their anti-rhGAA or inhibitory antibody status.  Regimen B consists of a 4-week cycle of 
weekly rituximab in combination with a 6-month regimen of biweekly methotrexate.  An 
optional, additional cycle of rituximab (up to 4 additional doses) may be administered 
within the first 6 months of the study, as described in Section 8.1. 
Patients on both regimens will receive IV infusions of Myozyme (20 mg/kg) qow for a minimum 
of 18 months or, if the patient is <6 months of age at the time of enrollment, until the patient is 
2 years of age. 
Any adjustments to a patient’s ITI regimen (e.g., a decrease in dose) may be made in 
consultation with Genzyme and the ITIRB, if medically indicated, in an effort to allow the 
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patient to safely continue in the study while maintaining the potential clinical benefit of the 
regimen (see Section 7.4). 
Clinical decline for patients regardless of CRIM status will be defined as decline in at least 1 of 
the following parameters as compared to the condition of the patient prior to beginning 
Myozyme treatment: 
Cardiac 
Persistence of a Left Ventricular Mass (LVM) Z-score ≥6 after a minimum of 6 months of 
treatment with Myozyme; OR 
Respiratory 
New development of respiratory failure requiring the use of ventilator assistance (invasive or 
non-invasive) after a minimum of 6 months of treatment with Myozyme.  Ventilator 
assistance must have been required for at least 4 weeks prior to study enrollment; OR 
Motor Skills 
For patients ≤2 years of age at study entry, failure to acquire at least 2 new gross motor 
milestones or loss of at least 2 previously acquired gross motor milestones (or a combination 
thereof) after a minimum of 6 months of treatment with Myozyme, e.g.: 
1. Turning head side to side (supine); 
2. Grasping small objects with hands; 
3. Transferring objects from hand to hand; 
4. Holding head upright with body supported; 
5. Rolling (supine to prone or prone to supine); 
6. Sitting (supported or unsupported); 
7. Walking (with support, i.e., cruising, or independently); 
8. Walking up stairs (with assistance or independently); OR 
Worsening of proximal upper extremity muscle weakness as determined by the Investigator 
through loss of functional use of the upper extremities after a minimum of 6 months of 
treatment with Myozyme; OR 
Progression to use of an assistive device for ambulation due to worsening of proximal lower 
extremity muscle weakness after a minimum of 6 months of treatment with Myozyme. 
Efficacy will be assessed by anti-rhGAA antibody titers; the evaluation of inhibitory antibody 
formation (activity and uptake); respiratory function as assessed by (a) the proportion of patients 
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who were alive and ventilator-free over the course of treatment, time to overall invasive 
ventilator-dependence, and ventilator-free survival time for patients who were ventilator-free at 
the onset of the study, and (b) the overall duration of ventilator support and the number of hours 
of ventilator use in the 24 hours preceding each infusion visit for patients who required ventilator 
use at the onset of the study; LVMI as assessed by echocardiogram (ECHO); and motor function 
and development as assessed by Gross Motor Function Measure-66 (GMFM-66), the Alberta 
Infantile Motor Scale (AIMS), and the Pompe Pediatric Evaluation of Disability Inventory 
(PEDI). 
Patient safety will be monitored continuously throughout the study and evaluated in terms of 
AEs graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI/CTCAE), Version 3.0 (dated 09 August 2006); vital sign parameters; 
physical examination findings; electrocardiogram (ECG) parameters; routine laboratory 
measurements (chemistry, hematology, urinalysis); lymphocyte subpopulations; an 
immunoglobulin panel; and pregnancy testing.  Specific attention will be given to any signs of 
infection or toxicity, including possible renal, hepatic, or pulmonary toxicity, or bone marrow 
suppression.  Additional immunology measurements will include anti-rhGAA IgE, serum 
tryptase, complement activation, and skin testing, when clinically indicated following moderate 
(Grade 2), severe (Grade 3), life-threatening (Grade 4), or recurrent mild (Grade 1) IARs to 
Myozyme that are suggestive of hypersensitivity; and circulating immune complex detection 
when clinically indicated by symptoms suggestive of immune complex disease.   
Research immunophenotyping and functional T cell assays will also be performed as exploratory 
measures.  Concomitant and pre-infusion medications and therapies will be monitored 
continuously throughout the study.   
An ITIRB will evaluate the safety and efficacy of each of the ITI regimens after each patient 
completes 1 month of treatment on a given regimen, after each patient completes 6 months of 
treatment on a given regimen, and, if applicable, after the patient completes an optional, 
additional cycle of rituximab (if applicable), as well on an expedited ad hoc basis, as outlined in 
the ITIRB Charter (which is maintained separately from the protocol).  The ITIRB will also 
provide recommendations about the risk/benefit profile of the ITI regimens; refer to Section 12.3 
for further details.  
An independent Allergic Reaction Review Board (ARRB) will be consulted on an ad hoc basis, 
as outlined in the ARRB Charter (which is also maintained separately from the protocol); refer to 
Section 12.4 for further details. 
For consistency, a central cardiologist will review all ECGs and ECHOs. 
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Following study completion, patients may receive commercial Myozyme treatment as prescribed 
by their treating physician.  To facilitate long-term data collection, patients will be encouraged to 
enroll in the Pompe Disease Registry after study completion. 
 
Figure 6-1 
Schematic of Patient Enrollment 
 
o 
Ab titer ≥25,600 
AND/OR 
o 
in vitro inhibition 
CRIM-positive 
patient 
CRIM-negative 
patient 
o 
Ab titer <25,600 
AND 
o 
No in vitro inhibition 
Clinical 
Decline 
NO Clinical 
Decline 
o 
Ab titer <25,600 
AND 
o 
NO in vitro inhibition 
Clinical 
Decline 
NO Clinical 
Decline 
Regimen A 
Regimen B
Not eligible 
 
 
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7. 
PATIENT POPULATION AND SELECTION 
It is planned that a total of 9 patients will initially be enrolled in the study.  Patients will be 
assigned to either Regimen A or Regimen B based on their qualifications for a given regimen.  
Regimens will enroll as patients present until a total of 9 patients are treated.  An attempt will be 
made to enroll a similar number of CRIM-positive and CRIM-negative patients on Regimen A, 
provided that sufficient number of qualified CRIM-negative patients can be identified within a 
reasonable study recruitment period.  Enrollment will proceed in a sequential manner within each 
treatment regimen such that ITIRB review of data from the first patient within a regimen (for the 
first month of treatment) is completed prior to enrollment of any further patients on that regimen.  
If the regimen appears to have an acceptable risk/benefit profile after the first 3 patients in a 
given regimen have completed 1 month of treatment, additional patients may be enrolled as they 
present, or as necessary, to further evaluate the ITI regimen.  Study patients will be enrolled at up 
to 9 centers. 
7.1 
Inclusion Criteria 
Patients must meet the following criteria to be enrolled in this study:   
1. The patient (and/or the patient’s legal guardian[s] if the patient is <18 years of age) must 
provide written informed consent prior to any study-related procedures being performed; 
2. The patient must have a clinical diagnosis of Pompe disease as defined by documented 
GAA deficiency (deficient endogenous GAA activity) in skin fibroblasts, muscle, or 
blood, or presence of 2 GAA mutations.  Consent will also be sought from the biological 
parent(s) for parental GAA mutational analysis, but is not a requirement for study 
eligibility; 
3. The patient (and/or the patient’s legal guardian[s] if the patient is <18 years of age) must 
have the ability to comply with the clinical protocol; 
4. If the patient is CRIM-positive, he/she must have received Myozyme therapy (20 mg/kg 
qow) for at least 6 consecutive months immediately prior to enrollment in the study.   
5. If the patient is CRIM-negative, he/she must have received at least 1 Myozyme infusion 
prior to enrollment in the study; 
6. Regimen A only:  
• The patient exhibits clinical decline (as defined in Section 6.1); 
• The patient has persistent high anti-rhGAA antibody titers (defined as at least 2 titers 
≥25,600 obtained at least 1 month apart) and/or has tested positive for antibodies that 
inhibit enzymatic activity and/or uptake of Myozyme.  
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7. Regimen B only:  
• The patient is CRIM-negative via Western blot analysis of skin fibroblasts; AND 
• The patient does NOT exhibit clinical decline (as defined in Section 6.1); OR 
• The patient is CRIM-negative via Western blot analysis of skin fibroblasts; AND 
• The patient exhibits clinical decline (as defined in Section 6.1); AND 
• The patient does NOT have persistent high anti-rhGAA antibody titers (defined as at 
least 2 titers ≥25,600 obtained at least 1 month apart) and has NOT tested positive for 
antibodies that inhibit enzymatic activity and/or uptake of Myozyme. 
Note that historical CRIM testing results by Western blot analysis (performed prior to 
enrollment) are acceptable, provided that written documentation of the laboratory results is 
available at the enrolling site. 
7.2 
Exclusion Criteria 
Patients will be excluded from this study if they do not meet the specific inclusion criteria, or if 
they meet the following exclusion criteria: 
1. The patient has any medical condition that, in the opinion of the Investigator, could 
interfere with the study regimens (i.e., Myozyme, cyclophosphamide, rituximab, IVIG, 
and/or methotrexate) or assessments; such conditions may include, but are not limited to, 
active human immunodeficiency virus infection, cancer, or tuberculosis; 
2. The patient is at risk of reactivation or is a carrier of Hepatitis B (e.g., Hepatitis B surface 
antigen is positive) or Hepatitis C (e.g., detectable Hepatitis C viral load by reverse 
transcriptase – polymerase chain reaction); 
3. The patient is at risk of reactivation or has positive serology suggestive of active infection 
for CMV, Herpes simplex, JC virus (PML), Parvovirus, or Epstein Barr virus; 
4. The patient is at risk of reactivation of tuberculosis or has regular contact (e.g., in the 
household) with individuals who are being actively treated for tuberculosis; 
5. The patient has low serum albumin, relative to institutional age-appropriate range, that is 
uncorrected; 
6. The patient has a major congenital abnormality; 
7. The patient has used any investigational product (other than Myozyme in those regions 
where the product is not commercially available and is considered investigational) within 
30 days prior to study enrollment; 
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8. The patient is pregnant or lactating; 
9. The patient has had or is required to have any live vaccination within 1 month prior to 
enrollment. 
At the discretion of the Investigator, clinical laboratory test results that are deemed to be due to 
transient illness may be repeated for the purpose of determining study eligibility. 
7.3 
Patient Withdrawal 
7.3.1 Patient Withdrawal From the Study 
Patient participation in this study is voluntary.  The patient (and/or the patient’s legal guardian(s) 
if the patient is <18 years of age) is free to withdraw consent and discontinue participation in the 
study at any time, and without prejudice to further treatment. 
Any female patient who becomes pregnant will be discontinued from the study. 
A patient’s participation in the study may also be discontinued at any time at the discretion of the 
Investigator.  The following may be justifiable reasons for the Investigator to remove a patient 
from the study: 
• Parents/guardians are non-compliant and will not adhere to study responsibilities, 
including failure to appear at study visits; 
• The patient was erroneously included in the study; 
• The patient develops an exclusion criterion or concurrent disease; 
• The patient suffers an intolerable AE; 
• The patient receives other investigational products, interventions, or procedures during 
the study; 
• The patient suffers severe toxicity or infection and supportive treatment and/or regimen 
adjustment are deemed to be inadequate to resolve the toxicity or infection, or are 
inconsistent with the patient’s ability to safely complete the protocol (see Section 7.3.2 
for guidelines); 
• The study is terminated by the Sponsor. 
For patients who discontinue early from the study, or if the study is prematurely terminated by 
the Sponsor, the Investigator or designee will contact the patient and/or the patient’s legal 
guardian(s) within 4 to 7 days after withdrawal or termination to obtain information about the 
reason(s) for discontinuation and to assess for any AEs.  The Investigator should collect 
information pertaining to new AEs and follow-up ongoing AEs.  In addition, the Investigator 
should immediately contact Genzyme to discuss the reasons for the patient’s discontinuation.   
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All patients should return to the clinic for the final clinical assessments (Week 75, Day 518 
assessments listed in Table 9-3) within 14 days, unless otherwise specified.  All AEs ongoing at 
the time of withdrawal or study termination require a 30-day follow up.  The Investigator will 
provide a written report on the Completion/Discontinuation section of the electronic case report 
form (eCRF), describing the reason for discontinuation.  The Investigator will attempt to collect 
all withdrawal assessments if a patient discontinues from the study.  The Investigator will be 
asked to follow all SAEs that were ongoing at the time of withdrawal or termination until 
resolution (and information reported to Genzyme Global Patient Safety and Risk Management 
[GPS-RM]), until the Investigator deems follow-up is no longer medically necessary, or until the 
patient is lost to follow-up.   
In addition, if a patient in Regimen B discontinues the study for any reason during the ITI 
treatment module, the Investigator will continue to follow-up with the patient for a period of at 
least 45 days after the last dose of rituximab is administered (at a medically appropriate 
frequency to be determined by the Investigator) to monitor for any new AEs that may be 
suggestive of immunosuppressant-induced toxicity and/or are secondary to immunosuppression. 
Because there have been documented incidents of delayed onset of AEs related to rituximab 
administration (Ram, 2009, Leukemia Lymphoma), it is recommended that physicians report any 
AEs suggestive of immunosuppressant-induced toxicity to the product manufacturer in addition 
to Genzyme as a spontaneous report.  For patients who have withdrawn consent or who have 
otherwise completed the clinical study, these data will not be included in the clinical study 
database, but will be maintained in the GPS-RM surveillance database. 
In the event that a patient dies, permission will be sought (through a separate informed consent 
form) from the next of kin or the patient’s legal guardian(s) for a research autopsy or post-
mortem research biopsy.  Samples collected from these procedures will be used for research 
purposes only and data will not be provided to the Investigator or be included in any study 
analyses. 
7.3.2 Patient Withdrawal From the Immune Tolerance Induction Regimen 
Patients will be carefully monitored for any signs of infection or toxicity during the study.  If any 
of the criteria below are met during administration of the ITI regimen, the regimen will be 
temporarily discontinued to permit further evaluation of the patient by the Investigator in 
consultation with Genzyme (and the ITIRB, as appropriate).  Additionally, the regimen may also 
be temporarily or permanently discontinued in response to other clinically significant findings, at 
the discretion of the Investigator. 
• The patient exhibits unacceptable renal toxicity, as defined by a >2x increase in serum 
creatinine from the baseline value with a resultant value that is above the normal range.  
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If a >2x increase from baseline is observed and the resultant value is still within the 
normal range, the patient may continue on the immunosuppressive regimen at the 
discretion of the Investigator; 
• The patient exhibits unacceptable liver toxicity, as defined by a >3x increase in AST or 
ALT from the respective baseline values and/or an increase in direct, indirect or total 
bilirubin of >3x the upper limit of normal; 
• The patient exhibits significant worsening of pulmonary symptoms; 
• The patient develops an infection that is resistant to treatment; 
• The patient exhibits signs of significant bone marrow suppression, as defined by a 
platelet count of <50,000/mm3 or a neutrophil count <500/mm3;  
• The patient has significant red cells in the urine and/or symptoms suggestive of severe 
hemorrhagic cystitis;  
• Any SAE occurring during the study that is ≥Grade 4 (according to NCI/CTCAE, 
Version 3.0), and assessed as related to any of the study medications or procedures. 
For the purpose of this study, if any of the above criteria are met or if the regimen is discontinued 
by the Investigator due to other clinically significant findings, the results will be considered 
indicative of a definite or possible stopping rule.  The Investigator is responsible for notifying the 
relevant Institutional Review Board (IRB) and Genzyme GPS-RM via phone, fax, or e-mail 
when a stopping rule has been met or when a possible stopping rule is being evaluated.  Any 
findings determined to be a stopping rule will be reported to the regulatory authorities by the 
Sponsor when appropriate.  See Section 9.7 for the specific stopping rules for this study. 
Pending the outcome of further evaluation of the patient (and, as appropriate, an ad hoc review 
of safety data conducted by the ITIRB as outlined in Section 12.3), the regimen may be 
permanently discontinued, continued at the same dose, or continued at an adjusted dose in select 
or all patients. 
7.3.3 Patient Replacement 
Given the small size of the AGLU03707 study, if a patient prematurely discontinues the study 
for any reason, additional patients may be enrolled to ensure that a sufficient number of patients 
complete the study to evaluate the efficacy and safety of the ITI regimens. 
7.4 
Adjustments to Dose or Dosing Schedule 
Pretreatment, rate reduction, or postponement of dosing (e.g., due to transient patient illness) are 
permitted, at the discretion of the Investigator, to prevent and/or manage adverse drug reactions.   
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In the event that a patient is unable to tolerate the per-protocol regimen despite the use of 
pretreatments, rate reduction, and/or supportive measures (see Section 8.3), an adjustment in the 
dose of Myozyme, cyclophosphamide, rituximab, methotrexate, and/or IVIG, may be made, if 
medically indicated, to enable a patient to safely continue in the study while maintaining the 
potential clinical benefit of the regimen.  All such dose adjustments must be discussed with and 
approved by the Genzyme GPS-RM Safety Officer or designee, prior to implementation.  At the 
discretion of Genzyme, such dose adjustments may also be reviewed by the ITIRB prior to 
implementation.   
A patient on Regimen B who completes the initial cycle of rituximab treatment may be 
considered for an optional, additional cycle of rituximab (up to 4 additional doses) within the 
first 6 months of the study, as described in Section 8.1, if it is felt that he/she would benefit from 
continuing the regimen, either because he/she responded favorably to the initial treatment cycle 
or because he/she failed to exhibit a satisfactory response to the initial treatment cycle in terms of 
clinical response and/or antibody titer.  This additional cycle must be completed within the first 
6 months of the study.   
7.5 
Study or Site Termination 
If the Study Director, Medical Monitor, GPS-RM Safety Officer, Investigator, Regulatory 
Authorities, or IRB discover conditions during the study that indicate that the study or site should 
be terminated, this action may be taken after appropriate consultation between the Investigator 
and Genzyme’s Medical Monitor.  Conditions that may warrant termination of the study include, 
but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the 
study; 
• The decision on the part of Genzyme to suspend or discontinue testing, evaluation, or 
development of the study drug; 
• Failure of the Investigator to comply with pertinent local and national regulations; 
• Submission of knowingly false information from the research facility to Genzyme, IRB or 
any national regulatory officials;  
• Non-adherence to protocol requirements. 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Guidelines. 
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8. 
TREATMENTS 
8.1 
Treatments Administered 
The treatments to be administered in this study are summarized below by regimen. 
Patients on Regimen A 
• Myozyme: 20 mg/kg IV qow for a minimum of 18 months or, if the patient is <6 months 
of age at the time of enrollment, until the patient is 2 years of age. 
• Cyclophosphamide: 250 mg/m2 IV every 4 weeks after Myozyme infusion for 6 months. 
The first 5 weeks of treatment for Regimen A are shown in Table 8-1 below. 
Table 8-1 
Treatment Regimen A 
 
W1a
W2a
W3a
W4a
W5a
 
D0 
D7 
D14 
D21 
D28 
Myozyme 
X 
 
X 
 
X 
Cyclophosphamideb
X 
 
 
 
X 
a Weeks 2 to 5 will be repeated through Week 24 for Myozyme and cyclophosphamide AND from Week 25 to 
Week 75 for Myozyme. 
b Refer to Table 9-1 for further information regarding the administration of cyclophosphamide. 
Note:  It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider IVIG 
administration at a dose of 400 mg/kg, regardless of age, if indicated per the individual Investigator’s clinical 
discretion. 
Key:  W=Week; D=Day 
 
Patients on Regimen B 
• Myozyme:  20 mg/kg IV qow for a minimum of 18 months or, if the patient is <6 months 
of age at the time of enrollment, until the patient is 2 years of age.  
• Rituximab:  375 mg/m2 (or 12.5 mg/kg in those patients with a BSA ≤0.5 m2) IV weekly 
for 4 weeks, beginning the day after the first Myozyme infusion.  An optional, additional 
4-week cycle of rituximab (up to 4 additional doses) may be administered within the first 
6 months of the study.  The administration of an additional cycle of rituximab must be 
discussed with and approved by the Genzyme GPS-RM Safety Officer, or designee, prior 
to implementation and may, at the discretion of Genzyme, also be reviewed with the 
ITIRB prior to implementation.  This additional cycle must be completed within the first 
6 months of the study.  If the additional cycle is approved, these data will be included in 
the 6-month periodic ITIRB review.  The total number of rituximab doses will not exceed 
8 doses. 
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• Methotrexate:  15 mg/m2 SC qow on the day after Myozyme infusion for 6 months 
(12 doses).  Folinic acid may be given at the discretion of the Investigator beginning 
24 hours after the dose of methotrexate. 
The first 6 weeks of treatment for Regimen B are shown in Table 8-2 below. 
Table 8-2 
Treatment Regimen B 
 
W1 
W2 
W3 
W4 
W5a
W6a
 
D0 
D1 
D8 
D14 
D15 
D22 
D28 
D29 
D35 
Myozyme 
X 
 
 
X 
 
 
X 
 
 
Rituximabb,c
 
X 
X 
 
X 
X 
 
 
 
Methotrexatec
 
X 
 
 
X 
 
 
X 
 
a Weeks 5 and 6 will be repeated through Week 24 for Myozyme and methotrexate AND from Week 25 to Week 75 
for Myozyme.   
b An optional, additional 4-week cycle of rituximab (up to 4 additional doses) may be administered as described 
above.  This additional cycle must be completed within the first 6 months of the study. 
c Refer to Table 9-2 for additional information pertaining to administration of rituximab and methotrexate. 
Note:  It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider IVIG 
administration at a dose of 400 mg/kg, regardless of age, if indicated per the individual Investigator’s clinical 
discretion. 
Key:  W=Week; D=Day 
 
For both treatment regimens, the Investigator or appropriate designee should evaluate the patient 
prior to the administration of any study medications (Myozyme, cyclophosphamide, rituximab, 
and/or methotrexate).  This should include a brief physical examination and review of the most 
recent laboratory tests and vital signs to specifically ensure that the patient is clinically stable and 
can tolerate administration of these agents.  Dosing should be postponed if the patient is acutely 
ill on a scheduled dosing day.  
Adjustments to the planned doses and/or dosing schedules for the study treatments are discussed 
in Section 7.4. 
8.1.1 Myozyme 
Patients will receive Myozyme (20 mg/kg qow) as an IV infusion, according to the Myozyme 
Investigator’s Brochure.  The total amount of Myozyme administered may be adjusted as needed 
to account for changes in body weight.   
Clinical management guidelines for Myozyme can be found in the local prescribing information.  
Myozyme should be infused in a dedicated IV line.  Infusions should be administered in a step-
wise manner.  Vital signs should be monitored as described in Section 9.4.4.  It is recommended 
that the infusion should begin at an initial rate of approximately 1 mg/kg/hour and may be 
incrementally augmented, if there are no signs of IARs, until a maximum rate of approximately 
7 mg/kg/hour is reached, as follows:  
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• Step 1: approximately 1 mg/kg/hour administered over a minimum of 30 minutes 
 – If no signs of IARs go to next step; 
• Step 2: approximately 3 mg/kg/hour administered over a minimum of 30 minutes 
 – If no signs of IARs go to next step;  
• Step 3: approximately 5 mg/kg/hour administered over a minimum of 30 minutes 
 – If no signs of IARs go to next step; 
• Step 4: approximately 7 mg/kg/hour administered for the remainder of the infusion.   
IARs are more likely to occur at higher infusion rates.  For this reason, the infusion rate may be 
slowed and/or temporarily stopped in the event of an IAR.   
The length of infusion is approximately 3.5 to 4 hours for a dose of 20 mg/kg.  Specific details 
pertaining to the infusion volumes and rates can be found in the Investigational Product Handling 
Manual. 
Patients should continue to be observed for occurrence of AEs for 2 hours after each infusion. 
Authorized medical personnel will be responsible for the administration of investigative agents 
throughout the study and should document in the medical record the rationale for making any 
changes to the administration steps outlined in this section. 
8.1.2 Cyclophosphamide 
Cyclophosphamide 250 mg/m2 will be given IV according to the local prescribing information 
(refer to Appendix 14.1).  
Patients in Regimen A who have cardiomegaly or hypertrophic cardiomyopathy will be admitted 
to the hospital for all cyclophosphamide infusions, and will remain in the hospital for 
observation for a minimum of 24 hours after completion of the infusion.   
A complete blood count (CBC) with differential, Chemistry, CK and CK-MB, and urinalysis 
should be performed prior to each cyclophosphamide infusion, and all laboratory results should 
be reviewed by the Investigator prior to the start of the infusion.  Results of the most recent 
immunoglobulin panel should also be reviewed prior to the infusion. 
Telemetry should be performed during each cyclophosphamide infusion to patients with 
cardiomegaly or hypertrophic cardiomyopathy from at least 10 minutes prior to the start of the 
infusion until at least 2 hours post-infusion.  Infusions will be discontinued in the event of 
serious or life-threatening cardiac arrhythmias, and may be adjusted or discontinued in response 
to any other clinically significant findings, at the discretion of the Investigator.  At the discretion 
of the Investigator, patients who develop clinically significant arrhythmias may also undergo 
additional cardiac monitoring. 
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Prior to dosing, Investigators should familiarize themselves with any relevant premedication 
requirements, contraindications, warnings, precautions for use, and the AE profile, as provided in 
the local prescribing information (refer to Appendix 14.1). 
8.1.3 Rituximab 
Rituximab 375 mg/m2 (or 12.5 mg/kg in those patients with a BSA ≤0.5 m2) will be given IV 
according to the local prescribing information (refer to Appendix 14.2).   
Patients in Regimen B will be admitted to the hospital for all rituximab infusions, and will 
remain in the hospital for observation for a minimum of 24 hours after completion of the 
infusion.   
The Investigator should consider pretreatment with antihistamines and acetaminophen as 
suggested in the rituximab local prescribing information (refer to Appendix 14.2).   
A CBC with differential, Chemistry, CK and CK-MB, and urinalysis will be performed prior to 
each rituximab infusion, and all laboratory results will be reviewed by the Investigator prior to 
the start of the infusion.  Results of the most recent immunoglobulin panel will also be reviewed 
prior to the infusion; an ad hoc immunoglobulin panel may be ordered at the discretion of the 
Investigator (depending upon when the most recent results were reported). 
Telemetry should be performed during each rituximab infusion from at least 10 minutes prior to 
the start of the infusion until at least 2 hours post-infusion.  Infusions will be discontinued in the 
event of serious or life-threatening cardiac arrhythmias, and may be adjusted or discontinued in 
response to any other clinically significant findings, at the discretion of the Investigator.  At the 
discretion of the Investigator, patients who develop clinically significant arrhythmias may also 
undergo additional cardiac monitoring. 
Prior to dosing, Investigators should familiarize themselves with any relevant premedication 
requirements, contraindications, warnings, precautions for use, and the AE profile for rituximab, 
as provided in the local prescribing information (refer to Appendix 14.2). 
8.1.4 Methotrexate 
Methotrexate 15 mg/m2 will be given SC according to the local prescribing information (refer to 
Appendix 14.3). 
A CBC with differential, Chemistry, CK and CK-MB, and urinalysis will be performed prior to 
each SC dose of methotrexate, and all laboratory results will be reviewed by the Investigator 
prior to the dose of methotrexate being administered.  Results of the most recent 
immunoglobulin panel should also be reviewed prior to dosing; an ad hoc immunoglobulin panel 
may be ordered at the discretion of the Investigator (depending upon when the most recent 
results were reported). 
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Folinic acid supplementation may be given at the discretion of the Investigator beginning 
24 hours after the dose of methotrexate. 
Prior to dosing, Investigators should familiarize themselves with any relevant premedication 
requirements, contraindications, warnings, precautions for use, and the AE profile, as provided in 
the local prescribing information (refer to Appendix 14.3). 
8.1.5 Intravenous Immunoglobulin 
It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider 
IVIG administration at a dose of 400 mg/kg, regardless of age, if indicated per the individual 
Investigator’s clinical discretion.   
Prior to dosing, Investigators should familiarize themselves with any relevant premedication 
requirements, contraindications, warnings, precautions for use, and the AE profile for IVIG, as 
provided in the local prescribing information (refer to Appendix 14.4). 
8.2 
Investigational Products 
Myozyme will be supplied as a lyophilized product in single-use 20 mL vials containing 
approximately 50 mg/vial of Myozyme.  This product must be stored in a secure location with 
limited access, under adequate refrigerated temperature conditions (2 degrees Celsius [°C] to 
8°C).  Re-constituted Myozyme should be protected from light. 
Commercial methotrexate sodium for injection (a formulation not containing benzyl alcohol) 
will be obtained by Genzyme and supplied in commercial packaging with appropriate 
supplemental labeling.  Methotrexate should be stored at controlled room temperature (20°C to 
25°C) and protected from light.   
A liquid concentrate of rituximab intended for IV administration via a dedicated line will be 
obtained by Genzyme and supplied in commercial packaging with appropriate supplemental 
labeling.  Rituximab must be stored under controlled, refrigerated conditions (2°C to 8°C) and 
protected from light.  
Lyophylized cyclophosphamide for IV injection or infusion will be obtained by Genzyme and 
supplied in commercial packaging with appropriate supplemental labeling.  Prior to 
reconstitution, cyclophosphamide must be stored at or below 25°C (the upper limit of controlled 
room temperature).  Reconstituted cyclophosphamide is chemically and physically stable for up 
to 24 hours at controlled room temperature and up to 6 days under refrigerated conditions; it does 
not contain any antimicrobial preservatives and thus care must be taken to assure the sterility of 
prepared solutions.  
IVIG (human) is a sterile, highly purified, and concentrated source of IgG antibodies, prepared 
from large pools of human plasma.  It is available as a 10%, ready-to-use, liquid formulation in 
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various brands.  It will be provided to participating sites for study patients, as defined in 
Section 8.1, in commercial packaging with supplemental labeling.  IVIG should be stored 
according to the manufacturer’s instructions. 
IVIG should be administered via a dedicated line, in a step-wise fashion, at the minimum rate of 
infusion, as practical.  Refer to the product-specific local prescribing information for infusion 
rates.  Investigators should be familiar with IVIG therapy and the risks associated with it.  
Administration should be conducted in accordance with the product’s local prescribing 
information and the institutional guidelines of the participating site. 
All investigational medications must be stored in a secure area with limited access.   
Additional details can be found in the Investigational Product Handling Manual.  For a full 
description of rituximab, methotrexate, cyclophosphamide, and IVIG storage instructions, refer 
to the respective local prescribing information (refer to Appendices 14.1 through 14.4). 
8.2.1 Receipt of Investigational Product 
If the shipment was received as stated, the Investigator or designee must place a check mark in 
the Received/Verified box, and then sign and date the Proof of Receipt (POR) form.  The form 
must then be faxed to Genzyme (number listed on POR form) within 48 hours of receipt.  If there 
are any discrepancies with the shipment, Genzyme should be contacted immediately (contact 
information is listed on the POR form).  A copy of this form must be retained in the site files.   
The clinical supplies are to be prescribed only by the Investigator(s) named on the US Food and 
Drug Administration Form 1572.  Under no circumstance will the Investigator or Sub-
Investigator allow the investigational products to be used other than as directed by the protocol.  
8.2.1.1 Packaging and Labeling 
Genzyme’s Clinical Pharmacy Research Services (CPRS) will manage packaging and labeling of 
the Investigational product. 
Vials of Myozyme will be packaged in appropriately sized kits.  Each vial and kit will be labeled 
with a single-panel label.  Label text will minimally include the contents of the vial, lot number, 
storage conditions, Genzyme’s name and address, and the statement “Caution:  New Drug - 
Limited by Federal (or US) law to investigational use.”  Each kit label will have a space for the 
patient’s identification number, date of birth, and initials to be handwritten by the clinical site 
upon receipt of product. 
Vials of cyclophosphamide, rituximab, methotrexate, and IVIG will be supplied in commercial 
packaging with appropriate supplemental labeling provided by Genzyme. 
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8.2.1.2 Treatment Preparation 
Infusions must be prepared by a qualified, authorized pharmacist (or designee) using aseptic 
technique.  The pharmacist or designee will determine the dose and quantity of vials required 
based on the patient’s weight (Myozyme, IVIG) or BSA (rituximab, methotrexate, 
cyclophosphamide), as determined monthly.  BSA area should be calculated using the Haycock 
formula (Haycock, 1978, J Pediatr): BSA (m2) = Height(0.3964) * Weight(0.5378) * 0.024265, where 
height is in cm and weight is in kg. 
Each vial of Myozyme is reconstituted with 10.3 mL of sterile water for injection to yield a 
5 mg/mL solution.  The volume required for the dose must be withdrawn from each vial slowly 
to avoid foaming.  The reconstituted solution should be further diluted into a fixed total volume 
of 0.9% sodium chloride for injection, dependant on patient weight (kg) and dose (mg/kg).  The 
concentration of the final solution must be between 0.5 to 4 mg/mL.  Further information on the 
preparation and administration of Myozyme is provided in the Investigational Product Handling 
Manual. 
For a full description of cyclophosphamide, rituximab, methotrexate, and IVIG preparation and 
administration instructions, refer to the respective local prescribing information (refer to 
Appendices 14.1 through 14.4). 
8.3 
Supportive Measures 
Necessary supportive measures for optimal medical care are to be given throughout the study as 
medically indicated, and according to the site’s guidelines and the judgment of the Investigator.  
Some general guidelines for the management of toxicity and infection are provided in the 
sections below.  Investigators should familiarize themselves with all warnings, contraindications, 
and precautions for use for cyclophosphamide, rituximab, methotrexate, and IVIG as provided in 
the respective local prescribing information.  
All concomitant medications and relevant supportive therapy must be recorded in the appropriate 
eCRF. 
8.3.1 Gastrointestinal Toxicity 
Gastrointestinal toxicity, including nausea, vomiting, and diarrhea, have been reported with 
methotrexate treatment.  Administration of methotrexate should be postponed for patients 
experiencing vomiting or diarrhea until the patients have recovered and are adequately 
re-hydrated (see Section 8.3.5).  
8.3.2 Nephrotoxicity 
Methotrexate-induced nephrotoxicity is due primarily to the precipitation of methotrexate and 
7-hydroxymethotrexate in renal tubules.  Close attention to renal function including adequate 
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hydration (see Section 8.3.5) and monitoring of serum creatinine levels is essential.  At the 
discretion of the Investigator, a prophylactic regimen of allopurinol may be administered (for 
urine alkalinization) to reduce the potential risk of renal toxicity.  Concomitant administration of 
other nephrotoxic agents should be avoided wherever possible. 
See also Section 7.3.2, Patient Withdrawal from the ITI Regimen. 
8.3.3 Hepatotoxicity 
Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged 
use.  Acutely, liver enzyme elevations are frequently seen, and are usually transient and 
asymptomatic, although not always predictive of subsequent hepatic disease.  Liver enzymes 
should be closely monitored for any sustained increases in AST or ALT that exceed the transient 
elevations that may occur secondary to muscle cell damage in patients with Pompe disease.  
Concomitant administration of other hepatotoxic agents should be avoided wherever possible.  
See also Section 7.3.2, Patient Withdrawal from the ITI Regimen. 
8.3.4 Pulmonary Toxicity 
Pulmonary symptoms (especially a dry non-productive cough) or a non-specific pneumonitis 
occurring during methotrexate therapy may be indicative of a potentially dangerous lesion, and 
can occur acutely and at any dose.   Therefore, any further deterioration in a patient’s pulmonary 
function following administration of methotrexate should be carefully investigated prior to 
resuming the ITI regimen, e.g., a chest X-ray may performed, if medically indicated.  
See also Section 7.3.2, Patient Withdrawal from the ITI Regimen. 
8.3.5 Hydration 
It is recommended that the patient’s fluid status be carefully monitored during administration of 
methotrexate to reduce the risk of potential renal and hepatic toxicity.  Careful monitoring of 
fluid status is also important during administration of cyclophosphamide to reduce the risk of 
hemorrhagic cystitis.  Patients should be well-hydrated prior to methotrexate or 
cyclophosphamide administration.  However, because patients with Pompe disease are at risk for 
cardiopulmonary complications, a cardiologist should be consulted regarding patients’ cardiac 
status to determine appropriate hydration and avoid volume overload. 
8.3.6 Infection 
Infection control is an integral part of the management of immunosuppressed patients, including 
children, adolescents, and adults.  It is recommended that the Investigator follow the infection 
control guidelines detailed in the Red Book (Red Book: Infection Control in Hospitalized 
Children and Physician Offices, 2003).  The patient and/or legal guardian(s) should be instructed 
in the techniques used to prevent the transmission of infections in the household.  
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Infection prophylaxis for P. jiroveci (formerly known as P. carinii) using Trimethoprim sulfa 
(Bactrim®) or alternate regimens at the age-appropriate recommended doses is advised for 
patients who are >6 years of age and have moderate (750 to1499 CD4 cell count) to severe (<750 
CD4 cell count) immunosuppression, as per the current guidelines for prophylaxis against 
P. jiroveci in immunocompromised children (Centers for Disease Control and Prevention, 1995) 
and available online (http://www.cdc.gov/mmwr/preview/mmwrhtml/00037275.htm).  
Prophylaxis for other opportunistic bacterial, fungal, and/or viral infections may also be 
considered at the discretion of the Investigator and in accordance with current pediatric 
antimicrobial prophylaxis guidelines (Red Book: Antimicrobial Prophylaxis, 2003). 
Patients should be monitored closely for any sign of infection, with consequent aggressive 
treatment and management, should this occur.  In selecting an antibiotic to treat the infection, 
attention should be given to potential drug interactions among the investigative agents and 
certain antibiotics.  For patients on Regimen B, sulfonamides and penicillins should be used with 
extreme caution due to the potential for these agents to reduce the renal clearance of 
methotrexate with a resultant increased risk of hematologic and/or GI toxicity.  It is 
recommended that an infectious disease specialist be consulted whenever any antimicrobial 
agent is to be administered for the treatment of active infection in patients receiving Regimen B. 
Vaccination with live virus is prohibited within 1 month prior to enrollment in this study and 
until a patient’s B cell count returns to normal, or at least 3 months following completion of the 
ITI regimen, whichever is longer.  While inactivated vaccines are permitted, the effectiveness of 
inactive virus given concomitantly with cyclophosphamide, rituximab, or methotrexate is 
questionable.  However, patients undergoing ITI regimens may benefit from specific 
immunizations directed at preventing infections by organisms to which they are particularly 
susceptible; special consideration should be given to the administration of pneumococcal, 
influenza, and/or meningococcal vaccines, and any other recommendations for 
immunosuppressed patients, as outlined in the Red Book (Red Book: Immunizations in Special 
Clinical Circumstances, 2003).   
Further information regarding infection prophylaxis and the treatment of active infection is 
provided in the SOM. 
See also Section 7.3.2, Patient Withdrawal from the ITI Regimen. 
8.3.7 Anaphylactic/Allergic Reactions 
Serious and potentially life-threatening hypersensitivity reactions, including anaphylaxis, have 
been reported following administration of Myozyme, rituximab, and cyclophosphamide, which 
could be worse in patients with advanced Pompe disease who may already have compromised 
cardiac and respiratory function.  Therefore, appropriate medical support measures, including 
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cardiopulmonary resuscitation equipment, should be readily available during administration of 
these agents.  All cyclophosphamide infusions to patients with cardiomegaly or hypertrophic 
cardiomyopathy and all rituximab infusions will occur in a hospital setting, and patients will 
remain in the hospital for a minimum of 24 hours post-infusion.   
Pretreatments may be administered prior to rituximab infusion as per guidelines in the local 
prescribing information.  Investigators should also familiarize themselves with the prescribing 
information on the management of rituximab AEs.   
Guidance on the management of Myozyme IARs, including recommended pretreatments, is 
provided in Appendix 1 of the current Myozyme Investigator’s Brochure. 
8.4 
Concomitant Medication/Therapy 
Other than those designated in the study regimen, no concomitant cytotoxic therapy or 
investigational therapy is allowed during the study.   
Patients on both regimens may not receive any live vaccines within 1 month prior to enrollment 
and until B cell count returns to normal or at least 3 months following completion of the ITI 
regimen, whichever is longer.  Use of alternative medications (e.g., herbal, botanical, etc) is 
strongly discouraged during the entire study period for all patients. 
Caution should be used when administering general anesthesia for the placement of a central 
venous catheter or other surgical procedures in infantile-onset Pompe disease patients with 
cardiac hypertrophy (see Section 4.4.1.3).  Caution should also be exercised in administering 
general anesthesia to patients receiving cyclophosphamide during the ITI Treatment Module for 
Regimen A (see Section 4.4.2.1). 
For patients receiving Regimen B, concomitant administration of NSAIDs is strongly 
discouraged for the duration of the ITI Treatment Module, due to reports of unexpectedly severe 
(sometimes fatal) bone marrow suppression, aplastic anemia, and GI toxicity with concomitant 
administration of methotrexate (usually in high dosage) along with some NSAIDs.  To the extent 
possible, use of nephrotoxic (e.g., vancomycin, amphotericin B, etc) and hepatotoxic (e.g., 
voriconazole, cyclosporine, etc) agents is also to be avoided for the duration of administration of 
the ITI regimen due to potential increased risk of nephrotoxicity and hepatotoxicity when 
administered in combination with methotrexate.  Sulfonamides and penicillins should be used 
with extreme caution due to the potential for these agents to reduce the renal clearance of 
methotrexate with a resultant increased risk of hematologic and/or GI toxicity; it is 
recommended that an infectious disease specialist be consulted whenever any antimicrobial 
agent is to be administered for the treatment of active infection in patients receiving this regimen.  
Folinic acid supplementation may be given at the discretion of the Investigator. 
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8.5 
Study Drug Misdosing or Overdosing 
In the event that a patient is misdosed or overdosed, refer to the Myozyme Investigator’s 
Brochure or the local prescribing information for the specific agents. 
8.6 
Dose Selection 
Selection of the doses of Myozyme, cyclophosphamide, rituximab, and methotrexate was based 
on nonclinical and clinical experience with the agents, as outlined in Section 4.2 for Myozyme 
and Section 4.3.1 to Section 4.3.3 for the immunosuppressant agents. 
8.7 
Blinding and Randomization 
This is an open-label study. 
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PROPRIETARY AND CONFIDENTIAL 
9. 
EFFICACY AND SAFETY VARIABLES 
9.1 
Efficacy and Safety Measurements Assessed and Study Schedule of 
Assessments 
The study will be conducted as outlined in the following sections.  Study assessments will be 
performed according to the Schedule of Assessments for the ITI treatment module 
(Months 1 through 6) and the follow-up module (Months 7 through 18).  The Schedules of 
Assessments for the Regimen A ITI treatment module and Regimen B ITI treatment module are 
provided in Table 9-1 and Table 9-2, respectively.  The Schedule of Assessments for the follow-
up module, which is identical for both regimens, is provided in Table 9-3.  The Schedule of 
Assessments for patients who enroll before 6 months of age and therefore must be on the study 
for longer than 18 months is provided in Appendix 14.6.  Specific details of the study 
assessments are provided in Section 9.2 through Section 9.6, and in the SOM. 
Guidance on the relative priority of each assessment is provided in the SOM, in the event that 
there is insufficient blood volume to complete all study laboratory assessments, or insufficient 
time to complete all assessments at a given study visit.  During the ITI treatment module, a visit 
window of ± 7 days will be permitted for the Pompe PEDI, GMFM-66, and AIMS assessments; 
all remaining assessments should be conducted at the indicated visit in the Schedule of 
Assessments.  A visit window of ± 2 weeks (14 days) will be permitted for all study assessments 
during the follow-up module; however, the visit window is ±1 week for Myozyme infusions.  
Eligible CRIM-negative patients will be followed for a minimum of 18 months on treatment or, 
if the patient is <6 months of age at the time of enrollment, until the patient is 2 years of age. 
 
 
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Table 9-1 
Schedule of Assessments – Regimen A ITI Treatment Module (Months 1 Through 6) 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
W0 
W1 
W2 
Weeks 3 and 4 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
 
BL 
D 
-1 
D 
0 
D 
1 
D 
8 
D
14 
D
15 
D 
20 
D 
22 
D 
28 
D 
29 
D 
42 
D 
43 
D 
56 
D 
57 
D 
70 
D 
71 
D 
84 
D 
85 
D 
98 
D 
99 
D 
112 
D 
113 
D 
126 
D 
127 
D 
140 
D 
141 
D 
154 
D 
155 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
Inclusion/Exclusion 
Criteria1
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical/ Pompe 
Disease History2
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Mutation 
Analysis3
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Parental GAA 
Mutation Analysis3
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing4
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Optional Porta-Catheter 
Placement 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination5
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Research 
Immunophenotyping 
 
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte 
Subpopulation Counts 
 
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional T cell Assay 
(ELISPOT) 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Immunoglobulin Panel6
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
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Table 9-1 
Schedule of Assessments – Regimen A ITI Treatment Module (Months 1 Through 6) (continued) 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
W0 
W1 
W2 
Weeks 3 and 4 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
 
BL 
D 
-1 
D 
0 
D 
1 
D 
8 
D
14 
D
15 
D 
20 
D 
22 
D 
28 
D 
29 
D 
42 
D 
43 
D 
56 
D 
57 
D 
70 
D 
71 
D 
84 
D 
85 
D 
98 
D 
99 
D 
112 
D 
113 
D 
126 
D 
127 
D 
140 
D 
141 
D 
154 
D 
155 
CBC with Differential6
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Chemistry, CK and 
CK-MB6
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis6
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Anti-rhGAA Antibody 
(IgG) Titers/Inhibitory 
Antibody Monitoring7
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECG 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECHO 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital Sign Monitoring 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Telemetry Monitoring8
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Cyclophosphamide9
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Myozyme Infusion 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pompe PEDI10
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GMFM-6610
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AIMS10
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ventilator Use 
Assessment 
Continuous Monitoring 
 
 
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Table 9-1 
Schedule of Assessments – Regimen A ITI Treatment Module (Months 1 Through 6) (continued) 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
W0 
W1 
W2 
Weeks 3 and 4 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
 
BL 
D 
-1 
D 
0 
D 
1 
D 
8 
D
14 
D
15 
D 
20 
D 
22 
D 
28 
D 
29 
D 
42 
D 
43 
D 
56 
D 
57 
D 
70 
D 
71 
D 
84 
D 
85 
D 
98 
D 
99 
D 
112 
D 
113 
D 
126 
D 
127 
D 
140 
D 
141 
D 
154 
D 
155 
Concomitant Medication 
Monitoring11
Continuous Monitoring 
Concomitant Therapy 
Monitoring11
Continuous Monitoring 
Adverse Event 
Monitoring2
Continuous Monitoring 
1 Includes, but is not limited to, confirmation of CRIM status, documentation of GAA enzyme deficiency, and anti-rhGAA titer levels (see Section 7.1). 
2 At screening/baseline, medical history will include an evaluation of retrospective, related AEs occurring while the patient was receiving Myozyme treatment prior to study entry (Section 9.6). 
3 Blood sample for patient gene mutation analysis must be obtained at baseline.  Testing performed prior to informed consent is allowed, provided that written results are provided to the site.  If consent is 
provided, samples also will be obtained from the biological parent(s) at baseline. 
4 Pregnancy testing for female patients of childbearing potential will be repeated on Day 0 if this occurs >14 days after the baseline test.  Pregnancy test results must be obtained prior to starting the ITI 
regimen, and patients with positive test results will be excluded (or withdrawn) from the study. 
5 In addition to the scheduled physical examinations, brief, physical assessments should also be performed prior to the administration of any study medications (Myozyme and cyclophosphamide) to 
specifically ensure that the patient is clinically stable and can tolerate administration of these agents. 
6 Results of the most recent laboratory tests (obtained on the day of the infusion) should be reviewed by Investigators prior to dosing with cyclophosphamide.  Results of the most recent immunoglobulin 
panel should also be reviewed prior to dosing. 
7 If a patient becomes anti-rhGAA (IgG) positive during the course of the study, he/she will also be tested every 2 months for the presence of inhibitory antibodies to Myozyme. 
8 Patients with cardiomegaly or hypertrophic cardiomyopathy will be admitted to the hospital for all cyclophosphamide infusions and will remain in the hospital for a minimum of 24 hours post-infusion. 
9 Patients should be well-hydrated prior to cyclophosphamide administration, but the patients’ cardiac status should be taken into account when determining appropriate amount of hydration. 
10 A visit window of ±7 days will be permitted for the Pompe PEDI, GMFM-66, and AIMS.  All remaining study assessments should be conducted at the indicated study visit during the ITI treatment 
module.  Eligible CRIM-negative patients will be followed for a minimum of 18 months on treatment or, if a patient is <6 months of age at the time of enrollment, until the patient is 2 years of age. 
11 All concomitant medications and therapies, including those given as prophylaxis or prior to an infusion, will be recorded in the eCRF. 
Note:  It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider IVIG administration at a dose of 400 mg/kg, regardless of age, if indicated per the individual 
Investigator’s clinical discretion. 
Key:  AIMS=Alberta Infantile Motor Scale; BL=baseline/screening; CBC=complete blood count; CK=creatine kinase; CK-MB=creatine kinase – myocardial band; CRIM=cross-reacting immunologic 
material; D=day; ECG= electrocardiogram; ECHO; echocardiogram; ELISPOT=enzyme-linked immunosorbent spot [assay]; GAA=acid α-glucosidase; GMFM-66=Gross Motor Function Measure-66; 
IgG=immunoglobulin G; IVIG=intravenous immunoglobulin; PEDI=Pediatric Evaluation of Disability Inventory; rhGAA=Recombinant human acid α-glucosidase; W=week 
 
 
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FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
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Table 9-2 
Schedule of Assessments – Regimen B ITI Treatment Module (Months 1 Through 6) 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
W0 
W1 
W2 
Weeks 3 and 4 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
 
BL 
D 
-1 
D 
0 
D 
1 
D 
8 
D 
14 
D 
15 
D 
22 
D 
28 
D 
29 
D 
42 
D 
43 
D 
56 
D 
57 
D 
70 
D 
71 
D 
84 
D 
85 
D 
98 
D 
99 
D 
112 
D 
113 
D 
126 
D 
127 
D 
140 
D 
141 
D 
154 
D 
155 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
Inclusion/Exclusion 
Criteria1
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical/ 
Pompe Disease History2
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Mutation 
Analysis3
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Parental GAA 
Mutation Analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing4
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Optional Porta-Catheter 
Placement 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination5
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Research 
Immunophenotyping 
 
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte 
Subpopulation Counts 
 
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional T cell Assay 
(ELISPOT) 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Immunoglobulin Panel6
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
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PROPRIETARY AND CONFIDENTIAL 
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Table 9-2 
Schedule of Assessments – Regimen B ITI Treatment Module (Months 1 Through 6) (continued) 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
W0 
W1 
W2 
Weeks 3 and 4 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
 
BL 
D 
-1 
D 
0 
D 
1 
D 
8 
D 
14 
D 
15 
D 
22 
D 
28 
D 
29 
D 
42 
D 
43 
D 
56 
D 
57 
D 
70 
D 
71 
D 
84 
D 
85 
D 
98 
D 
99 
D 
112 
D 
113 
D 
126 
D 
127 
D 
140 
D 
141 
D 
154 
D 
155 
CBC with Differential6
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Chemistry, CK and 
CK-MB6
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis6
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Anti-rhGAA Antibody 
(IgG) Titers/Inhibitory 
Antibody Monitoring7
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECG 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECHO 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital Sign Monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telemetry Monitoring8
 
 
 
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Myozyme Infusion 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Rituximab9,10,11,
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Methotrexate12,13
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pompe PEDI14
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GMFM-6614
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AIMS14
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ventilator Use 
Assessment 
Continuous Monitoring 
 
 
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FINAL: 01 OCTOBER 2009  
PROPRIETARY AND CONFIDENTIAL 
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Table 9-2 
Schedule of Assessments – Regimen B ITI Treatment Module (Months 1 Through 6) (continued) 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
W0 
W1 
W2 
Weeks 3 and 4 
W5 
W7 
W9 
W11 
W13 
W15 
W17 
W19 
W21 
W23 
 
BL 
D 
-1 
D 
0 
D 
1 
D 
8 
D 
14 
D 
15 
D 
22 
D 
28 
D 
29 
D 
42 
D 
43 
D 
56 
D 
57 
D 
70 
D 
71 
D 
84 
D 
85 
D 
98 
D 
99 
D 
112 
D 
113 
D 
126 
D 
127 
D 
140 
D 
141 
D 
154 
D 
155 
Concomitant Medication 
Monitoring15
Continuous Monitoring 
Concomitant Therapy 
Monitoring15
Continuous Monitoring 
Adverse Event 
Monitoring2
Continuous Monitoring 
1 Includes, but is not limited to, confirmation of CRIM status, documentation of GAA enzyme deficiency, and anti-rhGAA titer levels (see Section 7.1). 
2 At screening/baseline, medical history will include an evaluation of retrospective, related AEs occurring while the patient was receiving Myozyme treatment prior to study entry (Section 9.6). 
3 Blood sample for patient gene mutation analysis must be obtained at baseline.  Testing performed prior to informed consent is allowed, provided that written results are provided to the site.  If consent is 
provided, samples also will be obtained from the biological parent(s) at baseline. 
4 Pregnancy testing for female patients of childbearing potential will be repeated on Day 0 if this occurs >14 days after the baseline test.  Pregnancy test results must be obtained prior to starting the ITI 
regimen, and patients with positive test results will be excluded (or withdrawn) from the study. 
5 In addition to the scheduled physical examinations, brief, physical assessments should also be performed prior to the administration of any study medications (Myozyme, methotrexate, or rituximab) to 
ensure that the patient is clinically stable and can tolerate administration of these agents. 
6 Results for the most recent laboratory tests (obtained the preceding day prior to initiating the Myozyme infusion) should be reviewed by Investigators prior to dosing with rituximab and methotrexate.  
Results of the most recent immunoglobulin panel should also be reviewed prior to dosing. 
7 If a patient becomes anti-rhGAA (IgG) positive during the course of the study, he/she will also be tested every 2 months for the presence of inhibitory antibodies to Myozyme. 
8 Patients with cardiomegaly or hypertrophic cardiomyopathy will be admitted to the hospital for all cyclophosphamide infusions and will remain in the hospital for a minimum of 24 hours post-infusion. 
9 Patients will be admitted to the hospital for all rituximab infusions and will remain in the hospital for a minimum of 24 hours post-infusion.  Telemetry will be performed during all rituximab infusions 
from at least 10 minutes prior to the start of the infusion until at least 2 hours post-infusion. 
10 An optional, additional 4-week cycle of rituximab (up to 4 additional doses) may be administered as described in Section 8.1.  This additional cycle must be completed within the first 6 months of the 
study. 
11 Pre-infusion medication may be given as per rituximab treatment guidelines. 
12 Patients should be well-hydrated prior to methotrexate administration, but the patients’ cardiac status should be taken into account when determining appropriate amount of hydration. 
13 Folinic acid supplementation may be given at the discretion of the Investigator beginning 24 hours after the dose of methotrexate. 
14 A visit window of ±7 days will be permitted for the Pompe PEDI, GMFM-66, and AIMS.  All remaining study assessments should be conducted at the indicated study visit during the ITI treatment 
module.  Eligible CRIM-negative patients will be followed for a minimum of 18 months on treatment or, if a patient is <6 months of age at the time of enrollment, until the patient is 2 years of age. 
15 All concomitant medications and therapies, including those given as prophylaxis or prior to an infusion, will be recorded in the eCRF. 
Note:  It is recommended that the Investigator monitor a patient’s immunoglobulin levels and consider IVIG administration at a dose of 400 mg/kg, regardless of age, if indicated per the individual 
Investigator’s clinical discretion. 
Key:  AIMS=Alberta Infantile Motor Scale; BL=baseline/screening; CBC=complete blood count; CK=creatine kinase; CK-MB=creatine kinase – myocardial band; CRIM=cross-reacting immunologic 
material; D=day; ECG= electrocardiogram; ECHO; echocardiogram; ELISPOT=enzyme-linked immunosorbent spot [assay]; GAA=acid α-glucosidase; GMFM-66=Gross Motor Function Measure-66; 
IgG=immunoglobulin G; IVIG=intravenous immunoglobulin; PEDI=Pediatric Evaluation of Disability Inventory; rhGAA=Recombinant human acid α-glucosidase; W=week 
 
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Table 9-3 
Schedule of Assessments – Follow-up Module (Months 7 Through 18) 
Month 71
Month 81
Month 91
Month 101
Month 111
Month 121
Month 131
Month 141
Month 151
Month 161
Month 171
Month 181
EOS1
W25 W27 W29 W31 W33 W35 W37 W39 W41 W43 W45 W47 W49 W51 W53 W55 W57 W59 W61 W63 W65 W67 W69 W71 W732 W75 
 
D168 D182 D196 D210 D224 D238 D252 D266 D280 D294 D308 D322 D336 D350 D364 D378 D392 D406 D420 D434 D448 D462 D476 D490 D504 D518 
Physical Examination3
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Pregnancy Testing4
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Vital Sign Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Myozyme Infusion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Immunophenotyping 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Lymphocyte Subpopulation 
Counts 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Functional T cell Assay 
(ELISPOT) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Immunoglobulin Panel 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
CBC with Differential 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Chemistry, CK and CK-MB 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Anti-rhGAA Antibody (IgG) 
Titers/Inhibitory Antibody 
Monitoring5
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
ECG 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
ECHO 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
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PROPRIETARY AND CONFIDENTIAL 
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linical Protocol Number AGLU03707, Amendment 3 
 
 
 
GENZYME CORPORATION 
FINAL: 01 OCTOBER 2009  
PROPRIETARY AND CONFIDENTIAL 
Table 9-3 
Schedule of Assessments – Follow-up Module (Months 7 Through 18) (continued) 
Month 71
Month 81
Month 91
Month 101
Month 111
Month 121
Month 131
Month 141
Month 151
Month 161
Month 171
Month 181
EOS1
W25 W27 W29 W31 W33 W35 W37 W39 W41 W43 W45 W47 W49 W51 W53 W55 W57 W59 W61 W63 W65 W67 W69 W71 W732 W75 
 
D168 D182 D196 D210 D224 D238 D252 D266 D280 D294 D308 D322 D336 D350 D364 D378 D392 D406 D420 D434 D448 D462 D476 D490 D504 D518 
Pompe PEDI 
 
 
 
 
 
 
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GMFM-66 
 
 
 
 
 
 
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AIMS 
 
 
 
 
 
 
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ventilator Use Monitoring 
Continuous Monitoring 
Concomitant Medication 
Monitoring 
Continuous Monitoring 
Concomitant Therapy 
Monitoring 
Continuous Monitoring 
Adverse Event Monitoring 
Continuous Monitoring 
Key:  AIMS=Alberta Infantile Motor Scale; CBC=complete blood count; CK=creatine kinase; CK-MB=creatine kinase – myocardial band; D=day; ECG=electrocardiogram; ECHO; echocardiogram; 
ELISPOT=enzyme-linked immunosorbent spot [assay]; EOS=End-of-Study; GMFM-66=Gross Motor Function Measure-66; IgG=immunoglobulin G; IVIG=intravenous immunoglobulin; 
PEDI=Pediatric Evaluation and Disability Inventory; rhGAA=Recombinant human acid α-glucosidase; W=week 
1 A visit window of ±2 weeks will be permitted for all study assessments during the follow-up module.  For Myozyme infusions, the visit window is ±1 week. 
2 Patients who are <2 years of age at their W73 visit should continue in the study until they reach their second (i.e., 2 years of age) birthday.  Therefore, these patients should repeat the Schedule of 
Assessments at W25 and continue following the protocol until they reach this birthday (W75 visit will mimic W25 assessments, W77 visit will mimic W27 assessments, etc.).  At the patient’s second 
birthday visit, all End-of-Study (EOS) assessments should be performed for study completion.  See Appendix 14.6 for further details. 
3 In addition to the scheduled physical examinations, brief, physical assessments should also be performed prior to the administration of any study medications (Myozyme) to ensure that the patient is 
clinically stable and can tolerate administration of these agents. 
4 Pregnancy testing will be performed monthly for female patients of childbearing potential, and patients with positive test results will be withdrawn from the study. 
5 If a patient becomes anti-rhGAA (IgG) positive during the course of the study, he/she will also be tested every 2 months for the presence of inhibitory antibodies to Myozyme. 
M
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9.2 
Screening/Baseline Assessments 
Refer to Table 9-1 and Table 9-2 for the list of study assessments to be conducted at baseline. 
9.2.1 Informed Consent 
Prior to the start of any screening procedures, the participating physicians (or designated staff) 
will explain the nature of the study and its risks and benefits to the patient (and/or the patient’s 
legal guardian[s] if the patient is <18 years of age).  Each patient (and/or legal guardian[s]) will 
receive an informed consent form with patient information.  Ample time should be allotted for 
patients/guardians to read the information and ask questions.  The patient (and/or legal 
guardian[s]) will be informed of the right to withdraw from the study at any time, without 
prejudice. 
If the patient and/or legal guardian(s) agree to the patient’s participation, the patient (and/or legal 
guardian[s]) must sign the informed consent form.  A signed copy will be provided to the patient 
(and/or legal guardian[s]), and the original will be retained in the patient’s medical chart. 
In addition, each biological parent will be asked to provide a blood sample for GAA mutation 
analysis; a separate informed consent will be obtained for this procedure. 
9.2.2 Medical History, Demographics, Eligibility Criteria 
A complete medical/surgical/Pompe disease history will be obtained for each patient prior to 
commencing any study procedures.  Specific information will be recorded in the patient’s 
medical chart and the eCRF relating to any prior or existing medical conditions and surgical 
procedures involving the following systems: Infectious Diseases; Allergic; Metabolic/ 
Endocrine/Nutritional; Hematopoietic; Musculoskeletal, Dermatologic; Head, Eyes, Ears, Nose, 
and Throat (HEENT); Breasts; Respiratory; Cardiovascular; Gastrointestinal/Hepatic; 
Genitourinary/Renal; and Neurologic.  All prior history of ventilator use will be collected.  The 
following information will be collected as confirmation of a patient’s eligibility according to the 
study’s inclusion/exclusion criteria: 
• 
Clinical signs and symptoms of Pompe disease; 
• 
Family history of Pompe disease; 
• 
Anti-rhGAA titer levels (at least 2 titers obtained at least 1 month apart*; see Section 7.1) 
• 
GAA enzyme deficiency and GAA gene mutations, including method of diagnosis and 
result(s) (see also Sections 7.1 and 9.2.3); 
• 
CRIM status (see also Sections 7.1 and 9.2.4); 
                                                 
* Only the most recent titer value should be recorded in the eCRF. 
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• 
Relevant medical history including any co-existing conditions, as well as retrospective, 
related AEs (see also Section 9.6); 
• 
Pregnancy status for women of childbearing potential (see also Section 9.4.8). 
Additionally, the following demographic data will be collected: 
• 
Gender; 
• 
Date of birth;  
• 
Race/Ethnicity. 
9.2.3 Genotyping of the Human Acid Alpha-Glucosidase Gene 
DNA will be isolated from peripheral blood samples obtained from patients at baseline for GAA 
mutation analysis.  Note that historical GAA mutation analysis results (performed prior to 
enrollment) are acceptable, provided that written documentation of the laboratory results is 
available at the enrolling site.  When consent is provided, blood samples also will be obtained at 
baseline from the patient’s biological parent(s) for parental GAA mutation analysis.  Using 
established methods, DNA sequencing will be performed on samples to fully characterize both 
deleterious mutations and background variation within the GAA gene.  All samples will be 
analyzed by Genzyme, Framingham, MA. 
9.2.4 Cross-Reacting Immunologic Material Status Testing 
Note that historical CRIM testing results by Western blot analysis (performed prior to 
enrollment) are acceptable, provided that written documentation of the laboratory results is 
available at the enrolling site.  If, however, CRIM testing results are either not available or the 
previous testing was performed using a method other than Western blot assay on skin 
fibroblasts, the patient must have (new) CRIM testing performed to confirm eligibility.  This 
testing must be performed according to the procedures outlined in the SOM.  The Western blot 
assay detects the major protein forms of GAA known to exist in the cell, including 110, 95, 76, 
or 70 kilodalton forms.  A patient is considered CRIM positive if the presence of any bands 
corresponding to the apparent molecular weight of these forms of GAA is detected in samples 
prepared from patient fibroblasts in the Western blot assay. 
9.2.5 Optional Port-a-Catheter 
A central venous catheter may be inserted for this study, at the discretion of the Investigator, to 
facilitate routine and emergency IV treatment.  Caution should be used when administering 
general anesthesia for the placement of a central venous catheter in infantile-onset Pompe 
disease patients with cardiac hypertrophy (see Section 4.4.1.3).   
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Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase 
activity, potentiates the effect of succinylcholine chloride.  If a patient has been treated with 
cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted. 
9.3 
Efficacy Measurements 
9.3.1 Routine Recombinant Human Acid Alpha-Glucosidase Immunoglobulin G Antibody 
Testing 
Serum samples for anti-rhGAA IgG antibody testing will be obtained prior to each infusion at 
the time points indicated in Table 9-1 and Table 9-2.  This monitoring frequency will exceed the 
recommended frequency for patients on commercial therapy (i.e., every 3 months), as a more 
frequent assessment of anti-rhGAA IgG titer is required in this study to fully evaluate the 
antibody response during and following treatment with immunosuppressants. 
Anti-rhGAA IgG testing will be performed by Genzyme.  Refer to the SOM for guidelines on the 
collection and shipment of serum samples. 
9.3.2 Inhibitory Antibody Testing 
If a patient becomes anti-rhGAA (IgG) positive during the course of the study, he/she will also 
be tested every 2 months for the presence of inhibitory antibodies (enzyme activity and uptake) 
to Myozyme.  This testing will be done by Genzyme using the serum sample collected for anti-
rhGAA IgG antibody testing. 
9.3.3 Echocardiogram, Including Left Ventricular Mass Index 
M-mode, 2-dimensional, and Doppler mode echocardiography will be performed.  The primary 
cardiac outcome parameters (measured and derived) to be recorded using off-line review include:  
LVM, LVMI, left ventricular posterior wall thickness, ejection fraction, and shortening fraction. 
ECHOs will be performed according to procedures outlined in the SOM and Cardiology Manual, 
and reviewed by a central cardiologist.  A cardiologist at the study site should also review the 
ECHO in a timely manner for clinical management of the patient. 
9.3.4 Ventilator Use 
In the event that a patient requires ventilator support (invasive or non-invasive) at any time 
during the study, the patient and/or the patient’s legal guardian(s) will be asked to complete a 
daily ventilator use diary.  The daily ventilator use diary is only required to be completed for 
patients using ventilator support. 
The following data points will be captured in the eCRF:  the start date of first ventilator use and 
the reasons for first ventilator use; the average number of hours of ventilator use/day, biweekly 
average, collected from the time of first ventilator use and every 2 weeks thereafter (if 
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applicable) until (1) ventilator support is no longer needed, (2) patient death, or (3) end of the 
study (whichever occurs first); and the date and reason that ventilator use is no longer needed. 
If the patient requires ventilator support on more than 1 occasion during study treatment, the start 
date, start time, stop date, stop time, and reason for each episode of continuous ventilator support 
will be recorded, as will the average number of hours of ventilator use/day, measured biweekly 
average, until (1) ventilator support is no longer needed, (2) patient death, or (3) end of the study 
(whichever occurs first).  If applicable, the date on which tracheostomy was first performed will 
also be recorded. 
9.3.5 Motor Development and Functional Assessments 
Gross motor development and function will be assessed through administration of the 
GMFM-66, AIMS, and the Pompe PEDI.  All persons performing these assessments will be 
trained in order to minimize any test administration variability.  Each assessment will also be 
centrally scored by a trained clinician (e.g., physical therapist).  Details of each assessment are 
provided below and in the SOM. 
9.3.5.1 Gross Motor Function Measure 
The GMFM-66 (Russell, 2002, The Gross Motor Function Measure [GMFM-66 & GMFM-88] 
User’s Manual) will be administered to evaluate changes in motor function.  The GMFM-66 is a 
standardized observational instrument that has been designed and validated to measure change 
over time in the gross motor abilities of children with cerebral palsy.  The GMFM-66 is widely 
used internationally and is recognized as the gold standard for outcomes assessment in clinical 
interventions for individuals with cerebral palsy.  As the instrument is designed to evaluate 
change over time in individual patients, there is no age cutoff for administration of the 
GMFM-66. 
The GMFM consists of 66 items organized into 5 categories: 
• Lying and Rolling; 
• Sitting; 
• Crawling and Kneeling; 
• Standing; 
• Walking, Running, and Jumping. 
Items were selected to represent motor functions typically performed by children without motor 
impairments by 5 years of age.  Each item is scored on a 4-point Likert scale (i.e., 0 = cannot do; 
1 = initiates [<10% of the task]; 2 = partially completes [10 to <100 % of the task]; 3 = task 
completion; NT = not tested).  The score for each dimension is expressed as a percentage of the 
maximum score for that dimension.  The total score is obtained by adding the percentage scores 
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for each dimension and dividing the sum by the total number of dimensions.  Therefore, each 
dimension contributes equally to the total score.  The validity and reliability of the GMFM-66 
were established in patients with cerebral palsy using the GMFM-88, the original 88-item 
version of the test.  The GMFM-66 is comprised of 66 of the original 88 items.  The GMFM-88 
was validated on 136 children with cerebral palsy, 25 children with acute head injuries, and 
34 children without motor delays who ranged in age from 1 month to 4.3 years.  The GMFM-66 
utilizes a software scoring program called the Gross Motor Ability Estimator (GMAE) that 
converts the instrument from an ordinal scale to an interval scale based on an individual’s 
responses for the 66 items of the test.  This conversion system allows for a more precise 
estimation of the gross motor abilities of the tested individual.  The GMAE scoring system was 
developed using the results of a Rasch analysis performed on a sample of 537 children with 
cerebral palsy in Ontario, Canada.   
9.3.5.2 Alberta Infantile Motor Scale 
The AIMS (Piper, 1994, Motor Assessment of the Developing Infant) is an observational measure 
of infant motor performance from term through independent walking.  The AIMS assesses the 
sequential development of motor milestones in terms of progressive development and integration 
of antigravity muscle control.  An infant is encouraged to demonstrate skills he or she can 
accomplish spontaneously without the assistance of the examiner.  The role of the assessor is to 
observe and analyze the infant’s movements.  The AIMS is a norm-referenced test based on age- 
and sex-stratified normative data.  Scores will be adjusted to account for gestational age only for 
patients whose gestational age is <37 weeks. 
The AIMS was normalized using representative samples from the general population.  As such, 
this instrument allows for the comparison of tested children to healthy, same-age peers.  The 
AIMS covers normal motor development in infants from birth to 18 months of age.  The test can 
be used to monitor the progress of a child until he/she successfully achieves the highest level of 
age-equivalence on the test (18 months of age). 
In this study, the AIMS will be administered to all patients at study entry, provided they are at or 
below the highest level of age-equivalent performance for the test (i.e., independent walking), 
and the AIMS will continue to be administered to these patients until completion of the study to 
ascertain whether patients maintain any developmental gains achieved while on Myozyme 
therapy.  Test administration requires 20 to 30 minutes. 
9.3.5.3 Pompe Pediatric Evaluation of Disability Inventory  
A disease-specific version of the PEDI was developed to assess functional capabilities and 
performance in children with Pompe disease from 2 months through adolescence (Haley, 2003, 
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Pediatr Rehabil).  All patients will be administered the Pompe PEDI.  The Pompe PEDI includes 
all items from the original PEDI, as well as additional items in the Functional Skills, Mobility, 
and Self-Care domains to reflect clinically relevant functional skills for children with Pompe 
disease.  Norm-based scoring was developed for these new items, and scoring algorithms for the 
PEDI have been adjusted to reflect the additional normative data collected for the Pompe PEDI.  
The patient and/or the patient’s legal guardian(s) will complete the Pompe PEDI.  Test 
completion requires approximately 60 minutes.  Results are reported as raw score, normative 
standard score (with standard error), and scaled score (with standard error).   
9.4 Safety Measurements 
9.4.1 Physical Examination 
The physical examination should be performed as specified in the Schedule of Assessments (see 
Table 9-1, Table 9-2, and Table 9-3).  A physical examination will be performed using a 
standardized form with a checklist of items.  Each examination will include height, weight, and 
head circumference, as well the following assessments: General Appearance, Skin, HEENT, 
Lymph Nodes, Heart, Lungs, Abdomen, Extremities/Joints, Neurological, Mental Status, and 
Reflexes. 
If clinically significant changes from screening/baseline are noted in physical examinations, the 
changes will be documented as AEs on the AE eCRF.  Clinical significance is defined as any 
variation in physical findings which has medical relevance and may result in an alteration in 
medical care.  The Investigator will continue to monitor the patient until the parameter returns to 
screening/baseline levels or until the Investigator determines that follow-up is no longer 
medically necessary. 
9.4.2 Safety Laboratory Assessments 
The following hematology, chemistry, and urinalysis parameters will be measured: 
• CBC with differential; 
• Chemistry: albumin, alkaline phosphatase, ALT, AST, BUN, serum calcium, creatinine, 
direct and indirect bilirubin, glucose, lactate dehydrogenase, serum phosphorus, 
potassium, serum sodium, total bilirubin, total protein; 
• CK and CK-MB; 
• Urinalysis: urine color, specific gravity, pH, protein, glucose, ketones, and blood; 
microscopy, if clinically indicated. 
The Investigator has the discretion to order additional laboratory testing at additional intervals as 
indicated. 
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Analysis of blood and urine samples will be performed locally per the site’s procedures.  
Laboratory reports should be reviewed promptly and prior to treatment with any of the study 
medications to ensure the patient is not experiencing any toxicity and is stable enough to 
continue the ITI regimen.  Particular attention should be given to any changes in serum 
creatinine, BUN, platelets, white cell count, ALT, AST, or bilirubin, or the presence of red cells 
in the urine.  
The Investigator must indicate if out-of-range laboratory values are either clinically significant or 
not clinically significant.  It is anticipated that some laboratory values may be outside of the 
normal value range due to the underlying disease.  As in routine practice, the Investigators 
should use their clinical judgment when considering clinical significance.  Clinical significance 
is defined as any variation in laboratory parameters which has medical relevance and may result 
in an alteration in medical care.  If clinically significant laboratory changes from baseline are 
noted, the changes will be documented as AEs on the AE eCRF.  The Investigator will also 
assess the relationship of all clinically significant out-of-range values to study drugs as being not 
related, remote/unlikely, possible, probable, or definite.  The Investigator will continue to 
monitor the patient with additional laboratory assessments until (1) values have reached normal 
range and/or baseline levels, or (2) in the judgment of the Investigator, out-of-range values are 
not related to the administration of study drug or other protocol-specific procedures. 
9.4.3 Electrocardiogram 
A standard 12-lead ECG will assess the following:  heart rate, rhythm, RR interval, PR interval, 
QRS complex, QT interval, QTc interval, QRS axis, R voltage V6, S voltage V1, left ventricular 
hypertrophy criteria, right ventricular hypertrophy criteria, and repolarization changes.  The site 
cardiologist will review all ECGs for clinical management of the patient.  A central cardiologist 
will review the ECG for derivation of study data. 
If clinically significant changes from screening/baseline are noted in ECG findings, the changes 
will be documented as AEs on the AE eCRF.  Clinical significance is defined as any variation in 
ECG findings which has medical relevance and may result in an alteration in medical care.  The 
Investigator will continue to monitor the patient until the parameter returns to screening/baseline 
levels or until the Investigator determines that follow-up is no longer medically necessary. 
9.4.4 Vital Signs 
Vital signs, including systolic and diastolic blood pressures (mmHg), heart rate (beats per 
minute), respiratory rate (breaths/minute), and temperature (°C or °F) will be obtained and 
recorded at Day -1 and all subsequent visits with Myozyme, cyclophosphamide, rituximab, 
and/or methotrexate dosing.  During each Myozyme infusion, vital signs will be recorded 
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immediately prior to the infusion, every 30 minutes during the infusion, immediately prior to any 
change in the infusion rate (if the time point is different), and after completion of the 
post-infusion observation period (with a window of ±15 minutes for time points after the start of 
infusion).  In the event of an IAR to Myozyme, or if otherwise clinically indicated, additional 
vital sign measurements should be recorded.  Periodic vital sign monitoring will be performed 
prior to, during and/or after the administration of each immunosuppressant agent 
(cyclophosphamide, rituximab, methotrexate, IVIG) in accordance with the prescribing 
information for that agent, and at the discretion of the Investigator as clinically indicated. 
If clinically significant changes from baseline or pre-infusion are noted in vital signs, the 
changes will be documented as AEs on the AE eCRF.  Clinical significance is defined as any 
variation in vital signs which has medical relevance and may result in an alteration in medical 
care.  The Investigator will continue to monitor the patient until the parameter returns to normal 
range or baseline levels or until the Investigator determines that follow-up is no longer medically 
necessary. 
9.4.5 Electrocardiogram Monitoring by Telemetry 
Continuous ECG monitoring by telemetry will be performed on the days of cyclophosphamide 
infusions for patients on Regimen A who have cardiomegaly or hypertrophic cardiomyopathy, 
and on the days of rituximab infusions for all patients on Regimen B.  Telemetry will be 
performed for at least 10 minutes prior to the start of the infusion to establish a baseline, and will 
be obtained continuously until a minimum of 2 hours post-infusion.  Telemetry alarms will be set 
according to pre-defined criteria specified according to the site’s SOPs.  Infusions should be 
discontinued in the event of serious or life-threatening cardiac arrhythmias, and may be adjusted 
or discontinued in response to any other clinically significant findings, at the discretion of the 
Investigator.  At the discretion of the Investigator, patients who develop clinically significant 
arrhythmias may also undergo additional cardiac monitoring.   
If clinically significant changes from screening/baseline are noted in ECG findings, the changes 
will be documented as AEs on the AE eCRF.  Clinical significance is defined as any variation in 
ECG findings which has medical relevance and may result in an alteration in medical care.  The 
Investigator will continue to monitor the patient until the parameter returns to screening/baseline 
levels or until the Investigator determines that follow-up is no longer medically necessary. 
9.4.6 Lymphocyte Subpopulation Counts 
Blood samples will be collected for lymphocyte subpopulation counts, and shipped to a central 
laboratory designated by the Immune Tolerance Network for analysis.  Procedures for the 
collection, handling, and shipment of samples are provided in the SOM.  Laboratory reports for 
lymphocyte subpopulation counts will be made available by the central laboratory directly to the 
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Investigator in such time and manner as to assure appropriate clinical review.  Refer to the SOM 
for further details. 
9.4.7 Immunoglobulins Panel 
Blood samples will be collected for an immunoglobulin panel.  Analysis of immunoglobulin will 
be performed locally per the site’s procedures.  The results should be reviewed promptly and 
prior to treatment with any of the study medications. 
The Investigator must indicate if out-of-range values are either clinically significant or not 
clinically significant.  As in routine practice, the Investigators should use their clinical judgment 
when considering clinical significance.  Clinical significance is defined as any variation in these 
parameters which has medical relevance and may result in an alteration in medical care.  If 
clinically significant changes from baseline are noted in immunoglobulin values, the changes 
will be documented as AEs on the AE eCRF.  The Investigator will also assess the relationship 
of all clinically significant out-of-range values to study drugs as being not related, 
remote/unlikely, possible, probable, or definite.  The Investigator will continue to monitor the 
patient with additional assessments until (1) values have reached normal range and/or baseline 
levels, or (2) in the judgment of the Investigator, out-of-range values are not related to the 
administration of study drug or other protocol-specific procedures. 
9.4.8 Pregnancy Test and Use of Contraception 
The immunosuppressant agents administered in this study are known teratogens.  Therefore, 
pregnant and lactating women will be excluded from participation in the study, and other women 
of childbearing potential should be administered these agents only after due consideration of the 
potential risks and benefit to the patient. 
Female patients of childbearing potential must have a negative pregnancy test prior to starting 
the ITI regimen.  Pregnancy testing will be conducted at baseline and will be repeated on Day 0 
if that visit occurs >14 days after the baseline test.  Monthly pregnancy testing will be performed 
for the duration of a patient’s participation in the study.  In addition, all eligible female patients 
of childbearing potential and sexually mature males will be advised of the risks associated with 
immunosuppressant agents, and instructed to use a medically accepted method of contraception 
throughout the study. 
If a patient becomes pregnant anytime during her participation in the study, the patient must be 
discontinued from the study.  Pregnancy will be documented as the reason for study 
discontinuation.  The Investigator must notify Genzyme within 24 hours of first learning of the 
pregnancy, using the appropriate pregnancy notification form (refer to the SOM).  The patient 
should be followed until the outcome of the pregnancy is known (i.e., delivery, elective 
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termination, or spontaneous abortion).  If a partner of a male patient who has received Myozyme 
becomes pregnant, Genzyme should be notified and, similarly, the pregnancy should be followed 
until the outcome is known. 
Complications during pregnancy as well as pregnancy outcome, once known, must also be 
reported to Genzyme within 24 hours of knowledge using the pregnancy outcome form (refer to 
the SOM).  If the pregnancy results in the birth of a child, additional follow-up information may 
be requested. 
Note that pregnancy in and of itself is not an AE or an SAE.  Pregnancy should not be entered in 
the eCRF as an AE unless the Investigator suspects an interaction between the study treatment 
and the contraceptive method. 
9.5 Other Assessments 
9.5.1 Research Immunophenotyping 
Blood samples will be collected for research immunophenotyping and shipped to a central 
laboratory designated by the Immune Tolerance Network for analysis.  Procedures for the 
collection, handling, and shipment of samples are provided in the SOM.   
9.5.2 Functional T-Cell Assay 
Peripheral blood lymphocytes will be collected from whole blood, and shipped under appropriate 
conditions to the specified central immunology laboratory conducting the enzyme-linked 
immunosorbent spot (ELISPOT) assay designated by the Immune Tolerance Network.  
Procedures for collection, handling, and shipment of samples are provided in the SOM. 
9.5.3 Testing for Moderate, Severe, or Recurrent Infusion-Associated Reactions 
In the event that a patient experiences a moderate (Grade 2), severe (Grade 3), life-threatening 
(Grade 4), or recurrent mild (Grade 1) IAR to Myozyme, additional blood samples will be 
collected and sent to Genzyme for analysis as described in Sections 9.5.3.1 to 9.5.3.3.  At the 
request of Genzyme, after consultation with the Investigator, additional blood samples may be 
collected for recurrent IARs to Myozyme that are suggestive of a hypersensitivity reaction.  
Refer to the SOM for guidelines on the collection and shipment of samples.  Genzyme GPS-RM 
should be apprised of sample shipments.  Testing is conducted to gain additional information as 
to individuals’ responses to Myozyme, and is not intended as the sole means for clinical 
management of patients.  Suggested guidelines for the management of IARs during the event and 
pretreatment guidelines are summarized in Appendix 1 of the Myozyme Investigator’s Brochure.  
Skin testing may also be performed, if clinically indicated, as described in Section 9.5.3.4. 
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9.5.3.1 Complement Activation Testing 
In the event that a patient experiences a moderate (Grade 2), severe (Grade 3), life-threatening 
(Grade 4), or recurrent mild (Grade 1) IAR to Myozyme, a plasma sample will be drawn within 
1 to 2 hours of the event for complement activation testing, when clinically indicated. 
At the request of Genzyme, after consultation with the Investigator, a plasma sample for 
complement activation testing may also be collected for patients with recurrent IARs to 
Myozyme suggestive of a hypersensitivity reaction. 
9.5.3.2 Serum Tryptase Testing 
In the event that a patient experiences a moderate (Grade 2), severe (Grade 3), life-threatening 
(Grade 4), or recurrent mild (Grade 1) IAR to Myozyme, a serum sample will be drawn within 
1 to 2 hours of the event for serum tryptase testing, when clinically indicated. 
At the request of Genzyme, after consultation with the Investigator, a serum sample for tryptase 
testing may also be collected for patients with recurrent IARs to Myozyme suggestive of a 
hypersensitivity reaction. 
9.5.3.3 Serum Anti-Recombinant Human Acid Alpha-Glucosidase Immunoglobulin E 
Antibody Testing 
In the event that a patient experiences a moderate (Grade 2), severe (Grade 3), life-threatening 
(Grade 4), or recurrent mild (Grade 1) IAR to Myozyme, the patient should return to the study 
center no sooner than 3 days following the day of the event to have a serum sample collected that 
will be tested for anti-rhGAA IgE antibodies, when clinically indicated. 
At the request of Genzyme, after consultation with the Investigator, a serum sample for IgE 
testing may also be collected prior to the next scheduled Myozyme infusion for patients with 
recurrent IARs to Myozyme suggestive of a hypersensitivity reaction. 
9.5.3.4 Skin Testing 
Skin testing may be performed locally, following consultation with the Investigator, Sponsor, 
and ARRB, in patients who experience an IAR to Myozyme that meets the following criteria: 
• IAR is assessed as moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4) by 
the Investigator or is mild (Grade 1) recurrent;  
AND 
• IAR is suggestive of an IgE-mediated acute-type hypersensitivity reaction, with persistent 
symptoms of bronchospasm, hypotension, and/or urticaria requiring intervention OR any 
other signs or symptoms at the discretion of the Investigator or Genzyme. 
Refer to the SOM for skin testing procedures. 
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9.5.3.5 Circulating Immune Complexes 
In the event that a patient exhibits evidence of symptoms suggestive of Immune Complex 
Disease (e.g., proteinuria), serum samples will be obtained and sent to Genzyme for the 
evaluation of circulating immune complexes, in addition to the testing of prior serum samples 
that have been archived.  Immune complex results will be used as a tool to assist in the clinical 
evaluation of the patient, and clinical management will not be dependent solely on these results.  
The patient will continue to be monitored for immune complex symptomatology, and serum 
samples will continue to be obtained for the evaluation of circulating immune complexes, as 
appropriate.  Consideration for further evaluation of possible immune complex disease (i.e., renal 
biopsy) will be at the discretion of the Investigator.  Refer to the SOM for guidelines on the 
collection and shipment of serum samples. 
9.5.4 Concomitant Medications/Therapies 
From the time of informed consent through study completion, all medications and therapies (e.g., 
tube feeds) to treat AEs, for any long-term disease management, given as prophylaxis for this 
study, or administered as a pretreatment prior to infusion, will be recorded in the eCRFs. 
See also Section 8.4, Concomitant Medication/Therapy. 
9.6 Adverse Events 
AEs will be assessed at screening/baseline.  At every subsequent dosing visit (Myozyme, 
cyclophosphamide, rituximab, methotrexate, and/or IVIG), the patient will be assessed for any 
new AEs and changes in the status of any ongoing AEs since the previous visit. 
All AEs will be graded according to NCI/CTCAE, Version 3.0 (see Appendix 14.5). 
Any signs and symptoms experienced by the patient from the time of signing the informed 
consent form through the final study visit will be recorded in the eCRF. 
Since patients must have received Myozyme treatment prior to study enrollment, an assessment 
of retrospective, related AEs will be conducted at the screening/baseline visit.  Information will 
be solicited regarding AEs assessed as related (i.e., possibly, probably, or definitely related) to 
the administration of Myozyme that occurred during commercial Myozyme treatment up to the 
point of consent for AGLU03707.  This retrospective data will be recorded in the eCRFs and will 
be considered clinical study medical history data.  All AEs will then be prospectively captured 
and recorded for the remainder of the patient’s participation in the study.  GPS-RM will assess 
SAEs solicited as part of the retrospective data collection for possible submission to regulatory 
authorities as clinical study safety reports.  Serious, related events will be evaluated based upon 
local labeling for submission to international regulatory agencies in countries where Myozyme is 
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approved.  Day 1, for the determination of submission due date, will be based upon the day when 
Genzyme GPS-RM becomes aware of the retrospective SAE.   
After completion of the study (18 or 24 months) or early withdrawal from the study, due to 
potential long-term adverse effects related to the administration of immunosuppressant drugs, it 
is recommended that physicians report any AEs suggestive of immunosuppressant-induced 
toxicity to GPS-RM, in addition to the product manufacturer, as a spontaneous report.  These 
data will not be included in the clinical study database, but will be maintained in the GPS-RM 
database. 
9.6.1 Adverse Event Definition 
An AE is defined as any undesirable physical, psychological, or behavioral effect experienced by 
a patient or subject during his/her participation in an investigational study, in conjunction with 
the use of the drug or biologic, whether or not product-related.  This includes any untoward signs 
or symptoms experienced by the patient from the time of signing of the informed consent form 
until completion of the study. 
AEs may include, but are not limited to: 
• Subjective or objective symptoms spontaneously offered by the patient or subject and/or 
observed by the Investigator or medical staff; 
• Findings at physical examinations; 
• Laboratory abnormalities of clinical significance. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of the 
product are not considered AEs after treatment with Myozyme unless they reoccur after the 
patient has recovered from the preexisting condition or, in the opinion of the Investigator, they 
represent a clinically significant exacerbation in intensity or frequency. 
If a clinically significant worsening from baseline is noted, the changes will be documented as 
AEs on the AE eCRF.  Clinical significance is defined as any variation in signs, symptoms, or 
testing that has medical relevance and may result in an alteration in medical care.  The 
Investigator will continue to monitor the patient until the parameter returns to baseline or until 
the Investigator determines that follow-up is no longer medically necessary. 
All AEs will be noted in the eCRF, with a full description including the nature, date and time of 
onset and resolution, determination of seriousness, severity, corrective treatment, outcome, and 
relationship (i.e., not related, remote/unlikely, possibly, probably, or definitely) to Myozyme, 
cyclophosphamide, rituximab, methotrexate, and/or IVIG, as applicable to the regimen. 
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9.6.2 Serious Adverse Events 
An SAE is any AE that results in any of the following outcomes: 
• Death; 
• Life-threatening experience; 
• Required or prolonged inpatient hospitalization; 
• Persistent or significant disability/incapacity; 
• Congenital anomaly; or  
• Important medical events that may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above; 
• New invasive ventilator use. 
Life-threatening experience: Any AE that places the patient, in the view of the reporter, at 
immediate risk of death from the AE as it occurred, i.e., does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
Persistent or significant disability/incapacity: Any AE that results in a substantial disruption of a 
person’s ability to conduct normal life functions. 
Important medical events that may jeopardize the patient or subject, and may require medical or 
surgical intervention to prevent one of the outcomes listed above: AEs that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
Any new invasive ventilator use:  Due to the medical significance of any new ventilator use in 
this patient population, any new use of invasive ventilator support will be reported as an SAE.  If 
a patient requiring ventilator support becomes ventilator independent, the next instance of 
invasive ventilator support (if applicable) will be considered a new SAE.  
9.6.3 Severity Scoring 
The Investigator will be asked to assess the severity of each AE using the following categories: 
Grade 1, Grade 2, Grade 3, Grade 4, or Grade 5 based on the NCI/CTCAE, Version 3.0 
(provided in Appendix 14.5, and available online at http://ctep.cancer.gov/reporting/ctc.html).  
The CTCAE are also presented in the SOM.  AEs not explicitly included in the CTCAE will also 
be graded according to these definitions: 
Grade 1:  Mild (intervention/treatment not needed or symptomatic treatment);   
Grade 2:  Moderate (specific but non-invasive intervention; first line treatment may be given); 
Grade 3:  Severe (active diagnostic interventions/invasive or more intensive treatment); 
Grade 4:  Life-threatening or disabling (substantial hazard or risk; major intervention); 
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Grade 5:  Death. 
Each event should be evaluated to determine if the event also meets serious criteria 
(Section 9.6.2).  By ICH definition, Grade 4 and 5 events are SAEs and must be reported to 
Genzyme according to Section 9.6.5. 
9.6.4 Infusion-Associated Reactions 
IARs are defined as AEs that occur during either the Myozyme infusion or the observation 
period following the Myozyme infusion which are deemed to be related (i.e., possibly, probably, 
or definitely) to Myozyme.  At the discretion of the Investigator, AEs occurring after completion 
of the post-infusion observation period for Myozyme that are assessed as related to Myozyme 
may also be considered IARs.  These events should be reported to Genzyme GPS-RM within 
24 hours of the Investigator’s first knowledge of the event.  Refer to Section 9.5.3 for additional 
testing in the event a patient experiences a moderate (Grade 2), severe (Grade 3), life-threatening 
(Grade 4), or recurrent mild (Grade 1) IAR to Myozyme.  Suggested guidelines for the 
management of IARs, and pretreatment prior to subsequent dosing of Myozyme, are summarized 
in Appendix 1 of the Myozyme Investigator’s Brochure. 
Those reactions that occur during either the infusion or the post-infusion observation period of 
cyclophosphamide, methotrexate, rituximab, or IVIG, which are deemed to be related (i.e., 
probably, possibly, or definitely) to cyclophosphamide, methotrexate, rituximab, or IVIG will be 
considered AEs, but not IARs. 
9.6.5 Adverse Experience and Serious Adverse Experience Reporting 
The necessity and time requirements for reporting of AEs to Genzyme or designee and/or 
regulatory agencies are as follows: 
• All SAEs and IARs (non-serious and serious) will be reported within 24 hours of the 
Investigator’s first knowledge of the event, even if the experience does not appear to be 
related to the study drug(s).  Such communications are to be directed to: 
Global Patient Safety and Risk Management 
  
 
(phone: week days/after hours) 
 
 
 
• All SAEs and IARs will include a detailed description of the event(s).  Copies of relevant 
patient records, autopsy reports, and other documents may be requested by and will be 
sent to Genzyme GPS-RM Department. 
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Additionally, the Investigator or designee must notify the IRB of any SAE in accordance with 
the IRB’s policy.  Depending upon regional requirements, it is the responsibility of either the 
Investigator or Genzyme to notify the IRB.  All unexpected SAEs associated with the use of the 
study treatment will be reported to appropriate regulatory agencies by Genzyme within the 
required timeframes. 
Any AEs or SAEs experienced by the patient from the time of signing of the informed consent 
through completion of the final study assessments must be reported as described and recorded in 
the eCRF.  After completion of the final study assessments, all patients must be followed an 
additional 30 days.  At the follow-up assessment, outcome for ongoing AEs and SAEs should be 
documented in the eCRF as not yet recovered.  Ongoing SAEs should, however, continue to be 
followed (and information reported to GPS-RM) until resolution, until the Investigator deems 
follow-up is no longer medically necessary, or until the patient is lost to follow-up. 
For patients transitioning to commercial Myozyme prior to the 30-day follow-up assessment, 
follow-up contact should occur prior to the first infusion of commercial Myozyme to assess for 
ongoing AEs and SAEs.  At the 30-day follow-up assessment, outcome for AEs and SAEs 
ongoing at the time of follow-up contact should be documented in the eCRF.  Ongoing SAEs at 
the time of the 30-day follow-up assessment should continue to be followed (and information 
reported to GPS-RM) until resolution, until the Investigator deems follow-up is no longer 
medically necessary, or until the patient is lost to follow-up. 
9.7 Study Drug Administration Stopping Rules 
The independent ITIRB (Section 12.3) will assemble regularly to review safety data collected 
from ongoing clinical studies of Myozyme that may necessitate temporary or permanent 
discontinuation of treatment. 
Safety reviews will also occur on an expedited, ad hoc basis when 1 of the following scenarios 
occurs: 
• Fatal or life-threatening reaction to study drugs or procedures;  
• Occurrence of any other safety-related issues identified by Genzyme GPS-RM that pose a 
medical concern, including temporary discontinuation of the ITI regimen for any patient, 
as outlined in Section 7.3.2. 
After review, the ITIRB will recommend one of the following: 
• Continuation of study drug for all patients in AGLU03707; 
• Continuation of study drug (Myozyme, cyclophosphamide, rituximab, methotrexate, 
and/or IVIG), but with changes for all or selected patients in AGLU03707 (e.g., a change 
in dose for 1 or more patients; see Section 7.4);  
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• Discontinuation of study drug (either temporary or permanent) for all or selected patients 
in AGLU03707. 
After considering the ITIRB recommendations, final decisions regarding discontinuation of 
study drug for all or selected patients in AGLU03707 will be made by the Sponsor. 
In the event a significant safety concern arises, the Sponsor may immediately decide to 
discontinue study drug dosing for all clinical study patients prior to receipt of ITIRB 
recommendation.  Investigational sites will be notified within 24 hours of Genzyme’s 
notification of the event(s). 
All appropriate regulatory authorities and IRB(s) will be subsequently notified in the event of 
temporary or permanent discontinuation of study drug for all or selected patients. 
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10. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT 
10.1 
Recording of Data 
Data will be recorded in the eCRF designed by Genzyme’s Department of Biomedical Data 
Sciences and Informatics and Clinical Research, in collaboration with an electronic data capture 
(EDC) vendor.  Clinical data that are not recorded in the eCRF will be captured and transferred 
to Genzyme’s Department of Biomedical Data Sciences and Informatics. 
A Genzyme employee or designee will be responsible for entering patient data in the eCRF for 
the Pompe PEDI, AIMS, and GMFM-66 only.  The central cardiologist will enter all ECHO and 
ECG data in the eCRFs. 
10.2 
Data Quality Assurance 
Data entered in the eCRF must be verifiable against source documents at the investigational site.  
A clinical monitor from Genzyme or a representative of Genzyme will manually review the 
eCRFs against the source documents at the investigational site for validity and completeness.  
Refer to the Monitor’s Manual for further details. 
All data captured in the eCRFs will be made available to Genzyme or its designee for data 
management and analysis.  If necessary, the study site will be contacted for corrections and/or 
clarifications of the data. 
10.3 
Data Management 
Genzyme, working in close collaboration with an EDC vendor, will be responsible for: 
• Database creation and validation. 
Genzyme will be responsible for: 
• eCRF review and data validation. 
Prior to finalizing and locking the database, all decisions concerning the inclusion or exclusion 
of data for each patient will be determined by appropriate medical and statistical personnel.  Any 
and all exclusions related to either safety or efficacy will be documented in patient listings. 
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11. 
STATISTICAL METHODS AND PLANNED ANALYSES 
Prior to locking the database, all data editing will be complete.  The process of database lock and 
data analysis will follow the SOPs of Genzyme’s Department of Biomedical Data Sciences and 
Informatics.  This department also will perform analysis of the data collected from this study. 
Statistical analyses of all safety and efficacy measurements will be conducted on all patients who 
receive Myozyme under this protocol. 
All data will be presented in by-patient listings.  Graphical displays will be presented as 
appropriate.  Summary statistics will be produced as appropriate and meaningful.  Continuous 
variables will be summarized using descriptive statistics (number [n], mean, median, standard 
deviation, minimum, and maximum).  Categorical variables will be summarized using 
frequencies and percentages. 
No statistical testing will be conducted.  Missing data will not be imputed using statistical 
methods. 
Safety: 
All safety data will be presented in by-patient listings. 
The incidence of AEs will be summarized by severity, seriousness, relationship to treatment, and 
relationship to infusion.  Vital signs, physical examination findings, and ECG parameters will be 
summarized as appropriate.  The analyses of clinical laboratory measurements will be based 
upon the frequency of abnormal values and the frequency of clinically significant abnormal 
values.  Additional immunology measurements which include IgE, serum tryptase, complement 
activation, and skin testing results will be displayed in by-patient listings as will circulating 
immune complex detection results. 
Efficacy: 
All efficacy data will be presented in by-patient listings. 
Change from baseline in anti-rhGAA antibody titers and in inhibitory antibody formation 
(activity and uptake) will be presented.  Change from baseline in LVMI, GMFM-66 scores, 
AIMS scores, and Pompe PEDI scores will also be presented.  Summary statistics will be 
presented where appropriate.   
Overall survival will be presented as the proportion of patients alive at the end of the study. 
The proportion of patients who were alive and ventilator-free over the course of treatment, time 
to overall invasive ventilator-dependence, and ventilator-free survival time for patients who were 
ventilator-free at the onset of the study will be calculated.  The overall duration of ventilator 
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support and the number of hours of ventilator use in the 24 hours preceding each infusion visit 
for patients who required ventilator use at the onset of the study will also be calculated. 
Correlation among genotype, the level of α-glucosidase protein, and the presence of binding, 
anti-rhGAA IgG, and inhibitory antibodies over time will be explored in by-patient graphical 
displays, where appropriate. 
No statistical sample size calculations will be performed.  The sample size is based solely on 
clinical considerations, as the number of Pompe patients satisfying the inclusion/exclusion 
criteria is likely to be very small. 
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12. 
SPECIAL REQUIREMENTS AND PROCEDURES 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
principles of GCP regulations.  These requirements are stated in international regulations such as 
the ICH Guideline E6 Good Clinical Practice and local regulations such as the US Code of 
Federal Regulations (CFR) and the European Union (EU) Directive 2001/20/EC and EU 
Directive 2005/28/EC. 
12.1 
Institutional and Ethical Review 
Before enrollment of patients, this protocol, informed consent form, and relevant supporting 
information must be reviewed and approved by an IRB or Independent Ethics Committee (IEC) 
in compliance with ICH and local requirements such as 21 CFR 50 and 56 in the US.  Genzyme 
must receive the letter or certificate of approval from the IRB or IEC prior to delivery of clinical 
supplies. 
12.2 
Changes to the Conduct of the Study or Protocol 
No change in the study procedures shall be effected without the mutual agreement of the 
Investigator and Genzyme.  All significant changes to this protocol must be documented by 
signed protocol amendments.  If changes to the design of the study are made, the amendment 
must be submitted to and approved by the IRB or IEC, signed by the Investigator, returned to 
Genzyme, and submitted to the appropriate regulatory authority according to local regulations 
before changes can be implemented. 
12.3 
Immune Tolerance Induction Review Board 
An independent ITIRB, consisting of experts in the fields of immunology, rheumatology, 
transplantation, infectious disease, or oncology will be assembled by Genzyme.  The ITIRB will 
evaluate the safety and efficacy of each of the ITI regimens, as outlined in the ITIRB Charter 
(which is maintained separately from the study protocol).  The ITIRB will review all data 
available after each patient completes 1 month of treatment on a given ITI regimen, after each 
patient completes 6 months of treatment on a given ITI regimen, and, if applicable, after the 
patient completes an optional, additional cycle of rituximab, as well as on an expedited ad hoc 
basis, as outlined in the ITIRB Charter.  This review will be conducted separately for each 
regimen; however, enrollment and ITIRB review may proceed simultaneously for each regimen, 
i.e., 1 regimen does not need to be evaluated prior to enrolling patients on the other regimen.  
The ITIRB will provide recommendations about the risk/benefit profile of the ITI regimens.  If a 
regimen appears to have an acceptable risk/benefit profile after the first patient completes the 
first month of treatment, enrollment in the regimen may continue.  If the regimen appears to have 
an acceptable risk/benefit profile after the first 3 patients in a given regimen have completed 
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1 month of treatment, additional patients may be enrolled as they present, or as necessary, to 
further evaluate the ITI regimen. 
The ITIRB may also provide recommendations regarding the following:  administration of any 
additional cycles of rituximab in any single patient; adjustments to a patient’s ITI regimen to 
allow the patient to safely continue in the study while maintaining clinical benefit; and temporary 
or permanent discontinuation of an ITI regimen if signs of infection or toxicity occur during the 
study. 
Each member of the ITIRB will be a physician and will not be directly involved in the study.  
Each ITIRB member will be required to sign a contract agreement, which includes a 
confidentiality and financial disclosure statement, assuring no conflicts of interest as a condition 
for membership on the board.  These documents, along with all members’ curricula vitae, will be 
filed centrally within the study files at Genzyme, Cambridge, MA. 
Should any major safety issues arise, the final decision regarding the continuation of any or all 
patients in the study will be made by the Genzyme GPS-RM Safety Officer, or designee, and the 
ITIRB.  If there are no major safety concerns, patients will continue to receive treatment in the 
study. 
12.4 
Allergic Reaction Review Board 
An independent ARRB, appointed by Genzyme, may review information pertaining to IARs to 
Myozyme.  The ARRB will serve in a consultancy manner and will provide guidance on IAR 
management, as outlined in the ARRB Charter (which is maintained separately from the study 
protocol).  In addition, the independent ARRB will be consulted on an ad hoc basis as outlined in 
the ARRB Charter.  Communication with the board should be directed to members of the 
Genzyme GPS-RM group.   
The ARRB will consist of at least 1 member with expertise in allergy and/or immunology.  Each 
member of the ARRB will be a physician and will not be directly involved in the study.  Each 
ARRB member will be required to sign a contract agreement, which includes a confidentiality 
and financial disclosure statement, assuring no conflicts of interest as a condition for 
membership on the board.  These documents, along with all members’ curricula vitae, will be 
filed centrally within the protocol study files at Genzyme, Cambridge, MA. 
Should any major safety issues arise, the final decisions regarding the study will be made by the 
Genzyme GPS-RM Safety Officer, or designee, and the ARRB.   
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12.5 
Investigator’s Responsibilities 
12.5.1 Patient Informed Consent 
For every patient, appropriate informed consent will be obtained prior to the commencement of 
any study procedures, and will be documented according to national privacy regulations and 
other state and/or local laws relating to medical information.  It is the responsibility of the 
Investigator to obtain such consent.  Investigators will be expected to remain informed of and to 
ensure that the informed consent form is compliant with all applicable international and national 
authority regulations for clinical study conduct. 
In addition, the biological parents of the patient will be asked to provide consent for GAA 
mutation analysis. 
Genzyme and the Investigator will develop the informed consent form for submission to the IRB 
or IEC.  Upon approval by the IRB or IEC, the Investigator must furnish:  (1) a photocopy of the 
approved informed consent; and (2) the letter stating formal approval has been granted by the 
IRB or IEC prior to release of clinical supplies. 
Patient confidentiality will be maintained to the extent permitted by applicable laws and 
regulations.  It is the responsibility of the Investigator to report results of evaluations to the 
patient. 
12.5.2 Electronic Data Capture 
All non-external data, with the exception of the cardiac data and motor function and 
developmental assessments, will be entered by the site in the eCRFs in the EDC system designed 
by Genzyme’s Department of Biomedical Data Sciences and Informatics and Clinical Research, 
in collaboration with an EDC vendor.  The cardiac data will be entered in the EDC database by 
the central cardiologist assigned to the study.  Refer to the SOM for details.  A Genzyme 
employee or designee will enter the motor function and developmental assessment data into the 
EDC database.  Refer to the SOM for details. 
Copies of pertinent records in connection with the study, including patient charts, laboratory 
data, etc. will be made available to Genzyme on request in a timely manner throughout the 
course of the study, with due precaution towards protecting patient privacy.  Laboratory data that 
are not entered into the EDC system will be transferred to Genzyme Data Management.  
12.5.3 Record Retention 
Essential documents will be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a 
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longer period, however, if required by applicable regulatory requirements or by an agreement 
with Genzyme.  It is the responsibility of Genzyme to inform the Investigator/site as to when 
these documents no longer need to be retained.  
Essential documents are those documents that, individually and collectively, permit evaluation of 
the conduct of a study and the quality of the data produced.  These documents serve to 
demonstrate the compliance of the Investigator, Genzyme, and monitor with the standards of 
GCP and with all applicable regulatory requirements. 
Any or all of the documents should be available for audit by Genzyme or designee and 
inspection by the regulatory authority. 
12.5.4 Monitoring 
A representative of Genzyme will visit the Investigator periodically for the purpose of 
monitoring the progress of this study in accordance with GCP regulations.  It is the responsibility 
of the Investigator to be present or available for consultation during such scheduled monitoring 
visits.  During these routine visits, all data pertaining to a patient’s participation in this clinical 
investigation must be made available to the Monitor. 
An audit may be performed at any time during or after completion of the clinical study by 
Genzyme personnel or their designee.  All study-related documentation must be made available 
to the designated auditor. 
In addition, a representative of a regulatory agency may choose to inspect a study site at any time 
prior to, during, or after completion of the clinical study.  A Genzyme representative will be 
available to assist in the preparation for such an inspection.  All pertinent study data should be 
made available to the regulatory authority for verification, audit, or inspection purposes. 
12.5.5 Materials Control 
12.5.5.1 Receipt of Clinical Supplies 
A POR form, which details the quantity and description of the investigational product, will 
accompany the shipment of the investigational product from Genzyme to the Investigator or 
designee.  This receipt must be signed, dated, and returned to Genzyme or Genzyme 
representative by facsimile transmission.  A copy of the signed and dated POR form should be 
retained in the site pharmacy files.  Investigators or designees must ensure that the 
investigational product, while in their possession, is maintained in accordance with Section 8.2.1 
of this protocol.  Further instructions can be found in the Investigational Product Handling 
Manual. 
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12.5.5.2 Disposition of Unused Clinical Study Material 
All used Myozyme vials must be maintained at the clinical site until a Genzyme Clinical 
Research representative or designee performs accountability.  After the used Myozyme vials are 
accounted for, they should be destroyed by the study site, and their destruction should be 
documented in accordance with the Investigational Product Handling Manual (Disposition 
Authorization Form).  No used Myozyme vials should be destroyed unless authorized by a 
Genzyme CPRS representative or designee.   
All other used clinical study material can be disposed of per site/hospital regulations after proper 
documentation, using the respective accountability logs.  A Genzyme Clinical Research 
representative will reconcile accountability records on a periodic basis for clinical study 
materials used throughout the study. 
All unused clinical study material at the site must be maintained under adequate storage 
conditions in a limited-access area.  If any unused material remains on site at study completion, 
the site will be instructed to destroy or return the material to Genzyme only after accountability 
has been performed by a Genzyme Clinical Research representative and upon completion of the 
required destruction/return forms as supplied by Genzyme or designee.  No product should be 
destroyed or returned unless authorized by a Genzyme CPRS representative or designee.  Further 
instructions on the disposition of clinical study material can be found in the Investigational 
Product Handling Manual. 
12.5.6 Disclosure of Data 
All information obtained during the conduct of this study will be regarded as confidential, and 
written permission from Genzyme is required prior to disclosing any information relative to this 
study.  Submission to Genzyme for review and comment prior to submission to the publisher will 
be required at least 30 days prior to submission.  This requirement should not be construed as a 
means of restricting publication, but is intended solely to assure concurrence regarding data, 
evaluations, and conclusions and to provide an opportunity to share with the Investigator any 
new and/or unpublished information of which he/she may be unaware. 
12.5.7 Clinical Study Report 
If deemed appropriate by the Sponsor, an Investigator(s) shall be designated to sign the 
completed clinical study report at the end of this study. 
The signatory Investigator(s) shall be identified by the Sponsor upon the completion of the study, 
based upon:  
• Patient enrollment (i.e., the individual who enrolls the largest number of patients), or 
• The individual’s participation in the design of the study. 
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13. 
REFERENCES 
Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme 
deficiency — macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med. 
1991;324(21):1464-1470. 
Brady RO, Murray GJ, Oliver KL, et al. Management of neutralizing antibody to ceredase in a 
patient with type 3 Gaucher disease. Pediatrics. 1997;100(6):E11. 
Centers for Disease Control and Prevention. 1995 revised guidelines for prophylaxis against 
Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human 
immunodeficiency virus. MMWR. 1995;44(RR-4):1-11. 
Chen Y-T, Amalfitano A. Towards a molecular therapy for glycogen storage disease type II 
(Pompe disease). Mol Med Today. 2000;6:245-251. 
Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human 
α-galactosidase A replacement therapy in Fabry’s disease. N Engl J Med. 2001;345(1):9-16. 
Genzyme Corporation. Study ITR-333-1106, Evaluation of Immune Tolerance Induction 
Regimens to Ameliorate Antibody Responses to ERT. December 26, 2006. 
Hagemans MLC, Winkel LPF, Hop WCJ, Reuser AJJ, Van Doorn PA, Van der Ploeg AT. 
Disease severity in children and adults with Pompe disease related to age and disease duration. 
Neurology. 2005;64:2139-2141. 
Hagemans MLC, Winkel LPF, Van Doorn PA, et al. Clinical manifestation and natural course of 
late-onset Pompe’s disease in 54 Dutch patients. Brain. 2005;128:671-677. 
Haley SM, Fragala MA, Aseltine R, Pengsheng N, Skrinar AM. Development of a disease-
specific disability instrument for Pompe disease. Pediatr Rehabil. 2003;6(2):77-84. 
Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a 
height-weight formula validated in infants, children, and adults. J Pediatr. 1978;93(1):62-66. 
Hirschhorn R, Reuser AJJ. Glycogen Storage Disease Type II:  Acid α-Glucosidase (Acid 
Maltase) Deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic and 
Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:3389-3420. 
Hunley TE, Corzo D, Dudek D, et al. Nephrotic syndrome complicating α-glucosidase 
replacement therapy for Pompe disease. Pediatrics. 2004;114(4): 532-545. 
Ing RJ, Cook DR, Bengur RA, et al. Anaesthetic management of infants with glycogen storage 
disease type II: a physiological approach. Pediatr Anesth. 2004;14:514-519. 
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Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in mucopolysaccharidosis 
I. N Engl J Med. 2001;344(3):182-188. 
Laforêt P, Nicolino M, Eymard B, et al. Juvenile and adult-onset acid maltase deficiency in 
France: genotype-phenotype correlation. Neurology. 2000;55(8):1122-1128. 
Piper MC and Darrah J. Motor Assessment of the Developing Infant. Philadelphia: WB Saunders 
and Co; 1994. 
Ponce E, Moskovitz J, Grabowski G. Enzyme therapy in Gaucher disease type 1: effect of 
neutralizing antibodies to acid β-glucosidase. Blood. 1997;90(1):43-48. 
Raben N, Kanneboyina N, Lee E, et al. Targeted disruption of the acid α-glucosidase gene in 
mice causes an illness with critical features of both infantile and adult human glycogen storage 
disease type II. J Biol Chem. 1998;273(30):19086-19092. 
Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab 
therapy – rare but there! Leukemia Lymphoma. 2009; 50(7)1083-1095. 
Russell DJ, Rosenbaum PL, Avery LM, Lane M. Gross Motor Function Measure (GMFM-66 & 
GMFM-88) User’s Manual. In: Clinics in Developmental Medicine No. 159. London, UK: 
Mac Keith Press; 2002. 
van den Hout HMP, Hop W, van Diggelen OP, et al. The natural course of infantile Pompe’s 
disease: 20 original cases compared with 133 cases from the literature. Pediatrics. 
2003;112(2):332-340. 
Winkel LPF, Hagemans MLC, van Doorn PA, et al. The natural course of non-classic Pompe’s 
disease; a review of 225 published cases. J Neurol. 2005;252:875-884. 
Zhao H, Bailey LA, Grabowski GA. Enzyme therapy of Gaucher disease: clinical and 
biochemical changes during production of and tolerization for neutralizing antibodies. Blood 
Cells Mol Dis. 2003;30:90-96. 
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14. 
APPENDICES 
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14.1 
Cyclophosphamide United States Prescribing Information 
 
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CYTOXAN®
(cyclophosphamide for injection, USP)
CYTOXAN® Tablets
(cyclophosphamide tablets, USP)
DESCRIPTION
CYTOXAN® (cyclophosphamide for injection, USP) is a sterile white powder containing cyclophosphamide mono-
hydrate. CYTOXAN Tablets (cyclophosphamide tablets, USP) are for oral use and contain 25 mg or 50 mg cyclophosphamide
(anhydrous). Inactive ingredients in CYTOXAN Tablets are: acacia, FD&C Blue No. 1, D&C Yellow No. 10 Aluminum
Lake, lactose, magnesium stearate, starch, stearic acid, and talc. Cyclophosphamide is a synthetic antineo-
plastic drug chemically related to the nitrogen mustards. Cyclophosphamide is a white crystalline powder
with the molecular formula C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. The chemical name for
cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate.
Cyclophosphamide is soluble in water, saline, or ethanol and has the following structural formula:
CLINICAL PHARMACOLOGY
Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function
microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating
malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA. 
Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The
unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites,
but from 5 to 25% of the dose is excreted in urine as unchanged drug. Several cytotoxic and noncytotoxic
metabolites have been identified in urine and in plasma. Concentrations of metabolites reach a maximum in
plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is low but some
metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite
is responsible for either the therapeutic or toxic effects of cyclophosphamide. Although elevated levels of metabo-
lites of cyclophosphamide have been observed in patients with renal failure, increased clinical toxicity in such
patients has not been demonstrated.
INDICATIONS AND USAGE
Malignant Diseases
CYTOXAN, although effective alone in susceptible malignancies, is more frequently used concurrently or sequen-
tially with other antineoplastic drugs. The following malignancies are often susceptible to CYTOXAN treatment:
1. Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic
lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma.
2. Multiple myeloma.
3. Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute
blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in
children (CYTOXAN given during remission is effective in prolonging its duration).
4. Mycosis fungoides (advanced disease).
5. Neuroblastoma (disseminated disease). 
6. Adenocarcinoma of the ovary. 
7. Retinoblastoma.
8. Carcinoma of the breast.
Nonmalignant Disease
Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children:
CYTOXAN is useful in carefully selected cases of biopsy proven “minimal change” nephrotic syndrome in children
but should not be used as primary therapy. In children whose disease fails to respond adequately to appropriate
adrenocorticosteroid therapy or in whom the adrenocorticosteroid therapy produces or threatens to produce
intolerable side effects, CYTOXAN may induce a remission. CYTOXAN is not indicated for the nephrotic syndrome
in adults or for any other renal disease.
CONTRAINDICATIONS
Continued use of cyclophosphamide is contraindicated in patients with severely depressed bone marrow
function. Cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to
it. See WARNINGS and PRECAUTIONS.
WARNINGS
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Second malignancies have developed in some patients treated with cyclophosphamide used alone or in associ-
ation with other antineoplastic drugs and/or modalities. Most frequently, they have been urinary bladder, myelo-
proliferative, or lymphoproliferative malignancies. Second malignancies most frequently were detected in patients
treated for primary myeloproliferative or lymphoproliferative malignancies or nonmalignant disease in which immune
processes are believed to be involved pathologically.
In some cases, the second malignancy developed several years after cyclophosphamide treatment had been
discontinued. In a single breast cancer trial utilizing two to four times the standard dose of cyclophosphamide in
conjunction with doxorubicin a small number of cases of secondary acute myeloid leukemia occurred within two
years of treatment initiation. Urinary bladder malignancies generally have occurred in patients who previously had
hemorrhagic cystitis. In patients treated with cyclophosphamide-containing regimens for a variety of solid tumors,
isolated case reports of secondary malignancies have been published. One case of carcinoma of the renal pelvis
was reported in a patient receiving long-term cyclophosphamide therapy for cerebral vasculitis. The possibility
of cyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of
the drug.
Cyclophosphamide can cause fetal harm when administered to a pregnant woman and such abnormalities have
been reported following cyclophosphamide therapy in pregnant women. Abnormalities were found in two infants
and a six-month-old fetus born to women treated with cyclophosphamide. Ectrodactylia was found in two of the
three cases. Normal infants have also been born to women treated with cyclophosphamide during pregnancy,
including the first trimester. If this drug is used during pregnancy, or if the patient becomes pregnant while taking
(receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing
potential should be advised to avoid becoming pregnant.
Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development
of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal
function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients.
Amenorrhea associated with decreased estrogen and increased gonadotropin secretion develops in a signif-
icant proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses
within a few months after cessation of therapy. Girls treated with cyclophosphamide during prepubescence
generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with
apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late prepubescence has
been reported. Girls treated with cyclophosphamide during prepubescence subsequently have conceived.
Men treated with cyclophosphamide may develop oligospermia or azoospermia associated with increased
gonadotropin but normal testosterone secretion. Sexual potency and libido are unimpaired in these patients.
Boys treated with cyclophosphamide during prepubescence develop secondary sexual characteristics normally,
but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular
atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversi-
bility may not occur for several years after cessation of therapy. Men temporarily rendered sterile by cyclophos-
phamide have subsequently fathered normal children.
Urinary System
Hemorrhagic cystitis may develop in patients treated with cyclophosphamide. Rarely, this condition can be
severe and even fatal. Fibrosis of the urinary bladder, sometimes extensive, also may develop with or without
accompanying cystitis. Atypical urinary bladder epithelial cells may appear in the urine. These adverse effects
appear to depend on the dose of cyclophosphamide and the duration of therapy. Such bladder injury is thought
to be due to cyclophosphamide metabolites excreted in the urine. Forced fluid intake helps to assure an ample
output of urine, necessitates frequent voiding, and reduces the time the drug remains in the bladder. This helps
to prevent cystitis. Hematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but
it may persist. Medical and/or surgical supportive treatment may be required, rarely, to treat protracted cases of
severe hemorrhagic cystitis. It is usually necessary to discontinue cyclophosphamide therapy in instances of
severe hemorrhagic cystitis.
Cardiac Toxicity
Although a few instances of cardiac dysfunction have been reported following use of recommended doses of
cyclophosphamide, no causal relationship has been established. Acute cardiac toxicity has been reported with
doses as low as 2.4 g/m2 to as high as 26 g/m2, usually as a portion of an intensive antineoplastic multi-drug
regimen or in conjunction with transplantation procedures. In a few instances with high doses of cyclophosphamide,
severe, and sometimes fatal, congestive heart failure has occurred after the first cyclophosphamide dose.
Histopathologic examination has primarily shown hemorrhagic myocarditis. Hemopericardium has occurred
secondary to hemorrhagic myocarditis and myocardial necrosis. Pericarditis has been reported independent of
any hemopericardium.
No residual cardiac abnormalities, as evidenced by electrocardiogram or echocardiogram appear to be present
in patients surviving episodes of apparent cardiac toxicity associated with high doses of cyclophosphamide.
Cyclophosphamide has been reported to potentiate doxorubicin-induced cardiotoxicity.
Infections
Treatment with cyclophosphamide may cause significant suppression of immune responses. Serious, sometimes
fatal, infections may develop in severely immunosuppressed patients. Cyclophosphamide treatment may not
be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop viral, bacterial,
fungal, protozoan, or helminthic infections.  
Other
Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible
cross-sensitivity with other alkylating agents has been reported.
PRECAUTIONS
General
Special attention to the possible development of toxicity should be exercised in patients being treated with
cyclophosphamide if any of the following conditions are present.
1. Leukopenia
2. Thrombocytopenia 
3. Tumor cell infiltration of bone marrow
4. Previous X-ray therapy
5. Previous therapy with other cytotoxic agents 
6. Impaired hepatic function 
7. Impaired renal function
Laboratory Tests
During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored
regularly to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red
cells which may precede hemorrhagic cystitis.
Drug Interactions
The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic
administration of high doses of phenobarbital.
The physician should be alert for possible combined drug actions, desirable or undesirable, involving cyclo-
phosphamide even though cyclophosphamide has been used successfully concurrently with other drugs,
including other cytotoxic drugs.
Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity,
potentiates the effect of succinylcholine chloride.
If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist
should be alerted.
Adrenalectomy
Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the doses
of both replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient.
Wound Healing
Cyclophosphamide may interfere with normal wound healing.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
See WARNINGS for information on carcinogenesis, mutagenesis, and impairment of fertility.
Pregnancy
Pregnancy Category D
See WARNINGS.
Nursing Mothers
Cyclophosphamide is excreted in breast milk. Because of the potential for serious adverse reactions and the
potential for tumorigenicity shown for cyclophosphamide in humans, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety profile of CYTOXAN (cyclophosphamide) in pediatric patients is similar to that of the adult population
(see ADVERSE REACTIONS).
Geriatric Use
Insufficient data from clinical studies of CYTOXAN for malignant lymphoma, multiple myeloma, leukemia, mycosis
fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older
to determine whether they respond differently than younger patients. In two clinical trials in which cyclophosphamide
was compared with paclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma,
154 (28%) of 552 patients who received cyclophosphamide plus cisplatin were 65 years or older. Subset analyses
(<65 versus >65 years) from these trials, published reports of clinical trials of cyclophosphamide-containing
regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketing experience suggest that elderly
patients may be more susceptible to cyclophosphamide toxicities. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on
patient response (see DOSAGE AND ADMINISTRATION: Treatment of Malignant Diseases).
O
P
NH
N(CH2CH2Cl)2•H2O
O
Page 93
 

ADVERSE REACTIONS
Information on adverse reactions associated with the use of CYTOXAN (cyclophosphamide) is arranged according
to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence.
The most serious adverse reactions are described in the WARNINGS section.
Reproductive System
See WARNINGS for information on impairment of fertility.
Digestive System
Nausea and vomiting commonly occur with cyclophosphamide therapy. Anorexia and, less frequently, abdom-
inal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal
ulceration and jaundice occurring during therapy. These adverse drug effects generally remit when cyclophos-
phamide treatment is stopped.
Skin and Its Structures
Alopecia occurs commonly in patients treated with cyclophosphamide. The hair can be expected to grow back
after treatment with the drug or even during continued drug treatment, though it may be different in texture or
color. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in
nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been
received during postmarketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive
causal relationship to cyclophosphamide has not been established. 
Hematopoietic System
Leukopenia occurs in patients treated with cyclophosphamide, is related to the dose of drug, and can be used
as a dosage guide. Leukopenia of less than 2000 cells/mm3 develops commonly in patients treated with an
initial loading dose of the drug, and less frequently in patients maintained on smaller doses. The degree of
neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever
without documented infection has been reported in neutropenic patients.
Thrombocytopenia or anemia develop occasionally in patients treated with CYTOXAN. These hematologic ef-
fects usually can be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukope-
nia usually begins in 7 to 10 days after cessation of therapy.
Urinary System
See WARNINGS for information on cystitis and urinary bladder fibrosis.
Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with cyclo-
phosphamide. Such lesions usually resolve following cessation of therapy.
Infections
See WARNINGS for information on reduced host resistance to infections.
Carcinogenesis
See WARNINGS for information on carcinogenesis.
Respiratory System
Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis
has been reported in patients receiving high doses of cyclophosphamide over a prolonged period.
Other
Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible
cross-sensitivity with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion)
has been reported with the use of cyclophosphamide. Malaise and asthenia have been reported as part of the
postmarketing experience.
OVERDOSAGE
No specific antidote for cyclophosphamide is known. Overdosage should be managed with supportive
measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should
it occur.
DOSAGE AND ADMINISTRATION
Treatment of Malignant Diseases
Adults and Children
When used as the only oncolytic drug therapy, the initial course of CYTOXAN for patients with no hematologic
deficiency usually consists of 40 to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days.
Other intravenous regimens include 10 to 15 mg/kg given every 7 to 10 days or 3 to 5 mg/kg twice weekly.
Oral CYTOXAN dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.
Many other regimens of intravenous and oral CYTOXAN have been reported. Dosages must be adjusted in
accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective
guide for regulating dosage. Transient decreases in the total white blood cell count to 2000 cells/mm3
(following short courses) or more persistent reduction to 3000 cells/mm3 (with continuing therapy) are tolerated
without serious risk of infection if there is no marked granulocytopenia.
When CYTOXAN is included in combined cytotoxic regimens, it may be necessary to reduce the dose of
CYTOXAN as well as that of the other drugs.
CYTOXAN and its metabolites are dialyzable although there are probably quantitative differences depending
upon the dialysis system being used. Patients with compromised renal function may show some measurable changes
in pharmacokinetic parameters of CYTOXAN metabolism, but there is no consistent evidence indicating a need
for CYTOXAN dosage modification in patients with renal function impairment.
Treatment of Nonmalignant Diseases
Biopsy Proven “Minimal Change” Nephrotic Syndrome In Children
An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the incidence of
oligospermia and azoospermia increases if the duration of CYTOXAN treatment exceeds 60 days. Treatment
beyond 90 days increases the probability of sterility. Adrenocorticosteroid therapy may be tapered and discon-
tinued during the course of CYTOXAN therapy. See PRECAUTIONS concerning hematologic monitoring.
Preparation and Handling of Solutions
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to adminis-
tration, whenever solution and container permit.
Add the diluent to the vial and shake it vigorously to dissolve. If the powder fails to dissolve immediately and
completely, it is advisable to allow the vial to stand for a few minutes. Use the quantity of diluent shown below
to constitute the product:
For Direct Injection
CYTOXAN should be prepared for parenteral use by adding 0.9% sterile sodium chloride solution. Solutions of CYTOXAN
may be injected intravenously, intramuscularly, intraperitoneally, or intrapleurally if constituted by adding 0.9%
sterile sodium chloride solution.
For Infusion
CYTOXAN (cyclophosphamide) may be prepared for parenteral use by infusion using any of the following methods:
1. CYTOXAN constituted with 0.9% sterile sodium chloride may be infused without further dilution.
2. CYTOXAN constituted with 0.9% sterile sodium chloride may be infused following further dilution in the
following:
Dextrose Injection, USP (5% dextrose)
Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride)
5% Dextrose and Ringer’s Injection
Lactated Ringer’s Injection, USP
Sodium Chloride Injection, USP (0.45% sterile sodium chloride)
Sodium Lactate Injection, USP (1/6 molar sodium lactate)
3. CYTOXAN sterile powder may be prepared for parenteral use by infusion by adding Sterile Water for Injection,
USP. CYTOXAN, constituted in water, is hypotonic and should not be injected directly. Prior to infusion,
solutions of CYTOXAN sterile powder constituted in Sterile Water for Injection, USP must be further diluted
in one of the following:
Dextrose Injection, USP (5% dextrose)
Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride)
5% Dextrose and Ringer’s Injection
Lactated Ringer’s Injection, USP
Sodium Chloride Injection, USP (0.45% sterile sodium chloride)
Sodium Lactate Injection, USP (1/6 molar sodium lactate)
Stability of Constituted Parenteral Solutions
CYTOXAN (prepared for either direct injection or infusion) is chemically and physically stable for 24 hours at room
temperature or for six days in the refrigerator; it does not contain any antimicrobial preservative and thus care
must be taken to assure the sterility of prepared solutions.
The osmolarities of solutions of CYTOXAN constituted with water and 0.9% sterile sodium chloride solution
are found in the following table:
Isotonic 0.9% sterile sodium chloride solution has an osmolarity of 289 mOsm/L.
For Oral Administration
Extemporaneous liquid preparations of CYTOXAN for oral administration may be prepared by dissolving CYTOXAN
in Aromatic Elixir, N.F. Such preparations should be stored under refrigeration in glass containers and used
within 14 days.
HOW SUPPLIED
CYTOXAN® (cyclophosphamide for injection, USP) contains cyclophosphamide monohydrate and is supplied in
vials for single-dose use.
CYTOXAN (cyclophosphamide for injection, USP).
U.S. Patent No. 4,537,883
NDC 0015-0502-41
500 mg vial, carton of 1
NDC 0015-0505-41
1.0 g vial, carton of 1
NDC 0015-0506-41
2.0 g vial, carton of 1
Store vials at or below 77° F (25° C). During transport or storage of CYTOXAN vials, temperature influences
can lead to melting of the active ingredient, cyclophosphamide. Vials containing melted substance can be
visually differentiated. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected
phase or in droplets in the affected vials. Do not use CYTOXAN vials if there are signs of melting.
CYTOXAN® Tablets, 25 mg, and CYTOXAN Tablets, 50 mg, are white tablets with blue flecks containing
25 mg and 50 mg cyclophosphamide (anhydrous), respectively.
CYTOXAN Tablets (cyclophosphamide tablets, USP). 
NDC 0015-0503-01
50 mg, bottles of 100
NDC 0015-0504-01
25 mg, bottles of 100
Store tablets at or below 77°F (25°C); tablets will withstand brief exposure to temperatures up to 86°F (30°C),
but should be protected from temperatures above 86°F (30°C).
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines
on this subject have been published.1-8 There is no general agreement that all of the procedures recommended
in the guidelines are necessary or appropriate.
To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing
CYTOXAN sterile powder for injection, or bottles containing CYTOXAN tablets. This includes all handling
activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking
and inspection, transport within a facility, and dose preparation and administration.
REFERENCES
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice.
Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.
2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of
Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service
publication NIH 83-2621.
3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:
1590-1592.
4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987.
Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts
College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic
agents. Med J Aust. 1983;1:426-428.
6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai
Medical Center. CA Cancer J Clin. 1983;33:258-263.
7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and
hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.
8. Controlling occupational exposure to hazardous drugs. (OSHA Work-Practice Guidelines.) Am J Health-
Syst Pharm. 1996;53:1669-1685.
Vials Manufactured by:
Vials Distributed and Tablets Manufactured by:
Baxter Healthcare Corporation
Bristol-Myers Squibb Company
Deerfield, Illinois 60015 USA
Princeton, New Jersey 08543
Vials Made in Germany
Tablets Made in Italy
H4-B0001-09-05
1175025A2
Revised September 2005
USA 5638 0612 C 669
CYTOXAN and Diluent
mOsm/L
5 mL water per 100 mg cyclophosphamide (anhydrous)
74
5 mL 0.9% sterile sodium chloride solution per 100 mg cyclophosphamide (anhydrous)
374
Dosage Strength
CYTOXAN Contains Cyclophosphamide Monohydrate
Quantity of Diluent
500 mg
534.5 mg
25 mL
1 g
1069.0 mg
50 mL
2 g
2138.0 mg
100 mL
Page 94
 

Myozyme® (alglucosidase alfa) 
95 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
14.2 
Rituximab United States Prescribing Information 
 
GENZYME CORPORATION 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
Page 95
 

 
 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
Rituxan safely and effectively.  See full prescribing information 
for Rituxan. 
 
Rituxan (rituximab)  
Injection for Intravenous Use 
Initial U.S. Approval:  1997 
WARNING:  FATAL INFUSION REACTIONS, TUMOR LYSIS 
SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, 
and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 
(PML) 
See full prescribing information for complete boxed warning. 
• Fatal infusion reactions within 24 hours of Rituxan infusion occur; 
approximately 80% of fatal reactions occurred with first infusion.  
Monitor patients and discontinue Rituxan infusion for severe 
reactions (5.1). 
• Tumor lysis syndrome (5.2). 
• Severe mucocutaneous reactions, some with fatal outcomes (5.3). 
• PML resulting in death (5.4). 
 
--------------------------RECENT MAJOR CHANGES------------------------ 
Warnings and Precautions, PML (5.4) 
 
09/2008 
---------------------------INDICATIONS AND USAGE------------------------ 
Rituxan is a CD20-directed cytolytic antibody indicated for the treatment 
of the following: 
• Non-Hodgkin’s Lymphoma (NHL) (1.1) 
• Rheumatoid Arthritis (RA) in combination with methotrexate in adult 
patients with moderately-to severely-active RA who have inadequate 
response to one or more TNF antagonist therapies (1.2) 
 ------------------------DOSAGE AND ADMINISTRATION------------------ 
DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. 
• The dose for NHL is 375 mg/m2 (2.1). 
• The dose as a component of Zevalin (Ibritumomab tiuxetan) 
Therapeutic Regimen is 250 mg/m2 (2.2). 
• The dose for Rheumatoid Arthritis is two-1000 mg IV infusions 
separated by 2 weeks in combination with methotrexate.  
Methylprednisolone 100 mg IV or equivalent glucocorticoid is 
recommended 30 minutes prior to each infusion (2.3). 
---------------------DOSAGE FORMS AND STRENGTHS------------------ 
• 100 mg/10 mL and 500 mg/50 mL solution in a single-use vial (3). 
------------------------------CONTRAINDICATIONS-------------------------- 
None. 
-----------------------WARNINGS AND PRECAUTIONS-------------------- 
• Tumor lysis syndrome – administer prophylaxis and monitor renal 
function (5.2). 
• PML - monitor neurologic function.  Discontinue Rituxan (5.4). 
• Hepatitis B reactivation with fulminant hepatitis, sometimes fatal – 
screen high risk patients and monitor HBV carriers during and several 
months after therapy.  Discontinue Rituxan if reactivation occurs (5.5). 
• 
Cardiac arrhythmias and angina can occur and can be life threatening.  
Monitor patients with these conditions closely (5.7). 
• 
Bowel obstruction and perforation - evaluate complaints of abdominal 
pain (5.9). 
• 
Do not administer live virus vaccines prior to or during Rituxan (5.10). 
• 
Monitor CBC at regular intervals for severe cytopenias (5.11, 6.1). 
------------------------------ADVERSE REACTIONS--------------------------- 
• Non-Hodgkin’s Lymphoma (NHL) - Common adverse reactions 
( ≥ 25%) in clinical trials were:  infusion reactions, fever, lymphopenia, 
chills, infection and asthenia (6.1). 
• Rheumatoid Arthritis (RA) - Common adverse reactions ( ≥ 5%):  
hypertension, nausea, upper respiratory tract infection, arthralgia, 
pruritus, and pyrexia (6.2).  Other important adverse reactions include 
infusion reactions, serious infections, and cardiovascular events (6.2). 
 
To report SUSPECTED ADVERSE REACTIONS, contact Genentech 
at 1-888-835-2555 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch. 
-------------------------------DRUG INTERACTIONS-------------------------- 
• Renal toxicity when used in combination with cisplatin (5.8). 
-----------------------USE IN SPECIFIC POPULATIONS-------------------- 
• Pregnancy:  Limited human data; B-cell lymphocytopenia occurred in 
infants exposed in utero (8.1). 
• Nursing Mothers: Caution should be exercised when administered to a 
nursing woman (8.3). 
 
See 17 for PATIENT COUNSELING INFORMATION and 
Medication Guide. 
Revised: 09/2008 
 
Page 96
 

 
FULL PRESCRIBING INFORMATION:  CONTENTS* 
WARNING:  FATAL INFUSION REACTIONS, TUMOR 
LYSIS SYNDROME (TLS), SEVERE 
MUCOCUTANEOUS REACTIONS, and 
PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY (PML) 
1 
INDICATIONS AND USAGE 
1.1 
Non-Hodgkin’s Lymphoma (NHL) 
1.2 
Rheumatoid Arthritis 
2 
DOSAGE AND ADMINISTRATION 
2.1 
Administration 
2.2 
Recommended Dose for Non-Hodgkin’s Lymphoma 
(NHL) 
2.3 
Recommended Dose as a Component of Zevalin 
2.4 
Recommended Dose for Rheumatoid Arthritis 
2.5 
Recommended Concomitant Medications 
2.6 
Preparation for Administration 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Infusion Reactions 
5.2 
Tumor Lysis Syndrome (TLS) 
5.3 
Severe Mucocutaneous Reactions 
5.4 
Progressive Multifocal Leukoencephalopathy (PML) 
5.5 
Hepatitis B Virus (HBV) Reactivation 
5.6 
Other Viral Infections 
5.7 
Cardiovascular 
5.8 
Renal 
5.9 
Bowel Obstruction and Perforation 
5.10 
Immunization 
5.11 
Laboratory Monitoring 
5.12 
Concomitant Use with Biologic Agents and Disease 
Modifying Anti-Rheumatic Drugs (DMARDS) other 
than Methotrexate in RA 
5.13 
Use in RA Patients Who Have Not Had Prior 
Inadequate Response to Tumor Necrosis Factor 
(TNF) Antagonists 
5.14 
Retreatment in Patients with RA 
6 
ADVERSE REACTIONS 
6.1 
Clinical Trials Experience Non-Hodgkin’s 
Lymphoma 
6.2 
Clinical Trials Experience Rheumatoid Arthritis 
6.3 
Immunogenicity 
6.4 
Postmarketing Experience 
7 
DRUG INTERACTIONS 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
8.3 
Nursing Mothers 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
10 OVERDOSAGE 
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 
13.2 
Animal Toxicology and/or Pharmacology 
14 CLINICAL STUDIES 
14.1 
Relapsed or Refractory, Low-Grade or Follicular, 
CD20 Positive, B-Cell NHL 
14.2 
Previously Untreated, Follicular, CD20-Positive, 
B-Cell NHL 
14.3 
Non-Progressing, Low-Grade, CD20-Positive, B-Cell 
NHL Following First-Line CVP Chemotherapy 
14.4 
Diffuse Large B-Cell NHL (DLBCL) 
14.5 
Rheumatoid Arthritis (RA) 
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
17.1 
General Counseling Information 
17.2 
Medication Guide 
*Sections or subsections omitted from the full prescribing information are 
not listed. 
Page 97
 

 
 
 
FULL PRESCRIBING INFORMATION 
1 
WARNING:  FATAL INFUSION REACTIONS, TUMOR LYSIS 
2 
SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, 
3 
and  
4 
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 
5 
(PML) 
6 
Infusion Reactions 
7 
Rituxan administration can result in serious, including fatal infusion 
8 
reactions.  Deaths within 24 hours of Rituxan infusion have occurred.  
9 
Approximately 80% of fatal infusion reactions occurred in association 
10 
with the first infusion.  Carefully monitor patients during infusions.  
11 
Discontinue Rituxan infusion and provide medical treatment for 
12 
Grade 3 or 4 infusion reactions [see Warnings and Precautions (5.1), 
13 
Adverse Reactions (6.1)]. 
14 
Tumor Lysis Syndrome (TLS) 
15 
Acute renal failure requiring dialysis with instances of fatal outcome 
16 
can occur in the setting of TLS following treatment of non-Hodgkin’s 
17 
lymphoma (NHL) patients with Rituxan [see Warnings and 
18 
Precautions (5.2), Adverse Reactions (6)]. 
19 
Severe Mucocutaneous Reactions 
20 
Severe, including fatal, mucocutaneous reactions can occur in patients 
21 
receiving Rituxan [see Warnings and Precautions (5.3), Adverse 
22 
Reactions (6)]. 
23 
Progressive Multifocal Leukoencephalopathy (PML) 
24 
JC virus infection resulting in PML and death can occur in patients 
25 
receiving Rituxan [see Warnings and Precautions (5.4), Adverse 
26 
Reactions (6.4)]. 
27 
 
28 
1 INDICATIONS AND USAGE 
29 
1.1 Non–Hodgkin’s Lymphoma (NHL) 
30 
 Rituxan (rituximab) is indicated for the treatment of patients with: 
31 
• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell 
32 
NHL as a single agent 
33 
• Previously untreated follicular, CD20-positive, B-cell NHL in 
34 
combination with CVP chemotherapy 
35 
• Non-progressing (including stable disease), low-grade, CD20-positive, 
36 
B-cell NHL, as a single agent, after first-line CVP chemotherapy 
37 
• Previously untreated diffuse large B-cell, CD20-positive NHL in 
38 
combination with CHOP or other anthracycline-based chemotherapy 
39 
regimens 
40 
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1.2 Rheumatoid Arthritis 
41 
 Rituxan (rituximab) in combination with methotrexate is indicated to 
42 
reduce signs and symptoms and to slow the progression of structural 
43 
damage in adult patients with moderately-to severely- active rheumatoid 
44 
arthritis who have had an inadequate response to one or more TNF 
45 
antagonist therapies. 
46 
2 DOSAGE AND ADMINISTRATION 
47 
2.1 Administration 
48 
 DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
49 
 Premedicate before each infusion [see Dosage and Administration 
50 
(2.5)].  Administer only as an intravenous infusion [see Dosage and 
51 
Administration (2.5)]. 
52 
• First Infusion:  Initiate infusion at a rate of 50 mg/hr. In the absence of 
53 
infusion toxicity, increase infusion rate by 50 mg/hr increments every 
54 
30 minutes, to a maximum of 400 mg/hr. 
55 
• Subsequent Infusions:  Initiate infusion at a rate of 100 mg/hr.  In the 
56 
absence of infusion toxicity, increase rate by 100 mg/hr increments at 
57 
30-minute intervals, to a maximum of 400 mg/hr. 
58 
• Interrupt the infusion or slow the infusion rate for infusion reactions 
59 
[see Boxed Warning, Warnings and Precautions (5.1)].  Continue the 
60 
infusion at one-half the previous rate upon improvement of symptoms. 
61 
2.2 Recommended Dose for Non-Hodgkin’s Lymphoma (NHL) 
62 
 The recommended dose is 375 mg/m2 as an intravenous infusion 
63 
according to the following schedules: 
64 
• Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, 
65 
B-Cell NHL 
66 
Administer once weekly for 4 or 8 doses. 
67 
• Retreatment for Relapsed or Refractory, Low-Grade or Follicular, 
68 
CD20-Positive, B-Cell NHL 
69 
Administer once weekly for 4 doses. 
70 
• Previously Untreated, Follicular, CD20-Positive, B-Cell NHL 
71 
Administer on Day 1 of each cycle of CVP chemotherapy, for up to 
72 
8 doses. 
73 
• Non-progressing, Low-Grade, CD20-Positive, B-cell NHL, after 
74 
first-line CVP chemotherapy 
75 
Following completion of 6−8 cycles of CVP chemotherapy, administer 
76 
once weekly for 4 doses at 6-month intervals to a maximum of 
77 
16 doses. 
78 
• Diffuse Large B-Cell NHL 
79 
Administer on Day 1 of each cycle of chemotherapy for up to 
80 
8 infusions. 
81 
2.3 Recommended Dose as a Component of Zevalin 
82 
• Infuse rituximab 250 mg/m2 within 4 hours prior to the administration 
83 
of Indium-111-(In-111-) Zevalin and within 4 hours prior to the 
84 
administration of Yttrium-90- (Y-90-) Zevalin. 
85 
Page 99
 

 
 
• Administer Rituxan and In-111-Zevalin 7-9 days prior to Rituxan and 
86 
Y-90- Zevalin. 
87 
• Refer to the Zevalin package insert for full prescribing information 
88 
regarding the Zevalin therapeutic regimen. 
89 
2.4 Recommended Dose for Rheumatoid Arthritis 
90 
• Two-1000 mg intravenous infusions separated by 2 weeks. 
91 
• Glucocorticoids administered as methylprednisolone 100 mg 
92 
intravenous or its equivalent 30 minutes prior to each infusion are 
93 
recommended to reduce the incidence and severity of infusion reactions.  
94 
Safety and efficacy of retreatment have not been established in 
95 
controlled trials [see Warnings and Precautions (5.14)]. 
96 
•  Rituxan is given in combination with methotrexate. 
97 
2.5 Recommended Concomitant Medications 
98 
 Premedicate before each infusion with acetaminophen and an 
99 
antihistamine. 
100 
2.6 Preparation for Administration 
101 
 Use appropriate aseptic technique.  Parenteral drug products should be 
102 
inspected visually for particulate matter and discoloration prior to 
103 
administration.  Do not use vial if particulates or discoloration is present.  
104 
Withdraw the necessary amount of Rituxan and dilute to a final 
105 
concentration of 1 to 4 mg/mL in an infusion bag containing either 0.9% 
106 
Sodium Chloride, USP, or 5% Dextrose in Water, USP.  Gently invert the 
107 
bag to mix the solution.  Do not mix or dilute with other drugs.  Discard 
108 
any unused portion left in the vial. 
109 
3 DOSAGE FORMS AND STRENGTHS 
110 
 100 mg/10 mL single-use vial 
111 
 500 mg/50 mL single-use vial 
112 
4 CONTRAINDICATIONS 
113 
 None. 
114 
5 WARNINGS AND PRECAUTIONS 
115 
5.1 Infusion Reactions 
116 
 Rituxan can cause severe, including fatal, infusion reactions.  Severe 
117 
reactions typically occurred during the first infusion with time to onset of 
118 
30−120 minutes.  Rituxan-induced infusion reactions and sequelae include 
119 
urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary 
120 
infiltrates, acute respiratory distress syndrome, myocardial infarction, 
121 
ventricular fibrillation, cardiogenic shock, or anaphylactoid events. 
122 
 Premedicate patients with an antihistamine and acetaminophen prior to 
123 
dosing.  Institute medical management (e.g. glucocorticoids, epinephrine, 
124 
bronchodilators, or oxygen) for infusion reactions as needed.  Depending 
125 
on the severity of the infusion reaction and the required interventions, 
126 
consider resumption of the infusion at a minimum 50% reduction in rate 
127 
after symptoms have resolved.  Closely monitor the following patients: 
128 
those with pre-existing cardiac or pulmonary conditions, those who 
129 
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experienced prior cardiopulmonary adverse reactions, and those with high 
130 
numbers of circulating malignant cells ( ≥ 25,000/mm3). [See Boxed 
131 
Warning, Warnings and Precautions (5.7), Adverse Reactions (6.1).] 
132 
5.2 Tumor Lysis Syndrome (TLS) 
133 
 Rapid reduction in tumor volume followed by acute renal failure, 
134 
hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can 
135 
occur within 12−24 hours after the first infusion.  Fatal TLS cases have 
136 
occurred after administration of Rituxan.  A high number of circulating 
137 
malignant cells ( ≥ 25,000/mm3) or high tumor burden confers a greater 
138 
risk of TLS after rituximab.  Consider prophylaxis for TLS in patients at 
139 
high risk.  Correct electrolyte abnormalities, monitor renal function and 
140 
fluid balance, and administer supportive care, including dialysis as 
141 
indicated. [See Boxed Warning.] 
142 
5.3 Severe Mucocutaneous Reactions  
143 
 Mucocutaneous reactions, some with fatal outcome, can occur in 
144 
patients treated with Rituxan.  These reactions include paraneoplastic 
145 
pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, 
146 
vesiculobullous dermatitis, and toxic epidermal necrolysis.  The onset of 
147 
these reactions has varied from 1−13 weeks following Rituxan exposure.  
148 
Discontinue Rituxan in patients who experience a severe mucocutaneous 
149 
reaction.  The safety of readministration of Rituxan to patients with severe 
150 
mucocutaneous reactions has not been determined. [See Boxed Warning, 
151 
Adverse Reactions (6.1, 6.4).] 
152 
5.4 Progressive Multifocal Leukoencephalopathy (PML) 
153 
 JC virus infection resulting in PML and death can occur in 
154 
Rituxan-treated patients with hematologic malignancies or with 
155 
autoimmune diseases.  The majority of patients with hematologic 
156 
malignancies diagnosed with PML received Rituxan in combination with 
157 
chemotherapy or as part of a hematopoietic stem cell transplant.  The 
158 
patients with autoimmune diseases had prior or concurrent 
159 
immunosuppressive therapy. Most cases of PML were diagnosed within 
160 
12 months of their last infusion of Rituxan. 
161 
 Consider the diagnosis of PML in any patient presenting with new-onset 
162 
neurologic manifestations.  Evaluation of PML includes, but is not limited 
163 
to, consultation with a neurologist, brain MRI, and lumbar puncture.  
164 
Discontinue Rituxan and consider discontinuation or reduction of any 
165 
concomitant chemotherapy or immunosuppressive therapy in patients who 
166 
develop PML. [See Boxed Warning, Adverse Reactions (6.4).] 
167 
5.5 Hepatitis B Virus (HBV) Reactivation 
168 
 Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic 
169 
failure, and death can occur in patients with hematologic malignancies 
170 
treated with Rituxan.  The median time to the diagnosis of hepatitis was 
171 
approximately 4 months after the initiation of Rituxan and approximately 
172 
one month after the last dose. 
173 
Page 101
 

 
 
 Screen patients at high risk of HBV infection before initiation of 
174 
Rituxan.  Closely monitor carriers of hepatitis B for clinical and laboratory 
175 
signs of active HBV infection for several months following Rituxan 
176 
therapy.  Discontinue Rituxan and any concomitant chemotherapy in 
177 
patients who develop viral hepatitis, and institute appropriate treatment 
178 
including antiviral therapy.  Insufficient data exist regarding the safety of 
179 
resuming Rituxan in patients who develop hepatitis subsequent to HBV 
180 
reactivation. [See Adverse Reactions (6.4).] 
181 
5.6 Other Viral Infections 
182 
 The following additional serious viral infections, either new, 
183 
reactivated, or exacerbated, have been identified in clinical studies or 
184 
postmarketing reports.  The majority of patients received Rituxan in 
185 
combination with chemotherapy or as part of a hematopoietic stem cell 
186 
transplant.  These viral infections included cytomegalovirus, herpes 
187 
simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and 
188 
hepatitis C.  In some cases, the viral infections occurred as late as one year 
189 
following discontinuation of Rituxan and have resulted in death. [See 
190 
Adverse Reactions (6.1, 6.4).] 
191 
5.7 Cardiovascular 
192 
 Discontinue infusions for serious or life-threatening cardiac 
193 
arrhythmias.  Perform cardiac monitoring during and after all infusions of 
194 
Rituxan for patients who develop clinically significant arrhythmias, or 
195 
who have a history of arrhythmia or angina. [See Adverse Reactions (6.4).] 
196 
5.8 Renal 
197 
 Severe, including fatal, renal toxicity can occur after Rituxan 
198 
administration in patients with hematologic malignancies.  Renal toxicity 
199 
has occurred in patients with high numbers of circulating malignant cells 
200 
( ≥ 25,000/mm3) or high tumor burden who experience tumor lysis 
201 
syndrome and in patients with NHL administered concomitant cisplatin 
202 
therapy during clinical trials.  The combination of cisplatin and Rituxan is 
203 
not an approved treatment regimen.  Use extreme caution if this non-
204 
approved combination is used in clinical trials and monitor closely for 
205 
signs of renal failure.  Consider discontinuation of Rituxan for patients 
206 
with a rising serum creatinine or oliguria. 
207 
5.9 Bowel Obstruction and Perforation 
208 
 Abdominal pain, bowel obstruction and perforation, in some cases 
209 
leading to death, can occur in patients receiving Rituxan in combination 
210 
with chemotherapy.  In postmarketing reports, the mean time to 
211 
documented gastrointestinal perforation was 6 (range 1−77) days in 
212 
patients with NHL. Perform a thorough diagnostic evaluation and institute 
213 
appropriate treatment for complaints of abdominal pain, especially early in 
214 
the course of Rituxan therapy. [See Adverse Reactions (6.4).] 
215 
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5.10 
Immunization 
216 
 The safety of immunization with live viral vaccines following Rituxan 
217 
therapy has not been studied and vaccination with live virus vaccines is 
218 
not recommended.  Physicians should review the vaccination status of 
219 
patients with RA being considered for Rituxan treatment and follow the 
220 
Centers for Disease Control and Prevention (CDC) guidelines for adult 
221 
vaccination with non-live vaccines intended to prevent infectious disease 
222 
prior to therapy. 
223 
 For NHL patients, the benefits of primary or booster vaccinations 
224 
should be weighted against the risks of delay in initiation of Rituxan 
225 
therapy. 
226 
5.11 
Laboratory Monitoring 
227 
 Because Rituxan binds to all CD20-positive B lymphocytes (malignant 
228 
and nonmalignant), obtain complete blood counts (CBC) and platelet 
229 
counts at regular intervals during Rituxan therapy and more frequently in 
230 
patients who develop cytopenias [see Adverse Reactions (6.1)].  The 
231 
duration of cytopenias caused by Rituxan can extend months beyond the 
232 
treatment period. 
233 
5.12 
Concomitant Use with Biologic Agents and Disease Modifying 
234 
Anti-Rheumatic Drugs (DMARDS) other than Methotrexate in 
235 
RA 
236 
 Limited data are available on the safety of the use of biologic agents or 
237 
DMARDs other than methotrexate in patients exhibiting peripheral B-cell 
238 
depletion following treatment with rituximab.  Observe patients closely for 
239 
signs of infection if biologic agents and/or DMARDs are used 
240 
concomitantly. 
241 
5.13 
Use in RA Patients Who Have Not Had Prior Inadequate 
242 
Response to Tumor Necrosis Factor (TNF) Antagonists 
243 
 While efficacy of Rituxan was supported in two well-controlled trials in 
244 
patients with RA with prior inadequate responses to non-biologic 
245 
DMARDs, a favorable risk benefit relationship has not been established in 
246 
this population.  The use of Rituxan in patients with RA who have not had 
247 
prior inadequate response to one or more TNF antagonists is not 
248 
recommended [see Clinical Studies (14.5)]. 
249 
5.14 
Retreatment in Patients with RA 
250 
 Safety and efficacy of retreatment have not been established in 
251 
controlled trials.  A limited number of patients have received two to 
252 
five courses (two infusions per course) of treatment in an uncontrolled 
253 
setting.  In clinical trials in patients with RA, most of the patients who 
254 
received additional courses did so 24 weeks after the previous course and 
255 
none were retreated sooner than 16 weeks. 
256 
6 ADVERSE REACTIONS 
257 
 The following adverse reactions are discussed in greater detail in other 
258 
sections of the labeling: 
259 
Page 103
 

 
 
• Infusion reactions [see Warnings and Precautions (5.1)] 
260 
• Tumor lysis syndrome [see Warnings and Precautions (5.2)] 
261 
• Mucocutaneous reactions [see Warnings and Precautions (5.3)] 
262 
• Progressive multifocal leukoencephalopathy [see Warnings and 
263 
Precautions (5.4)] 
264 
• Hepatitis B reactivation with fulminant hepatitis [see Warnings and 
265 
Precautions (5.5)] 
266 
• Other viral infections [see Warnings and Precautions (5.6)] 
267 
• Cardiac arrhythmias [see Warnings and Precautions (5.7)] 
268 
• Renal toxicity [see Warnings and Precautions (5.8)] 
269 
• Bowel obstruction and perforation [see Warnings and Precautions 
270 
(5.9)] 
271 
 
272 
 The most common adverse reactions of Rituxan (incidence  ≥ 25%) 
273 
observed in patients with NHL are infusion reactions, fever, chills, 
274 
infection, asthenia, and lymphopenia. 
275 
 The most important serious adverse reactions of Rituxan are infusion 
276 
reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B 
277 
reactivation with fulminant hepatitis, PML, other viral infections, cardiac 
278 
arrhythmias, renal toxicity, and bowel obstruction and perforation. 
279 
6.1 Clinical Trials Experience Non-Hodgkin’s Lymphoma 
280 
 Because clinical trials are conducted under widely varying conditions, 
281 
adverse reaction rates observed in the clinical trials of a drug cannot be 
282 
directly compared to rates in the clinical trials of another drug and may not 
283 
reflect the rates observed in practice. 
284 
 The data described below reflect exposure to Rituxan in 1606 patients, 
285 
with exposures ranging from a single infusion up to 6−8 months.  Rituxan 
286 
was studied in both single-agent and active-controlled trials (n = 356 and 
287 
n= 1250).  These data were obtained in adults with low-grade, follicular, 
288 
or DLBCL NHL.  Most patients received Rituxan as an infusion of 375 
289 
mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in 
290 
combination with chemotherapy for up to 8 doses, or following 
291 
chemotherapy for up to 16 doses. 
292 
Infusion Reactions 
293 
 In the majority of patients with NHL, infusion reactions consisting of 
294 
fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, 
295 
bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or 
296 
hypertension occurred during the first Rituxan infusion.  Infusion reactions 
297 
typically occurred within 30 to 120 minutes of beginning the first infusion 
298 
and resolved with slowing or interruption of the Rituxan infusion and with 
299 
supportive care (diphenhydramine, acetaminophen, and intravenous 
300 
saline).  The incidence of infusion reactions was highest during the first 
301 
infusion (77%) and decreased with each subsequent infusion. [See Boxed 
302 
Warning, Warnings and Precautions (5.1).] 
303 
Page 104
 

 
 
Infections 
304 
 Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, 
305 
occurred in less than 5% of patients with NHL in the single-arm studies.  
306 
The overall incidence of infections was 31% (bacterial 19%, viral 10%, 
307 
unknown 6%, and fungal 1%). [See Warnings and Precautions (5.4), (5.5), 
308 
(5.6).] 
309 
 In randomized, controlled studies where Rituxan was administered 
310 
following chemotherapy for the treatment of follicular or low-grade NHL, 
311 
the rate of infection was higher among patients who received Rituxan. In 
312 
diffuse large B-cell lymphoma patients, viral infections occurred more 
313 
frequently in those who received Rituxan. 
314 
Cytopenias and hypogammaglobulinemia 
315 
 In patients with NHL receiving rituximab monotherapy, NCI-CTC 
316 
Grade 3 and 4 cytopenias were reported in 48% of patients.  These 
317 
included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia 
318 
(3%), and thrombocytopenia (2%).  The median duration of lymphopenia 
319 
was 14 days (range, 1−588 days) and of neutropenia was 13 days (range, 
320 
2−116 days).  A single occurrence of transient aplastic anemia (pure red 
321 
cell aplasia) and two occurrences of hemolytic anemia following Rituxan 
322 
therapy occurred during the single-arm studies. 
323 
 In studies of monotherapy, Rituxan-induced B-cell depletion occurred 
324 
in 70% to 80% of patients with NHL.  Decreased IgM and IgG serum 
325 
levels occurred in 14% of these patients. 
326 
Single-Agent Rituxan 
327 
 Adverse reactions in Table 1 occurred in 356 patients with relapsed or 
328 
refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in 
329 
single-arm studies of Rituxan administered as a single agent [see Clinical 
330 
Studies (14.1)].  Most patients received Rituxan 375 mg/m2 weekly for 
331 
4 doses. 
332 
Page 105
 

 
 
Table 1 
Incidence of Adverse Reactions in  ≥ 5% of Patients with 
Relapsed or Refractory, Low-Grade or Follicular NHL, 
Receiving Single-agent Rituxan (N = 356)a,b 
 
All Grades 
(%) 
Grade 3 and 4 
(%) 
Any Adverse Reactions 
99 
57 
Body as a Whole 
86 
10 
Fever 
53 
1 
Chills 
33 
3 
Infection 
31 
4 
Asthenia 
26 
1 
Headache 
19 
1 
Abdominal Pain 
14 
1 
Pain 
12 
1 
Back Pain 
10 
1 
Throat Irritation 
9 
0 
Flushing 
5 
0 
Heme and Lymphatic System  
67 
48 
Lymphopenia 
48 
40 
Leukopenia 
14 
4 
Neutropenia 
14 
6 
Thrombocytopenia 
12 
2 
Anemia 
8 
3 
Skin and Appendages 
44 
2 
Night Sweats 
15 
1 
Rash 
15 
1 
Pruritus 
14 
1 
Urticaria 
8 
1 
Respiratory System 
38 
4 
Increased Cough 
13 
1 
Rhinitis 
12 
1 
Bronchospasm 
8 
1 
Dyspnea 
7 
1 
Sinusitis 
6 
0 
Metabolic and Nutritional Disorders 
38 
3 
Angioedema 
11 
1 
Hyperglycemia 
9 
1 
Peripheral Edema 
8 
0 
LDH Increase 
7 
0 
 
333 
Page 106
 

 
 
Table 1 (cont’d) 
Incidence of Adverse Reactions in  ≥ 5% of Patients 
with Relapsed or Refractory, Low-Grade or Follicular 
NHL, Receiving Single-agent Rituxan (N = 356)a,b 
 
All Grades 
(%) 
Grade 3 and 4 
(%) 
Digestive System 
37 
2 
Nausea 
23 
1 
Diarrhea 
10 
1 
Vomiting 
10 
1 
Nervous System 
32 
1 
Dizziness 
10 
1 
Anxiety 
5 
1 
Musculoskeletal System 
26 
3 
Myalgia 
10 
1 
Arthralgia 
10 
1 
Cardiovascular System 
25 
3 
Hypotension 
10 
1 
Hypertension 
6 
1 
 a Adverse reactions observed up to 12 months following Rituxan. 
 b Adverse reactions graded for severity by NCI-CTC criteria. 
 
334 
 In these single-arm Rituxan studies, bronchiolitis obliterans occurred 
335 
during and up to 6 months after Rituxan infusion. 
336 
Rituxan in Combination with Chemotherapy 
337 
 Adverse reactions information below is based on 1250 patients who 
338 
received Rituxan in combination with chemotherapy or following 
339 
chemotherapy. 
340 
Rituxan in Combination with Chemotherapy for Low-Grade NHL 
341 
 In Study 4, patients in the R-CVP arm experienced a higher incidence 
342 
of infusional toxicity and neutropenia compared to patients in the CVP 
343 
arm.  The following adverse reactions occurred more frequently (≥ 5%) in 
344 
patients receiving R-CVP compared to CVP alone:  rash (17% vs. 5%), 
345 
cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus 
346 
(10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). 
347 
[See Clinical Studies (14.2).] 
348 
 In Study 5, the following adverse reactions were reported more 
349 
frequently ( ≥ 5%) in patients receiving Rituxan following CVP compared 
350 
to patients who received no further therapy:  fatigue (39% vs. 14%), 
351 
anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), 
352 
infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), 
353 
hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), 
354 
arthralgia (12% vs. 3%), and weight gain (11% vs. 4%).  Neutropenia was 
355 
the only Grade 3 or 4 adverse reaction that occurred more frequently 
356 
Page 107
 

 
 
(≥ 2%) in the Rituxan arm compared with those who received no further 
357 
therapy (4% vs. 1%). [See Clinical Studies (14.3).] 
358 
Rituxan in Combination with Chemotherapy for DLBCL 
359 
 In Studies 6 and 7, [see Clinical Studies (14.4)], the following adverse 
360 
reactions, regardless of severity, were reported more frequently ( ≥ 5%) in 
361 
patients age  ≥ 60 years receiving R-CHOP as compared to CHOP alone: 
362 
pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder 
363 
(29% vs. 21%), and chills (13% vs. 4%).  Detailed safety data collection in 
364 
these studies was primarily limited to Grade 3 and 4 adverse reactions and 
365 
serious adverse reactions. 
366 
 In Study 7, a review of cardiac toxicity determined that supraventricular 
367 
arrhythmias or tachycardia accounted for most of the difference in cardiac 
368 
disorders (4.5% for R-CHOP vs. 1.0% for CHOP). 
369 
 The following Grade 3 or 4 adverse reactions occurred more frequently 
370 
among patients in the R-CHOP arm compared with those in the CHOP 
371 
arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%).  
372 
Other Grade 3 or 4 adverse reactions occurring more frequently among 
373 
patients receiving R-CHOP were viral infection (Study 7), neutropenia 
374 
(Studies 7 and 8), and anemia (Study 8). 
375 
6.2 Clinical Trials Experience Rheumatoid Arthritis 
376 
 The types of adverse reactions observed in patients with RA were 
377 
similar to those seen in patients with non-Hodgkin’s lymphoma [see 
378 
Warnings and Precautions (5), Adverse Reactions (6.1)].  Specific safety 
379 
considerations in this indication are discussed below. 
380 
 Where specific percentages are noted, these data are based on 
381 
938 patients treated in Phase 2 and 3 studies of Rituxan (2 × 1000 mg) or 
382 
placebo administered in combination with methotrexate. 
383 
 
384 
Page 108
 

 
 
Table 2 
Incidence of All Adverse Reactions* Occurring in  ≥ 2%  
and at Least 1% Greater than Placebo Among Rheumatoid 
Arthritis Patients in Clinical Studies Up to Week 24 (Pooled) 
Preferred Term 
Placebo + MTX 
N = 398 
n (%) 
Rituxan + MTX 
N = 540 
n (%) 
Hypertension 
21 (5) 
43 (8) 
Nausea 
19 (5) 
41 (8) 
Upper Respiratory Tract 
Infection 
23 (6) 
37 (7) 
Arthralgia 
14 (4) 
31 (6) 
Pyrexia 
8 (2) 
27 (5) 
Pruritus 
5 (1) 
26 (5) 
Chills 
9 (2) 
16 (3) 
Dyspepsia 
3 ( < 1) 
16 (3) 
Rhinitis 
6 (2) 
14 (3) 
Paresthesia 
3 ( < 1) 
12 (2) 
Urticaria 
3 ( < 1) 
12 (2) 
Abdominal Pain Upper 
4 (1) 
11 (2) 
Throat Irritation 
0 (0) 
11 (2) 
Anxiety 
5 (1) 
9 (2) 
Migraine 
2 ( < 1) 
9 (2) 
Asthenia 
1 ( < 1) 
9 (2) 
*Coded using MedDRA. 
 
385 
Infusion Reactions 
386 
 In Rituxan RA placebo-controlled studies, 32% of Rituxan-treated 
387 
patients experienced an adverse reaction during or within 24 hours 
388 
following their first infusion, compared to 23% of placebo-treated patients 
389 
receiving their first infusion.  The incidence of adverse reactions during 
390 
the 24-hour period following the second infusion, Rituxan or placebo, 
391 
decreased to 11% and 13%, respectively.  Acute infusion reactions 
392 
(manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, 
393 
sneezing, throat irritation, cough, and/or bronchospasm, with or without 
394 
associated hypotension or hypertension) were experienced by 27% of 
395 
Rituxan-treated patients following their first infusion, compared to 19% of 
396 
placebo-treated patients receiving their first placebo infusion.  The 
397 
incidence of these acute infusion reactions following the second infusion 
398 
of Rituxan or placebo decreased to 9% and 11%, respectively.  Serious 
399 
acute infusion reactions were experienced by  < 1% of patients in either 
400 
treatment group.  Acute infusion reactions required dose modification 
401 
(stopping, slowing, or interruption of the infusion) in 10% and 2% of 
402 
patients receiving rituximab or placebo, respectively, after the first course.  
403 
The proportion of patients experiencing acute infusion reactions decreased 
404 
with subsequent courses of Rituxan.  The administration of intravenous 
405 
glucocorticoids prior to Rituxan infusions reduced the incidence and 
406 
severity of such reactions, however, there was no clear benefit from the 
407 
Page 109
 

 
 
administration of oral glucocorticoids for the prevention of acute infusion 
408 
reactions.  Patients in clinical studies also received antihistamines and 
409 
acetaminophen prior to Rituxan infusions. 
410 
Infections 
411 
 In RA clinical studies, 39% of patients in the Rituxan group 
412 
experienced an infection of any type compared to 34% of patients in the 
413 
placebo group.  The most common infections were nasopharyngitis, upper 
414 
respiratory tract infections, urinary tract infections, bronchitis, and 
415 
sinusitis. 
416 
 The incidence of serious infections was 2% in the Rituxan-treated 
417 
patients and 1% in the placebo group.  One fatal infection 
418 
(bronchopneumonia) occurred with rituximab monotherapy during the 
419 
24-week, placebo-controlled period in one of the Phase 2 RA studies.  In 
420 
107 Rituxan-treated RA patients with active disease, subsequent treatment 
421 
with a TNF inhibitor was associated with a higher rate of serious 
422 
infections.  Six serious infections were observed in 100.8 patient years 
423 
(0.06 per patient year) prior to exposure and 9 were observed in 97.8 
424 
patient years (0.09 per patient year) after exposure. 
425 
Cardiac Adverse Reactions 
426 
 The incidence of serious cardiovascular events in the double-blind part 
427 
of the RA clinical trials was 1.7% and 1.3% in Rituxan and placebo 
428 
treatment groups, respectively.  Three cardiovascular deaths occurred 
429 
during the double-blind period of the RA studies including all rituximab 
430 
regimens (3/769 = 0.4%) as compared to none in the placebo treatment 
431 
group (0/389). 
432 
 Since patients with RA are at increased risk for cardiovascular events 
433 
compared with the general population, patients with RA should be 
434 
monitored throughout the infusion and Rituxan should be discontinued in 
435 
the event of a serious or life-threatening cardiac event. 
436 
Hypophosphatemia and hyperuricemia 
437 
 In the 24-week, double-blind RA clinical trial program, newly-
438 
occurring hypophosphatemia (<2.0 mg/dl) was observed in 12% (67/540) 
439 
of patients on Rituxan versus 10% (39/398) of patients on placebo.  
440 
Hypophosphatemia was more common in patients who received 
441 
corticosteroids. Newly-occurring hyperuricemia (>10 mg/dl) was observed 
442 
in 1.5% (8/540) of patients on Rituxan versus 0.3% (1/398) of patients on 
443 
placebo. 
444 
 
At any time after treatment with up to seven courses of Rituxan, at 
445 
least one episode of newly-occurring hypophosphatemia was observed in 
446 
23% (245/1048) of patients and newly-occurring hyperuricemia was 
447 
observed in 3% (32/1048) of patients. 
448 
 
449 
6.3 Immunogenicity 
450 
 As with all therapeutic proteins, there is a potential for immunogenicity.  
451 
The observed incidence of antibody (including neutralizing antibody) 
452 
Page 110
 

 
 
positivity in an assay is highly dependent on several factors including 
453 
assay sensitivity and specificity, assay methodology, sample handling, 
454 
timing of sample collection, concomitant medications, and underlying 
455 
disease.  For these reasons, comparison of the incidence of antibodies to 
456 
Rituxan with the incidence of antibodies to other products may be 
457 
misleading. 
458 
 Using an ELISA assay, anti-human anti-chimeric antibody (HACA) 
459 
was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL 
460 
receiving single-agent Rituxan.  Three of the four patients had an objective 
461 
clinical response. 
462 
 A total of 118/1053 patients (11%) with RA tested positive for HACA 
463 
at any time after treatment with Rituxan.  Limited data are available on the 
464 
safety or efficacy of Rituxan retreatment in patients who develop HACA.  
465 
Of the 8 patients who experienced serious acute infusion reactions, 2 were 
466 
subsequently found to be HACA-positive.  Approximately 12% (14/118) 
467 
of patients who were HACA-positive had a subsequent infusion reaction 
468 
of any severity.  The clinical relevance of HACA formation in 
469 
rituximab-treated patients is unclear. 
470 
6.4 Postmarketing Experience 
471 
 The following adverse reactions have been identified during post-
472 
approval use of Rituxan in hematologic malignancies.  Because these 
473 
reactions are reported voluntarily from a population of uncertain size, it is 
474 
not always possible to reliably estimate their frequency or establish a 
475 
causal relationship to drug exposure.   
Decisions to include these 
476 
reactions in labeling are typically based on one or more of the following 
477 
factors:  (1) seriousness of the reaction, (2) frequency of reporting, or (3) 
478 
strength of causal connection to Rituxan. 
479 
• Hematologic:  prolonged pancytopenia, marrow hypoplasia, and late-
480 
onset neutropenia, hyperviscosity syndrome in Waldenstrom’s 
481 
macroglobulinemia. 
482 
• Cardiac:  fatal cardiac failure. 
483 
• Immune/Autoimmune Events:  uveitis, optic neuritis, systemic 
484 
vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular 
485 
arthritis, and vasculitis with rash. 
486 
• Infection:  viral infections, including progressive multifocal 
487 
leukoencephalopathy (PML), increase in fatal infections in 
488 
HIV-associated lymphoma, and a reported increased incidence of Grade 
489 
3 and 4 infections in patients with previously treated lymphoma without 
490 
known HIV infection. 
491 
• Neoplasia:  disease progression of Kaposi’s sarcoma. 
492 
• Skin:  severe mucocutaneous reactions. 
493 
• Gastrointestinal:  bowel obstruction and perforation. 
494 
• Pulmonary:  fatal bronchiolitis obliterans and pneumonitis (including 
495 
interstitial pneumonitis). 
496 
Page 111
 

 
 
7 DRUG INTERACTIONS 
497 
 Formal drug interaction studies have not been performed with Rituxan.  
498 
In clinical trials of patients with RA, concomitant administration of 
499 
methotrexate or cyclophosphamide did not alter the pharmacokinetics of 
500 
rituximab. 
501 
8 USE IN SPECIFIC POPULATIONS 
502 
8.1 Pregnancy 
503 
 Category C:  There are no adequate and well-controlled studies of 
504 
rituximab in pregnant women.  Postmarketing data indicate that B-cell 
505 
lymphocytopenia generally lasting less than six months can occur in 
506 
infants exposed to rituximab in-utero.  Rituximab was detected postnatally 
507 
in the serum of infants exposed in-utero.   
508 
 Non-Hodgkin’s lymphoma and moderate-severe rheumatoid arthritis 
509 
are serious conditions that require treatment.  Rituximab should be used 
510 
during pregnancy only if the potential benefit to the mother justifies the 
511 
potential risk to the fetus. 
512 
 Reproduction studies in cynomolgus monkeys at maternal exposures 
513 
similar to human therapeutic exposures showed no evidence of teratogenic 
514 
effects.  However, B-cell lymphoid tissue was reduced in the offspring of 
515 
treated dams.  The B-cell counts returned to normal levels, and 
516 
immunologic function was restored within 6 months of birth. 
517 
  
518 
8.3 Nursing Mothers 
519 
 It is not known whether Rituxan is secreted into human milk.  However, 
520 
Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG 
521 
is excreted in human milk.  Published data suggest that antibodies in 
522 
breast milk do not enter the neonatal and infant circulations in substantial 
523 
amounts.  The unknown risks to the infant from oral ingestion of Rituxan 
524 
should be weighed against the known benefits of breastfeeding. 
525 
8.4 Pediatric Use 
526 
 The safety and effectiveness of Rituxan in pediatric patients have not 
527 
been established. 
528 
8.5 Geriatric Use 
529 
Diffuse Large B-Cell NHL 
530 
 Among patients with DLBCL evaluated in three randomized, 
531 
active-controlled trials, 927 patients received Rituxan in combination with 
532 
chemotherapy.  Of these, 396 (43%) were age 65 or greater and 123 (13%) 
533 
were age 75 or greater.  No overall differences in effectiveness were 
534 
observed between these patients and younger patients.  Cardiac adverse 
535 
reactions, mostly supraventricular arrhythmias, occurred more frequently 
536 
among elderly patients.  Serious pulmonary adverse reactions were also 
537 
more common among the elderly, including pneumonia and pneumonitis. 
538 
Page 112
 

 
 
Low-Grade or Follicular Non-Hodgkin’s Lymphoma 
539 
 Clinical studies of Rituxan in low-grade or follicular, CD20-positive, 
540 
B-cell NHL did not include sufficient numbers of patients aged 65 and 
541 
over to determine whether they respond differently from younger subjects. 
542 
Rheumatoid Arthritis 
543 
 Among the 517 patients in the Phase 3 RA study, 16% were 
544 
65−75 years old and 2% were 75 years old and older.  Response rates and 
545 
adverse reactions were similar in the older (age ≥ 65 years) and younger 
546 
(age < 65 years) patients. 
547 
10 OVERDOSAGE 
548 
 There has been no experience with overdosage in human clinical trials.  
549 
Single doses of up to 500 mg/m2 have been given in dose-escalation 
550 
clinical trials. 
551 
11 DESCRIPTION 
552 
 Rituxan (rituximab) is a genetically engineered chimeric 
553 
murine/human monoclonal IgG1 kappa antibody directed against the CD20 
554 
antigen. Rituximab has an approximate molecular weight of 145 kD.  
555 
Rituximab has a binding affinity for the CD20 antigen of approximately 
556 
8.0 nM. 
557 
 Rituximab is produced by mammalian cell (Chinese Hamster Ovary) 
558 
suspension culture in a nutrient medium containing the antibiotic 
559 
gentamicin.  Gentamicin is not detectable in the final product.  Rituxan is 
560 
a sterile, clear, colorless, preservative-free liquid concentrate for 
561 
intravenous administration.  Rituxan is supplied at a concentration of 
562 
10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials.  
563 
The product is formulated in 9 mg/mL sodium chloride, 7.35 mg/mL 
564 
sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Water for 
565 
Injection.  The pH is 6.5. 
566 
12 CLINICAL PHARMACOLOGY 
567 
12.1 
Mechanism of Action 
568 
 Rituximab binds specifically to the antigen CD20 (human 
569 
B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic 
570 
transmembrane protein with a molecular weight of approximately 35 kD 
571 
located on pre-B and mature B lymphocytes.  The antigen is expressed 
572 
on > 90% of B-cell non-Hodgkin’s lymphomas (NHL), but the antigen is 
573 
not found on hematopoietic stem cells, pro-B-cells, normal plasma cells or 
574 
other normal tissues.  CD20 regulates an early step(s) in the activation 
575 
process for cell cycle initiation and differentiation, and possibly functions 
576 
as a calcium ion channel.  CD20 is not shed from the cell surface and does 
577 
not internalize upon antibody binding.  Free CD20 antigen is not found in 
578 
the circulation. 
579 
 B cells are believed to play a role in the pathogenesis of rheumatoid 
580 
arthritis (RA) and associated chronic synovitis.  In this setting, B cells may 
581 
be acting at multiple sites in the autoimmune/inflammatory process, 
582 
Page 113
 

 
 
including through production of rheumatoid factor (RF) and other 
583 
autoantibodies, antigen presentation, T-cell activation, and/or pro-
584 
inflammatory cytokine production. 
585 
 Mechanism of Action:  The Fab domain of rituximab binds to the CD20 
586 
antigen on B lymphocytes, and the Fc domain recruits immune effector 
587 
functions to mediate B-cell lysis in vitro.  Possible mechanisms of cell 
588 
lysis include complement-dependent cytotoxicity (CDC) and 
589 
antibody-dependent cell mediated cytotoxicity (ADCC).  The antibody has 
590 
been shown to induce apoptosis in the DHL-4 human B-cell lymphoma 
591 
line. 
592 
 Normal Tissue Cross-reactivity:  Rituximab binding was observed on 
593 
lymphoid cells in the thymus, the white pulp of the spleen, and a majority 
594 
of B lymphocytes in peripheral blood and lymph nodes.  Little or no 
595 
binding was observed in the non-lymphoid tissues examined. 
596 
12.2 
Pharmacodynamics 
597 
 Administration of Rituxan resulted in a rapid and sustained depletion of 
598 
circulating and tissue-based B cells.  Among 166 patients in Study 1, 
599 
circulating CD19-positive B cells were depleted within the first three 
600 
weeks with sustained depletion for up to 6 to 9 months post-treatment in 
601 
83% of patients.  B-cell recovery began at approximately 6 months and 
602 
median B-cell levels returned to normal by 12 months following 
603 
completion of treatment. 
604 
 There were sustained and statistically significant reductions in both IgM 
605 
and IgG serum levels observed from 5 through 11 months following 
606 
rituximab administration; 14% of patients had IgM and/or IgG serum 
607 
levels below the normal range. 
608 
 In RA patients, treatment with Rituxan induced depletion of peripheral 
609 
B lymphocytes, with all patients demonstrating near complete depletion 
610 
within 2 weeks after receiving the first dose of Rituxan.  The majority of 
611 
patients showed peripheral B-cell depletion for at least 6 months, followed 
612 
by subsequent gradual recovery after that timepoint.  A small proportion 
613 
of patients (4%) had prolonged peripheral B-cell depletion lasting more 
614 
than 3 years after a single course of treatment. 
615 
 In RA studies, total serum immunoglobulin levels, IgM, IgG, and IgA 
616 
were reduced at 6 months with the greatest change observed in IgM.  
617 
However, mean immunoglobulin levels remained within normal levels 
618 
over the 24-week period.  Small proportions of patients experienced 
619 
decreases in IgM (7%), IgG (2%), and IgA (1%) levels below the lower 
620 
limit of normal.  The clinical consequences of decreases in 
621 
immunoglobulin levels in RA patients treated with Rituxan are unclear. 
622 
 Treatment with rituximab in patients with RA was associated with 
623 
reduction of certain biologic markers of inflammation such as 
624 
interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein 
625 
(SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), 
626 
anti-citrullinated peptide (anti-CCP), and RF. 
627 
Page 114
 

 
 
12.3 
Pharmacokinetics 
628 
 Pharmacokinetics were characterized in 203 NHL patients receiving 
629 
375 mg/m2 rituximab weekly by IV infusion for 4 doses.  The mean Cmax 
630 
increased with each successive infusion and was 486 mcg/mL (range, 
631 
78−997 mcg/mL) following the fourth infusion. Peak and trough serum 
632 
levels of rituximab were inversely correlated with pretreatment circulating 
633 
CD19-positive B cells and tumor burden.  Rituximab was detectable in the 
634 
serum of patients 3 to 6 months after completion of treatment. 
635 
 The pharmacokinetic profile of rituximab when administered as 
636 
6 infusions of 375 mg/m2 in combination with 6 cycles of CHOP 
637 
chemotherapy was similar to that seen with rituximab alone. 
638 
 Based on a population pharmacokinetic analysis of data from 298 NHL 
639 
patients who received rituximab once weekly or once every three weeks, 
640 
the estimated median terminal elimination half-life was 22 days (range, 
641 
6.1 to 52 days).  Patients with higher CD19-positive cell counts or larger 
642 
measurable tumor lesions at pretreatment had a higher clearance.  
643 
However, dose adjustment for pretreatment CD19 count or size of tumor 
644 
lesion is not necessary.  Age and gender had no effect on the 
645 
pharmacokinetics of rituximab. 
646 
 Following administration of 2 doses of rituximab in patients with 
647 
rheumatoid arthritis, the mean Cmax values were 183 mcg/mL (CV = 24%) 
648 
for the 2 × 500 mg dose and 370 mcg/mL (CV = 25%) for the 
649 
2 × 1000 mg dose, respectively.  Following 2 × 1000 mg rituximab dose, 
650 
mean volume of distribution at steady state was 4.3L (CV = 28%).  Mean 
651 
systemic serum clearance of rituximab was 0.01L/h (CV = 38%), and 
652 
mean terminal elimination half-life after the second dose was 19 days 
653 
(CV = 32%). 
654 
 Female patients with RA (n = 86) had a 37% lower clearance of 
655 
rituximab than male patients with RA (n = 25).  The gender difference in 
656 
rituximab clearance does not necessitate any dose adjustment because 
657 
safety and efficacy of rituximab do not appear to be influenced by gender. 
658 
 The pharmacokinetics of rituximab have not been studied in children 
659 
and adolescents.  No formal studies were conducted to examine the effects 
660 
of either renal or hepatic impairment on the pharmacokinetics of 
661 
rituximab. 
662 
13 NONCLINICAL TOXICOLOGY 
663 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
664 
 No long-term animal studies have been performed to establish the 
665 
carcinogenic or mutagenic potential of Rituxan or to determine potential 
666 
effects on fertility in males or females. 
667 
13.2 
Animal Toxicology and/or Pharmacology 
668 
Reproductive Toxicology Studies 
669 
 An embryo-fetal developmental toxicity study was performed on 
670 
pregnant cynomolgus monkeys.  Pregnant animals received rituximab via 
671 
Page 115
 

 
 
the intravenous route during early gestation (organogenesis period; post-
672 
coitum days 20 through 50).  Rituximab was administered as loading 
673 
doses on post-coitum (PC) days 20, 21 and 22, at 15, 37.5 or 
674 
75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 
675 
100 mg/kg/week.  The 100 mg/kg/week dose resulted in 80% of the 
676 
exposure (based on AUC) of those achieved following a dose of 2 grams 
677 
in humans. Rituximab crosses the monkey placenta.  Exposed offspring 
678 
did not exhibit any teratogenic effects but did have decreased lymphoid 
679 
tissue B cells. 
680 
 A subsequent pre- and postnatal reproductive toxicity study in 
681 
cynomolgus monkeys was completed to assess developmental effects 
682 
including the recovery of B cells and immune function in infants exposed 
683 
to rituximab in utero.  Animals were treated with a loading dose of 0, 15, 
684 
or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, 
685 
or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 
686 
20 through postpartum Day 78, PC Day 76 through PC Day 134, and from 
687 
PC day 132 through delivery and postpartum Day 28. Regardless of the 
688 
timing of treatment, decreased B cells and immunosuppression were noted 
689 
in the offspring of rituximab-treated pregnant animals.  The B-cell counts 
690 
returned to normal levels, and immunologic function was restored within 
691 
6 months postpartum. 
692 
14 CLINICAL STUDIES 
693 
14.1 
Relapsed or Refractory, Low-Grade or Follicular, 
694 
CD20-Positive, B-Cell NHL 
695 
 The safety and effectiveness of Rituxan in relapsed, refractory CD20+ 
696 
NHL were demonstrated in 3 single-arm studies enrolling 296 patients. 
697 
Study 1 
698 
 A multicenter, open-label, single-arm study was conducted in 
699 
166 patients with relapsed or refractory, low-grade or follicular, B-cell 
700 
NHL who received 375 mg/m2 of Rituxan given as an intravenous 
701 
infusion weekly for 4 doses.  Patients with tumor masses > 10 cm or with 
702 
> 5000 lymphocytes/µL in the peripheral blood were excluded from the 
703 
study. 
704 
 Results are summarized in Table 3.  The median time to onset of 
705 
response was 50 days. Disease-related signs and symptoms (including 
706 
B-symptoms) resolved in 64% (25/39) of those patients with such 
707 
symptoms at study entry. 
708 
Study 2 
709 
 In a multicenter, single-arm study, 37 patients with relapsed or 
710 
refractory, low-grade NHL received 375 mg/m2 of Rituxan weekly for 
711 
8 doses.  Results are summarized in Table 3. 
712 
Study 3 
713 
 In a multicenter, single-arm study, 60 patients received 375 mg/m2 of 
714 
Rituxan weekly for 4 doses.  All patients had relapsed or refractory, 
715 
Page 116
 

 
 
low-grade or follicular, B-cell NHL and had achieved an objective clinical 
716 
response to Rituxan administered 3.8−35.6 months (median 14.5 months) 
717 
prior to retreatment with Rituxan.  Of these 60 patients, 5 received more 
718 
than one additional course of Rituxan.  Results are summarized in Table 3. 
719 
Bulky Disease 
720 
 In pooled data from studies 1 and 3, 39 patients with bulky (single 
721 
lesion > 10 cm in diameter) and relapsed or refractory, low-grade NHL 
722 
received Rituxan 375 mg/m2 weekly for 4 doses.  Results are summarized 
723 
in Table 3. 
724 
 
725 
Table 3 
Summary of Rituxan Efficacy Data by Schedule and Clinical Setting 
 
Study 1 
Weekly × 4 
N = 166 
Study 2 
Weekly × 8 
N = 37 
Study 1 and 
Study 3 
Bulky 
disease, 
Weekly × 4 
N = 39a 
Study 3 
Retreatment, 
Weekly × 4 
N = 60 
Overall Response Rate 
48% 
57% 
36% 
38% 
Complete Response 
Rate 
6% 
14% 
3% 
10% 
Median Duration of 
Responseb, c, d  
(Months) [Range] 
11.2 
[1.9 to 42.1+] 
13.4 
[2.5 to 36.5+] 
6.9 
[2.8 to 25.0+] 
15.0 
[3.0 to 25.1+] 
 a Six of these patients are included in the first column.  Thus, data from 296 intent-to-
treat patients are provided in this table. 
 b Kaplan-Meier projected with observed range. 
 c “+” indicates an ongoing response. 
 d Duration of response:  interval from the onset of response to disease progression. 
 
726 
14.2 
Previously Untreated, Follicular, CD20-Positive, B-Cell NHL 
727 
Study 4 
728 
 A total of 322 patients with previously untreated follicular NHL were 
729 
randomized (1:1) to receive up to eight 3-week cycles of CVP 
730 
chemotherapy alone (CVP) or in combination with Rituxan 375 mg/m2 on 
731 
Day 1 of each cycle (R-CVP) in an open-label, multicenter study.  The 
732 
main outcome measure of the study was progression-free survival (PFS) 
733 
defined as the time from randomization to the first of progression, relapse, 
734 
or death. 
735 
 Twenty-six percent of the study population was  > 60 years of age, 99% 
736 
had Stage III or IV disease, and 50% had an International Prognostic 
737 
Index (IPI) score  ≥ 2.  The results for PFS as determined by a blinded, 
738 
independent assessment of progression are presented in Table 4.  The 
739 
point estimates may be influenced by the presence of informative 
740 
censoring.  The PFS results based on investigator assessment of 
741 
progression were similar to those obtained by the independent review 
742 
assessment. 
743 
 
744 
Page 117
 

 
 
Table 4 
Efficacy Results in Study 4 
Study Arm 
 
R-CVP 
N=162 
CVP 
N=160 
Median PFS (years)a 
2.4 
1.4 
Hazard ratio (95% CI)b 
0.44 (0.29, 0.65) 
 a p < 0.0001, two-sided stratified log-rank test. 
 b Estimates of Cox regression stratified by center.  
 
745 
14.3 
Non-Progressing Low-Grade, CD20-Positive, B-Cell NHL 
746 
Following First-Line CVP Chemotherapy 
747 
Study 5 
748 
 A total of 322 patients with previously untreated low-grade, B-cell NHL 
749 
who did not progress after 6 or 8 cycles of CVP chemotherapy were 
750 
enrolled in an open-label, multicenter, randomized trial.  Patients were 
751 
randomized (1:1) to receive Rituxan, 375 mg/m2 intravenous infusion, 
752 
once weekly for 4 doses every 6 months for up to 16 doses or no further 
753 
therapeutic intervention.  The main outcome measure of the study was 
754 
progression-free survival defined as the time from randomization to 
755 
progression, relapse, or death.  Thirty-seven percent of the study 
756 
population was  > 60 years of age, 99% had Stage III or IV disease, and 
757 
63% had an IPI score  ≥ 2.   
758 
 There was a reduction in the risk of progression, relapse, or death 
759 
(hazard ratio estimate in the range of 0.36 to 0.49) for patients randomized 
760 
to Rituxan as compared to those who received no additional treatment. 
761 
14.4 
Diffuse Large B-Cell NHL (DLBCL) 
762 
 The safety and effectiveness of Rituxan were evaluated in three 
763 
randomized, active-controlled, open-label, multicenter studies with a 
764 
collective enrollment of 1854 patients.  Patients with previously untreated 
765 
diffuse large B-cell NHL received Rituxan in combination with 
766 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 
767 
other anthracycline-based chemotherapy regimens. 
768 
Study 6 
769 
 A total of 632 patients age  ≥ 60 years with DLBCL (including primary 
770 
mediastinal B-cell lymphoma) were randomized in a 1:1 ratio to treatment 
771 
with CHOP or R-CHOP.  Patients received 6 or 8 cycles of CHOP, each 
772 
cycle lasting 21 days.  All patients in the R-CHOP arm received 4 doses of 
773 
Rituxan 375 mg/m2 on Days -7 and -3 (prior to Cycle 1) and 48−72 hours 
774 
prior to Cycles 3 and 5.  Patients who received 8 cycles of CHOP also 
775 
received Rituxan prior to cycle 7.  The main outcome measure of the study 
776 
was progression-free survival, defined as the time from randomization to 
777 
the first of progression, relapse, or death.  Responding patients underwent 
778 
a second randomization to receive Rituxan or no further therapy. 
779 
 Among all enrolled patients, 62% had centrally confirmed DLBCL 
780 
histology, 73% had Stage III−IV disease, 56% had IPI scores  ≥ 2, 86% 
781 
Page 118
 

 
 
had ECOG performance status of  < 2, 57% had elevated LDH levels, and 
782 
30% had two or more extranodal disease sites involved.  Efficacy results 
783 
are presented in Table 5.  These results reflect a statistical approach which 
784 
allows for an evaluation of Rituxan administered in the induction setting 
785 
that excludes any potential impact of Rituxan given after the second 
786 
randomization. 
787 
 Analysis of results after the second randomization in Study 6 
788 
demonstrates that for patients randomized to R-CHOP, additional Rituxan 
789 
exposure beyond induction was not associated with further improvements 
790 
in progression-free survival or overall survival. 
791 
Study 7 
792 
 A total of 399 patients with DLBCL, age  ≥ 60 years, were randomized 
793 
in a 1:1 ratio to receive CHOP or R-CHOP.  All patients received up to 
794 
eight 3-week cycles of CHOP induction; patients in the R-CHOP arm 
795 
received Rituxan 375 mg/m2 on Day 1 of each cycle.  The main outcome 
796 
measure of the study was event-free survival, defined as the time from 
797 
randomization to relapse, progression, change in therapy, or death from 
798 
any cause.  Among all enrolled patients, 80% had Stage III or IV disease, 
799 
60% of patients had an age-adjusted IPI  ≥ 2, 80% had ECOG 
800 
performance status scores  < 2, 66% had elevated LDH levels, and 52% 
801 
had extranodal involvement in at least two sites.  Efficacy results are 
802 
presented in Table 5. 
803 
Study 8 
804 
 A total of 823 patients with DLBCL, aged 18−60 years, were 
805 
randomized in a 1:1 ratio to receive an anthracycline-containing 
806 
chemotherapy regimen alone or in combination with Rituxan.  The main 
807 
outcome measure of the study was time to treatment failure, defined as 
808 
time from randomization to the earliest of progressive disease, failure to 
809 
achieve a complete response, relapse, or death.  Among all enrolled 
810 
patients, 28% had Stage III−IV disease, 100% had IPI scores of  ≤ 1, 99% 
811 
had ECOG performance status of  < 2, 29% had elevated LDH levels, 49% 
812 
had bulky disease, and 34% had extranodal involvement.  Efficacy results 
813 
are presented in Table 5. 
814 
 
815 
Page 119
 

 
 
Table 5 
Efficacy Results in Studies 6, 7, and 8 
Study 6 
(n = 632) 
 
Study 7 
(n = 399) 
 
Study 8 
(n = 823) 
 
R-CHOP  CHOP 
 R-CHOP  CHOP 
 R-Chemo  Chemo 
Main outcome 
Progression-free 
survival 
(years) 
 Event-free survival 
(years) 
 Time to treatment 
failure (years) 
Median of main 
outcome measure 
3.1 
1.6 
 
2.9 
1.1 
 
NEb 
NEb 
Hazard ratiod 
0.69a 
 
0.60a 
 
0.45a 
Overall survival at 
2 yearsc 
74% 
63% 
 
69% 
58% 
 
95% 
86% 
Hazard ratiod 
0.72a 
 
0.68a 
 
0.40a 
 a Significant at p < 0.05, 2-sided. 
 b NE = Not reliably estimable. 
 c Kaplan-Meier estimates. 
 d R-CHOP vs. CHOP.    
 
816 
 In Study 7, overall survival estimates at 5 years were 58% vs. 46% for 
817 
R-CHOP and CHOP, respectively. 
818 
14.5 
Rheumatoid Arthritis (RA) 
819 
 The efficacy and safety of Rituxan were evaluated in 517 patients with 
820 
active disease who were receiving methotrexate and had a prior inadequate 
821 
response to at least one TNF inhibitor.  Patients were ≥ 18 years, 
822 
diagnosed with RA according to American College of Rheumatology 
823 
(ACR) criteria, and had at least 8 swollen and 8 tender joints.  Patients 
824 
received 2 doses of either Rituxan 1000 mg or placebo as an intravenous 
825 
infusion on days 1 and 15, in combination with continued methotrexate 
826 
10−25 mg weekly. 
827 
 Efficacy was assessed at 24 weeks.  Glucocorticoids were given 
828 
intravenously prior to each Rituxan infusion and orally on a tapering 
829 
schedule from baseline through Day 16. 
830 
 The proportions of Rituxan (1000 mg) treated patients achieving 
831 
ACR 20, 50, and 70 responses in this study is shown in Table 6. 
832 
 
833 
Page 120
 

 
 
Table 6 
ACR Responses at Week 24 in 
Placebo-Controlled Study (Percent of Patients) 
(Modified Intent-to-Treat Population) 
Response 
Placebo + MTX 
n = 201 
Rituxan + MTX 
n = 298 
51% 
ACR 20 
18% 
p < 0.0001 
27% 
ACR 50 
5% 
p < 0.0001 
12% 
ACR 70 
1% 
p < 0.0001 
 
834 
 Improvement was also noted for all components of ACR response 
835 
following treatment with Rituxan, as shown in Table 7. 
836 
Table 7 
Components of ACR Response 
(Modified Intent-to-Treat Population) 
Placebo + MTX 
(n = 201) 
Rituxan + MTX 
(n = 298) 
Parameter 
(median) 
Baseline 
Wk 24 
Baseline 
Wk 24 
Tender Joint Count 
31.0 
27.0 
33.0 
13.0* 
Swollen Joint Count 
20.0 
19.0 
21.0 
9.5* 
Physician Global Assessment a 
71.0 
69.0 
71.0 
36.0* 
Patient Global Assessment a 
73.0 
68.0 
71.0 
41.0* 
Paina 
68.0 
68.0 
67.0 
38.5* 
Disability Index (HAQ) b 
2.0 
1.9 
1.9 
1.5* 
CRP (mg/dL) 
2.4 
2.5 
2.6 
0.9* 
 a Visual Analogue Scale:  0 = best, 100 = worst. 
 b Disability Index of the Health Assessment Questionnaire:  0 = best, 3 = worst. 
 * p < 0.001, Rituxan + MTX vs. Placebo + MTX. 
 
837 
 The time course of ACR 20 response for this study is shown in 
838 
Figure 1.  Although both treatment groups received a brief course of 
839 
intravenous and oral glucocorticoids, resulting in similar benefits at 
840 
week 4, higher ACR 20 responses were observed for the Rituxan group by 
841 
week 8 and were maintained through week 24 after a single course of 
842 
treatment (2 infusions) with Rituxan.  Similar patterns were demonstrated 
843 
for ACR 50 and 70 responses. 
844 
Page 121
 

 
 
Figure 1 
ACR 20 Responses Over 24 Weeks 
0 
10 
20 
30 
40 
50 
60 
70 
80 
90 
100
0 
4 
8 
12 
16 
20 
24 
Weeks 
Placebo (n=201) 
Rituxan 2x1000mg (n=298) 
Percent ACR 20 Responders 
 
 
845 
 
846 
 While the efficacy of Rituxan was supported by two well-controlled 
847 
trials in RA patients who had inadequate responses to non-biologic 
848 
DMARDs, but who had not failed TNF antagonist therapy, a favorable 
849 
risk benefit relationship has not been established in this population [see 
850 
Warnings and Precautions (5.13)]. 
851 
Radiographic Response 
852 
Structural joint damage was assessed radiographically and 
853 
expressed as changes in Sharp-Genant Total Score and its components, 
854 
joint space narrowing score and erosion score.  The results are shown in 
855 
Table 8.  Rituxan plus MTX slowed the progression of structural damage 
856 
compared to placebo plus MTX at 56 weeks.   
857 
 
858 
Page 122
 

 
 
 
859 
16 HOW SUPPLIED/STORAGE AND HANDLING 
860 
 Rituxan vials [100 mg (NDC 50242-051-21) and 500 mg 
861 
(NDC 50242-053-06)] are stable at 2°C−8°C (36°F−46°F).  Do not use 
862 
beyond expiration date stamped on carton.  Rituxan vials should be 
863 
protected from direct sunlight.  Do not freeze or shake. 
864 
 Rituxan solutions for infusion may be stored at 2°C−8°C (36°F−46°F) 
865 
for 24 hours.  Rituxan solutions for infusion have been shown to be stable 
866 
for an additional 24 hours at room temperature.  However, since Rituxan 
867 
solutions do not contain a preservative, diluted solutions should be stored 
868 
refrigerated (2°C−8°C).  No incompatibilities between Rituxan and 
869 
polyvinylchloride or polyethylene bags have been observed. 
870 
17 PATIENT COUNSELING INFORMATION 
871 
 See Medication Guide (17.2). 
872 
17.1 
General Counseling Information 
873 
 Patients should be provided the Rituxan Medication Guide and provided 
874 
an opportunity to read prior to each treatment session.  Because caution 
875 
should be exercised in administering Rituxan to patients with active 
876 
infections, it is important that the patient’s overall health be assessed at 
877 
each visit and any questions resulting from the patient’s reading of the 
878 
Medication Guide be discussed. 
879 
 Rituxan is detectable in serum for up to six months following 
880 
completion of therapy.  Individuals of childbearing potential should use 
881 
effective contraception during treatment and for 12 months after Rituxan 
882 
therapy. 
883 
Table 8 
Mean Radiographic Change From Baseline to 56 Weeks 
Parameter 
Placebo + 
MTX 
(n=184) 
Mean 
Change 
Rituxan + 
MTX 
(n=273) 
Mean 
Change 
Treatment 
Difference 
(Placebo - 
Rituxan) 
95% CI for 
the 
Treatment 
Difference 
Sharp-Genant 
Total Score 
2.31 
1.00 
1.31 
(0.48, 2.14) 
 
 
 
 
 
Total Joint Space 
Narrowing 
Score 
0.99 
0.41 
0.58 
(0.18, 0.98) 
 
 
 
 
 
Total Erosion 
Score 
1.32 
0.59 
0.73 
(0.22, 1.24) 
 
 
 
 
 
Page 123
 

 
 
17.2 
Medication Guide 
884 
MEDICATION GUIDE 
885 
RITUXAN® (ri-tuk´-san) 
886 
(rituximab) 
887 
Read the Medication Guide given to you before you start Rituxan and 
888 
before each Rituxan infusion.  The information may have changed.  This 
889 
Medication Guide does not take the place of talking to your doctor about 
890 
your medical condition or your treatment.  Talk with your doctor if you 
891 
have any questions about your treatment with Rituxan. 
892 
What is the most important information I should know about 
893 
Rituxan? 
894 
Rituxan can cause serious side effects including: 
895 
• Progressive Multifocal Leukoencephalopathy (PML) 
896 
• 
PML is a rare brain infection.  PML usually causes death or severe 
897 
disability. 
898 
• 
Call your doctor right away if you notice any new or worsening 
899 
medical problems, such as a new or sudden change in thinking, 
900 
walking, strength, vision, or other problems that have lasted over 
901 
several days. 
902 
• 
PML usually happens in patients with weakened immune systems. 
903 
• 
PML can occur during treatment with Rituxan or after treatment 
904 
has finished. 
905 
• 
There is no known treatment, prevention, or cure for PML. 
906 
•   
Infusion reactions.  Tell your doctor or get medical treatment right 
907 
away if you get hives, swelling, dizziness, blurred vision, drowsiness, 
908 
headache, cough, wheezing, or have trouble breathing while receiving 
909 
or after receiving Rituxan. 
910 
•   
Tumor Lysis Syndrome (TLS).  TLS is caused by the fast 
911 
breakdown of certain types of cancer cells.  TLS can cause kidney 
912 
failure and the need for dialysis treatment.  Patients receiving Rituxan 
913 
for non-Hodgkin’s lymphoma (NHL) may get TLS.  Your doctor will 
914 
check you for TLS. 
915 
•   
Severe skin reactions.  Tell your doctor or get medical treatment 
916 
right away if you get any of these symptoms:  painful sores on your 
917 
skin or in your mouth, ulcers, blisters, or peeling skin while receiving 
918 
or after receiving Rituxan. 
919 
See “What are possible side effects with Rituxan?” for other serious 
920 
side effects. 
921 
What is Rituxan? 
922 
Rituxan is a prescription medicine used in adults: 
923 
•   
alone or with other anti-cancer medicines to treat certain types of 
924 
NHL. 
925 
•   
with another medicine called methotrexate to reduce the signs and 
926 
symptoms of Rheumatoid Arthritis (RA) after at least one other 
927 
medicine called a tumor necrosis factor (TNF) inhibitor has been used 
928 
and did not work well. 
929 
Page 124
 

 
 
Rituxan has not been studied in children. 
930 
What should I tell my doctor before treatment with Rituxan? 
931 
Tell your doctor about all of your medical conditions, including if you: 
932 
•   
had a severe infusion reaction to Rituxan in the past. 
933 
•   
have an infection or have an infection that will not go away or that 
934 
keeps coming back. 
935 
•   
have or had hepatitis (liver) infection.  See “What are the possible 
936 
side effects of Rituxan?” If so, your doctor should check you closely 
937 
for signs of hepatitis infection during treatment with Rituxan and for 
938 
several months after treatment ends. 
939 
•   
are scheduled to receive any vaccinations.  You should not receive 
940 
live vaccines after you receive Rituxan. 
941 
•   
have heart or lung problems. 
942 
•   
are pregnant or planning to become pregnant.  It is not known if 
943 
Rituxan can harm your unborn baby. 
944 
•   
are breastfeeding.  It is not known if Rituxan passes into human breast 
945 
milk.  You should not breastfeed while being treated with Rituxan and 
946 
after finishing treatment, until blood tests show that there is no 
947 
Rituxan in your blood. 
948 
Tell your doctor about all the medicines you take, including prescription 
949 
and nonprescription medicines, vitamins, or herbal supplements.  If you 
950 
have RA, especially tell your doctor if you take or have taken another 
951 
medicine called a TNF inhibitor or a DMARD (disease modifying 
952 
anti-rheumatic drug). 
953 
How do I receive Rituxan? 
954 
•   
Rituxan is given through a needle placed in a vein (IV or intravenous 
955 
infusion), in your arm.  Talk to your doctor about how you will 
956 
receive Rituxan. 
957 
•   
Your doctor may prescribe medicines before each infusion of Rituxan 
958 
to reduce side effects of infusions (such as fever and chills). 
959 
•   
Your doctor should do regular blood tests to check for side effects to 
960 
Rituxan. 
961 
Before each Rituxan treatment, your doctor or nurse will ask you 
962 
questions about your general health to make sure that Rituxan is still right 
963 
for you.  Tell your doctor or nurse about any new symptoms, and 
964 
symptoms that get worse over a few days or that will not go away. 
965 
Page 125
 

 
 
What are the possible side effects of Rituxan? 
966 
The “What is the most important information I should know about 
967 
Rituxan?” section lists certain serious and life-threatening side effects 
968 
with Rituxan.  Rituxan can cause other serious and life-threatening side 
969 
effects including: 
970 
•   
Hepatitis B virus reactivation.  Tell your doctor if you had 
971 
hepatitis B virus or are a carrier of hepatitis B virus.  Receiving 
972 
Rituxan could cause the hepatitis B virus to become an active 
973 
infection again.  This may cause serious liver problems and death.  
974 
People with active liver disease due to hepatitis B should stop 
975 
receiving Rituxan. 
976 
•   
Heart problems.  Tell your doctor about any heart problems you 
977 
have including chest pain (angina) and irregular heart beats.  Rituxan 
978 
can cause chest pain and irregular heart beats which may require 
979 
treatment. 
980 
•   
Infections.  Rituxan can increase your chances for getting infections.  
981 
Call your doctor right away if you have a cough that will not go away, 
982 
fever, chills, congestion, or any flu-like symptoms while receiving 
983 
Rituxan.  These symptoms may be signs of a serious infection. 
984 
•   
Stomach and bowel problems.  Serious stomach and bowel 
985 
problems have been seen when Rituxan has been used with 
986 
anti-cancer medicines in some patients with non-Hodgkin’s 
987 
lymphoma.  Call your doctor right away if you have any stomach area 
988 
pain during treatment with Rituxan. 
989 
Common side effects during Rituxan infusions include: 
990 
•   fever 
• headache 
991 
•   chills and shakes 
• nausea 
992 
•   itching 
• hives 
993 
• 
cough 
• sneezing 
994 
• 
throat irritation or tightness 
995 
 
996 
Other side effects with Rituxan include: 
997 
•   aching joints 
998 
•   upper respiratory tract infection 
999 
•   decreased blood cell counts 
1000 
•   lung problems 
1001 
 
1002 
Tell your doctor about any side effect that bothers you or that does not go 
1003 
away.  These are not all of the possible side effects with Rituxan.  Ask 
1004 
your doctor for more information. 
1005 
General Information about Rituxan 
1006 
Page 126
 

 
 
This Medication Guide provides a summary of the most important 
1007 
information about Rituxan.  Medicines are sometimes prescribed for 
1008 
purposes other than those listed in a Medication Guide.  If you would like 
1009 
more information or have any questions, talk with your doctor.  You can 
1010 
ask your doctor for information about Rituxan that is written for 
1011 
healthcare professionals.  You can also visit www.Rituxan.com or call 
1012 
1-877-474-8892. 
1013 
What are the ingredients in Rituxan? 
1014 
Active ingredient:  rituximab 
1015 
Inactive ingredients:  sodium chloride, sodium citrate dihydrate, 
1016 
polysorbate 80, and water for injection. 
1017 
 
1018 
Jointly Marketed by:  Biogen Idec Inc. and Genentech USA, Inc. 
1019 
 
1020 
Manufactured by: 
1021 
Genentech, Inc.  
1022 
1 DNA Way  
1023 
South San Francisco, CA 94080-4990 
1024 
2008 Biogen Idec Inc. and Genentech, Inc. 
1025 
Revised 09/2008                   (4835505) 
1026 
This Medication Guide has been approved by the U.S. Food and Drug 
1027 
Administration. 
1028 
Page 127
 

Myozyme® (alglucosidase alfa) 
128 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
14.3 
Methotrexate United States Prescribing Information 
 
GENZYME CORPORATION 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
Page 128
 

Div-MTX-P07
METHOTREXATE INJECTION, USP
METHOTREXATE FOR INJECTION, USP
Rx ONLY
WARNINGS
METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWL-
EDGE AND EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY.
BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH
CAN BE FATAL):
METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING
NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR
RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT, DIS-
ABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO
OTHER FORMS OF THERAPY.
DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREX-
ATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND
RHEUMATOID ARTHRITIS.
PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW,
LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.)
PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE
RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGH-
OUT THERAPY.
THE USE OF METHOTREXATE HIGH DOSE REGIMENS RECOMMENDED
FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE
AND ADMINISTRATION.) HIGH DOSE REGIMENS FOR OTHER NEOPLAS-
TIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVAN-
TAGE HAS NOT BEEN ESTABLISHED.
METHOTREXATE FORMULATIONS AND DILUENTS CONTAINING
PRESERVATIVES MUST NOT BE USED FOR INTRATHECAL OR HIGH
DOSE METHOTREXATE THERAPY.
1. Methotrexate has been reported to cause fetal death and/or congenital
anomalies. Therefore, it is not recommended for women of childbearing poten-
tial unless there is clear medical evidence that the benefits can be expected to
outweigh the considered risks. Pregnant women with psoriasis or rheumatoid
arthritis should not receive methotrexate (See CONTRAINDICATIONS).
2. Methotrexate elimination is reduced in patients with impaired renal
function, ascites, or pleural effusions. Such patients require especially
careful monitoring for toxicity, and require dose reduction or, in some
cases, discontinuation of methotrexate administration.
3. Unexpectedly severe (sometimes fatal) bone marrow suppression,
aplastic anemia, and gastrointestinal toxicity have been reported with con-
comitant administration of methotrexate (usually in high dosage) along
with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRE-
CAUTIONS, Drug Interactions.)
4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally
only after prolonged use. Acutely, liver enzyme elevations are frequently
seen. These are usually transient and asymptomatic, and also do not appear
predictive of subsequent hepatic disease. Liver biopsy after sustained use
often shows histologic changes, and fibrosis and cirrhosis have been report-
ed; these latter lesions may not be preceded by symptoms or abnormal liver
function tests in the psoriasis population. For this reason, periodic liver biop-
sies are usually recommended for psoriatic patients who are under long-term
treatment. Persistent abnormalities in liver function tests may precede
appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
(See PRECAUTIONS, Organ System Toxicity, Hepatic.)
5. Methotrexate-induced lung disease, including acute or chronic intersti-
tial pneumonitis, is a potentially dangerous lesion, which may occur
acutely at any time during therapy and has been reported at low doses. It
is not always fully reversible and fatalities have been reported. Pulmonary
symptoms (especially a dry, nonproductive cough) may require interrup-
tion of treatment and careful investigation.
6. Diarrhea and ulcerative stomatitis require interruption of therapy; other-
wise, hemorrhagic enteritis and death from intestinal perforation may occur.
7. Malignant lymphomas, which may regress following withdrawal of
methotrexate, may occur in patients receiving low-dose methotrexate and,
thus, may not require cytotoxic treatment. Discontinue methotrexate first and,
if the lymphoma does not regress, appropriate treatment should be instituted.
8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syn-
drome” in patients with rapidly growing tumors. Appropriate supportive
and pharmacologic measures may prevent or alleviate this complication.
9. Severe, occasionally fatal, skin reactions have been reported following
single or multiple doses of methotrexate. Reactions have occurred within
days of oral, intramuscular, intravenous, or intrathecal methotrexate
administration. Recovery has been reported with discontinuation of ther-
apy. (See PRECAUTIONS, Organ System Toxicity, Skin.)
10. Potentially fatal opportunistic infections, especially Pneumocystis
carinii pneumonia, may occur with methotrexate therapy.
11. Methotrexate given concomitantly with radiotherapy may increase the
risk of soft tissue necrosis and osteonecrosis.
DESCRIPTION
Methotrexate is an antimetabolite used in the treatment of certain neoplastic dis-
eases, severe psoriasis, and adult rheumatoid arthritis. Chemically methotrexate is
L-(+)-N-[p-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]-benzoyl]glutamic
acid. The structural formula is:
C20H22N8O5
M.W.=454.44
Methotrexate for injection and Methotrexate injection (Preservative Free) products
are sterile and non-pyrogenic and may be given by the intramuscular, intravenous,
intra-arterial or intrathecal route. (See DOSAGE AND ADMINISTRATION.)
Methotrexate Injection, USP, isotonic liquid, preservative free, for single use only,
is available in 25 mg/mL, 2 mL (50 mg), 4 mL (100 mg), 8 mL (200 mg), and 
10 mL (250 mg) vials.
Each 25 mg/mL, 2 mL, 4 mL, 8 mL, and 10 mL vial contains methotrexate sodium
equivalent to 50 mg, 100 mg, 200 mg, and 250 mg methotrexate respectively, and
the following inactive ingredients: sodium chloride 0.490% w/v and water for injec-
tion qs ad 100% v. Sodium hydroxide and, if necessary, hydrochloric acid are
added to adjust the pH to approximately 8.5. The 2 mL, 4 mL, 8 mL, and 10 mL
solutions contain approximately 0.43 mEq, 0.86 mEq, 1.72 mEq, and 2.15 mEq of
sodium per vial, respectively, and are isotonic solutions. 
Methotrexate for Injection, USP, lyophilized, preservative free, for single use only,
is available in 1 gram vials.
Each 1 gram vial of lyophilized powder contains methotrexate sodium equivalent
to 1 gram methotrexate. Contains no preservative. Sodium hydroxide and, if nec-
essary, hydrochloric acid are added during manufacture to adjust the pH. The 
1 gram vial contains approximately 7 mEq sodium.
CLINICAL PHARMACOLOGY
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced
to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-
carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore,
methotrexate interferes with DNA synthesis, repair, and cellular replication.
Actively proliferating tissues such as malignant cells, bone marrow, fetal cells,
buccal and intestinal mucosa and cells of the urinary bladder are in general more
sensitive to this effect of methotrexate. When cellular proliferation in malignant tis-
sues is greater than in most normal tissues, methotrexate may impair malignant
growth without irreversible damage to normal tissues.
The mechanism of action in rheumatoid arthritis is unknown; it may affect immune
function. Two reports describe in vitro methotrexate inhibition of DNA precursor
uptake by stimulated mononuclear cells, and another describes in animal pol-
yarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and
suppressed IL 2 production. Other laboratories, however, have been unable to
demonstrate similar effects. Clarification of methotrexate’s effect on immune activ-
ity and its relation to rheumatoid immunopathogenesis await further studies. 
In patients with rheumatoid arthritis, effects of methotrexate on articular swelling
and tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clear-
ly ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evi-
dence that it induces remission of rheumatoid arthritis nor has a beneficial effect
been demonstrated on bone erosions and other radiologic changes which result in
impaired joint use, functional disability, and deformity. 
Most studies of methotrexate in patients with rheumatoid arthritis are relatively short
term (3 to 6 months). Limited data from long-term studies indicate that an initial clin-
ical improvement is maintained for at least two years with continued therapy. 
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased
over normal skin. This differential in proliferation rates is the basis for the use of
methotrexate to control the psoriatic process.
Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the
treatment of patients with non-metastatic osteosarcoma. The original rationale for
high dose methotrexate therapy was based on the concept of selective rescue of nor-
mal tissues by leucovorin. More recent evidence suggests that high dose methotrex-
ate may also overcome methotrexate resistance caused by impaired active transport,
decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of
dihydrofolic acid reductase resulting from gene amplification, or decreased polyglu-
tamation of methotrexate. The actual mechanism of action is unknown.
In a 6-month double-blind, placebo-controlled trial of 127 pediatric patients with juve-
nile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean
duration of disease, 5.1 years) on background nonsteroidal anti-inflammatory drugs
(NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m2
provided significant clinical improvement compared to placebo as measured by either
the physician’s global assessment, or by a patient composite (25% reduction in the
articular-severity score plus improvement in parent and physician global assessments
of disease activity). Over two-thirds of the patients in this trial had polyarticular-course
JRA, and the numerically greatest response was seen in this subgroup treated with 
10 mg/m2/wk methotrexate. The overwhelming majority of the remaining patients had
systemic-course JRA. All patients were unresponsive to NSAIDs; approximately one-
third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2
was not significantly more effective than placebo in this trial. 
Two Pediatric Oncology Group studies (one randomized and one non-randomized)
demonstrated a significant improvement in relapse-free survival in patients with
non-metastatic osteosarcoma, when high dose methotrexate with leucovorin res-
cue was used in combination with other chemotherapeutic agents following surgi-
cal resection of the primary tumor. These studies were not designed to demon-
strate the specific contribution of high dose methotrexate/leucovorin rescue ther-
apy to the efficacy of the combination. However, a contribution can be inferred
from the reports of objective responses to this therapy in patients with metastatic
osteosarcoma, and from reports of extensive tumor necrosis following preopera-
tive administration of this therapy to patients with non-metastatic osteosarcoma.
Pharmacokinetics
Absorption - In adults, oral absorption appears to be dose dependent. Peak serum
levels are reached within one to two hours. At doses of 30 mg/m2 or less,
methotrexate is generally well absorbed with a mean bioavailability of about 60%.
The absorption of doses greater than 80 mg/m2 is significantly less, possibly due
to a saturation effect.
In leukemic pediatric patients, oral absorption of methotrexate also appears to be
dose dependent and has been reported to vary widely (23% to 95%). A twenty-fold
difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar
after a 20 mg/m2 dose) has been reported. Significant interindividual variability has
also been noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m2
dose) and fraction of dose absorbed. The absorption of doses greater than 
40 mg/m2 has been reported to be significantly less than that of lower doses. Food
has been shown to delay absorption and reduce peak concentration. Methotrexate
is generally completely absorbed from parenteral routes of injection. After intra-
muscular injection, peak serum concentrations occur in 30 to 60 minutes. As in
leukemic pediatric patients, a wide interindividual variability in the plasma concen-
trations of methotrexate has been reported in pediatric patients with JRA.
Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m2/week
in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar
(range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 
2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours. In pediatric patients
receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), or for
JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to range from
0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively.
Distribution - After intravenous administration, the initial volume of distribution is
approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution
is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes
with reduced folates for active transport across cell membranes by means of a single
carrier-mediated active transport process. At serum concentrations greater than 
100 micromolar, passive diffusion becomes a major pathway by which effective intra-
cellular concentrations can be achieved. Methotrexate in serum is approximately 50%
protein bound. Laboratory studies demonstrate that it may be displaced from plasma
albumin by various compounds including sulfonamides, salicylates, tetracyclines, chlo-
ramphenicol, and phenytoin.
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeu-
tic amounts when given orally or parenterally. High CSF concentrations of the drug
may be attained by intrathecal administration.
In dogs, synovial fluid concentrations after oral dosing were higher in inflamed
than uninflamed joints. Although salicylates did not interfere with this penetration,
prior prednisone treatment reduced penetration into inflamed joints to the level of
normal joints. 
Metabolism - After absorption, methotrexate undergoes hepatic and intracellular
metabolism to polyglutamated forms which can be converted back to methotrex-
ate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate
reductase and thymidylate synthetase. Small amounts of methotrexate polygluta-
mates may remain in tissues for extended periods. The retention and prolonged
drug action of these active metabolites vary among different cells, tissues and
tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at
doses commonly prescribed. Accumulation of this metabolite may become signif-
icant at the high doses used in osteogenic sarcoma. The aqueous solubility of 
7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound.
Methotrexate is partially metabolized by intestinal flora after oral administration.
Half-Life - The terminal half-life reported for methotrexate is approximately 3 to 
10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or
low-dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high
doses of methotrexate, the terminal half-life is 8 to 15 hours.
Excretion - Renal excretion is the primary route of elimination and is dependent
upon dosage and route of administration. With IV administration, 80 to 90% of the
administered dose is excreted unchanged in the urine within 24 hours. There is
limited biliary excretion amounting to 10% or less of the administered dose.
Enterohepatic recirculation of methotrexate has been proposed.
Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear
elimination due to saturation of renal tubular reabsorption has been observed in psori-
atic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as con-
current use of drugs such as weak organic acids that also undergo tubular secretion,
can markedly increase methotrexate serum levels. Excellent correlation has been report-
ed between methotrexate clearance and endogenous clearance.
Methotrexate clearance rates vary widely and are generally decreased at higher
doses. Delayed drug clearance has been identified as one of the major factors
responsible for methotrexate toxicity. It has been postulated that the toxicity of
methotrexate for normal tissues is more dependent upon the duration of exposure to
the drug rather than the peak level achieved. When a patient has delayed drug elim-
ination due to compromised renal function, a third space effusion, or other causes,
methotrexate serum concentrations may remain elevated for prolonged periods.
The potential for toxicity from high dose regimens or delayed excretion is reduced
by the administration of leucovorin calcium during the final phase of methotrexate
plasma elimination. Pharmacokinetic monitoring of methotrexate serum concen-
trations may help identify those patients at high risk for methotrexate toxicity and
aid in proper adjustment of leucovorin dosing. Guidelines for monitoring serum
methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of
methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION.
Methotrexate has been detected in human breast milk. The highest breast milk to
plasma concentration ratio reached was 0.08:1.
INDICATIONS AND USAGE
Neoplastic Diseases: Methotrexate is indicated in the treatment of gestational
choriocarcinoma, chorioadenoma destruens and hydatidiform mole.
In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of
meningeal leukemia and is used in maintenance therapy in combination with other
chemotherapeutic agents. Methotrexate is also indicated in the treatment of
meningeal leukemia.
Methotrexate is used alone or in combination with other anticancer agents in the treat-
ment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis
fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell
and small cell types. Methotrexate is also used in combination with other chemother-
apeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas.
H2N
NH2
CH3
HOOCCH2CH2
CH2N
CONH
COOH
H
C
N
N
N
N
Methotrexate in high doses followed by leucovorin rescue in combination with
other chemotherapeutic agents is effective in prolonging relapse-free survival in
patients with non-metastatic osteosarcoma who have undergone surgical resec-
tion or amputation for the primary tumor.
Psoriasis: Methotrexate is indicated in the symptomatic control of severe, recalci-
trant, disabling psoriasis that is not adequately responsive to other forms of ther-
apy, but only when the diagnosis has been established, as by a biopsy and/or after
dermatologic consultation. It is important to ensure that a psoriasis “flare” is not
due to an undiagnosed concomitant disease affecting immune responses.
Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid
Arthritis: Methotrexate is indicated in the management of selected adults with
severe, active rheumatoid arthritis (ACR criteria), or children with active polyartic-
ular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic
response to, or are intolerant of, an adequate trial of first-line therapy including full
dose nonsteroidal anti-inflammatory agents (NSAIDs). 
Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possi-
bility of increased toxicity with concomitant use of NSAIDs including salicylates
has not been fully explored. (See PRECAUTIONS, Drug Interactions.) Steroids
may be reduced gradually in patients who respond to methotrexate. Combined use
of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or
cytotoxic agents, has not been studied and may increase the incidence of adverse
effects. Rest and physiotherapy as indicated should be continued. 
CONTRAINDICATIONS
Methotrexate can cause fetal death or teratogenic effects when administered to a
pregnant woman. Methotrexate is contraindicated in pregnant women with psori-
asis or rheumatoid arthritis and should be used in the treatment of neoplastic dis-
eases only when the potential benefit outweighs the risk to the fetus. Women of
childbearing potential should not be started on methotrexate until pregnancy is
excluded and should be fully counseled on the serious risk to the fetus (see PRE-
CAUTIONS) should they become pregnant while undergoing treatment. Pregnancy
should be avoided if either partner is receiving methotrexate; during and for a min-
imum of 3 months after therapy for male patients, and during and for at least one
ovulatory cycle after therapy for female patients (see Boxed WARNINGS).
Because of the potential for serious adverse reactions from methotrexate in breast
fed infants, it is contraindicated in nursing mothers.
Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver dis-
ease or other chronic liver disease should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evi-
dence of immunodeficiency syndromes should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have preexisting blood
dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or
significant anemia, should not receive methotrexate.
Patients with known hypersensitivity to methotrexate should not receive the drug.
WARNINGS
See Boxed WARNINGS.
Methotrexate formulations and diluents containing preservatives must not be used
for intrathecal or high dose methotrexate therapy. 
PRECAUTIONS
General: Methotrexate has the potential for serious toxicity (see Boxed WARN-
INGS). Toxic effects may be related in frequency and severity to dose or frequen-
cy of administration but have been seen at all doses. Because they can occur at
any time during therapy, it is necessary to follow patients on methotrexate close-
ly. Most adverse reactions are reversible if detected early. When such reactions do
occur, the drug should be reduced in dosage or discontinued and appropriate cor-
rective measures should be taken. If necessary, this could include the use of leu-
covorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer.
(See OVERDOSAGE.) If methotrexate therapy is reinstituted, it should be carried
out with caution, with adequate consideration of further need for the drug and
increased alertness as to possible recurrence of toxicity.
The clinical pharmacology of methotrexate has not been well studied in older indi-
viduals. Due to diminished hepatic and renal function as well as decreased folate
stores in this population, relatively low doses should be considered, and these
patients should be closely monitored for early signs of toxicity.
Some of the effects mentioned under ADVERSE REACTIONS, such as dizziness
and fatigue, may affect the ability to drive or operate machinery. 
Information for Patients: Patients should be informed of the early signs and symp-
toms of toxicity, of the need to see their physician promptly if they occur, and the
need for close follow-up, including periodic laboratory tests to monitor toxicity.
Both the physician and pharmacist should emphasize to the patient that the rec-
ommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that
mistaken daily use of the recommended dose has led to fatal toxicity. Prescriptions
should not be written or refilled on a PRN basis. 
Patients should be informed of the potential benefit and risk in the use of
methotrexate. The risk of effects on reproduction should be discussed with both
male and female patients taking methotrexate.
Laboratory Tests: Patients undergoing methotrexate therapy should be closely
monitored so that toxic effects are detected promptly. Baseline assessment should
include complete blood count with differential and platelet counts, hepatic enzymes,
renal function tests, and a chest X-ray. During therapy of rheumatoid arthritis and
psoriasis, monitoring of these parameters is recommended: hematology at least
monthly, renal function and liver function every 1 to 2 months. More frequent mon-
itoring is usually indicated during antineoplastic therapy. During initial or changing
doses, or during periods of increased risk of elevated methotrexate blood levels
(e.g., dehydration), more frequent monitoring may also be indicated.
Transient liver function test abnormalities are observed frequently after methotrex-
ate administration and are usually not cause for modification of methotrexate ther-
apy. Persistent liver function test abnormalities, and/or depression of serum albu-
min may be indicators of serious liver toxicity and require evaluation. (See PRE-
CAUTIONS, Organ System Toxicity, Hepatic.)
A relationship between abnormal liver function tests and fibrosis or cirrhosis of the
liver has not been established for patients with psoriasis. Persistent abnormalities
in liver function tests may precede appearance of fibrosis or cirrhosis in the
rheumatoid arthritis population.
Pulmonary function tests may be useful if methotrexate-induced lung disease is
suspected, especially if baseline measurements are available.
Drug Interactions: Nonsteroidal anti-inflammatory drugs should not be adminis-
tered prior to or concomitantly with the high doses of methotrexate, such as used
in the treatment of osteosarcoma. Concomitant administration of some NSAIDs
with high dose methotrexate therapy has been reported to elevate and prolong
serum methotrexate levels, resulting in deaths from severe hematologic and gas-
trointestinal toxicity.
Caution should be used when NSAIDs or salicylates are administered concomitant-
ly with lower doses of methotrexate. These drugs have been reported to reduce the
tubular secretion of methotrexate in an animal model and may enhance its toxicity.
Despite the potential interactions, studies of methotrexate in patients with rheuma-
toid arthritis have usually included concurrent use of constant dosage regimens of
NSAIDs, without apparent problems. It should be appreciated, however, that the
doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than
those used in psoriasis and that larger doses could lead to unexpected toxicity. 
Methotrexate is partially bound to serum albumin, and toxicity may be increased
because of displacement by certain drugs, such as salicylates, phenylbutazone,
phenytoin, and sulfonamides. Renal tubular transport is also diminished by
probenecid; use of methotrexate with this drug should be carefully monitored.
In the treatment of patients with osteosarcoma, caution must be exercised if high-
dose methotrexate is administered in combination with a potentially nephrotoxic
chemotherapeutic agent (e.g., cisplatin).
Methotrexate increases the plasma levels of mercaptopurine. The combination of
methotrexate and mercaptopurine may therefore require dose adjustment. 
Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad
spectrum antibiotics, may decrease intestinal absorption of methotrexate or inter-
fere with the enterohepatic circulation by inhibiting bowel flora and suppressing
metabolism of the drug by bacteria.
Penicillins may reduce the renal clearance of methotrexate; increased serum con-
centrations of methotrexate with concomitant hematologic and gastrointestinal
toxicity have been observed with high and low dose methotrexate. Use of
methotrexate with penicillins should be carefully monitored.
The potential for increased hepatotoxicity when methotrexate is administered with
other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been
reported in such cases. Therefore, patients receiving concomitant therapy with
methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sul-
fasalazine) should be closely monitored for possible increased risk of hepatotoxicity.
Methotrexate may decrease the clearance of theophylline; theophylline levels
should be monitored when used concurrently with methotrexate.
Vitamin preparations containing folic acid or its derivatives may decrease respons-
es to systemically administered methotrexate. Preliminary animal and human
studies have shown that small quantities of intravenously administered leucovorin
enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 
3 orders of magnitude lower than the usual methotrexate concentrations following
intrathecal administration. However, high doses of leucovorin may reduce the effi-
cacy of intrathecally administered methotrexate.
Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sul-
famethoxazole has been reported rarely to increase bone marrow suppression in
patients receiving methotrexate, probably by decreased tubular secretion and/or
additive antifolate effect.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No controlled human data
exist regarding the risk of neoplasia with methotrexate. Methotrexate has been eval-
uated in a number of animal studies for carcinogenic potential with inconclusive
results. Although there is evidence that methotrexate causes chromosomal damage
to animal somatic cells and human bone marrow cells, the clinical significance
remains uncertain. Non-Hodgkin's lymphoma and other tumors have been report-
ed in patients receiving low-dose oral methotrexate. However, there have been
instances of malignant lymphoma arising during treatment with low-dose oral
methotrexate, which have regressed completely following withdrawal of methotrex-
ate, without requiring active anti-lymphoma treatment. Benefits should be weighed
against the potential risks before using methotrexate alone or in combination with
other drugs, especially in pediatric patients or young adults. Methotrexate causes
embryotoxicity, abortion, and fetal defects in humans. It has also been reported to
cause impairment of fertility, oligospermia and menstrual dysfunction in humans,
during and for a short period after cessation of therapy.
Pregnancy, Teratogenic Effects, Pregnancy Category X: Psoriasis and rheumatoid
arthritis: Methotrexate is in Pregnancy Category X (See CONTRAINDICATIONS).
Nursing Mothers: See CONTRAINDICATIONS.
Pediatric Use: Safety and effectiveness in pediatric patients have been established only in
cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis. 
Published clinical studies evaluating the use of methotrexate in children and adoles-
cents (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to
that observed in adults with rheumatoid arthritis. (See CLINICAL PHARMACOLOGY,
ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)
Methotrexate injectable formulations containing the preservative benzyl alcohol
are not recommended for use in neonates. There have been reports of fatal “gasp-
ing syndrome” in neonates (children less than one month of age) following the
administration of intravenous solutions containing the preservative benzyl alcohol.
Symptoms include a striking onset of gasping respiration, hypotension, bradycar-
dia, and cardiovascular collapse. 
Serious neurotoxicity, frequently manifested as generalized or focal seizures, has
been reported with unexpectedly increased frequency among pediatric patients with
acute lymphoblastic leukemia who were treated with intermediate-dose intravenous
methotrexate (1 gm/m2). (See PRECAUTIONS, Organ System Toxicity, Neurologic.)
Geriatric Use: Clinical studies of methotrexate did not include sufficient numbers
of subjects age 65 and over to determine whether they respond differently from
younger subjects. In general, dose selection for an elderly patient should be cau-
tious reflecting the greater frequency of decreased hepatic and renal function,
decreased folate stores, concomitant disease or other drug therapy (i.e., that inter-
fere with renal function, methotrexate or folate metabolism) in this population (see
PRECAUTIONS, Drug Interactions). Since decline in renal function may be asso-
ciated with increases in adverse events and serum creatinine measurements may
over estimate renal function in the elderly, more accurate methods (i.e., creatinine
clearance) should be considered. Serum methotrexate levels may also be helpful.
Elderly patients should be closely monitored for early signs of hepatic, bone mar-
row and renal toxicity. In chronic use situations, certain toxicities may be reduced
by folate supplementation. Post-marketing experience suggests that the occur-
rence of bone marrow suppression, thrombocytopenia, and pneumonitis may
increase with age. See Boxed WARNINGS and ADVERSE REACTIONS.
Organ System Toxicity: Gastrointestinal - If vomiting, diarrhea, or stomatitis
occur, which may result in dehydration, methotrexate should be discontinued until
recovery occurs. Methotrexate should be used with extreme caution in the pres-
ence of peptic ulcer disease or ulcerative colitis.
Hematologic - Methotrexate can suppress hematopoiesis and cause anemia, aplastic
anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients
with malignancy and preexisting hematopoietic impairment, the drug should be used
with caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128),
leukopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets
<100,000/mm3) in 6 patients, and pancytopenia in 2 patients.
In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediate-
ly if there is a significant drop in blood counts. In the treatment of neoplastic dis-
eases, methotrexate should be continued only if the potential benefit warrants the
risk of severe myelosuppression. Patients with profound granulocytopenia and
fever should be evaluated immediately and usually require parenteral broad-spec-
trum antibiotic therapy.
Hepatic - Methotrexate has the potential for acute (elevated transaminases) and
chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal;
it generally has occurred after prolonged use (generally two years or more) and
after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotox-
icity appeared to be a function of total cumulative dose and appeared to be
enhanced by alcoholism, obesity, diabetes, and advanced age. An accurate inci-
dence rate has not been determined; the rate of progression and reversibility of
lesions is not known. Special caution is indicated in the presence of preexisting
liver damage or impaired hepatic function.
In psoriasis, liver function tests, including serum albumin, should be performed
periodically prior to dosing but are often normal in the face of developing fibrosis
or cirrhosis. These lesions may be detectable only by biopsy. The usual recom-
mendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of
therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each
additional 1 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to dis-
continuation of the drug; mild fibrosis normally suggests a repeat biopsy in 
6 months. Milder histologic findings such as fatty change and low grade portal
inflammation are relatively common pretherapy. Although these mild changes are
usually not a reason to avoid or discontinue methotrexate therapy, the drug should
be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have
been reported as risk factors for hepatotoxicity; other risk factors, similar to those
observed in psoriasis, may be present in rheumatoid arthritis but have not been
confirmed to date. Persistent abnormalities in liver function tests may precede
appearance of fibrosis or cirrhosis in this population. There is a combined reported
experience in 217 rheumatoid arthritis patients with liver biopsies both before and
during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with
a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%)
case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin
stain is more sensitive for early fibrosis and its use may increase these figures. It
is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and at 4 to 8 week intervals
in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biop-
sy should be performed for patients with a history of excessive alcohol consump-
tion, persistently abnormal baseline liver function test values or chronic hepatitis
B or C infection. During therapy, liver biopsy should be performed if there are per-
sistent liver function test abnormalities or there is a decrease in serum albumin
below the normal range (in the setting of well controlled rheumatoid arthritis).
If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa),
methotrexate may be continued and the patient monitored as per recommendations
listed above. Methotrexate should be discontinued in any patient who displays per-
sistently abnormal liver function tests and refuses liver biopsy or in any patient
whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb, or IV).
Infection or Immunologic States - Methotrexate should be used with extreme cau-
tion in the presence of active infection, and is usually contraindicated in patients
with overt or laboratory evidence of immunodeficiency syndromes. Immunization
may be ineffective when given during methotrexate therapy. Immunization with live
virus vaccines is generally not recommended. There have been reports of dissem-
inated vaccinia infections after smallpox immunizations in patients receiving
methotrexate therapy. Hypogammaglobulinemia has been reported rarely.
Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia
may occur with methotrexate therapy. When a patient presents with pulmonary
symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
Neurologic - There have been reports of leukoencephalopathy following intra-
venous administration of methotrexate to patients who have had craniospinal irra-
diation. Serious neurotoxicity, frequently manifested as generalized or focal
seizures, has been reported with unexpectedly increased frequency among pedi-
atric patients with acute lymphoblastic leukemia who were treated with intermedi-
ate-dose intravenous methotrexate (1 gm/m2). Symptomatic patients were com-
monly noted to have leukoencephalopathy and/or microangiopathic calcifications
on diagnostic imaging studies. Chronic leukoencephalopathy has also been report-
ed in patients who received repeated doses of high-dose methotrexate with leu-
covorin rescue even without cranial irradiation. Discontinuation of methotrexate
does not always result in complete recovery.
A transient acute neurologic syndrome has been observed in patients treated with
high dosage regimens. Manifestations of this stroke-like encephalopathy may
include confusion, hemiparesis, transient blindness, seizures and coma. The exact
cause is unknown.
Page 129
 

Drug*
Dose*
Treatment Week 
After Surgery
Methotrexate
12 g/m2 IV as 4 hour 
4,5,6,7,11,12,15,
infusion (starting dose)
16,29,30,44,45
Leucovorin
15 mg orally every six hours 
for 10 doses starting at 24 hours after 
start of methotrexate infusion.
Doxorubicin† as a single drug 30 mg/m2/day IV x 3 days
8,17
Doxorubicin†
50 mg/m2 IV
20,23,33,36
Cisplatin†
100 mg/m2 IV
20,23,33,36
Bleomycin†
15 units/m2 IV x 2 days
2,13,26,39,42
Cyclophosphamide†
600 mg/m2 IV x 2 days
2,13,26,39,42
Dactinomycin†
0.6 mg/m2 IV x 2 days
2,13,26,39,42
*Link MP, Goorin AM, Miser AW, et al; The effect of adjuvant chemotherapy on
relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of
Med 1986; 314(No.25): 1600-1606.
†See each respective package insert for full prescribing information. Dosage mod-
ifications may be necessary because of drug-induced toxicity.
When these higher doses of methotrexate are to be administered, the following
safety guidelines should be closely observed.
GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE
1.
Administration of methotrexate should be delayed until recovery if:
• the WBC count is less than 1500/microliter
• the neutrophil count is less than 200/microliter
• the platelet count is less than 75,000/microliter
• the serum bilirubin level is greater than 1.2 mg/dL
• the SGPT level is greater than 450 U
• mucositis is present, until there is evidence of healing
• persistent pleural effusion is present; this should be drained dry prior to infusion.
2.
Adequate renal function must be documented.
a. Serum creatinine must be normal, and creatinine clearance must be greater
than 60 mL/min, before initiation of therapy.
b. Serum creatinine must be measured prior to each subsequent course of ther-
apy. If serum creatinine has increased by 50% or more compared to a prior value,
the creatinine clearance must be measured and documented to be greater than
60 mL/min (even if the serum creatinine is still within the normal range).
3.
Patients must be well hydrated, and must be treated with sodium bicarbonate
for urinary alkalinization.
a. Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initia-
tion of the methotrexate infusion. Continue hydration at 125 mL/m2/hr
(3 liters/m2/day) during the methotrexate infusion, and for 2 days after the
infusion has been completed.
b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leu-
covorin calcium therapy. This can be accomplished by the administration of sodi-
um bicarbonate orally or by incorporation into a separate intravenous solution.
4.
Repeat serum creatinine and serum methotrexate 24 hours after starting
methotrexate and at least once daily until the methotrexate level is below 
5x10-8 mol/L (0.05 micromolar).
5.
The table below provides guidelines for leucovorin calcium dosage based upon
serum methotrexate levels. (See table below.‡)
Patients who experience delayed early methotrexate elimination are likely to devel-
op nonreversible oliguric renal failure. In addition to appropriate leucovorin thera-
py, these patients require continuing hydration and urinary alkalinization, and close
monitoring of fluid and electrolyte status, until the serum methotrexate level has
fallen to below 0.05 micromolar and the renal failure has resolved. If necessary,
acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in
these patients.
6.
Some patients will have abnormalities in methotrexate elimination, or abnor-
malities in renal function following methotrexate administration, which are sig-
nificant but less severe than the abnormalities described in the table below.
These abnormalities may or may not be associated with significant clinical toxi-
city. If significant clinical toxicity is observed, leucovorin rescue should be
extended for an additional 24 hours (total 14 doses over 84 hours) in subse-
quent courses of therapy. The possibility that the patient is taking other medica-
tions which interact with methotrexate (e.g., medications which may interfere
with methotrexate binding to serum albumin, or elimination) should always be
reconsidered when laboratory abnormalities or clinical toxicities are observed.
CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.
Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis 
Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules
1.
Single oral doses of 7.5 mg once weekly.†
2.
Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a
course once weekly.†
†Methotrexate Sodium Tablets for oral administration are available.
Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting
dose is 10 mg/m2 given once weekly.
For either adult RA or polyarticular-course JRA dosages may be adjusted gradually
to achieve an optimal response. Limited experience shows a significant increase in
the incidence and severity of serious toxic reactions, especially bone marrow sup-
pression, at doses greater than 20 mg/wk in adults. Although there is experience
with doses up to 30 mg/m2/wk in children, there are too few published data to
assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in chil-
dren. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk
(0.65 to 1 mg/kg/wk) may have better absorption and fewer gastrointestinal side
effects if methotrexate is administered either intramuscularly or subcutaneously.
Therapeutic response usually begins within 3 to 6 weeks and the patient may con-
tinue to improve for another 12 weeks or more.
The optimal duration of therapy is unknown. Limited data available from long-term
studies in adults indicate that the initial clinical improvement is maintained for at
least two years with continued therapy. When methotrexate is discontinued, the
arthritis usually worsens within 3 to 6 weeks.
The patient should be fully informed of the risks involved and should be under con-
stant supervision of the physician. (See Information for Patients under PRECAU-
TIONS.) Assessment of hematologic, hepatic, renal, and pulmonary function
should be made by history, physical examination, and laboratory tests before
beginning, periodically during, and before reinstituting methotrexate therapy (see
PRECAUTIONS). Appropriate steps should be taken to avoid conception during
methotrexate therapy (see PRECAUTIONS and CONTRAINDICATIONS).
All schedules should be continually tailored to the individual patient. An initial test
dose may be given prior to the regular dosing schedule to detect any extreme sen-
sitivity to adverse effects (see ADVERSE REACTIONS). Maximal myelosuppression
usually occurs in 7 to 10 days.
Psoriasis: Recommended Starting Dose Schedules
1.
Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until ade-
quate response is achieved.†
2.
Divided oral dosage schedule: 2.5 mg at 12 hour intervals for three doses.†
†Methotrexate Sodium Tablets for oral administration are available.
Dosages in each schedule may be gradually adjusted to achieve optimal clinical
response; 30 mg/week should not ordinarily be exceeded.
Once optimal clinical response has been achieved, each dosage schedule should
be reduced to the lowest possible amount of drug and to the longest possible rest
period. The use of methotrexate may permit the return to conventional topical ther-
apy, which should be encouraged.
Handling and Disposal: Procedures for proper handling and disposal of anticancer
drugs should be considered. Several guidelines on this subject have been pub-
lished.1-7 There is no general agreement that all of the procedures recommended
in the guidelines are necessary or appropriate.
Reconstitution of Lyophilized Powders: Reconstitute immediately prior to use. 
Methotrexate for injection should be reconstituted with an appropriate sterile, pre-
servative free medium such as 5% dextrose solution, USP or sodium chloride
injection, USP. The 1 gram vial should be reconstituted with 19.4 mL to a con-
centration of 50 mg/mL. When high doses of methotrexate are administered by IV
infusion, the total dose is diluted in 5% dextrose solution, USP. 
For intrathecal injection, reconstitute to a concentration of 1 mg/mL with an appro-
priate sterile, preservative free medium such as sodium chloride injection, USP. 
Dilution Instructions for Liquid Methotrexate Injection: Isotonic liquid, preserva-
tive free, for single use only. 
If desired, the solution may be further diluted immediately prior to use with an
appropriate sterile, preservative free medium such as 5% dextrose solution, USP
or sodium chloride injection, USP. 
Parenteral drug products should be inspected visually for particulate matter and dis-
coloration prior to administration, whenever solution and container permit.
HOW SUPPLIED
Methotrexate Injection, USP (preservative free) is supplied in a single-dose vial
containing 25 mg/mL of methotrexate as the base in the following package
strengths:
NDC 55390-031-10
50 mg in 2 mL (10 vials to a carton)
NDC 55390-032-10
100 mg in 4 mL (10 vials to a carton)
NDC 55390-033-10
200 mg in 8 mL (10 vials to a carton)
NDC 55390-034-10
250 mg in 10 mL (10 vials to a carton)
Methotrexate for Injection, USP (preservative free) is supplied in a 1 gram, single-
dose vial of lyophilized powder containing 1 gram methotrexate as the base in the
following package strength:
NDC 55390-143-01
1 gram Vial (individually boxed)
Store at room temperature 20° to 25°C (68° to 77°F). See USP controlled room
temperature. Protect from light.
REFERENCES
1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH
Publication No. 83-2621. For sale by the Superintendent of Documents, U.S.
Government Printing Office, Washington, D.C. 20402.
2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA,
March 15, 1985.
3. National Study Commission on Cytotoxic Exposure-Recommendations for Handling
Cytotoxic Agents. Available from Louis P. Jeffrey, Sc. D., Chairman, National Study
Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied
Health Sciences, 179 Longwood Ave., Boston, Massachusetts 02115.
4. Clinical Oncological Society of Australia; Guidelines and Recommendations for
Safe-Handling of Antineoplastic Agents. Med J Australia 1: 426-428, 1983.
5. Jones RB et al. Safe Handling of Chemotherapeutic Agents: A Report from the
Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians: Sept/Oct, 258-
263, 1983.
6. American Society of Hospital Pharmacists Technical Assistance Bulletin on
Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 47:1033-1049, 1990.
7. Controlling occupational exposure to hazardous drugs (OSHA Work-Practice
Guidelines). AM J Health Syst Pharm 1996: 53: 1669-1685.
Manufactured by:
Manufactured for:
Ben Venue Laboratories, Inc.
Bedford Laboratories™
Bedford, OH 44146
Bedford, OH 44146
November 2007
Div-MTX-P07
‡LEUCOVORIN RESCUE SCHEDULES FOLLOWING TREATMENT WITH
HIGHER DOSES OF METHOTREXATE
Clinical Situation
Laboratory Findings
Leucovorin Dosage 
and Duration
Normal
Serum methotrexate level
15 mg PO, IM or IV q 6
Methotrexate
approximately 10 micromolar 
hours for 60 hours (10 
Elimination
at 24 hours after 
doses starting at 24 
administration, 1 micromolar 
hours after start of 
at 48 hours, and less than 0.2 
methotrexate infusion).
micromolar at 72 hours.
Delayed Late
Serum methotrexate level
Continue 15 mg PO, IM
Methotrexate
remaining above 0.2
or IV q 6 hours, until 
Elimination
micromolar at 72 hours, and
methotrexate level is less
more than 0.05 micromolar at
than 0.05 micromolar.
96 hours after administration.
Delayed Early
Serum methotrexate level of 
150 mg IV q 3 hours, until 
Methotrexate
50 micromolar or more at 24
methotrexate level is less
Elimination and/or
hours, or 5 micromolar or
than 1 micromolar; then
Evidence of Acute
more at 48 hours after
15 mg IV q 3 hours, until
Renal Injury
administration, OR; a 100% or 
methotrexate level is less
greater increase in serum 
than 0.05 micromolar.
creatinine level at 24 hours 
after methotrexate administration 
(e.g., an increase from 0.5 mg/dL 
to a level of 1 mg/dL or more).
After the intrathecal use of methotrexate, the central nervous system toxicity which
may occur can be classified as follows: acute chemical arachnoiditis manifested by
such symptoms as headache, back pain, nuchal rigidity, and fever; sub-acute
myelopathy characterized by paraparesis/paraplegia associated with involvement
with one or more spinal nerve roots; chronic leukoencephalopathy manifested by
confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This con-
dition can be progressive and even fatal.
Pulmonary - Pulmonary symptoms (especially a dry, nonproductive cough) or a
nonspecific pneumonitis occurring during methotrexate therapy may be indicative
of a potentially dangerous lesion and require interruption of treatment and careful
investigation. Although clinically variable, the typical patient with methotrexate
induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infil-
trate on chest X-ray; infection (including pneumonia) needs to be excluded. This
lesion can occur at all dosages.
Renal – Methotrexate may cause renal damage that may lead to acute renal failure.
High doses of methotrexate used in the treatment of osteosarcoma may cause
renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the
precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules.
Close attention to renal function including adequate hydration, urine alkalinization
and measurement of serum methotrexate and creatinine levels are essential for
safe administration.
Skin - Severe, occasionally fatal, dermatologic reactions, including toxic epidermal
necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and ery-
thema multiforme, have been reported in children and adults, within days of oral, intra-
muscular, intravenous, or intrathecal methotrexate administration.  Reactions were
noted after single or multiple, low, intermediate or high doses of methotrexate in patients
with neoplastic and non-neoplastic diseases.
Other Precautions - Methotrexate should be used with extreme caution in the pres-
ence of debility.
Methotrexate exits slowly from third space compartments (e.g., pleural effusions or
ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In
patients with significant third space accumulations, it is advisable to evacuate the fluid
before treatment and to monitor plasma methotrexate levels.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet
radiation. Radiation dermatitis and sunburn may be “recalled” by the use of
methotrexate.
ADVERSE REACTIONS
IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE
RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERI-
OUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN
THE PRECAUTIONS SECTION. THAT SECTION SHOULD ALSO BE CONSULTED
WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH
METHOTREXATE.
The most frequently reported adverse reactions include ulcerative stomatitis,
leukopenia, nausea, and abdominal distress. Other frequently reported adverse
effects are malaise, undue fatigue, chills and fever, dizziness and decreased resist-
ance to infection.
Other adverse reactions that have been reported with methotrexate are listed below
by organ system. In the oncology setting, concomitant treatment and the underly-
ing disease make specific attribution of a reaction to methotrexate difficult.
Alimentary System - gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting,
diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis,
pancreatitis.
Blood and Lymphatic System Disorders - suppressed hematopoiesis, anemia,
aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranu-
locytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (includ-
ing reversible). Hypogammaglobulinemia has been reported rarely. 
Cardiovascular - pericarditis, pericardial effusion, hypotension, and thromboem-
bolic events (including arterial thrombosis, cerebral thrombosis, deep vein throm-
bosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).
Central Nervous System - headaches, drowsiness, blurred vision, transient blind-
ness, speech impairment including dysarthria and aphasia, hemiparesis, paresis
and convulsions have also occurred following administration of methotrexate.
Following low doses, there have  been occasional reports of transient subtle cog-
nitive dysfunction, mood alteration, unusual cranial sensations, leukoen-
cephalopathy, or encephalopathy.
Hepatobiliary Disorders - hepatotoxicity, acute hepatitis, chronic fibrosis and cir-
rhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations. 
Infection - There have been case reports of sometimes fatal opportunistic infec-
tions in patients receiving methotrexate therapy for neoplastic and non-neoplastic
diseases. Pneumocystis carinii pneumonia was the most common opportunistic
infection. There have also been reports of infections, pneumonia, cytomegalovirus
infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis;
histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and dissemi-
nated H. simplex.
Musculoskeletal System - stress fracture.
Ophthalmic - conjunctivitis, serious visual changes of unknown etiology.
Pulmonary System – respiratory fibrosis, respiratory failure, alveolitis, interstitial
pneumonitis; deaths have been reported, and chronic interstitial obstructive pul-
monary disease has occasionally occurred. 
Skin - erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary
changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema mul-
tiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis,
skin ulceration, and exfoliative dermatitis.
Urogenital System - severe nephropathy or renal failure, azotemia, cystitis, hematuria,
proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, men-
strual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal
death, fetal defects.
Other rarer reactions related to or attributed to the use of methotrexate such as nodu-
losis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis,
sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis, and
osteonecrosis. Anaphylactoid reactions have been reported.
Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies: The approximate
incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reac-
tions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid
arthritis treated with low-dose oral (7.5 to 15 mg/wk) pulse methotrexate, are listed
below. Virtually all of these patients were on concomitant nonsteroidal anti-inflam-
matory drugs and some were also taking low dosages of corticosteroids. Hepatic
histology was not examined in these short-term studies. (See PRECAUTIONS.)
Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.
Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than
100,000/mm3).
Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia
(WBC less than 3000/mm3), pancytopenia, dizziness.
Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 
7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of
1%. (See PRECAUTIONS.)
Other less common reactions included decreased hematocrit, headache, upper
respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye dis-
comfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge. 
Adverse Reactions in Psoriasis: There are no recent placebo-controlled trials in
patients with psoriasis. There are two literature reports (Roenigk, 1969, and
Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated
with methotrexate. Dosages ranged up to 25 mg per week and treatment was
administered for up to four years. With the exception of alopecia, photosensitivity,
and “burning of skin lesions” (each 3 to 10%), the adverse reaction rates in these
reports were very similar to those in the rheumatoid arthritis studies. Rarely,
painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad
Dermatol 35: 835-838, 1996).
Adverse Reactions in JRA Studies: The approximate incidences of adverse reac-
tions reported in pediatric patients with JRA treated with oral, weekly doses of
methotrexate (5 to 20 mg/m2/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtu-
ally all patients were receiving concomitant nonsteroidal anti-inflammatory drugs,
and some also were taking low doses of corticosteroids): elevated liver function
tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%;
stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%;
and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/wk in
JRA, the published data for doses above 20 mg/m2/wk are too limited to provide
reliable estimates of adverse reaction rates. 
OVERDOSAGE
Leucovorin is indicated to diminish the toxicity and counteract the effect of inad-
vertently administered overdosages of methotrexate. Leucovorin administration
should begin as promptly as possible. As the time interval between methotrexate
administration and leucovorin initiation increases, the effectiveness of leucovorin
in counteracting toxicity decreases. Monitoring of the serum methotrexate con-
centration is essential in determining the optimal dose and duration of treatment
with leucovorin. 
In cases of massive overdosage, hydration and urinary alkalinization may be necessary
to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules.
Generally speaking, neither hemodialysis nor peritoneal dialysis have been shown to
improve methotrexate elimination. However, effective clearence of methotrexate has
been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall,
SM et al: Am J Kidney Dis 28(6): 846-854, 1996).
Accidental intrathecal overdosage may require intensive systemic support, high-
dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventricu-
lolumbar perfusion.
In postmarketing experience, overdose with methotrexate has generally occurred
with oral and intrathecal administration, although intravenous and intramuscular
overdose have also been reported. 
Reports of oral overdose often indicate accidental daily administration instead of
weekly (single or divided doses). Symptoms commonly reported following oral
overdose include those symptoms and signs reported at pharmacologic doses,
particularly hematologic and gastrointestinal reaction. For example, leukopenia,
thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis,
stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastroin-
testinal bleeding. In some cases, no symptoms were reported. There have been
reports of death following overdose. In these cases, events such as sepsis or sep-
tic shock, renal failure, and aplastic anemia were also reported. 
Symptoms of intrathecal overdose are generally central nervous system (CNS)
symptoms, including headache, nausea and vomiting, seizure or convulsion, and
acute toxic encephalopathy. In some cases, no symptoms were reported. There
have been reports of death following intrathecal overdose. In these cases, cere-
bellar herniation associated with increased intracranial pressure, and acute toxic
encephalopathy have also been reported. 
There are published case reports of intravenous and intrathecal carboxypeptidase
G2 treatment to hasten clearance of methotrexate in cases of overdose. 
DOSAGE AND ADMINISTRATION
Neoplastic Diseases: Oral administration in tablet form is often preferred when low
doses are being administered since absorption is rapid and effective serum levels are
obtained. Methotrexate sodium (preservative free) injectable products may be given by
the intramuscular, intravenous, intra-arterial, or intrathecal route. Parenteral drug prod-
ucts should be inspected visually for particulate matter and discoloration prior to admin-
istration whenever solution and container permit.
Choriocarcinoma and Similar Trophoblastic Diseases - Methotrexate is adminis-
tered orally or intramuscularly in doses of 15 to 30 mg daily for a 5-day course.
Such courses are usually repeated for 3 to 5 times as required, with rest periods
of one or more weeks interposed between courses, until any manifesting toxic
symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24-hour
quantitative analysis of urinary chorionic gonadatropin (hCG), which should return
to normal or less than 50 IU/24 hr usually after the third or fourth course and usu-
ally be followed by a complete resolution of measurable lesions in 4 to 6 weeks.
One to two courses of methotrexate after normalization of hCG is usually recom-
mended. Before each course of the drug careful clinical assessment is essential.
Cyclic combination therapy of methotrexate with other antitumor drugs has been
reported as being useful.
Since hydatidiform mole may precede choriocarcinoma, prophylactic chemother-
apy with methotrexate has been recommended.
Chorioadenoma destruens is considered to be an invasive form of hydatidiform
mole. Methotrexate is administered in these disease states in doses similar to
those recommended for choriocarcinoma.
Leukemia - Acute lymphoblastic leukemia in pediatric patients and young adoles-
cents is the most responsive to present day chemotherapy. In young adults and
older patients, clinical remission is more difficult to obtain and early relapse is
more common.
Methotrexate alone or in combination with steroids was used initially for induction
of remission in acute lymphoblastic leukemias. More recently corticosteroid ther-
apy, in combination with other antileukemic drugs or in cyclic combinations with
methotrexate included, has appeared to produce rapid and effective remissions.
When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with
60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients
treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with
other agents appears to be the drug of choice for securing maintenance of drug-
induced remissions. When remission is achieved and supportive care has pro-
duced general clinical improvement, maintenance therapy is initiated, as follows:
methotrexate is administered 2 times weekly either by mouth or intramuscularly in total
weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously
every 14 days. If and when relapse does occur, reinduction of remission can again usu-
ally be obtained by repeating the initial induction regimen.
A variety of combination chemotherapy regimens have been used for both induc-
tion and maintenance therapy in acute lymphoblastic leukemia. The physician
should be familiar with the new advances in antileukemic therapy.
Meningeal Leukemia - In the treatment or prophylaxis of meningeal leukemia,
methotrexate must be administered intrathecally. Preservative free methotrexate is
diluted to a concentration of 1 mg/mL with an appropriate sterile, preservative free
medium such as 0.9% Sodium Chloride Injection, USP.
The cerebrospinal fluid volume is dependent on age and not body surface area. The
CSF is at 40% of the adult volume at birth and reaches the adult volume in sever-
al years.
Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg)
has been reported to result in low CSF methotrexate concentrations and reduced
efficacy in pediatric patients and high concentrations and neurotoxicity in adults.
The following dosage regimen is based on age instead of body surface area:
Age (years)
Dose (mg)
<1
6
1
8
2
10
3 or older
12
In one study in patients under the age of 40, this dosage regimen appeared to result
in more consistent CSF methotrexate concentrations and less neurotoxicity.
Another study in pediatric patients with acute lymphocytic leukemia compared the
above regimen to a dose of 12 mg/m2 (maximum 15 mg). A significant reduction
in the rate of CNS relapse was observed in the group whose dose was based on age.
Because the CSF volume and turnover may decrease with age, a dose reduction
may be indicated in elderly patients.
For the treatment of meningeal leukemia, intrathecal methotrexate may be given at
intervals of 2 to 5 days. However, administration at intervals of less than 1 week
may result in increased subacute toxicity. Methotrexate is administered until the
cell count of the cerebrospinal fluid returns to normal. At this point one additional
dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the
same as for treatment except for the intervals of administration. On this subject, it
is advisable for the physician to consult the medical literature.
Untoward side effects may occur with any given intrathecal injection and are com-
monly neurological in character. Large doses may cause convulsions.
Methotrexate given by the intrathecal route appears significantly in the systemic
circulation and may cause systemic methotrexate toxicity. Therefore, systemic
antileukemic therapy with the drug should be appropriately adjusted, reduced or
discontinued. Focal leukemic involvement of the central nervous system may not
respond to intrathecal chemotherapy and is best treated with radiotherapy.
Lymphomas - In Burkitt’s Tumor, Stages I-II, methotrexate has produced pro-
longed remissions in some cases. Recommended dosage is 10 to 25 mg/day oral-
ly for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with
other antitumor agents. Treatment in all stages usually consists of several cours-
es of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage
III may respond to combined drug therapy with methotrexate given in doses of
0.625 to 2.5 mg/kg daily.
Mycosis Fungoides (cutaneous T cell lymphoma) – Therapy with methotrexate as
a single agent appears to produce clinical responses in up to 50% of patients treat-
ed. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or
cessation is guided by patient response and hematologic monitoring. Methotrexate
has also been administered twice weekly in doses ranging from 15 to 37.5 mg in
patients who have responded poorly to weekly therapy. Combination chemothera-
py regimens that include intravenous methotrexate administered at higher doses
with leucovorin rescue have been utilized in advanced stages of the disease.
Osteosarcoma - An effective adjuvant chemotherapy regimen requires the adminis-
tration of several cytotoxic chemotherapeutic agents. In addition to high-dose
methotrexate with leucovorin rescue, these agents may include doxorubicin, cis-
platin, and the combination of bleomycin, cyclophosphamide and dactinomycin
(BCD) in the doses and schedule shown in the table below. The starting dose for
high dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to
produce a peak serum methotrexate concentration of 1,000 micromolar 
(10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 
15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tol-
erate oral medication, leucovorin is given IV or IM at the same dose and schedule.
Page 130
 

Myozyme® (alglucosidase alfa) 
131 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
 
14.4 
Intravenous Immunoglobulin United States Prescribing Information 
 
GENZYME CORPORATION 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
Page 131
 

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use GAMUNEX®, Immune
Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, safely and
effectively. See full prescribing information for GAMUNEX.
GAMUNEX (Immune Globulin Intravenous [Human], 10% Caprylate/Chromatography
Purified) 10% Liquid Preparation
Initial U.S. Approval: 2003
WARNING: ACUTE RENAL DYSFUNCTION and FAILURE
See full prescribing information for complete boxed warning.
• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may be
associated with Immune Globulin Intravenous (Human) (IGIV) products in
predisposed patients.
• Renal dysfunction and acute renal failure occur more commonly in patients
receiving IGIV products containing sucrose. GAMUNEX does not contain sucrose.
• Administer IGIV products at the minimum concentration available and the minimum
infusion rate practicable.
-----------------------------------RECENT MAJOR CHANGES-----------------------------------
• Indications and Usage, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
(1.3)
09/2008
• Dosage and Administration, Chronic Inflammatory Demyelinating Polyneuropathy
(CIDP) (2.4)
09/2008
• Dosage and Administration, Primary Humoral Immunodeficiency (2.2)
10/2008
------------------------------------------INDICATIONS AND USAGE----------------------------------------
GAMUNEX is an immune globulin intravenous (human), 10% liquid indicated for treatment of:
• Primary Humoral Immunodeficiency (PI) (1.1)
• Idiopathic Thrombocytopenic Purpura (ITP) (1.2)
• Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (1.3) 
-------------------------------------DOSAGE AND ADMINISTRATION--------------------------------------
• Intravenous Use Only
Indication
Dose
Initial Infusion rate
Maintenance infusion rate
(if tolerated)
PI (2.2)
300-600 mg/kg
1 mg/kg/min
8 mg/kg/min
Every 3-4 weeks
ITP (2.3)
2 g/kg
1 mg/kg/min
8 mg/kg/min
CIDP (2.4)
loading dose: 2 g/kg
2 mg/kg/min
8 mg/kg/min
maintenance dose: 1 g/kg
Every 3 weeks
• Ensure that patients with pre-existing renal insufficiency are not volume depleted;
discontinue GAMUNEX if renal function deteriorates. (5.2)
• For patients at risk of renal dysfunction or thrombotic events, administer GAMUNEX at
the minimum infusion rate practicable. (5.2)
------------------------------------DOSAGE FORMS AND STRENGTHS------------------------------------
GAMUNEX is supplied in 1 g, 2.5 g, 5 g, 10 g, or 20 g single use bottles. (3)
1 g
10 mL
2.5 g
25 mL
5 g
50 mL
10 g
100 mL
20 g
200 mL
---------------------------------------------CONTRAINDICATIONS---------------------------------------------
• Anaphylactic or severe systemic reactions to human immunoglobulin (4)
• IgA deficient patients with antibodies against IgA and a history of hypersensitivity (4)
--------------------------------------WARNINGS AND PRECAUTIONS--------------------------------------
• IgA deficient patients with antibodies against IgA are at greater risk of developing severe
hypersensitivity and anaphylactic reactions. Epinephrine should be available immediately
to treat any acute severe hypersensitivity reactions. (5.1)
• Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output
in patients at risk of developing acute renal failure. (5.2)
• Hyperproteinemia, increased serum viscosity and hyponatremia occur in patients
receiving IGIV therapy. (5.3)
• Thrombotic events have occurred in patients receiving IGIV therapy. Monitor patients with
known risk factors for thrombotic events; consider baseline assessment of blood
viscosity for those at risk of hyperviscosity. (5.4)
• Aseptic Meningitis Syndrome has been reported with GAMUNEX and other IGIV
treatments, especially with high doses or rapid infusion. (5.5)
• Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC
sequestration. (5.6)
• IGIV recipients should be monitored for pulmonary adverse reactions (TRALI). (5.7)
• The product is made from human plasma and may contain infectious agents, e.g.,
viruses and, theoretically, the Creutzfeldt-Jakob disease agent. (5.9)
---------------------------------------------ADVERSE REACTIONS---------------------------------------------
• PI – Most common drug related adverse reactions during clinical trials were headache
and cough. (6.1)
• ITP – Most common drug related adverse reactions during clinical trials were headache,
vomiting, fever, and nausea. (6.1)
• CIDP – Most common drug related adverse reactions during clinical trials were headache
and fever. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Talecris Biotherapeutics, Inc. at
1-800-520-2807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
---------------------------------------------DRUG INTERACTIONS---------------------------------------------
• The passive transfer of antibodies may interfere with the response to live viral vaccines. (7)
• The passive transfer of antibodies may confound the results of serological testing. (7)
--------------------------------------USE IN SPECIFIC POPULATIONS -------------------------------------
• In patients over age 65 or in any patient at risk of developing renal insufficiency, do not
exceed the recommended dose, and infuse GAMUNEX at the minimum infusion rate
practicable. (8.5)
• Pregnancy: no human or animal data. Use only if clearly needed. (8.1)
08939392/08939393
See Section 17 for PATIENT COUNSELING INFORMATION.
Revised: October 2008
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Treatment of Primary Humoral Immunodeficiency 
1.2
Treatment of Idiopathic Thrombocytopenic Purpura
1.3
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
2
DOSAGE AND ADMINISTRATION
2.1
Preparation and Handling
2.2
Treatment of Primary Humoral Immunodeficiency 
2.3
Treatment of Idiopathic Thrombocytopenic Purpura
2.4
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
2.5
Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Sensitivity
5.2 Renal Failure
5.3 Hyperproteinemia
5.4 Thrombotic Events 
5.5 Aseptic Meningitis Syndrome (AMS)
5.6 Hemolysis
5.7 Transfusion-related Acute Lung Injury (TRALI)
5.8 Volume Overload
5.9 General
5.10 Laboratory Tests 
6
ADVERSE REACTIONS
6.1 Adverse Drug Reaction Overview
6.2 Clinical Trials Adverse Drug Reactions
6.3 Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy 
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
14
CLINICAL STUDIES
14.1 Primary Immunodeficiency 
14.2 Idiopathic Thrombocytopenic Purpura
14.3 Chronic Inflammatory Demyelinating Polyneuropathy
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
Page 132
 

Talecris Biotherapeutics, Inc.
FULL PRESCRIBING INFORMATION
Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography
Purified
GAMUNEX®
10% Liquid Preparation
WARNING: ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE
Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic
nephrosis and death.
1 Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency,
diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs.
Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of
infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the
licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. GAMUNEX
does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer. (See Dosage and Administration [2.5] and Warnings and
Precautions [5.2] for important information intended to reduce the risk of acute renal failure.)
1
INDICATIONS AND USAGE
Gamunex is an immune globulin intravenous (human) 10% liquid indicated for the treatment of:
1.1
Primary Humoral Immunodeficiency (PI)
GAMUNEX is indicated as replacement therapy of primary humoral immunodeficiency. This includes, but is not limited to, congenital
agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe
combined immuno deficiencies.
2–9
1.2
Idiopathic Thrombocytopenic Purpura (ITP)
GAMUNEX is indicated in Idiopathic Thrombocytopenic Purpura to rapidly raise platelet counts to prevent bleeding or to allow a patient with
ITP to undergo surgery.
10–15
1.3
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
GAMUNEX is indicated for the treatment of CIDP to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapse.
2
DOSAGE AND ADMINISTRATION
For intravenous use only.
GAMUNEX consists of 9%–11% protein in 0.16–0.24 M glycine. The buffering capacity of GAMUNEX is 35.0 mEq/L (0.35 mEq/g protein). A
dose of 1 g/kg body weight therefore represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole blood in a
normal individual is 45–50 mEq/L of blood, or 3.6 mEq/kg body weight.16 Thus, the acid load delivered with a dose of 1 g/kg of GAMUNEX
would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.
2.1
Preparation and Handling
• GAMUNEX should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container
permit. Do not use if turbid.
• Do not freeze. Solutions that have been frozen should not be used.
• The GAMUNEX vial is for single use only. GAMUNEX contains no preservative. Any vial that has been entered should be used promptly.
Partially used vials should be discarded.
• GAMUNEX should be infused using a separate line by itself, without mixing with other intravenous fluids or medications the subject might
be receiving.
• GAMUNEX is not compatible with saline. If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W). No other drug
interactions or compatibilities have been evaluated.
• Content of vials may be pooled under aseptic conditions into sterile infusion bags and infused within 8 hours after pooling.
• Do not mix with immune globulin intravenous (IGIV) products from other manufacturers.
• Do not use after expiration date.
2.2
Treatment of Primary Humoral Immunodeficiency
As there are significant differences in the half-life of IgG among patients with primary immunodeficiencies, the frequency and amount of
immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response.
The dose of GAMUNEX for replacement therapy in primary immune deficiency diseases is 300 to 600 mg/kg body weight (3-6 mL/kg)
administered every 3 to 4 weeks. The dosage may be adjusted over time to achieve the desired trough levels and clinical responses.
If a patient routinely receives a dose of less than 400 mg/kg of GAMUNEX every 3 to 4 weeks (less than 4 mL/kg), and is at risk of measles
exposure (i.e., traveling to a measles endemic area), administer a dose of  at least 400 mg/kg (4 mL/kg) just prior to the expected measles
exposure. If a patient has been exposed to measles, a dose of 400 mg/kg (4 mL/kg) should be administered as soon as possible after exposure.
Page 133
 

2.3
Treatment of Idiopathic Thrombocytopenic Purpura
GAMUNEX may be administered at a total dose of 2 g/kg, divided in two doses of 1 g/kg (10 mL/kg) given on two consecutive days or into
five doses of 0.4 g/kg (4 mL/kg) given on five consecutive days. If after administration of the first of two daily 1 g/kg (10 mL/kg) doses, an
adequate increase in the platelet count is observed at 24 hours, the second dose of 1g/kg body weight may be withheld.
Forty-eight ITP subjects were treated with 2 g/kg GAMUNEX, divided in two 1 g/kg doses (10 mL/kg) given on two successive days. With this
dose regimen 35/39 subjects (90%) responded with a platelet count from less than or equal to 20 x109/L to more than or equal to 50 x109/L
within 7 days after treatment.
17
The high dose regimen (1 g/kg  1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be
a concern.
2.4
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
GAMUNEX may be initially administered as a total loading dose of 2 g/kg (20 mL/kg) given in divided doses over two to four consecutive days.
GAMUNEX may be administered as a maintenance infusion of 1 g/kg (10 mL/kg) administered over 1 day or divided into two doses of 0.5
g/kg (5 mL/kg) given on two consecutive days, every 3 weeks.
2.5
Administration
GAMUNEX should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Do not use if turbid and/or if discoloration is observed.
Only administer intravenously. GAMUNEX should be at room temperature during administration.
Only 18 gauge needles should be used to penetrate the stopper for dispensing product from the 10 mL vial; 16 gauge needles or dispensing
pins should only be used with 25 mL vial sizes and larger. Needles or dispensing pins should only be inserted once and be within the stopper
area delineated by the raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the ring.
GAMUNEX® vial size
Gauge of needle to penetrate stopper
10 mL
18 gauge
25, 50, 100, 200 mL
16 gauge
Any vial that has been opened should be used promptly. Partially used vials should be discarded.
If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W).
Rate of Administration
It is recommended that GAMUNEX should initially be infused at a rate of 0.01 mL/kg per minute (1 mg/kg per minute) for the first 30 minutes.
If well-tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg per minute). 
Indication
Initial infusion rate
Maximum infusion rate
(first 30 minutes)
(if tolerated)
PI 
1 mg/kg/min
8 mg/kg/min
ITP
1 mg/kg/min
8 mg/kg/min
CIDP
2 mg/kg/min
8 mg/kg/min
Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to
disappear promptly.
Ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue GAMUNEX if renal function deteriorates.
For patients at risk of renal dysfunction or thromboembolic events, administer GAMUNEX at the minimum infusion rate practicable.
Incompatibilities
GAMUNEX is not compatible with saline. If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W). No other drug
interactions or compatibilities have been evaluated.
Shelf Life
GAMUNEX may be stored for 36 months at 2-8ºC (36-46ºF) from the date of manufacture AND product may be stored at temperatures not
to exceed 25ºC (77ºF) for up to 6 months any time during the 36 month shelf life, after which the product must be immediately discarded.
Special Precautions for Storage
Do not freeze. Frozen product should not be used.
Do not use after expiration date.
3
DOSAGE FORMS AND STRENGTH
GAMUNEX is supplied in 1 g, 2.5 g, 5 g, 10 g, or 20 g single use bottles.
• 1 g in 10 mL solution 
• 2.5 g in 25 mL solution 
• 5 g in 50 mL solution 
• 10 g in 100 mL solution 
• 20 g in 200 mL solution 
Page 134
 

4
CONTRAINDICATIONS
• GAMUNEX is contraindicated in individuals with acute severe hypersensitivity reactions to Immune Globulin (Human).
• GAMUNEX contains trace amounts of IgA. It is contraindicated in IgA deficient patients with antibodies against IgA and history of hyper sensitivity.
(See Description [11])
5
WARNINGS AND PRECAUTIONS 
5.1
Sensitivity 
Severe hypersensitivity reactions may occur. In case of hypersensitivity, IGIV infusion should be immediately discontinued and appropriate
treatment instituted. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction. (See Patient
Counseling Information [17])
GAMUNEX contains trace amounts of IgA (average 46 micrograms/mL). It is contraindicated in IgA deficient patients with antibodies against
IgA and history of hypersensitivity. (See Patient Counseling Information [17])
5.2
Renal Failure
Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV. Periodic monitoring of renal function and urine output
is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including
measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of GAMUNEX and again at
appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. (See Patient Counseling
Information [17]) For patients judged to be at risk for developing renal dysfunction and/or at risk of developing thrombotic events, it may be
prudent to reduce the amount of product infused per unit time by infusing GAMUNEX at a rate less than 8 mg IG/kg/min (0.08 mL/kg/min).
(See Boxed Warning) (See Dosage and Administration [2.5])
5.3
Hyperproteinemia
Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV therapy. The hyponatremia is likely to be
a pseudohyponatremia as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap. Distinguishing true hypona-
tremia from pseudohyponatremia is clinically critical, as treatment aimed at decreasing serum free water in patients with pseudohyponatremia
may lead to volume depletion, a further increase in serum viscosity and a disposition to thromboembolic events.
18
5.4
Thrombotic Events
Thrombotic events have been reported in association with IGIV.19–21 Patients at risk may include those with a history of atherosclerosis,
multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization
and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies
for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients
at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or
monoclonal gammopathies.
5.5
Aseptic Meningitis Syndrome (AMS) 
An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human)
treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.22–24 The syndrome usually
begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal
rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive
with pleocytosis up to several thousand cells per cu mm, predominantly from the granulocytic series, and elevated protein levels up to several
hundred mg/dl. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to
rule out other causes of meningitis. It appears that patients with a history of migraine may be more susceptible. (See Patient Counseling
Information [17])
5.6
Hemolysis 
Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo
coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.
25–27 Hemolytic anemia can
develop subsequent to IGIV therapy due to enhanced RBC sequestration. IGIV recipients should be monitored for clinical signs and symptoms
of hemolysis.
28 If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be
done. (See Patient Counseling Information [17])
5.7
Transfusion-related Acute Lung Injury (TRALI)
There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered
IGIV.
29 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and
typically occurs within 1-6 hrs after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory
support. 
IGIV recipients should be monitored for pulmonary adverse reactions. (See Patient Counseling Information [17]) If TRALI is suspected,
appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum.
5.8
Volume Overload
The high dose regimen (1 g/kg  1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be
a concern.
Page 135
 

5.9
General
Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the
Creutzfeldt-Jakob (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by
the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1-800-520-2807]. The physician should discuss the risks and
benefits of this product with the patient, before prescribing or administering it to the patient. (See Patient Counseling Information [17])
5.10 Laboratory Tests
If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done.
If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient
serum.
Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for
hyper viscosity, including those with cryoglobulins, fasting chylo micro nemia/markedly high triacylglycerols (triglycerides), or monoclonal
gammopathies. 
6
ADVERSE REACTIONS
6.1
Adverse Drug Reaction Overview
The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX for PI was an exacerbation of autoimmune pure
red cell aplasia in one subject.
The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX for ITP was myocarditis in one subject that occurred
50 days post study drug infusion and was not considered drug related.
The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX for CIDP was pulmonary embolism (PE) in one
subject with a history of PE.
The most common drug related adverse reactions observed at a rate 5% in subjects with PI were headache, cough, injection site reaction,
nausea, pharyngitis and urticaria.
The most common drug related adverse reactions observed at a rate 5% in subjects with ITP were headache, vomiting, fever, nausea, back
pain and rash.
The most common drug related adverse reactions observed at a rate 5% in subjects with CIDP were headache, fever, chills, hypertension,
rash, nausea and asthenia.
6.2
Clinical Trials Adverse Drug Reactions
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates
in other clinical trials and may not reflect the rates observed in practice.
Adverse events similar to those previously reported with the administration of intravenous and intramuscular immunoglobulin products may
occur. Cases of reversible aseptic meningitis, migraine, isolated cases of reversible hemolytic anemia and reversible increases in liver function
tests have been observed with GAMUNEX. Immediate anaphylactic reactions can possibly occur (<0.01%). Epinephrine should be available
for treatment of any acute anaphylactoid reaction. (see Warnings and Precautions [5.1])
Treatment of Primary Humoral Immunodeficiency
The following table shows the number of subjects treated with GAMUNEX in clinical trials to study PI, and the reason for discontinuation due
to adverse events:
Table 1: Reasons for Discontinuation Due to Adverse Events: All PI Studies
Study Number
Number of Subjects 
Number of Subjects Discontinued 
Adverse Event
Treated with GAMUNEX®
Due to Adverse Events
100152
18
0
-----
100174
20
1
Coombs negative hypochromic anemia*
100175
87
1
Autoimmune pure red cell aplasia*
* Both events were considered unrelated to study drug as per the investigator.
In study 100175, 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion. Generally, diphenhy-
dramine and acetaminophen were used.
Page 136
 

Any adverse events in trial 100175, irrespective of the causality assessment, are given in the following table.
Table 2: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100175)
Adverse Event
GAMUNEX®
GAMIMUNE® N, 10%
No. of subjects: 87
No. of subjects: 85
No. of subjects with AE 
No. of subjects with AE
(percentage of all subjects)
(percentage of all subjects)
Cough increased
47 (54%)
46 (54%)
Rhinitis
44 (51%)
45 (53%)
Pharyngitis
36 (41%)
39 (46%)
Headache
22 (25%)
28 (33%)
Fever
24 (28%)
27 (32%)
Diarrhea
24 (28%)
27 (32%)
Asthma
25 (29%)
17 (20%)
Nausea
17 (20%)
22 (26%)
Ear Pain
16 (18%)
12 (14%)
Asthenia
9 (10%)
13 (15%)
The subset of drug related adverse events in trial 100175 reported by at least 5% of subjects during the 9-month treatment are given in the
following table.
Table 3: Subjects with At Least One Drug Related Adverse Event (Study 100175)
Drug Related Adverse Event
GAMUNEX®
GAMIMUNE® N, 10%
No. of subjects: 87
No. of subjects: 85
No. of subjects with drug related
No. of subjects with drug related
AE (percentage of all subjects)
AE (percentage of all subjects)
Headache
7 (8%)
8 (9%)
Cough increased
6 (7%)
4 (5%)
Injection site reaction
4 (5%)
7 (8%)
Nausea
4 (5%)
4 (5%)
Pharyngitis
4 (5%)
3 (4%)
Urticaria
4 (5%)
1 (1%)
Adverse events, which were reported by at least 5% of subjects, were also analyzed by frequency and in relation to infusions administered.
The analysis is displayed in the following table.
Table 4: Adverse Event Frequency (Study 100175)
Adverse Event
GAMUNEX®
GAMIMUNE® N, 10%
No. of infusions: 825
No. of infusions: 865
No. of AE 
No. of AE 
(percentage of all infusions)
(percentage of all infusions)
Cough increased
All
154 (18.7%)
148 (17.1%)
Drug related
14 (1.7%)
11 (1.3%)
Pharyngitis
All
96 (11.6%)
99 (11.4%)
Drug related
7 (0.8%)
9 (1.0%)
Headache
All
57 (6.9%)
69 (8.0%)
Drug related
7 (0.8%)
11 (1.3%)
Fever
All
41 (5.0%)
65 (7.5%)
Drug related
1 (0.1%)
9 (1.0%)
Nausea
All
31 (3.8%)
43 (5.0%)
Drug related
4 (0.5%)
4 (0.5%)
Urticaria
All
5 (0.6%)
8 (0.9%)
Drug related
4 (0.5%)
5 (0.6%)
The mean number of adverse events per infusion that occurred during or on the same day as an infusion was 0.21 in both the GAMUNEX
and GAMIMUNE® N, Immune Globulin Intravenous (Human), 10%, treatment groups.
Page 137
 

In all three trials in primary humoral immundeficiencies, the maximum infusion rate was 0.08 mL/kg/min (8 mg/kg/min). The infusion rate
was reduced for 11 of 222 exposed subjects (7 GAMUNEX, 4 GAMIMUNE N, 10%) at 17 occasions. In most instances, mild to moderate
hives/urticaria, itching, pain or reaction at infusion site, anxiety or headache was the main reason. There was one case of severe chills. There
were no anaphylactic or anaphylactoid reactions to GAMUNEX or GAMIMUNE N, 10%. 
In trial 100175, serum samples were drawn to monitor the viral safety at baseline and one week after the first infusion (for parvovirus B19),
eight weeks after first and fifth infusion, and 16 weeks after the first and fifth infusion of IGIV (for hepatitis C) and at any time of premature
discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT,
Polymerase Chain Reaction (PCR)), and serological testing. There were no treatment emergent findings of viral transmission for either
GAMUNEX or GAMIMUNE N, 10%.
30–32
Treatment of Idiopathic Thrombocytopenic Purpura
The following table shows the number of subjects treated with GAMUNEX in clinical trials to study ITP, and the reason for discontinuation due
to adverse events: 
Table 5: Reasons for Discontinuation Due to Adverse Events: All ITP Studies
Study Number
Number of Subjects 
Number of Subjects 
Adverse Event
Treated with GAMUNEX®
Discontinued Due to Adverse Events
100213
28
1
Hives
100176
48
1
Headache, Fever, Vomiting
One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX. The death was judged to be
unrelated to GAMUNEX.
No pre-medication with corticosteroids was permitted by the protocol. Twelve (12) ITP subjects treated in each treatment group were pretreated
with medication prior to infusion. Generally, diphenhydramine and/or acetaminophen were used. More than 90% of the observed drug related
adverse events were of mild to moderate severity and of transient nature. 
The infusion rate was reduced for 4 of the 97 exposed subjects (1 GAMUNEX, 3 GAMIMUNE N, 10%) on 4 occasions. Mild to moderate headache,
nausea, and fever were the reported reasons. There were no anaphylactic or anaphylactoid reactions to GAMUNEX or GAMIMUNE N, 10%.
Any adverse events in trial 100176, irrespective of the causality assessment, reported by at least 5% of subjects during the 3-month trial are
given in the following table.
Table 6: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100176)
Adverse Event
GAMUNEX®
GAMIMUNE® N, 10%
No. of subjects: 48
No. of subjects: 49
No. of subjects with AE 
No. of subjects with AE 
(percentage of all subjects)
(percentage of all subjects)
Headache
28 (58%)
30 (61%)
Ecchymosis, Purpura
19 (40%)
25 (51%)
Hemorrhage (All systems)
14 (29%)
16 (33%)
Epistaxis
11 (23%)
12 (24%)
Petechiae
10 (21%)
15 (31%)
Fever
10 (21%)
7 (14%)
Vomiting
10 (21%)
10 (20%)
Nausea
10 (21%)
7 (14%)
Thrombocytopenia
7 (15%)
8 (16%)
Accidental injury
6 (13%)
8 (16%)
Rhinitis
6 (13%)
6 (12%)
Pharyngitis
5 (10%)
5 (10%)
Rash
5 (10%)
6 (12%)
Pruritis
4 (8%)
1 (2%)
Asthenia
3 (6%)
5 (10%)
Abdominal Pain
3 (6%)
4 (8%)
Arthralgia
3 (6%)
6 (12%)
Back Pain
3 (6%)
3 (6%)
Dizziness
3 (6%)
3 (6%)
Flu Syndrome
3 (6%)
3 (6%)
Neck Pain
3 (6%)
1 (2%)
Anemia
3 (6%)
0 (0%)
Dyspepsia
3 (6%)
0 (0%)
Page 138
 

The subset of drug related adverse events in trial 100176 reported by at least 5% of subjects during the 3-month trial are given in the following table.
Table 7: Subjects with At Least One Drug Related Adverse Event (Study 100176)
Drug Related Adverse Event
GAMUNEX®
GAMIMUNE® N, 10%
No. of subjects: 48
No. of subjects: 49
No. of subjects with drug related
No. of subjects with drug related
AE (percentage of all subjects)
AE (percentage of all subjects)
Headache
24 (50%)
24 (49%)
Vomiting
6 (13%)
8 (16%)
Fever
5 (10%)
5 (10%)
Nausea
5 (10%)
4 (8%)
Back Pain
3 (6%)
2 (4%)
Rash
3 (6%)
0 (0%)
Serum samples were drawn to monitor the viral safety of the ITP subjects at baseline, nine days after the first infusion (for parvovirus B19),
and 3 months after the first infusion of IGIV and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B,
HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, PCR), and serological testing. There were no treatment related
emergent findings of viral transmission for either GAMUNEX®, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography
Purified, or GAMIMUNE® N, Immune Globulin Intravenous (Human), 10%.
17
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
In study 100538, 113 subjects were exposed to GAMUNEX and 95 were exposed to Placebo. (See Clinical Studies [14.3]) As a result of the
study design, the drug exposure with GAMUNEX was almost twice that of Placebo, with 1096 GAMUNEX infusions versus 575 Placebo
infusions. Therefore, adverse reactions are reported per infusion (represented as frequency) to correct for differences in drug exposure between
the 2 groups. The majority of loading-doses were administered over 2 days. The majority of maintenance-doses were administered over 1 day.
Infusions were administered in the mean over 2.7 hours. 
The following table shows the numbers of subjects per treatment group in the CIDP clinical trial, and the reason for discontinuation due to
adverse events: 
Table 8: Reasons for Discontinuation Due to Adverse Events: CIDP
Number of Subjects
Number of Subjects Discontinued due to Adverse Events
Adverse Event
GAMUNEX®
113
3 (2.7%)
Urticaria, Dyspnea, Bronchopneumonia
Placebo
95
2 (2.1%)
Cerebrovascular Accident, Deep Vein Thrombosis
Adverse events reported by at least 5% of subjects in any treatment group irrespective of causality are shown in the following table.
Table 9: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100538)
MedDRA 
GAMUNEX®
Placebo
Preferred Term 
a
No. of subjects: 113
No. of subjects: 95
No. of 
No. of 
Incidence
No. of 
No. of 
Incidence 
Subjects
Adverse 
density 
b
Subjects
Adverse 
density 
b
(%)
Events 
(%)
Events
Any Adverse Event
85 (75)
377
0.344
45 (47)
120
0.209
Headache
36 (32)
57
0.052
8 (8)
15
0.026
Pyrexia (fever)
15 (13)
27
0.025
0
0
0
Hypertension
10 (9)
20
0.018
4 (4)
6
0.010
Rash
8 (7)
13
0.012
1 (1)
1
0.002
Arthralgia
8 (7)
11
0.010
1 (1)
1
0.002
Asthenia
9 (8)
10
0.009
3 (3)
4
0.007
Chills
9 (8)
10
0.009
0
0
0
Back pain
9 (8)
10
0.009
3 (3)
3
0.005
Nausea
7 (6)
9
0.008
3 (3)
3
0.005
Dizziness
7 (6)
3
0.006
1 (1)
1
0.002
Influenza
6 (5)
6
0.005
2 (2)
2
0.003
a Reported in >
—5% of subjects in any treatment group irrespective of causality.
b Calculated by the total number of adverse events divided by the number of infusions received (1096 for GAMUNEX and 575 for Placebo)
Drug-related adverse events reported by at least 5% of subjects in any treatment group are reported in the table below. The most common
drug-related events with GAMUNEX were headache and pyrexia:
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Table 10: Subjects with At Least One Drug Related Adverse Event (Study 100538)
MedDRA 
GAMUNEX®
Placebo
Preferred Term 
a
No. of subjects: 113
No. of subjects: 95
No. of 
No. of 
Incidence
No. of 
No. of 
Incidence 
Subjects
Adverse 
density 
b
Subjects
Adverse 
density 
b
(%)
Events 
(%)
Events
Any drug-related 
adverse event
62 (55)
194
0.177
16 (17)
25
0.043
Headache
31 (27)
44
0.040
6 (6)
7
0.012
Pyrexia (fever)
15 (13)
26
0.024
0
0
0
Chills
8 (7)
9
0.008
0
0
0
Hypertension
7 (6)
16
0.015
3 (3)
3
0.005
Rash
6 (5)
8
0.007
1 (1)
1
0.002
Nausea
6 (5)
7
0.006
3 (3)
3
0.005
Asthenia
6 (5)
6
0.005
0
0
0
a Reported in >
—5% of subjects in any treatment group.
b Calculated by the total number of adverse events divided by the number of infusions received (1096 for GAMUNEX and 575 for Placebo)
Laboratory Abnormalities
During the course of the clinical program, ALT and AST elevations were identified in some subjects. 
• For ALT, in the primary humoral immunodeficiency (PI) study (100175) treatment emergent elevations above the upper limit of normal were
transient and observed among 14/80 (18%) of subjects in the GAMUNEX group versus 5/88 (6%) of subjects in the GAMIMUNE N, 10%
group (p = 0.026).
• In the ITP study which employed a higher dose per infusion, but a maximum of only two infusions, the reverse finding was observed among
3/44 (7%) of subjects in the GAMUNEX group versus 8/43 (19%) of subjects in the GAMIMUNE N, 10% group (p = 0.118).
• In the CIDP study (100538), 15/113 (13%) of subjects in the GAMUNEX group and 7/95 (7%) in the Placebo group (p=0.168) had a
treatment emergent transient elevation of ALT.
Elevations of ALT and AST were generally mild (<3 times upper limit of normal), transient, and were not associated with obvious symptoms
of liver dysfunction.
GAMUNEX may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4 class. Direct antiglobulin tests (DAT or direct
Coombs tests), which are carried out in some centers as a safety check prior to red blood cell transfusions, may become positive temporarily.
Hemolytic events not associated with positive DAT findings were observed in clinical trials.
17, 30–33
6.3
Postmarketing Experience
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably
estimate the frequency of these reactions or establish a causal relationship to product exposure.
GAMUNEX Postmarketing Experience
The following adverse reactions have been identified and reported during the post marketing use of GAMUNEX:
• Hematologic: Hemolytic anemia
• Infections and Infestations: Aseptic meningitis
General
The following adverse reactions have been identified and reported during the post marketing use of IGIV products
34:
• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea,
bronchospasm
• Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
• Neurological: Coma, loss of consciousness, seizures/convulsions, tremor
• Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
• Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs test)
• General/Body as a Whole: Pyrexia, rigors
• Musculoskeletal: Back pain
• Gastrointestinal: Hepatic dysfunction, abdominal pain
7
DRUG INTERACTIONS
GAMUNEX may be diluted with 5% dextrose in water (D5/W). Admixtures of GAMUNEX with other drugs and intravenous solutions have not
been evaluated. It is recommended that GAMUNEX be administered separately from other drugs or medications which the patient may be
receiving. The product should not be mixed with IGIVs from other manufacturers.
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The infusion line may be flushed before and after administration of GAMUNEX with 5% dextrose in water.
Various passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing.
Antibodies in GAMUNEX may interfere with the response to live viral vaccines such as measles, mumps and rubella. Physicians should be
informed of recent therapy with IGIVs, so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months
from the time of IGIV administration. (See Patient Counseling Information [17])
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy 
Pregnancy Category C. Animal reproduction studies have not been conducted with GAMUNEX. It is not known whether GAMUNEX can cause
fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMUNEX should be given to a pregnant woman
only if clearly needed. 
8.3
Nursing Mothers
GAMUNEX has not been evaluated in nursing mothers.
8.4
Pediatric Use
Treatment of Primary Immunodeficiency
GAMUNEX was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI subjects (Study 100175) exposed to
GAMUNEX were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that vomiting was more
frequently reported in pediatrics (3 of 18 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels. 
One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX. The death was judged to be
unrelated to GAMUNEX.
Treatment of Idiopathic Thrombocytopenic Purpura
GAMUNEX was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of the acute ITP subjects (Study 100176) exposed to
GAMUNEX were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that fever was more
frequently reported in pediatrics (6 of 12 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels.
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
The safety and effectiveness of GAMUNEX has not been established in pediatric subjects with CIDP.
8.5
Geriatric Use
Patients > 65 years of age may be at increased risk for developing certain adverse reactions such as thromboembolic events and acute renal
failure. (See Boxed Warning, Warnings and Precautions [5.2]) Clinical studies of GAMUNEX did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects.
Table 11: Clinical Studies of GAMUNEX® by Age Group
Number of Subjects
Clinical Study
Indication
< 65 years
 65 years
100175
PI
78
9
100152
PI
18
0
100174
PI
20
0
10039
PI
19
0
100213
ITP
22
6
100176
ITP
44
4
10038
ITP
18
3
100538
CIDP
44
15
11
DESCRIPTION
GAMUNEX is a ready-to-use sterile solution of human immune globulin protein for intravenous administration. GAMUNEX consists of 9%–11%
protein in 0.16–0.24 M glycine. Not less than 98% of the protein has the electrophoretic mobility of gamma globulin. GAMUNEX contains
trace levels of fragments, IgA (average 0.046 mg/mL), and IgM. The distribution of IgG subclasses is similar to that found in normal serum.
GAMUNEX doses of 1 g/kg correspond to a glycine dose of 0.15 g/kg. While toxic effects of glycine administration have been reported,35 the
doses and rates of administration were 3 – 4 fold greater than those for GAMUNEX. In another study, it was demonstrated that intravenous
bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects.
36 Caprylate is a saturated medium-chain (C8) fatty acid of
plant origin. Medium chain fatty acids are considered to be essentially non-toxic. Human subjects receiving medium chain fatty acids parenterally
have tolerated doses of 3.0 to 9.0 g/kg/day for periods of several months without adverse effects.37 Residual caprylate concentrations in the final
container are no more than 0.216 g/L (1.3 mmol/L).The measured buffer capacity is 35 mEq/L and the osmolality is 258 mOsmol/kg solvent,
which is close to physiological osmolality (285-295 mOsmol/kg). The pH of GAMUNEX is 4.0 – 4.5. GAMUNEX contains no preservative and
is latex-free.
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GAMUNEX is made from large pools of human plasma by a combination of cold ethanol fractionation, caprylate precipitation and filtration,
and anion-exchange chromatography. Isotonicity is achieved by the addition of glycine. GAMUNEX is incubated in the final container (at the
low pH of 4.0 – 4.3), for a minimum of 21 days at 23° to 27°C. The product is intended for intravenous administration.
The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory
spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: human immunodeficiency virus,
type I (HIV-1) as the relevant virus for HIV-1 and HIV–2; bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; pseudorabies virus
(PRV) as a model for large DNA viruses (e.g., herpes viruses); Reo virus type 3 (Reo) as a model for non-enveloped viruses and for its
resistance to physical and chemical inactivation; hepatitis A virus (HAV) as relevant non-enveloped virus, and porcine parvovirus (PPV) as a
model for human parvovirus B19.
Overall virus reduction was calculated only from steps that were mechanistically independent from each other and truly additive. In addition,
each step was verified to provide robust virus reduction across the production range for key operating parameters.
Table 12: Log10 Virus Reduction
Log10 Virus Reduction
Process Step
Enveloped Viruses
Non-enveloped Viruses
HIV
PRV
BVDV
Reo
HAV
PPV
Caprylate Precipitation/Depth Filtration
C/I a
C/I
2.7
 3.5
 3.6
4.0
Caprylate Incubation
 4.5
 4.6
 4.5
NA b
NA
NA
Depth Filtration d
CAP
c
CAP
CAP
 4.3
 2.0
3.3
Column Chromatography
 3.0
 3.3
4.0
 4.0
 1.4
4.2
Low pH Incubation (21 days)
 6.5
 4.3
 5.1
NA
NA
NA
Global Reduction
 14.0
 12.2
 16.3
 7.5
 5.0
8.2
a C/I - Interference by caprylate precluded determination of virus reduction for this step. Although removal of viruses is likely to occur at the
caprylate precipitation/depth filtration step, BVDV is the only enveloped virus for which reduction is claimed. The presence of caprylate
prevents detection of other, less resistant enveloped viruses and therefore their removal cannot be assessed.
b Not Applicable – This step has no effect on non-enveloped viruses.
c CAP - The presence of caprylate in the process at this step prevents detection of enveloped viruses, and their removal cannot be assessed.
d Some mechanistic overlap occurs between depth filtration and other steps. Therefore, Talecris Biotherapeutics, Inc. has chosen to exclude
this step from the global virus reduction calculations.
Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible
spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.
38-42
Several of the individual production steps in the GAMUNEX manufacturing process have been shown to decrease TSE infectivity of that experi-
mental model agent. TSE reduction steps include two depth filtrations (in sequence, a total of  6.6 logs). These studies provide reasonable
assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed. 
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Treatment of Primary Humoral Immunodeficiency
GAMUNEX supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria or their toxins. The mechanism of action in
PI has not been fully elucidated.
Treatment of Idiopathic Thrombocytopenic Purpura
The mechanism of action of high doses of immunoglobulins in the treatment of Idiopathic Thrombocytopenic Purpura (ITP) has not been fully
elucidated.
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
The precise mechanism of action in CIDP has not been fully elucidated.
12.3 Pharmacokinetics
Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX in 38 subjects with Primary Humoral
Immunodeficiencies given 3 infusions 3 or 4 weeks apart of test product at a dose of 100-600 mg/kg body weight per infusion. One trial
compared the pharmacokinetic characteristics of GAMUNEX to GAMIMUNE N, 10% (study 100152), and the other trial compared the
pharmacokinetics of GAMUNEX (10% strength) with a 5% concentration of this product (study 100174). The ratio of the geometric least
square means for dose-normalized IgG peak levels of GAMUNEX and GAMIMUNE N, 10% was 0.996. The corresponding value for the
dose-normalized area under the curve (AUC) of IgG levels was 0.990. The results of both PK parameters were within the pre-established
limits of 0.080 and 1.25. Similar results were obtained in the comparison of GAMUNEX 10% to a 5% concentration of GAMUNEX.
31, 32
Page 142
 

The main pharmacokinetic parameters of GAMUNEX, measured as total IgG in study 100152 are displayed below:
Table 13: PK Parameters of GAMUNEX® and GAMIMUNE® N, 10% (Study 100152)
GAMUNEX®
GAMIMUNE® N, 10%
N
Mean
SD
Median
N
Mean
SD
Median
Cmax 
(mg/mL)
17
19.04
3.06
19.71
17
19.31
4.17
19.30
Cmax-norm
(kg/mL)
17
0.047
0.007
0.046
17
0.047
0.008
0.047
AUC(0-tn)a
(mg*hr/mL)
17
6746.48
1348.13
6949.47
17
6854.17
1425.08
7119.86
AUC(0-tn)norma
(kg*hr/mL)
17
16.51
1.83
16.95
17
16.69
2.04
16.99
T1⁄2
b
(days)
16
35.74
8.69
33.09
16
34.27
9.28
31.88
a Partial AUC: defined as pre-dose concentration to the last concentration common across both treatment periods in the same patient.
b only 15 subjects were valid for the analysis of T1/2
The two pharmacokinetic trials with GAMUNEX show the IgG concentration/time curve follows a biphasic slope with a distribution phase of
about 5 days characterized by a fall in serum IgG levels to about 65-75% of the peak levels achieved immediately post-infusion. This phase
is followed by the elimination phase with a half-life of approximately 35 days.
31, 32 IgG trough levels were measured over nine months in the
therapeutic equivalence trial (100175). Mean trough levels were 7.8 +/- 1.9 mg/mL for the GAMUNEX treatment group and 8.2 +/- 2.0
mg/mL for the GAMIMUNE N, 10% control group.
30
14
CLINICAL STUDIES
14.1 Treatment of Primary Humoral Immunodeficiency
In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies (study 100175)
GAMUNEX was demonstrated to be at least as efficacious as GAMIMUNE N, 10% in the prevention of any infection, i.e. validated plus clinically
defined, non-validated infections of any organ system, during a nine month treatment period. Twenty six subjects were excluded from the Per
Protocol analysis (2 due to non-compliance and 24 due to protocol violations). The endpoint was the proportion of subjects with at least one
of the following validated infections: pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis.
Table 14: Primary Endpoint Per Protocol Analysis (Study 100175)
GAMUNEX®
GAMIMUNE® N, 10%
Mean Difference
p-Value
(n=73)
(n=73)
(90% confidence interval)
No. of subjects with
No. of subjects with 
at least one infection
at least one infection
Validated Infections
9 (12%)
17 (23%)
-0.117
0.06
(-0.220, -0.015)
Acute Sinusitis
4 (5%)
10 (14%)
Exacerbation of 
Chronic Sinusitis
5 (7%)
6 (8%)
Pneumonia
0 (0%)
2 (3%)
Any Infection
56 (77%)
57 (78%)
-0.020
0.78
(Validated plus 
(-0.135, 0.096)
Clinically defined 
non-validated Infections)
The annual rate of validated infections (Number of Infections/year/subject) was 0.18 in the group treated with GAMUNEX and 0.43 in the group
treated with GAMIMUNE N, 10% (p=0.023). The annual rates for any infection (validated plus clinically-defined, non-validated infections of
any organ system) were 2.88 and 3.38, respectively (p=0.300).30, 43
14.2 Treatment of Idiopathic Thrombocytopenic Purpura
A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to prove the hypothesis that GAMUNEX was at
least as effective as GAMIMUNE N, 10% in raising platelet counts from less than or equal to 20 x109/L to more than 50 x109/L within 7 days
after treatment with 2 g/kg IGIV (study 100176). Twenty-four percent of the subjects were less than or equal to 16 years of age.
GAMUNEX was demonstrated to be at least as effective as GAMIMUNE N, 10% in the treatment of adults and children with acute or
chronic ITP.
11
Page 143
 

Table 15: Platelet Response of Per Protocol Analysis (Study 100176)
GAMUNEX®
GAMIMUNE® N, 10%
Mean Difference
(n=39)
(n=42)
(90% confidence interval)
By Day 7
35 (90%)
35 (83%)
0.075
(-0.037, 0.186)
By Day 23
35 (90%)
36 (86%)
0.051
(-0.058, 0.160)
Sustained for 7 days
29 (74%)
25 (60%)
0.164
(0.003, 0.330)
A trial was conducted to evaluate the clinical response to rapid infusion of GAMUNEX in patients with ITP. The study involved 28 chronic ITP
subjects, wherein the subjects received 1 g/kg GAMUNEX on three occasions for treatment of relapses. The infusion rate was randomly
assigned to 0.08, 0.11, or 0.14 mL/kg/min (8, 11 or 14 mg/kg/min). Pre-medication with corticosteroids to alleviate infusion-related intolerability
was not permitted. Pre-treatment with antihistamines, anti-pyretics and analgesics was permitted. The average dose was approximately 1 g/kg
body weight at all three prescribed rates of infusion (0.08, 0.11 and 0.14 mL/kg/min). All patients were administered each of the three planned
infusions except seven subjects. Based on 21 patients per treatment group, the a posteriori power to detect twice as many drug-related adverse
events between groups was 23%. Of the seven subjects that did not complete the study, five did not require additional treatment, one withdrew
because he refused to participate without concomitant medication (prednisone) and one experienced an adverse event (hives); however, this
was at the lowest dose rate level (0.08 mL/kg/min). 
14.3 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
A multi-center, randomized, double-blind Placebo-controlled trial (study 100538, The Immune Globulin Intravenous (Human), 10%
Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMUNEX.44 This study included two separately
randomized study periods to assess whether GAMUNEX was more effective than Placebo for the treatment of CIDP (assessed in the Efficacy
Period for up to 24 weeks) and whether long-term administration of GAMUNEX could maintain long-term benefit (assessed in the 24 week
Randomized Withdrawal Period).
In the Efficacy Period, there was a requirement for Rescue (crossover) to the alternate study drug if the subject did not improve and maintain
this improvement until the end of the 24 week treatment period. Subjects entering the Rescue phase followed the same dosing and schedule
as in the Efficacy period. Any subject who was Rescued (crossed over) and did not improve and maintain this improvement was withdrawn
from the study. 
Subjects who completed 24 weeks treatment in the Efficacy period or Rescue phase and responded to therapy were eligible for entry into a
double-blind Randomized Withdrawal Period. Eligible subjects were re-randomized to GAMUNEX or Placebo. Any subject who relapsed was
withdrawn from the study.
The Efficacy Period and the Rescue treatment started with a loading dose of 2 g/kg bw of GAMUNEX or equal volume of Placebo given over
2-4 consecutive days. All other infusions (including the first infusion of the Randomized Withdrawal Period) were given as maintenance doses
of 1 g/kg bw (or equivalent volume of Placebo) every three weeks.
The Responder rates of the GAMUNEX and Placebo treatment groups was measured by the INCAT score. The INCAT (Inflammatory Neuropathy
Cause and Treatment) scale is used to assess functional disability of both upper and lower extremities in demyelinating polyneuropathy. The
INCAT scale has upper and lower extremity components (maximum of 5 points for upper (arm disability) and maximum of 5 points for lower
(leg disability)) that add up to a maximum of 10-points (0 is normal and 10 is severely incapacitated).
45 At the start of the efficacy portion of
the study, the INCAT scores were as follows: Upper Extremity mean was 2.2 ± 1.0, and median was 2.0 with a range of 0 to 5; Lower Extremity
mean was 1.9 ± 0.9, and median was 2.0 with a range of 1 to 5; Total Overall Score mean was 4.2 ± 1.4, and median was 4.0 with a range
of 2 to 9. A Responder was defined as a subject with at least 1-point improvement from baseline in the adjusted INCAT score that was
maintained through 24 weeks. 
Significantly more subjects with CIDP responded to GAMUNEX: 28 of 59 subjects (47.5%) responded to GAMUNEX compared with 13 of
58 subjects (22.4%) administered Placebo (25% difference; [95% CI: 7%-43%]; p=0.006). The study included both subjects who were IGIV
naive and subjects who had previous IGIV experience. The outcome was influenced by the group of subjects who experienced prior therapy
with IGIV, as shown by the outcomes table, below. 
Time to relapse for the subset of 57 subjects who previously responded to GAMUNEX was evaluated: 31 were randomly reassigned to continue
to receive GAMUNEX and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued
to receive GAMUNEX experienced a significantly longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of
relapse was 13% with GAMUNEX versus 45% with Placebo (hazard ratio, 0.19 [95% confidence interval, 0.05, 0.70]).
Page 144
 

Table 16: Outcomes in Intent-to-Treat Population Efficacy Period
GAMUNEX®
Placebo
Efficacy Period
Responder
Non-Responder
Responder
Non-Responder
p-value
a
All Subjects
28/59 (47.5%)
31/59 (52.5%)
13/58 (22.4%)
45/58 (77.6%)
0.006
IGIV - Naïve Subjects
17/39 (43.6%)
22/39 (56.4%)
13/46 (28.3%)
33/46 (71.7%)
0.174
IGIV - Experienced Subjects
11/20 (55.0%)
9/20 (45.0%)
0/12 (0%)
12/12 (100%)
0.002
a p-value based on Fisher’s exact method
The following table shows outcomes for the Rescue Phase (which are supportive data):
Table 17: Outcomes in Rescue Phase
GAMUNEX®
Placebo
Rescue Phase
Success
Failure
Success
Failure
p-value
a
All Subjects
25/45 (55.6%)
20/45 (44.4%)
6/23 (26.1%)
17/23 (73.9%)
0.038
IGIV - Naïve Subjects
19/33(57.6%)
14/33 (42.4%)
6/18 (33.3%)
12/18 (66.7%)
0.144
IGIV - Experienced Subjects
6/12 (50%)
6/12 (50%)
0/5 (0%)
5/5(100%)
0.102
a p-value based on Fisher’s exact method
The following Kaplan-Meier curves show the outcomes for the Randomized Withdrawal Period:
Figure 1: Outcome for Randomized Withdrawal Period
Secondary Endpoint
Time to Relapse
p-valuea
Randomized Withdrawal Period
p= 0.011
a p-value based on log-rank test
15
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6. Pruzanski W, et al. Relationship of the dose of intravenous gammaglobulin to the prevention of infections in adults with common
variable immunodeficiency. Inflammation, 1996. 20(4): p. 353-9.
7. Roifman CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and
chronic lung disease. Lancet, 1987. 1(8541): p. 1075-7.
8. Sorensen RU, Polmar SH. Efficacy and safety of high-dose intravenous immune globulin therapy for antibody deficiency
syndromes. Am J Med, 1984. 76(3A): p. 83-90.
9. Stephan JL, et al. Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome
in 117 patients. J Pediatr, 1993. 123(4): p. 564-72.
10. Blanchette VS, Kirby MA, and Turner C. Role of intravenous immunoglobulin G in autoimmune hematologic disorders. Semin
Hematol, 1992. 29(3 Suppl 2): p. 72-82.
11. Lazarus AH, Freedman J, Semple JW. Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP):
mechanisms of action. Transfus Sci, 1998. 19(3): p. 289-94.
12. Semple JW, Lazarus AH, Freedman J. The cellular immunology associated with autoimmune thrombocytopenic purpura: an
update. Transfus Sci, 1998. 19(3): p. 245-51.
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13. Imbach PA. Harmful and beneficial antibodies in immune thrombocytopenic purpura. Clin Exp Immunol, 1994. 97(Suppl 1): p. 25-30.
14. Bussel JB. Fc receptor blockade and immune thrombocytopenic purpura. Semin Hematol, 2000. 37(3): p. 261-6.
15. Imbach P, et al. Immunthrombocytopenic purpura as a model for pathogenesis and treatment of auto immunity. Eur J Pediatr, 1995.
154(9 Suppl 4): p. S60-4.
16. Guyton A. Textbook of Medical Physiology. 5th Edition. 1976, Philadelphia: W.B. Saunders. 499-500.
17. Cyrus P, F.G., Kelleher J, Schwartz L. A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety, and Efficacy
of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Idiopathic (Immune)
Thrombocytopenic Purpura (ITP), 2000. Report on file.
18. Steinberger BA, Ford SM, Coleman TA. Intravenous Immunoglobulin Therapy Results in Post-infusional Hyperproteinemia, Increased
Serum Viscosity, and Pseudohyponatremia. Am J Hematol 73:97-100 (2003).
19. Dalakas MC. High-dose intravenous Immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology,
44:223-226.
20. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous
immunoglobulin in elderly patients. Lancet 1986;2:217-218.
21. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am
J Hematol 2000; 65,30-34.
22. Casteels-Van Daele M, et al. Intravenous immune globulin and acute aseptic meningitis [letter]. N Engl J Med, 1990. 323(9): p. 614-5.
23. Kato E, et al. Administration of immune globulin associated with aseptic meningitis [letter]. Jama, 1988. 259(22): p. 3269-71.
24. Scribner CL, et al. Aseptic meningitis and intravenous immunoglobulin therapy [editorial; comment]. Ann Intern Med, 1994. 121(4): p. 305-6.
25. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26:
410-412.
26. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood
1993;15:3789.
27. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle & Nerve 1997;20:1142-1145.
28. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead
to enhanced erythrocyte sequestration. J Autoimmune 1999;13:129-135.
29. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001:41:264-268.
30. Kelleher J, F.G., Cyrus P, Schwartz L. A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety and Efficacy
of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Immune
Deficiency (PID), 2000. Report on file.
31. Bayever E, M.F., Sundaresan P, Collins S. Randomized, Double-Blind, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety,
Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10%
(Control) in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100152). MMRR-1512/1, 1999.
32. Lathia C, E.B., Sundaresan PR, Schwartz L. A Randomized, Open-Label, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the
Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 5% with IGIV-Chromatography 10% in Patients with Primary
Humoral Immune Deficiency (BAY-41-1000-100174). 2000.
33. Kelleher J, S.L. IGIV-C 10% Rapid Infusion Trial in Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2001. Report on file.
34. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003; 17,241-251.
35. Hahn RG, Stalberg HP, Gustafsson SA. Intravenous infusion of irrigating fluids containing glycine or mannitol with and without ethanol.
J Urol, 1989. 142(4): p. 1102-5.
36. Tai VM, M.E., Lee-Brotherton V, Manley JJ, Nestmann ER, Daniels JM. Safety Evaluation of Intravenous Glycine in Formulation
Development. in J Pharm Pharmaceut Sci. 2000.
37. Traul KA, et al. Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol, 2000. 38(1): p. 79-98.
38. Stenland CJ, Lee DC, Brown P, et al. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of
therapeutic proteins from human plasma. Transfusion 2002. 42(11):1497-500.
39. Lee DC, Stenland CJ, Miller JL, et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible
spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 2001. 41(4):449-55.
40. Lee DC, Stenland CJ, Hartwell RC, et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of
the prion protein. J Virol Methods 2000. 84(1):77-89.
41. Cai K, Miller JL, Stenland CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35.
42. Trejo SR, Hotta JA, Lebing W, et al. Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process.
Vox Sang 2003. 84(3):176-87.
43. Data on File.
44. Hughes RAC, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate/chromatography purified) for the treatment of chronic
inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized Placebo-controlled trial. Lancet Neurol 2008. 7:136-144.
45. Hughes R, Bensa S, Willison H, Van den BP, Comi G, Illa I, et al. Randomized controlled trial of intravenous immunoglobulin versus
oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001 Aug;50(2):195-201.
Page 146
 

16
HOW SUPPLIED/STORAGE AND HANDLING
GAMUNEX is supplied in single-use, tamper evident vials (shrink band) containing the labeled amount of functionally active IgG. The three
larger vial size labels incorporate integrated hangers. The components used in the packaging for GAMUNEX are latex-free.
GAMUNEX is supplied in the following sizes:
NDC Number
Size
Grams Protein
13533-645-12
10 mL
1.0
13533-645-15
25 mL
2.5
13533-645-20
50 mL
5.0
13533-645-71
100 mL 10.0
13533-645-24
200 mL 20.0 
GAMUNEX may be stored for 36 months at 2 - 8°C (36 - 46°F), AND product may be stored at temperatures not to exceed 25°C (77°F) for
up to 6 months anytime during the 36 month shelf life, after which the product must be immediately used or discarded. Do not freeze. Do
not use after expiration date.
17
PATIENT COUNSELING INFORMATION 
(See Boxed Warning and Warnings and Precautions Sections) 
Inform patients to immediately report the following to their physician:
• signs and symptoms of renal failures, such as decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath
• signs and symptoms of aseptic meningitis, such as headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements,
nausea, and vomiting
• signs and symptoms of hemolysis, such as fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine
• signs and symptoms of TRALI, such as severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and
fever. TRALI typically occurs within 1 to 6 hours following transfusion.
Inform patients that GAMUNEX is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses, and,
theoretically, the CJD agent). Inform patients that the risk GAMUNEX may transmit an infectious agent has been reduced by screening plasma
donors for prior exposure to certain viruses, by testing the donated plasma for certain virus infections and by inactivating and/or removing
certain viruses during manufacturing.
Inform patients that administration of IgG may interfere with the response to live viral vaccines such as measles, mumps and rubella. Inform
patients to notify their immunizing physician of therapy with GAMUNEX.
Manufactured by:
Rx only 
Talecris Biotherapeutics, Inc.
Research Triangle Park, NC 27709 USA 
08939392/08939393
U.S. License No. 1716
October 2008
Page 147
 

M
C
yozyme® (alglucosidase alfa) 
148 
linical Protocol Number AGLU03707, Amendment 3 
 
 
 
GENZYME CORPORATION 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
14.5 
National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 3.0 (09 August 2006) 
 
 
Page 148
 

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 
Page 149

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 150

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 
Page 151

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 
Page 152

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 153

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 
Page 154

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 
Page 155

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 
Page 156

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Page 157

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 158

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 159

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  
Page 160

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 161

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  
Page 162

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 
Page 163

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 
Page 164

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 165

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 
Page 166

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 167

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 
Page 168

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  
Page 169

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 
Page 170

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 
Page 171

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 
Page 172

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 
Page 173

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
Page 174

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
Page 175

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  
Page 176

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Page 177

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 178

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Page 179

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Page 180

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Page 181

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 
Page 182

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 183

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
Page 184

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 185

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 
Page 186

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 
Page 187

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Page 188

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 
Page 189

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 
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METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
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March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
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MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 
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MUSCULOSKELETAL/SOFT TISSUE 
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Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
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March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 
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MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 
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MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 
Page 195

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
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March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 
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NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 
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NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
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March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 
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NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
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March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 
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NEUROLOGY 
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Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
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March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 200

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 
Page 201

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 
Page 202

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 
Page 203

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 
Page 204

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 
Page 205

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 
Page 206

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 
Page 207

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Page 208

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 
Page 209

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 
Page 210

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 211

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 
Page 212

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 
Page 213

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 
Page 214

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Page 215

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 
Page 216

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Page 217

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 218

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 
Page 219

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
Page 220

Myozyme® (alglucosidase alfa) 
 
221 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
14.6 
Additional Study Visits: Weeks 77 Through 105 
 
W771
W791
W811
W831
W851
W871
W891
W911
W931
W951
W971
W991
W1011
W1031
W1051
Physical Examination2
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy Testing3
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital Sign Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Myozyme Infusion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Immunophenotyping 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Lymphocyte Subpopulation 
Counts 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Functional T cell Assay 
(ELISPOT) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Immunoglobulin Panel 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CBC with Differential 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Chemistry, CK and CK-MB 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Anti-rhGAA Antibody (IgG) 
Titers/Inhibitory Antibody 
Monitoring4
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ECG 
 
 
 
 
 
X
X
 
 
 
 
 
 
 
 
 
 
ECHO 
 
 
 
 
 
X
X
 
 
 
 
 
 
 
 
 
 
Pompe PEDI 
 
 
 
 
 
X
X
 
 
 
 
 
 
 
 
 
 
GMFM-66 
 
 
 
 
 
X
X
 
 
 
 
 
 
 
 
 
 
AIMS 
 
 
 
 
 
X
X
 
 
 
 
 
 
 
 
 
 
 
GENZYME CORPORATION 
 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
 
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Myozyme® (alglucosidase alfa) 
 
222 
Clinical Protocol Number AGLU03707, Amendment 3 
 
 
Additional Study Visits: Weeks 77 Through 105 (continued) 
 
W771
W791
W811
W831
W851
W871
W891
W911
W931
W951
W971
W991
W1011
W1031
W1051
Ventilator Use Monitoring 
Continuous Monitoring 
Concomitant Medication 
Monitoring 
Continuous Monitoring 
Concomitant Therapy 
Monitoring 
Continuous Monitoring 
Adverse Event Monitoring 
Continuous Monitoring 
1 A visit window of ±2 weeks will be permitted for all additional study visits.  For Myozyme infusions, the visit window is ±1 week. 
2 In addition to the scheduled physical examinations, brief, physical assessments should also be performed prior to the administration of any study medications (Myozyme) to ensure that the patient is 
clinically stable and can tolerate administration of these agents. 
3 Pregnancy testing will be performed monthly for female patients of childbearing potential, and patients with positive test results will be withdrawn from the study. 
4 If a patient becomes anti-rhGAA (IgG) positive during the course of the study, he/she will also be tested every 2 months for the presence of inhibitory antibodies to Myozyme. 
Note:  Appendix 14.6 provides a Schedule of Assessments for those patients who were <2 years of age at their W75 study visit and thus are required to continue following the protocol until they reach 
their second birthday (i.e., reach 2 years of age), at which time all EOS assessments should be performed for study completion.  See Table 9-3 for further details. 
Key:  AIMS=Alberta Infantile Motor Scale; CBC=complete blood count; CK=creatine kinase; CK-MB=creatine kinase – myocardial band; ECG=electrocardiogram; ECHO; echocardiogram; 
ELISPOT=enzyme-linked immunosorbent spot [assay]; EOS=End-of-Study; GMFM-66=Gross Motor Function Measure-66; IgG=immunoglobulin G; IVIG=intravenous immunoglobulin; 
PEDI=Pediatric Evaluation and Disability Inventory; rhGAA=Recombinant human acid α-glucosidase; W=week 
 
 
GENZYME CORPORATION 
 
FINAL: 01 OCTOBER 2009 
PROPRIETARY AND CONFIDENTIAL 
Page 222