Specified Drug-use Survey of Fomepizole Intravenous Infusion "Takeda" (All-case Surveillance)
Conditions: Ethylene Glycol Poisoning, Methanol Poisoning
Sponsor: Takeda

Clinical Study Protocol 
NCT Number: NCT02415712 
Title: Drug Use Surveillance of Fomepizole Intravenous Infusion "Takeda" (All-Case 
Surveillance) 
Study Number: Fomepizole-5001 
Document Version and Date: Version 6 / 27-Sep-2022 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
 
 
 
 
DRUG USE SURVEILLANCE PROTOCOL 
Drug Use Surveillance of Fomepizole Intravenous 
Infusion “Takeda” 
(All-Case Surveillance) 
 
 
 
 
 
 
 
 
Sponsor  
Takeda Pharmaceutical Company Limited 
Protocol Number 
Fomepizole- 5001 
Version Number 
Version 6 
Prepared on 
27 September 2022 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

 
TABLE OF CONTENTS 
1.0 
BACKGROUND .......................................................................................................................................... 1 
2.0 
OBJECTIVES ............................................................................................................................................... 1 
3.0 
PLANNED SAMPLE SIZE AND RATIONALE ......................................................................................... 1 
3.1 
Planned Sample Size ............................................................................................................................... 1 
3.2 
Rationale .................................................................................................................................................. 1 
4.0 
SURVEILLANCE POPULATION ............................................................................................................... 1 
5.0 
DOSAGE AND ADMINISTRATION .......................................................................................................... 1 
6.0 
PLANNED NUMBER OF SURVEILLANCE SITES BY DEPARTMENT ................................................ 2 
7.0 
METHODS ................................................................................................................................................... 2 
7.1 
Observation Period .................................................................................................................................. 2 
7.2 
Patient Enrollment Method...................................................................................................................... 2 
7.3 
Surveillance Site Recruitment and Contracting ....................................................................................... 2 
7.4 
Completion and Submission of Case Report Forms ................................................................................ 2 
7.5 
Actions To Be Taken In Response To Serious Adverse Events ............................................................... 3 
8.0 
PLANNED DURATION OF SURVEILLANCE .......................................................................................... 3 
9.0 
SURVEILLANCE DATA ELEMENTS ........................................................................................................ 3 
9.1 
Contact Form Data Elements ................................................................................................................... 3 
9.2 
Case Report Form Data Elements ........................................................................................................... 3 
9.2.1 
Case Report Form Cover Sheet .......................................................................................................... 3 
9.2.2 
Patient Demographics and Baseline Characteristics .......................................................................... 3 
9.2.3 
Treatment Details ............................................................................................................................... 4 
9.2.4 
Tests and Observations ....................................................................................................................... 4 
9.2.5 
Adverse Events ................................................................................................................................... 5 
10.0 
ANALYSES AND METHODS .................................................................................................................... 7 
10.1 
Patient Disposition .................................................................................................................................. 7 
10.2 
Patient Demographics and Baseline Characteristics................................................................................ 7 
10.3 
Treatment Details .................................................................................................................................... 7 
10.4 
Safety ....................................................................................................................................................... 8 
10.4.1 
Adverse Event Incidence Data ........................................................................................................... 8 
10.4.2 
Factors Potentially Affecting Safety ................................................................................................... 8 
10.5 
Efficacy ................................................................................................................................................... 8 
10.5.1 
Time Course of Arterial Blood pH ..................................................................................................... 8 
10.5.2 
Time Course of Poisoning/Toxicity Test Parameters .......................................................................... 8 
10.5.3 
Time Course of Toxic Symptoms ....................................................................................................... 8 
10.5.4 
Outcomes ............................................................................................................................................ 8 
10.5.5 
Factors Potentially Affecting Efficacy................................................................................................ 9 
11.0 
REGISTRATION OF SURVEILLANCE INFORMATION ......................................................................... 9 
12.0 
SURVEILLANCE ADMINISTRATIVE STRUCTURE .............................................................................. 9 
12.1 
Administrative Structure for Postmarketing Surveillance and Other Related Tasks ............................... 9 
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13.0 
MEDICAL ADVISOR .................................................................................................................................. 9 
14.0 
CENTRAL ENROLLMENT CENTER ........................................................................................................ 9 
15.0 
CONTRACT RESEARCH ORGANIZATIONS .......................................................................................... 9 
16.0 
OTHER NECESSARY INFORMATION ................................................................................................... 10 
16.1 
Protocol Amendments ........................................................................................................................... 10 
16.2 
Handling of Any Issues or Uncertainties ............................................................................................... 10 
 
Appendix Schedule of Assessments ......................................................................................................................... 10 
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1 
1.0 
BACKGROUND 
To date, there have been no clinical studies of fomepizole intravenous infusion (brand name: 
“Takeda”; herein “fomepizole IV”) in Japan,  
and there are virtually no reports in the literature or elsewhere on the use of fomepizole IV in 
Japanese individuals. As such, there is a need to evaluate the safety and efficacy of fomepizole 
IV used by Japanese individuals in clinical practice. 
The Drug Use Surveillance described in this Protocol (herein “the Surveillance” or “the DUS”) 
was therefore planned to evaluate the safety and efficacy of fomepizole IV when used in clinical 
practice to treat patients with ethylene glycol and methanol poisoning. The DUS will be 
conducted in compliance with Japan’s Ministerial Ordinance on Good Postmarketing Study 
Practice (GPSP) and other relevant regulatory requirements. 
 
2.0 
OBJECTIVES 
To evaluate the safety and efficacy of fomepizole IV when used in clinical practice to treat 
Japanese patients with ethylene glycol and methanol poisoning. 
 
3.0 
PLANNED SAMPLE SIZE AND RATIONALE 
3.1 Planned Sample Size 
All patients confirmed to have received fomepizole IV during the 7 years since it was first 
marketed in Japan 
 
3.2 Rationale 
The planned sample size was selected to enable the submission of DUS results within the 
specified period following the end of the reexamination period. 
 
4.0 
SURVEILLANCE POPULATION 
The DUS will target all patients confirmed to have received fomepizole IV. 
 
5.0 
DOSAGE AND ADMINISTRATION 
The standard dosage will consist of an initial dose of 15 mg/kg, second through fifth doses of 
10 mg/kg, and sixth and subsequent doses of 15 mg/kg fomepizole IV to be administered 
every 12 hours by IV infusion over a period of at least 30 minutes. 
When administered in combination with hemodialysis, fomepizole IV will be given as 
follows. 
At start of 
dialysis 
 
If less than 6 hours have elapsed since the previous infusion, do not administer 
fomepizole IV immediately before starting dialysis. 
If 6 or more hours have elapsed since the previous infusion, administer 
fomepizole IV immediately before starting dialysis. 
During 
dialysis 
Administer fomepizole IV every 4 hours after starting dialysis. 
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At end of 
dialysis 
 
If less than 1 hour has elapsed since the previous infusion, do not administer 
fomepizole IV at the end of dialysis. 
If between 1 and 3 hours have elapsed since the previous infusion, administer 
fomepizole IV at 50% of the standard dose at the end of dialysis. 
If more than 3 hours have elapsed since the previous infusion, administer 
fomepizole IV immediately after the end of dialysis. 
After end 
of dialysis 
 
Administer fomepizole IV every 12 hours after the previous infusion. 
 
 
6.0 
PLANNED NUMBER OF SURVEILLANCE SITES BY DEPARTMENT 
All sites where fomepizole IV is administered 
 
7.0 
METHODS 
7.1 Observation Period 
From the start of treatment with fomepizole IV until hospital discharge (or until transfer to 
another department) 
 
7.2 Patient Enrollment Method 
Patients will be enrolled retrospectively using a central enrollment procedure and transmitted 
via fax. Specifically, the surveillance site investigator (herein “the investigator”) will fill out the 
enrollment details of patients treated with fomepizole IV on the “Contact Form” enclosed in the 
drug product packaging (see section 9.1) and will then send the completed form by fax to the 
Central Enrollment Center (see section 12.3). 
 
7.3 Surveillance Site Recruitment and Contracting 
The DUS will be conducted using paper-based Case Report Forms (CRFs). A representative of 
Takeda Pharmaceutical Company Limited (herein “Takeda representative”) will contact medical 
institutions where fomepizole IV has definitely or potentially been administered, and will 
explain the objectives and details of the DUS using the “Request to Participate in Drug Use 
Surveillance,” “Outline of the Drug Use Surveillance” and “Sample Case Report Form.” The 
medical institutions that agree to participate in the DUS (i.e., the surveillance sites) will sign a 
written agreement, and the investigators will be requested to perform the required surveillance 
tasks within the specified surveillance period. 
 
7.4 Completion and Submission of Case Report Forms 
The investigators will fill out a CRF for each enrolled patient and will submit the completed 
CRFs to Takeda Pharmaceutical within approximately 1 month of the end of the observation 
period. 
 
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7.5 Actions To Be Taken In Response To Serious Adverse Events 
If a serious adverse event (SAE) occurs, the investigator will immediately notify the Takeda 
representative. The investigator will also provide additional details of the SAE if requested by 
the Takeda representative. 
 
8.0 
PLANNED DURATION OF SURVEILLANCE 
Surveillance period: From the start of fomepizole IV marketing in Japan until 30 June 2022 
Patient enrollment period: From the start of fomepizole IV marketing in Japan until 31 January 
2022N.B.) 
N.B.) Patients will not be enrolled (i.e., Contact Forms sent via fax will not be accepted) from 1 
February 2022 onwards even if they had received fomepizole IV on or before 31 January 
2022. 
 
9.0 
SURVEILLANCE DATA ELEMENTS 
The investigator will fill out the following surveillance information (herein “data elements”) on 
the Contact Form and CRF. The DUS schedule is presented in the Appendix. 
9.1 Contact Form Data Elements 
1) Surveillance data elements 
Name of surveillance site, name of investigator filling out the Contact Form, contact details, 
reason for using fomepizole IV, start date of fomepizole IV treatment, patient identification 
(ID) number, patient initials, sex, age (at start of fomepizole IV treatment) 
2) Surveillance timing 
At patient enrollment 
 
9.2 Case Report Form Data Elements 
9.2.1 Case Report Form Cover Sheet 
Date of last CRF entry, name of investigator filling out the CRF 
 
9.2.2 Patient Demographics and Baseline Characteristics 
1) Surveillance data elements 
Diagnosis, hypersensitivity factors (Y/N, details), concurrent (coexisting) disease*1 (Y/N, 
details), previous medical history (Y/N, details), height, body weight, alcohol consumption 
(Y/N; at time of poisoning), pregnancy (Y/N; females only)*2, level of consciousness, 
circumstances of poisoning (ingested substance and amount, time and date ingested, route 
of ingestion, reason ingested) 
*1 Disease/s the patient has at the start of fomepizole IV treatment 
*2 The Takeda representative must be notified immediately if a patient is found to be 
pregnant. Pursuant to a request by the Takeda representative, the investigator will 
submit detailed information on the pregnancy using the Pregnancy Form (including, 
where feasible, details on the outcome of the pregnancy such as premature delivery). 
2) Surveillance timing 
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At the start of treatment with fomepizole IV 
However, the diagnosis should be recorded in the CRF during the observation period. 
 
9.2.3 Treatment Details 
1) Surveillance data elements 
Administration of fomepizole IV (number of infusions, dose per infusion, infusion dose 
per body weight, treatment duration, and reason for discontinuing fomepizole IV 
treatment), interventions/procedures (other than pharmacotherapy) (Y/N, details), 
administration of medications (other than fomepizole IV) (Y/N, drug name/s and reason/s 
for use) 
2) Surveillance timing 
The period from the start to the end of treatment with fomepizole IV (herein “fomepizole 
IV treatment period”) 
However, surveillance of the data elements ‘interventions/procedures (other than 
pharmacotherapy)’ and ‘administration of medications (other than fomepizole IV)’ will be 
performed from the time of poisoning until completion of the final fomepizole IV infusion. 
 
9.2.4 Tests and Observations 
9.2.4.1 
Vital Signs 
1) Tests and observations 
Pulse rate, blood pressure (systolic/diastolic), respiratory rate, body temperature 
2) Surveillance timing 
Test timepoints at the start of fomepizole IV dosing, 0.5 hr post-infusion, 4 hr post-
infusion, 8 hr post-infusion, 12 hr post-infusion, 16 hr post-infusion, 20 hr post-
infusion, 24 hr post-infusion, every 12 hours from >24 hr post-infusion, at completion 
of final infusion, 12 hr after completion of final infusion, 24 hr after completion of 
final infusion 
 
9.2.4.2 
Laboratory Tests 
1) Tests 
RBC count, WBC count, platelet count, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl transpeptidase (gamma-GTP), serum 
creatinine, BUN 
2) Surveillance timing 
Test timepoints at the start of fomepizole IV dosing, 0.5 hr post-infusion, 4 hr post-
infusion, 8 hr post-infusion, 12 hr post-infusion, 16 hr post-infusion, 20 hr post-
infusion, 24 hr post-infusion, every 12 hours from >24 hr post-infusion, at completion 
of final infusion, 12 hr after completion of final infusion, 24 hr after completion of 
final infusion 
 
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9.2.4.3 
Poisoning/Toxicity Tests 
1) Tests and observations 
· 
Arterial blood gas analyses 
Arterial blood pH, arterial partial pressure of carbon dioxide (PaCO2), arterial 
partial pressure of oxygen (PaO2) 
, bicarbonate ion, base excess (BE) 
· 
Anion gap 
· 
Blood ethylene glycol concentration 
· 
Blood glycolic acid concentration 
· 
Blood methanol concentration 
· 
Blood formic acid concentration 
· 
Osmotic pressure gap 
2) Surveillance timing 
Test timepoints at the start of fomepizole IV dosing, 0.5 hr post-infusion, 4 hr post-
infusion, 8 hr post-infusion, 12 hr post-infusion, 16 hr post-infusion, 20 hr post-
infusion, 24 hr post-infusion, every 12 hours from >24 hr post-infusion, at completion 
of final infusion, 12 hr after completion of final infusion, 24 hr after completion of 
final infusion 
 
9.2.4.4 
Toxic Symptoms 
1) Observations 
Presence or absence (Y/N) of toxic symptoms 
2) Surveillance timing 
At the start and at the end of treatment with fomepizole IV 
 
9.2.4.5 
Outcomes 
1) Observations 
Outcome and sequelae details 
2) Surveillance timing 
At hospital discharge (or transfer to another department) 
 
9.2.5 Adverse Events 
1) Surveillance data elements 
Presence or absence (Y/N) of adverse event (herein “AE”; see Table 1), AE term, date of 
onset, seriousness and reason for assessment as serious (see Table 2), reason for 
discontinuing fomepizole IV, date of outcome assessment, outcome, causal relationship 
with fomepizole IV* (see Table 3) 
If the AE outcome is “not recovered/not resolved” or “unknown” or the causal 
relationship is deemed “not evaluable,” the patient should be followed to the extent 
possible. 
* If the causal relationship with fomepizole IV is deemed ‘not related,’ the investigator shall record the 
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rationale for this assessment. Alternatively, if the causal relationship is deemed ‘not evaluable,’ the 
investigator shall provide the reason for this assessment. 
N.B.) Points to consider when assessing AEs: 
Although abnormal worsening of the target disease (e.g., worsening beyond the expected natural 
course of the disease) should be assessed as an AE, any expected worsening of the target disease 
should not be assessed as an AE. 
2) Surveillance timing 
The period from the start of fomepizole IV dosing until 24 hours after completion of the 
final infusion 
 
Table 1 Definition of Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product during the course of a clinical investigation, and that does not necessarily have 
a clear causal relationship with this pharmaceutical product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a pharmaceutical product, whether 
or not considered related to the pharmaceutical product. 
The following events are also handled as AEs: 
· 
Signs and symptoms appearing in breastfed infants of female patients receiving the 
pharmaceutical product 
· 
Signs and symptoms appearing in children receiving the pharmaceutical product 
· 
Signs and symptoms appearing as a result of occupational exposure to the pharmaceutical product 
· 
Signs and symptoms appearing after administration of a counterfeit of a pharmaceutical product 
manufactured and marketed by Takeda Pharmaceutical 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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interventions/procedures (other than pharmacotherapy), administration of medications (i.e., 
drugs other than fomepizole IV) and other relevant variables. 
 
10.4 Safety 
The following data will be tabulated in the Safety Analysis Set. AEs will be summarized by 
Preferred Term (PT) and System Organ Class (SOC) using the Japanese translation of Medical 
Dictionary for Regulatory Activities (MedDRA/J). 
10.4.1 Adverse Event Incidence Data 
AE incidences will be tabulated by category, time of onset, seriousness, causal relationship 
with fomepizole IV and other relevant variables. 
 
10.4.2 Factors Potentially Affecting Safety 
AE incidences will be tabulated by patient demographics and baseline characteristics (e.g., 
sex, age, alcohol consumption [Y/N]), treatment details (administration of fomepizole IV, 
interventions/procedures [other than pharmacotherapy], administration of medications [other 
than fomepizole IV]) and presence/absence (Y/N) of toxic symptoms. 
 
10.5 Efficacy 
The following data will be tabulated in the Efficacy Analysis Set. 
10.5.1 Time Course of Arterial Blood pH 
Summary statistics will be calculated for arterial blood pH test values and for absolute 
change from baseline at each assessment timepoint (i.e., the test value at each assessment 
timepoint after the start of fomepizole IV dosing minus the baseline test value at the start of 
fomepizole IV dosing). 
 
10.5.2 Time Course of Poisoning/Toxicity Test Parameters 
Summary statistics will be calculated for each poisoning/toxicity test value at each 
assessment timepoint; specifically PaCO2, PaO2, bicarbonate ion, BE, anion gap, blood 
ethylene glycol concentration, blood glycolic acid concentration, blood methanol 
concentration, blood formic acid concentration and osmotic pressure gap. 
 
10.5.3 Time Course of Toxic Symptoms 
The numbers of patients with and without toxic symptoms at the start of fomepizole IV 
treatment (i.e., at baseline) and at completion of the final fomepizole IV infusion and the 
proportions of these patient subsets relative to the Efficacy Analysis Set will be tabulated. 
Presence or absence of toxic symptoms at baseline will also be cross-tabulated against those 
at completion of the final fomepizole IV infusion. 
 
10.5.4 Outcomes 
The numbers of patients with each outcome at hospital discharge (or at transfer to another 
department) and the proportions of these patient subsets relative to the Efficacy Analysis 
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Set will be calculated, and the details of any sequelae will be described. 
 
10.5.5 Factors Potentially Affecting Efficacy 
Summary statistics for time course of arterial blood pH will be calculated by patient 
demographics and baseline characteristics (e.g., sex, age, alcohol consumption [Y/N]), 
treatment details (administration of fomepizole IV, interventions/procedures [other than 
pharmacotherapy], administration of medication [other than fomepizole IV]) and 
presence/absence (Y/N) of toxic symptoms. 
 
11.0 
REGISTRATION OF SURVEILLANCE INFORMATION 
Takeda Pharmaceutical Company Limited will register information about this DUS on the 
following publicly-accessible websites prior to commencing the surveillance. 
· 
Japic Clinical Trials Information website, Japan Pharmaceutical Information Center (JAPIC):  
Japan Pharmaceutical Information Center-Clinical Trials Information 
· 
ClinicalTrials.gov clinical trials registry, U.S. National Institutes of Health (NIH): ClinicalTrials.gov 
 
12.0 
SURVEILLANCE ADMINISTRATIVE STRUCTURE 
12.1 Administrative Structure for Postmarketing Surveillance and Other Related Tasks 
See the attached document. 
 
13.0 
MEDICAL ADVISOR 
Advises on the preparation and revision of the Protocol and other documents pertaining to this 
DUS. 
Also advises on various medical decisions pertaining to the conduct of this DUS. 
 
 
14.0 
CENTRAL ENROLLMENT CENTER 
EPS Corporation 
 
 
15.0 
CONTRACT RESEARCH ORGANIZATIONS 
(1) 
PRA Health Sciences Co., Ltd. 
Address: 4-1-3 Kyutaro-machi , Chuo-ku, Osaka City  
Contracted operations: Data management operations, archiving and storage of records, 
postmarketing surveillance support operations 
 
(2) 
EPS Corporation 
Address: 2-23 Shimomiyabi-cho, Shinjuku-ku, Tokyo 
Contracted operations: Data management operations, statistical analyses, medical writing 
 
(3) 
PharField Corporation 
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Address: 2-8-20 Saga, Koto-ku, Tokyo 
Contracted operations: Monitoring operations 
 
(4) 
WysiWyg Co., Ltd. 
Address: 2-21-2 Hatchobori, Chuo-ku, Tokyo 
Contracted operations: Medical writing 
 
16.0 
OTHER NECESSARY INFORMATION 
16.1 Protocol Amendments 
The DUS Protocol will be revised and amended during the surveillance period where necessary 
based on information obtained in relation to the study progress, the onset of ADRs or serious 
ADRs that were not expected based on the PRECAUTIONS section of the Japanese Package 
Insert, any increases in the frequency of known ADRs, and the appropriateness of the 
surveillance data elements, etc. The Protocol will also be amended as required during the 
surveillance period where deemed necessary in response to a partial change in the approved 
Dosage and Administration and/or Indications specified in the marketing authorization, etc. 
 
16.2 Handling of Any Issues or Uncertainties 
If any safety or efficacy issues are identified, measures to address these issues shall be 
investigated based on careful scrutiny of the available data. 
 
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Document History 
 
Version 
Date 
Comments 
original version 
2014/12/22 
New document 
2nd version 
2015/4/1 
Additions and clarifications concerning the contracted operations 
of CROs 
3rd version 
2017/6/2 
Clarifications and changes & additions to the CROs 
4th version 
2021/1/26 
Clarifications and changes & additions to the CROs 
5th version 
2022/4/28 
The appended Administrative Structure for Postmarketing 
Surveillance Operations chart 
6th version 
2022/9/27 
Changes & additions to the CROs and additions to the CRO 
contracted operations 
 
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