Pharmaceutical Interview Form: One Name

Translated from Japanese to English - www.onlinedoctranslator.
com
Revised April 2021 (12th edition) Japanese standard product classification number 873969
Pharmaceutical interview form

IF description procedure of Japan Hospital Pharmacist Association 2018 (2019 update version) Created according to
Persistent Selective DPP-4 Inhibitor-Therapeutic Agent for Type 2 Diabetes-
Toleragliptin succinate tablets
100mg: Film-coated lock with double-sided

Agent shape score line 50mg: Film-coated lock
25mg: Film coated lock
Regulations for manufacturing agents Prescription drugs (Caution-Use according to the prescription of a doctor, etc.)
Compass Case ・ Including amount Contains 100mg, 50mg and 25mg of toleragliptin in 1 tablet
Japanese name: Toleragliptin succinate (JAN)

one General Name
Western name: Trelagliptin Succinate (JAN)
100mg, 50mg 25mg
Manufacture, sale, approval

Manufacturing and marketing approval date March 26, 2015 August 21, 2019
date, drug price standard listing,
Sales start date NHI drug price standard listing date May 20, 2015 November 27, 2019
Sales start date May 28, 2015 December 3, 2019
Manufacture, sale (import),

Manufacturer: Takeda Pharmaceutical Company Limited
Proposal / sales company name
Contact information for medical representatives
Takeda Pharmaceutical Company Limited Medicine Counseling Room
Inquiry window mouth Toll free number 0120-566-587

Reception hours 9:00 to 17:30 (Saturdays, Sundays, and holidays, excluding our holidays)
This IF was prepared based on the description in the package insert revised in April 2020.
For the latest information, please check the drug information search page of Pharmaceuticals and Medical Devices Agency.
Since this drug was partially evaluated and approved based on clinical studies including non-domestic approved dosages and doses, the test results
including some non-domestic approved dosages and doses are listed. However, they do not recommend off-label use.
Outline of Guide for Using Pharmaceutical Interview Form-Japan Hospital Pharmacist Association-
(Revised in April 2020)
1. 1. Background of creating the drug interview form
As basic summary information of ethical drugs, there is a ethical drug package insert (hereinafter referred to as “package insert”). When medical
professionals such as doctors and pharmacists utilize information on the proper use of medicines necessary for daily work in the medical field, more
detailed information supporting the information contained in the package insert may be required. Information has been supplemented by requesting
additional information from pharmaceutical information personnel (hereinafter referred to as MR) of pharmaceutical companies and asking questions. At
this time, the drug interview form (hereinafter abbreviated as IF) was born as an item list to comprehensively obtain the necessary information.
In 1988, the 2nd Academic Subcommittee of the Japan Hospital Pharmacy Association (hereinafter referred to as "Nichiyaku") formulated the
position of IF, the IF description format, and the IF description procedure. , 2008 and 2013, the Japan Disease Drugs and Pharmaceuticals
Information Committee revised the IF description guidelines.
IF description procedure Since 2008, it has become a principle to provide IF as electronic data such as PDF. As a result, if
there is a major revision of the package insert, an IF with additional data on the basis of the revision will be provided
promptly. The latest version of IF is available on the Pharmaceuticals and Medical Devices Agency (PMDA) Medical Drug
Information Search page (http://www.pmda.go.jp/PmdaSearch/iyakuSearch/). Since 2009, Nikkei Yakuhin has established the
"Interview Form Study Group" as an organization to examine IF information for new drugs, and examines and examines
whether each IF is appropriate as appropriate usage information to supplement the package insert. There is.
In line with the change in the package insert description procedure in 2019, the IF description procedure 2018 has been announced, and an updated
version has been formulated to prepare information related to the "Guidelines for Sales Information Provision Activities for Prescription Drugs".
2. What is IF
IF is "Supplementary information such as package inserts, information for quality control of medicines, information for prescription design,
information for dispensing, which are necessary for medical staff such as doctors and pharmacists in daily work. As a comprehensive individual
drug manual that summarizes information for proper use of drugs, information for pharmaceutical patient care, etc., Nikkei Yakuhin has
formulated the description procedure for pharmacists, etc. It is positioned as "academic material that is requested to be produced and provided
by companies involved in the manufacture, sale or sale of
The item arrangement described in the IF conforms to the IF description procedure established by Nikkei Yakuhin, and with some
exceptions, information within the scope of approval is described. However, matters related to the confidentiality of pharmaceutical companies
and matters that users should evaluate, judge, and provide themselves are not included in the IF. In other words, the IF provided by a
pharmaceutical company is premised on the user's own evaluation, judgment, clinical application, and recognition that it provides the necessary
complement.
The provision of IF is based on electronic data, and bookbinding by pharmaceutical companies is not essential.
3. 3. When using IF
The location of the electronic IF is set on the PMDA's ethical drug information retrieval page. Pharmaceutical companies create and
provide IFs in accordance with the “Guide for Creating Pharmaceutical Interview Forms”, but based on the origin of IFs, for
information that is lacking in the medical field or information that is difficult to describe when creating IFs, MRs of pharmaceutical
companies, etc. It is necessary for the users themselves to enhance the content and improve the usability of IF through interviews with.
In addition, regarding matters related to precautions for use that are revised from time to time, until the IF is revised, documents that
clarify the revised contents provided by pharmaceutical companies, or various drug information provision services, etc. In addition to
being prepared by pharmacists themselves, it is necessary to check the latest package insert on the PMDA's Pharmaceuticals and
Medical Devices Information Search page before using IF.
In addition, "V.5. Clinical results" and "XII. Reference materials", which are described from the viewpoint of proper use and ensuring safety, "XIII.
Items related to "Remarks" may contain information that has not been approved, and you should be careful in
handling it.
Four. Points to keep in mind when using
I would like you to utilize IF as an indispensable source of drug information in your daily work. IF is positioned as an
academic material for the proper use of drugs, which is created and provided by companies involved in the manufacture,
sale or sale of the drug in response to a request from Nikkei Yakuhin, but the description and expression are based on the
Pharmaceutical Machinery Law. There are some restrictions such as advertising rules, guidelines for sales information
provision activities for ethical drugs, and the Code of Practice of Pharmaceutical Cooperatives. According to the sales
information provision activity guidelines, it is permissible for pharmaceutical companies to provide information on
unapproved drugs and unapproved usage, etc., in response to requests from healthcare professionals. It is necessary to
recognize that the contents of IF should be enhanced by the users themselves through the literature search of. It is the
pharmacist's duty to confirm the scientific basis of the information obtained from pharmaceutical companies, identify its
objectivity, and ensure proper use in the medical field, and utilize IF to make daily work even more valuable. I want you.
eye Next
I. Items related to the overview

1. 1. Development history 2. Therapeutic properties of the product 1
3. Pharmaceutical properties of the product 4. Characteristics that should be 1
known regarding proper use 5. Approval conditions and restrictions on distribution 1
and use 1
(1) Approval conditions (2) For distribution and use Restrictions on 2

6. Overview of RMP 2
2
II. Items related to names

1. 1. Brand name
(1) Japanese name 3

(2) Western name 3
(3) Origin of the name 3
2. common name
(1) Japanese name (nomenclature) (2) Western name (Nomenclature) 3

(3) Stem 3. Structural formula or demonstrative formula 4. 3
Molecular formula and molecular weight 5. Chemical name (nomenclature) or 3
essence 6. Trivial names, aliases, abbreviations, symbol numbers 3
3
3
3
III. Items related to active ingredients

1. 1. Physicochemical properties
(1) Appearance / properties Four

(2) Solubility Four
(3) Hygroscopicity Four
(4) Melting point (decomposition point), boiling point, freezing point Four
(5) Acid-base dissociation constant (6) Partition coefficient Four
(7) Other main index values 2. Stability of the active ingredient under various Four
conditions 3. Confirmation test method and quantitative method for active Four
ingredients Four
Five
Ⅳ. Items related to pharmaceutical products
1. 1. Dosage form
(1) Distinction of dosage form (2) Appearance of the formulation And properties 6
6
(3) Identification code 6
(4) Physical characteristics of the product 6
(5) Others 2. Composition of pharmaceutical product 6
(1) Content of active ingredient (active ingredient) and additives (2) Concentration of 6
electrolyte, etc. (3) Calorie 7
7
3. 3. Composition and volume of the attached solution 4. Titer 7
5. Contamination that may be mixed in 6. Stability of the product under various 7
conditions 7. Preparation method and stability after dissolution 8. 7
Combination change with other agents (physicochemical change) 9. Dissolution 7
10. Container / packaging 9
9
9
(1) Information on containers / packaging that requires attention and containers / packaging with Ten
a special appearance (2) Packaging (3) Reserve capacity Ten
(4) Container material 11. Materials provided separately Ten
12. Others Ten
Ten
Ten
V. Items related to treatment

1. 1. Efficacy or effect 11 2. Precautions related to efficacy or effect
11 3. Dosage and administration
(1) Explanation of usage and dosage 11 (2) Setting of usage and dosage
Background / Grounds 11 4. Precautions related to usage and dosage
12 5. Clinical results
(1) Clinical data package 14 (2) Clinical pharmacology study 15

(3) Dose-response search test 17 (4) Verification test 18 (5)
Patient / pathological examination 33 (6) Therapeutic use

33 (7)
Others 33
VI. Items related to medicinal pharmacology
1. 1. Pharmacologically related compounds or groups of compounds 34 2. Pharmacological

action
(1) Site of action / mechanism of action 34 (2) Test results supporting drug efficacy
34 41
(3) Onset time / duration of action
VII. Items related to pharmacokinetics

1. 1. Changes in blood concentration
(1) Therapeutically effective blood concentration 42 (2) Confirmed in clinical trials

Blood concentration 42 (3)
Poisoning area 44 (4) Meals and concomitant medications Impact
44 2. Drug kinetic parameters
(1) Analysis method 46 (2) Absorption rate constant

46 46 46
(3) Disappearance rate constant
(4) Clearance
(5) Volume of distribution 46 (6)
Others ................ 46 3. Population analysis
(1) Analysis method 46 (2)

Parameter fluctuation factors 46 4. Absorption 47 5.
distribution
(1) Blood-brain barrier crossing 47 (2) Blood-placental barrier Passability

47 48 48
(3) Transferability to milk
(4) Translocation to cerebrospinal fluid
(5) Migration to other organizations 49

(6) Plasma protein binding rate 50 6. metabolism
(1) Metabolic site and metabolic pathway 50 (2) Enzymes involved in metabolism (2)
CYP, etc.) molecular species, contribution rate 50 (3)
Presence / absence of first pass effect and its ratio 51 (4)
Presence / absence of activity of metabolites, activity ratio, abundance ratio 51 7.
Excretion 51 8. Information about transporters 51 9. Removal
rate by dialysis, etc. 52 10. Patients with a specific background 52
11. Others 53
VIII. Items related to safety (precautions for use, etc.)

1. 1. Warning content and its reason 54 2. Contraindications and their reasons
54 3. Precautions and reasons related to efficacy or effect 54 4. Precautions related to
usage and dosage and their reasons 54 5. Important basic precautions and their reasons
55 6. Precautions regarding patients with specific backgrounds
(1) Patients with complications / medical history 56 56 56

(2) Patients with renal dysfunction
(3) Patients with hepatic dysfunction
(4) Those who have fertility 56

(5) Pregnant women 57 (6) Lactating women
57 57 57
(7) Children, etc.
(8) Elderly people
7. 7. Interaction
(1) Contraindications for combined use and their reasons 59 59

(2) Precautions for combined use and the reason
8. 8. Side effects
(1) Serious side effects and initial symptoms 61

(2) Other side effects 63 9. Effect on clinical test results 65 10.
Overdose 66 11. Precautions for application 66
12. Other notes
(1) Information based on clinical use 66 (2) Information based on non-clinical studies
66
IX. Items related to non-clinical trials

1. 1. Pharmacological test
(1) Pharmacological drug efficacy test 67 (2) Safety pharmacological test

67 (3) Other pharmacological tests
67
2. Toxicity test
(1) Single-dose toxicity test 67 68

(2) Repeated dose toxicity test
(3) Genotoxicity test 69 69

(4) Carcinogenicity test
(5) Reproductive developmental toxicity test 69

(6) Topical irritation test 69 (7) Other special toxicity 69
X. Items related to management matters

1. 1. Regulation classification 70 2. Validity period 70 3.
Storage method in the packaged state 70 4. Handling Precautions
70 5. Materials for patients 70 6. Same ingredient / same effect drug
70 7. International Birth Date 70 8. Manufacturing and marketing approval date and
approval number, drug price standard listing date, sales start date 70 9. Date and details of
indication, addition of effect, addition of dosage and administration, etc. 71 10. Reexamination
result, date of publication of reevaluation result and its contents 71 11. Reexamination
period 71 12. Information on dosing period restrictions 71 13.
Various codes 71 14. Precautions for insurance benefits 71
Ⅺ. Literature
1. 1. References 72 2. Other references 72
Ⅻ. Reference material
1. 1. Sales status in major foreign countries 73 2. Overseas clinical support information

73
XIII. remarks
1. 1. Reference information for making clinical decisions regarding dispensing and medication support 74
(1) Crushing 74 (2) Disintegration / suspension And the passability of the tube
administration tube 75 2. Other related materials 77
I. Items related to the overview
1. 1. Development history
Toleragliptin succinate is a dipeptidyl peptidase-4 (DPP-4) inhibitor created by Takeda California,

Inc. and is a glucagon-like peptide-1 (GLP-1). Blood glucose dependence through increased concentration
It is a type 2 diabetes treatment drug that has an insulin secretagogue action. It was confirmed in domestic clinical results that the DPP-4 inhibitory activity
was sustained for 1 week by administration of this drug, and good medication adherence can be expected by reducing the number of doses taken by
administration once a week.
This drug (100 mg tablet and 50 mg tablet) includes a non-inferiority study with Nessina tablets (alogliptin benzoate) conducted in
patients with type 2 diabetes who have insufficient glycemic control even after dietary and exercise therapy. The efficacy and safety of
each type of clinical trial were examined, and in March 2015, manufacturing and marketing approval was obtained for the indication of
"type 2 diabetes".
In August 2019, we obtained manufacturing and marketing approval for Zafatec 25 mg tablets.
2. Therapeutic properties of the product
(1) The world's first oral hypoglycemic drug administered once a week. (2) It
showed an excellent hypoglycemic effect when administered once a week.
(""V.5. (3) Dose-response search test"as well as"V.5. (4) Verification testSee section)
(3) It showed strong DPP-4 inhibitory activity when administered once a week.
(""VI.2. (2) Tests to support drug efficacy 1) and 2) ”)

(4) Hypoglycemia, pemphigoid, acute pancreatitis, and intestinal obstruction may occur as serious side effects.
(""VIII. 8. (1) Serious side effects and initial symptomsSee section)
In this material, HbA1c (JDS value) at the time of initial approval was converted by HbA1c (NGSP value) = 1.02 × HbA1c (JDS
value) +0.25.
3. 3. Pharmaceutical properties of the product
Not applicable
Four. Characteristics that should be known regarding proper use
Materials related to proper use, guidelines for promoting optimal use, etc. presence or absence
RMP Yes
Materials created as additional risk minimization activities-Materials Yes
for healthcare professionals
For patients taking Zafatec tablets (Patient medication precautions: overdose
Events related to giving / overdose)

・ Patient materials
For patients taking Zafatec tablets (Patient medication precautions: hypoglycemia)
For patients taking Zafatec tablets (Patient medication precautions: overdose
Events related to giving / overdose)

Optimal use promotion guidelines Nothing
Notice of precautions for insurance application Nothing
(As of April 2021)
－ 1－
Five. Approval conditions and restrictions on distribution and use
(1) Approval conditions
Formulate a drug risk management plan and implement it appropriately. (""Ⅰ.6. Overview of RMPSee section)
(2) Restrictions on distribution and use
Not applicable
6. RMP overview
■ Overview of Pharmaceutical Risk Management Plan (RMP)
Safety considerations
[Important identified risks] [Significant potential risk] [Important shortage information]
・ Hypoglycemia ・ Skin disorders ・ At the time of administration to patients with renal dysfunction
・ Acute pancreatitis safety

・ Arrhythmia associated with prolonged QT / QTc interval ・ When administered to patients with hepatic dysfunction ・ Intestinal
obstruction safety
·Infection ・ Safety when administered to the elderly
·Malignant tumor ・ Impact on cardiovascular risk

・ Events related to overdose / overdose
・ Pemphigoid
Effectiveness considerations
Effectiveness during long-term administration under actual conditions of use
↓ Activities for safety monitoring based on the above ↓ Activities for risk minimization based on the above
Overview of Pharmacovigilance Monitoring Plan Overview of risk minimization plan
Normal drug safety monitoring activities Normal risk minimization activities
Additional Pharmacovigilance Monitoring Activities Additional risk minimization plan
・ Zafatec Tablets Specific Use Results Survey "Type 2 Diabetes" ・ Patient materials
Disease long-term administration " [For patients taking Zafatec tablets (Sickness
・ Zafatec Tablets Specific Usage Results Survey "Advanced kidney machine Precautions for medication: hypoglycemia) and
Type 2 diabetes with dysfunction or end-stage renal disease For patients taking Zafatec tablets (patients)
Survey on long-term use in patients " Precautions for overdose: Overdose / overdose
Outline of efficacy survey / test plan (Events related to)]
・ Zafatec Tablets Specific Use Results Survey "Type 2 Diabetes" ・ Materials for medical professionals
Long-term administration " [For patients taking Zafatec tablets (patients)

Material for explaining people: Related to overdose / overdose
Event)]
・ Ingenuity in packaging form of this drug
For the latest information, check the drug information search page of Pharmaceuticals and Medical Devices Agency.
－ 2－
II. Items related to names
1. 1. Brand name
(1) Japanese name
The Fatech®Tablets 100mg

Zafatec®Tablets 50mg
The Fatech®Tablets 25mg
(2) Western name
Zafatek® Tablets 100mg

(3) Origin of the name
It is derived from The first technology of weekly DPP-4i because it is the first oral diabetes drug to
be administered once a week.
2. common name
(1) Japanese name (nomenclature)
Toleragliptin succinate (JAN)
(2) Western name (nomenclature)
Trelagliptin Succinate (JAN) , Trelagliptin (r-INN)
(3) Stem
DPP-4 inhibitor: -gliptin
3. 3. Structural formula or demonstrative formula
Four. Molecular formula and molecular weight
Molecular formula: C18H20FNFiveO2・ CFourH6OFour
Molecular weight: 475.47
Five. Chemical name (nomenclature) or essence
2-{6
( [ -(3R) --3-Aminopiperidin-1-yl] -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
(1 2H) --yl} methyl) --4-fluorobenzonitrile monosuccinate
6. Trivial name, alias, abbreviation, symbol number
Development code: SYR-472
－ 3－
III. Items related to active ingredients
1. 1. Physicochemical properties
(1) Appearance / properties
White to almost white crystals or crystalline powder.

(Takeda Pharmaceutical / Pharmaceutical Science)
(2) Solubility
It is freely soluble in water or dimethyl sulfoxide, sparingly soluble in methanol, sparingly soluble in
ethanol (99.5), tetrahydrofuran or diethylamine, and extremely sparingly soluble in acetonitrile or 2-
propanol.
(3) Hygroscopicity
None (stored at 25 ° C / 75% RH for 7 days)

(4) Melting point (decomposition point), boiling point, freezing point
Melting point: 187.1 ° C
(5) Acid-base dissociation constant
pKa: 8.6 (titration method)
(6) Partition coefficient
■ Partition coefficient between 1-octanol and various pH aqueous solutions (25 ° C)
a)
pH Partition coefficient log P (log Co / Cw)
3.0 -2.6
5.0 － 1.9
7.0 7.0 -0.99
9.0 0.55
11.0 0.75
a) Co / Cw = 1-octanol phase toleragliptin succinate concentration / aqueous phase toleragliptin succinate concentration
(7) Other main index values

20
Specific rotation [α]D: + 16.7 ° (0.25g, dimethyl sulfoxide, 25mL, 100mm)
2. Stability of the active ingredient under various conditions
Storage conditions
test Preservation form Retention period result

temperature Humidity
Long-term storage test 25 ℃ 60% RH Polyethylene bag (sealed) 36 months No change
- Four-
3. 3. Confirmation test method and quantitative method for active ingredients
Confirmation test method
(1) Ultraviolet-visible absorbance measurement method
(2) Infrared absorption spectrum measurement method (potassium bromide tablet
method) (3) Qualitative reaction (succinate)
Quantitative method
Liquid chromatography
- Five-
Ⅳ. Items related to pharmaceutical products
1. 1. Dosage form
(1) Distinguishing dosage forms
Zafatec Tablets 100mg: Film-coated tablets with double-sided score line
Zafatec Tablets 50mg : Film coated lock

Zafatec Tablets 25mg : Film coated lock
(2) Appearance and properties of the product
Zafatec Tablets 100mg Zafatec Tablets 50mg Zafatec Tablets 25mg

Tablet color Light red Light yellow red yellow
Top surface
shape Bottom surface
side
Major axis 11.0 Major axis 8.2

Size (mm) Diameter 6.1
Minor diameter 5.6 Minor diameter 4.7
Thickness (mm) About 3.8 About 3.1 About 3.3
Mass (mg) About 187 About 93 About 93
(3) Identification code
Tablets 100 mg:◯D389 (Formulation label: None) Display site: Tablet / PTP sheet
Tablet 50 mg:◯D388 (Formulation label: None) Display site: Tablet / PTP sheet
Tablets 25 mg: None (Formation label: Zafatec 25) Labeled site: Tablets / PTP sheet
(4) Physical characteristics of the product
(5) Other
Not applicable
2. Composition of pharmaceutical product
(1) Content of active ingredient (active ingredient) and additives
Brand name Zafatec Tablets 100mg Zafatec Tablets 50mg Zafatec Tablets 25mg
In 1 tablet In 1 tablet In 1 tablet
Toleragliptin succinic acid Toleragliptin succinic acid Toleragliptin succinic acid

Active ingredient
133 mg as salt (66.5 mg as tolera salt (33.25 mg as tolera salt)
100 mg as glyptin) 50 mg as glyptin) 25 mg as glyptin) D-mannitol, crystalline
D-mannitol, crystalline D-mannitol, crystalline cement
Lurose, Croscarmello Loose, Croscarmello Loose, Cross Calmero
Susodium, hydroxyssodium, hydroxyssodium, hydroxypropylcellulose,
fpropylcellulose, fpropylcellulose, stearylnaphthylumalate stearylnatrieumalate
Additive stearylnatrieumate, hypromellose, macum, hypromellose, macum,
hypromellose, Rogor Oxide 6000, Titanium Oxide, Rogor 6000, Titanium Oxide,
Titanium, Yellow Iron Dioxide, Iron Dioxide, Iron Tricarbonate, Carnauba Row
Yellow Sanitate
Iron, carnauba wax
－ 6－
(2) Concentration of electrolyte, etc.
Not applicable
(3) Calorie
Not applicable
3. 3. Composition and volume of attached solution
Not applicable
Four. titer
Not applicable
Five. Contamination that may be mixed
6. Stability of the product under various conditions
The stability of Zafatec tablets 50 mg and 25 mg was as follows.

Storage conditions

temperature Humidity light
Long-term storage test 25 ℃ 60% RH ― PTP + paper box 36 months No change
D65 light source

Optical stability test Nariyuki Nariyuki No packaging: Petri dish 1.2 million lx ･ h No change
(2500lx)
The stability of Zafatec Tablets 100 mg was as follows.

Storage conditions

temperature Humidity light
Long-term storage test 25 ℃ 60% RH ― PTP + paper box 48 months No change
D65 light source

Optical stability test Nariyuki Nariyuki No packaging: Petri dish 1.2 million lx ･ h No change
(2500lx)
■ Stability during tablet splitting
After dividing 100 mg of Zafatec tablets, the results were observed under the conditions of 25 ° C / 75% RH and a white fluorescent
lamp. As a result, no particular problematic changes in appearance, content, dissolution, etc. were observed up to 100 days later.
Storage conditions: 25 ° C / 75% RH, white fluorescent lamp (500lx x 24h = 12000lx ・ h / day) (Plastic plate) Zafatec Tablets 100mg (Lot
No.Z643C01)
Measurement item initial 1 month 2 months 3 months 100 days
(Half-tablet film part) Light red No change No change No change No change

Appearance (color / shape)
(Divided surface) White No change No change No change No change
(%)
Related substances (total amount) 0.46 0.44 0.43 0.44 0.43
content(%) 99.0 98.7 96.5 97.8 98.4
[Residual rate in parentheses] (100.0) (99.7) (97.5) (98.8) (99.4)
Dissolution Fit Fit Fit Fit Fit
－ 7－
■ Stability in unwrapped state
When Zafatec tablets 100 mg, 50 mg and 25 mg are stored under the conditions of 25 ° C / 75% RH, dark place (brown glass
bottle, opening), or 40 ° C / 75% RH, dark place (glass bottle, opening), any No particular problematic changes in appearance,
content, dissolution, etc. were observed until 6 months later.
Storage conditions: 25 ° C / 75% RH, dark place (glass bottle,
opening) Zafatec Tablets 25mg (Lot No.Z643K01)
Measurement item initial 1 month 3 months 6 months
Yellow film
Appearance (color / shape) No change No change No change
Coated lock
Related substances (total amount) (%) 0.48 0.50 0.49 0.49
content(%) 99.0 98.3 98.6 98.7
[Residual rate in ()] (100.0) (99.3) (99.6) (99.7)
Dry weight loss (%) 0.9 3.6 3.6 3.6
Enantiomer (%) Less than the quantification limit ― ― Less than the quantification limit
Hardness (N) 95 63 63 60
Dissolution Fit Fit Fit Fit
Zafatec Tablets 50mg (Lot No.Z643B01)

Light yellow-red film

Coated lock
content(%) 99.4 99.2 98.7 98.9
[Residual rate in ()] (100.0) (99.8) (99.3) (99.5)
Dry weight loss (%) 1.1 3.6 3.6 3.5
Hardness (N) 103 78 78 83 77

Zafatec Tablets 100mg (Lot No.Z643C01)

Light red double-sided secant

Film coated lock
content(%) 98.4 98.8 98.6 98.7
[Residual rate in ()] (100.0) (100.4) (100.2) (100.3)
Dry weight loss (%) 1.0 3.6 3.6 3.5
Hardness (N) 147 108 111 107

－ 8－
Storage conditions: 40 ° C / 75% RH, dark place (glass bottle,
opening) Zafatec Tablets 25mg (Lot No.Z643K01)
Yellow film
Coated lock
content(%) 99.0 98.8 98.5 98.5
[Residual rate in ()] (100.0) (99.8) (99.5) (99.5)
Dry weight loss (%) 0.9 3.4 3.4 3.5 3.3
Hardness (N) 95 75 75 70
Zafatec Tablets 50mg (Lot No.Z643B01)

Light yellow-red film

Coated lock
content(%) 99.4 99.5 98.6 98.8
[Residual rate in ()] (100.0) (100.1) (99.2) (99.4)
Dry weight loss (%) 1.1 3.2 3.2 3.2
Hardness (N) 103 84 88 81

Zafatec Tablets 100mg (Lot No.Z643C01)

Light red double-sided secant

Film coated lock
content(%) 98.4 98.5 98.7 98.1
[Residual rate in ()] (100.0) (100.1) (100.3) (99.7)
Dry weight loss (%) 1.0 3.2 3.2 3.2
Hardness (N) 147 122 121 112

7. 7. Preparation method and stability after dissolution
Not applicable
8. 8. Combination change with other agents (physicochemical change)
Not applicable
9. Dissolution
Dissolution test method / paddle method
－ 9－
Ten. Container / packaging
(1) Information on containers / packaging that requires attention and containers / packaging with a special appearance
Not applicable
(2) Packaging
PTP with patient package

Zafatec Tablets 100mg : 20 tablets (2 tablet sheets x 10)
(3) Reserve capacity
Not applicable
(4) Container material
PTP sheet, paper box
11. Materials provided separately
Not applicable
12. others
Not applicable
- Ten-
V. Items related to treatment
1. 1. Efficacy or effect
Four. Efficacy or effect
Type 2 diabetes
2. Precautions related to efficacy or effect
Five. Precautions related to efficacy or effect
The application of this drug should be considered only when the effects are insufficient after sufficient diet and exercise
therapy, which are the basics of diabetes treatment.
<Commentary>
Diet and exercise therapy are the basics of diabetes treatment, and you should be instructed to do so even during administration of this drug.
3. 3. Dosage and administration
(1) Explanation of usage and dosage
6. Dosage and administration
The usual adult dosage is 100 mg of toleragliptin given orally once a week.
<Commentary>
For dose reduction in patients with renal dysfunction, seeV. 4. Precautions related to usage and dosagePlease refer to the
section.
(2) Background and basis for setting usage and dosage
In a phase I single-dose study (CPH-001 study) in healthy Japanese adult males, a single dose of 100 mg of this drug
confirmed that DPP-4 activity inhibition persisted until 1 week after administration. ..
In addition, in an overseas phase II dose-ranging study (Study 007: 100 mg of this drug once a week, Study 006: 100 mg of this drug
once a day) in type 2 diabetic patients, the results of administration for 12 weeks were shown. When compared with each placebo
group, there was no significant difference in efficacy and safety between weekly and daily doses.
Based on these results, we conducted a domestic phase II dose-ranging study (CCT-001 study) in which 12.5 to 200 mg of this drug was administered once a
week to patients with type 2 diabetes. As a result, the amount of change in HbA1c at the end of treatment decreased almost as the dose increased, but the
amount of change in HbA1c in the 100 mg group of this drug was not significantly different from that of the 200 mg group of this drug. .. In addition, the
average value of the DPP-4 activity inhibition rate 7 days after the final administration of this drug in the 100 mg group of this drug was maintained at 77.43%
and 70%, and the trough value (administration) of the existing daily-administered DPP-4 inhibitor. It was confirmed that it was about the same as the DPP-4
inhibition rate (about 70% or more) (immediately before), and no major problem was observed in the safety of this drug up to the 200 mg group.
Based on the results of this domestic phase II dose-ranging study (CCT-001 study), it was judged that the dose of this drug in the phase
III study should be 100 mg, which is less exposed, and 100 mg of this drug should be administered once a week. Therefore, a domestic
phase III verification study (CCT-002 study) and a phase III single-term or combined long-term administration study (OCT-001 study)
were conducted. In the CCT-002 study, non-inferiority of the 100 mg group to the 25 mg group of alogliptin was verified, and the
incidence of adverse events was similar in the 25 mg group of alogliptin and the placebo group, and safety. There were no major
problems.
In the OCT-001 study, long-term efficacy of 100 mg of this drug once weekly was confirmed in monotherapy and combination
therapy, and DPP-4 activity inhibition was sustained. In terms of safety, no major problems were observed with monotherapy
and combination therapy.
Furthermore, in a bioequivalence study and a dietary effect study (CPH-009 study) in healthy Japanese adult males, it was
considered that the pharmacokinetics and pharmacodynamic effects of this drug were not affected by diet. .. Based on the
above results, the dosage and administration of this drug was set as "Usually, for adults, 100 mg of toleragliptin is orally
administered once a week" in both monotherapy and combination therapy.
－ 11－
Four. Precautions related to usage and dosage
7. 7. Precautions related to usage and dosage
7.1In patients with moderate or higher renal dysfunction, the blood concentration of this drug increases due to delayed excretion, so the
dose should be reduced according to the degree of renal function, referring to the table below. [See 9.2.1, 9.8, 16.6.1] Dosage for
patients with moderate or higher renal dysfunction
Creatinine
Serum creatinine
clearance Dose
(Mg / dL)
Note 1)
(Ccr, mL / min)
Patients with moderate renal dysfunction Male: 1.4 <~≤2.4
30≤~ <50 50mg, once a week
Female: 1.2 <~≤2.0
Patients with severe renal dysfunction / Male:> 2.4
<30 25mg, Once a week
Patients with end-stage renal diseaseNote 2) Female:> 2.0
Note 1) Conversion value equivalent to Ccr (age 60 years, weight 65 kg) Note 2) For patients with end-stage renal disease, the time
relationship between administration of this drug and hemodialysis does not matter.
7.2 Patients should be instructed on the following points when administering. ・ This drug should be taken once a week
and should be taken on the same day of the week. ・ If you forget to take this drug, take only the prescribed dose
when you notice it, and then take it on the specified day of the week.
<Commentary>
7.1 As a result of examining the pharmacokinetics of a single dose of 50 mg of toleragliptin in patients with renal dysfunction overseas,
those with mild renal dysfunction (50 <Ccr ≤ 80 mL / min) and those with moderate renal dysfunction (50 <Ccr ≤ 80 mL / min) 30
≤ Ccr ≤ 50 mL / min) , Severe renal dysfunction (Ccr <30 mL / min) and end-stage renal disease patients (patients requiring
hemodialysis) (6 patients in each group), their gender, age (± 10 years), weight (± 20%) And race-matched health
Exposure of unchanged toleragliptin (AUC) compared to adults

Note a
(0−tlqc) ) Are about 1.56 times, 2.06 times, respectively
It was 3.01 times and 3.68 times. (""VII.10. Patients with a specific background(1) ”) Therefore, it is not necessary to adjust the
dose of this drug for patients with mild renal dysfunction.For patients with moderate renal dysfunction, the dose was reduced
to half (50 mg) of the usual dose (100 mg) in order to achieve the same level of exposure as healthy adults.
On the other hand, for patients with severe renal dysfunction and end-stage renal disease, 1/4 of the usual dose (25 mg) is considered
appropriate, but there is no experience of using this drug for patients with severe renal dysfunction or higher. , This drug was
contraindicated. However, in a subsequent Japanese clinical study in which 25 mg tablets of this drug were administered once a week to
patients with type 2 diabetes mellitus with severe renal dysfunction or end-stage renal disease, the efficacy of once weekly administration
of 25 mg tablets of this drug And safety was examined. From the results of this testFor patients with severe renal dysfunction and end-
stage renal disease, 1/4 of the usual dose (25 mg once a week) was considered appropriate. (""V.5 ( . Four)
Verification test 1) See section ➂)
In addition, as a result of examining the effect of renal dysfunction on safety in a combined analysis of domestic clinical studies in
patients with type 2 diabetes (50 mg 51 patients and 100 mg 850 patients as toleragliptin, administration period 12 to 52 weeks), it
was moderate. Although the number of patients with severe renal dysfunction (Ccr <50 mL / min) was small (50 mg 0 cases and
100 mg 16 cases as toleragliptin), adverse events specific to renal dysfunction patients (by Ccr) and their There was no clear
tendency for the frequency of expression.
Note a) Area under the plasma concentration time curve from 0 hour to the time when the concentration above the lower limit of quantification was last measured.
－ 12－
Reference: Glomerular clearance (Ccr)
The creatinine clearance can be estimated from the serum creatinine level, gender, age and body weight by the
following formula (Cockcroft-Gault formula).
(140-age) x weight (kg)

Ccr (mL / min)= =
Serum creatinine level (mg / dL) x 72
The above formula is for men, and women multiply this value by 0.85. This drug is taken once a week, not
7.2 daily. Take on the same day of the week every week, and instruct not to take more than the prescribed
dose. If you have a consultation that you made a mistake in the usage or dosage, please refer to the
following for guidance.
➀ If you forget to take this drug
Take the prescribed dose when you notice it, and then take it on a predetermined day of the week. If you
notice it after the next scheduled date, instruct to take only one tablet when you notice it, and then take
it as scheduled. Never take 2 tablets at once.
➁ If you take the medicine before the next scheduled date, or if you take 2 tablets at the same time If you have any symptoms
that you are interested in, instruct your doctor or pharmacist to consult immediately. The next one should be taken on a
predetermined day of the week as scheduled.
For safety information on daily administration of this drug overseas, please refer to "VIII. 8. (2) Other side effects
(Reference) Refer to the section "Frequency of side effects in daily administration test of toleragliptin".
This drug is the first oral diabetes drug to be taken once a week. Provide sufficient medication guidance to
patients.
We have prepared an underlay and medication precautions for use in patient guidance, so please
contact our staff if necessary.
Note: Dosage and administration of this drug
- 13-
Five. Clinical results
(1) Clinical data package

■ At the time of initial approval (100 mg tablet and 50 mg tablet)
evaluation implementation
Purpose of the test subject Exam design
area
phase
reference
Double-blind, randomized, plastic

◎ Domestic Ⅰ single dose study Healthy adult males (110 cases)
Sevo control, parallel group comparison
Double-blind, randomized,
◎ Repeated dose study Healthy adult males (24 cases)
Rasebo control, parallel group comparison
Double-blind, randomized,
◎ Ⅱ Dose-ranging study Type 2 diabetic patients (321 cases)
Rasebo control, parallel group comparison
Drug mutual with glimepiride

◎ Healthy adult males (12 cases) Open-label
Action test
◎ Ⅲ
Long-term administration alone or long-term combination
Type 2 diabetic patients (680 cases) Open-label
Administration test
Double-blind, randomized, allo

◎ Verification test Type 2 diabetic patients (243 cases) Glyptin control and placebo
Reference control, comparison between parallel groups
◎ Open-label trial Type 2 diabetic patients (14 cases) Open-label
Healthy adult boy

Bioequivalence and diet Open-label, randomized, 2x2
◎ (Bioequivalence test: 24 cases
Impact test crossover
Dietary effect test: 12 cases)
Double-blind (excluding positive controls)
), Random allocation by stratification, plastic

◎ Australia Ⅰ QT / QTc evaluation test Healthy adults (260 cases)
Sevo and positive controls, between parallel groups
Comparison
For patients with renal dysfunction Healthy adults (24 cases)

○ United States Open-label, parallel-group comparison
Clinical pharmacology study Patients with renal dysfunction (24 cases)
For patients with liver dysfunction Healthy adults (8 cases)

○ Open-label, parallel-group comparison
Clinical pharmacology study Patients with hepatic dysfunction (8 cases)
Drug interaction with metformin Open-label, randomized, 2x2

○ Healthy adult males (48 cases)
Test crossover
Caffeine, Torbutami
De, Dextrome Torfa
○ Healthy adults (18 cases) Open-label
Drug phase with midazolam
Interaction test
USA, Double-blind, stratified randomized

○ Meki II Dose-ranging study (daily administration) Type 2 diabetic patients (385 patients) With, placebo and active drug pair
Shiko Teru, comparison between parallel groups
◎: Evaluation material, ○: Reference material
■ When additional dosage form approval (25 mg tablet) and precautions for use are revised (contraindications for administration to patients with severe renal dysfunction and
end-stage renal failure are lifted)
evaluation implementation
Purpose of the test subject Exam design
area
phase
reference
Open-label, randomized, 2x2

◎ Ⅰ Bioequivalence test Healthy adult male (24 cases)
Crossover (1005 test)
Domestic
Multicenter, double-blind, random
Severe renal dysfunction or end-stage renal failure
Allocation, placebo control, parallel
◎ Ⅲ Validate long-term administration study Type 2 diabetic patients with all complications
Group comparison and multicenter, non-group
(107 cases)
Blinded (Trial 3003)
◎: Evaluation material
- 14-
(2) Clinical pharmacology study
1) Tolerance test
1) Single dose test1)

A single oral dose of 3.125 mg, 6.25 mg, 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 800 mg or placebo as
toleragliptin in healthy adult males (110 patients) 30 minutes before breakfast or under breakfast fasting. bottom.
The number of subjects who developed one or more adverse events was 1/8 (12.5%) in the 200 mg group and 1/8
(12.5%) in the 100 mg (administered under fasting) group. The causal relationship was denied. No adverse events
were seen in the other groups.

(Material at the time of initial approval: March 2015)
2) Repeated administration test2)
In healthy adult males (24 patients), 100 mg, 200 mg or placebo of toleragliptin was administered as a single dose 30 minutes before the start
of breakfast (1st day), and 3 days later and 30 minutes before the start of breakfast, once daily 11 Repeated administration for daily days (4th
to 14th days). The subjects who developed adverse events were 1/6 (16.7%) in the placebo group and 1/9 (11.1%) in the 200 mg group, not in
the 100 mg group. The adverse event for which a causal relationship with the investigational drug could not be ruled out was rash in 1 patient
(200 mg group).
2) QT / QTc evaluation test[Overseas data]3)
In healthy adults (260 patients), 200 mg and 800 mg of toleragliptin and 400 mg of moxifloxacin as a placebo or
positive control were orally administered as a single dose 1 to 1.5 hours after breakfast.
The upper limit of the 90% confidence intervals on both sides of the adjusted mean difference (trelagliptin 200 mg group-placebo
group) from the baseline with the same time interval of the QTcF interval exceeded 10 msec at all evaluation points. However, the
maximum value was 5.85 msec 6 hours after administration.
The upper limit of the bilateral 90% confidence interval for the adjusted mean difference (trelagliptin 800 mg-placebo
group) from baseline with time-matched QTcF intervals is 10 msec 1.5-8 hours after dosing. The maximum value was
13.77 msec 2 hours after administration.
The lower limit of the bilateral 90% confidence interval for the adjusted mean difference (moxyfloxacin 400 mg-
placebo group) from baseline in time-matched QTcF intervals is 5 msec 2-6 hours after dosing. This test was
shown to be analytically sensitive.
－ 15－
3) Bioequivalence test
With the standard preparation of toleragliptin 50 mg and the test preparation of toleragliptin 25 mg, two
toleragliptin 25 mg tablets or one toleragliptin 50 mg tablet are breakfast for healthy adult males (24 patients)
by the 2 × 2 crossover method. The bioequivalence of a single oral administration under fasting was examined.
AUC of toleragliptin, the primary endpoint168The (mean value) was 2767 ng · h / mL for 2 tablets of 25 mg of
toleragliptin and 2811 ng · h / mL for 1 tablet of 50 mg of toleragliptin. Similarly, the primary endpoint, CmaxThe
(mean value) was 203.2 ng / mL for 2 tablets of 25 mg of toleragliptin and 233.5 ng / mL for 1 tablet of 50 mg of
toleragliptin.
AUC168And CmaxThe point estimation value [bilateral 90% confidence interval] of the difference between the adjusted mean values converted to
the natural logarithm in (2 25 mg tablets-1 tablet 50 mg) is ln (0.983).[Ln (0.966), ln (1.000)] and ln (0.879) [Ln (0.804),
ln (0.960)], and the 90% confidence intervals on both sides were in the range of ln (0.80) to ln (1.25).
■ Analysis of plasma pharmacokinetic parameters
90% confidence interval on both sides b)

Parameters Point estimate a)
[lower limit, upper limit]
--0.0170 --0.0344-0.0004
AUC168(Ng ・ h / mL)
ln (0.983) [Ln (0.966) -ln (1.000)]
--0.1292 --0.2177－‑0.0406
Cmax(Ng / mL)
ln (0.879) [Ln (0.804) -ln (0.960)]
a) Difference in adjusted mean value between administration of 2 toleragliptin 25 mg tablets and administration of 1 toleragliptin 50 mg tablet (trelag)
Liptin 25 mg tablets 2 tablets-1 toleragliptin 50 mg tablets 1 tablet)
b) AUC168 And Cmax After the natural logarithm conversion, these are set as the dependent variable, formulation, group (administration order), and timing as fixed effects.
Analysis of variance
There were no adverse events, deaths, other serious adverse events, or adverse events leading to the discontinuation of the study in this study. In addition,
there were no hypoglycemia-related adverse events, intestinal obstruction-related adverse events, acute pancreatitis-related adverse events, or QT / QTc
interval extension-related adverse events that were specified as particularly noteworthy adverse events.
Hematological tests, blood biochemical tests and urinalysis, vital signs (systolic blood pressure, diastolic blood pressure, pulse
rate, respiratory rate and body temperature), body weight and 12-lead electrocardiogram are all clinically significant. No
change was seen.
As described above, there was no problem in the safety of a single oral administration of two toleragliptin 25 mg tablets and
one toleragliptin 50 mg tablet to healthy Japanese adult males under fasting, and the tolerability was good. It has also been
shown that these formulations are bioequivalent.

(Material at the time of approval of additional dosage form: August 2019)
－ 16－
(3) Dose-response search test
Placebo-controlled, double-blind, controlled trial (dose-ranging study)Four)
12.5 mg, 25 mg, 50 mg, 100 mg, and 200 mg of toleragliptin were administered once a week to examine the
clinical dose of toleragliptin in patients with type 2 diabetes who had insufficient glycemic control even after
Purpose of clinical trial
diet and exercise therapy. The efficacy and safety of these patients were examined by a placebo-based,
randomized, double-blind, parallel-group comparison method.
Clinical trial design Multicenter, double-blind, randomized, placebo-controlled, parallel-group comparison
Types of clinical trials Phase II, dose-ranging study
subject Type 2 diabetic patients with inadequate glycemic control even after diet and exercise therapy
(1) 4 weeks after the start of the control observation period (-4 weeks) HbA1 ( c JDS value)Is 6.5% or more and less than 10.0%
Those whose HbA1c difference between (-8 weeks) and 4 weeks after the start of the control observation period (-4 weeks) is
(2) At the start of the control observation period
Main selection criteria within 10% of the HbA1c value at the start of the control observation period (-8 weeks).
(3) At the start of the control observation period Those who have been on a certain diet and exercise therapy (if any) for the past 4
weeks or more up to (-8 weeks)
Main exclusion criteria (-8 weeks)Those who have taken diabetes medication for the past 4 weeks and during the control observation period
At the beginning of the control observation period
321 cases (trelagliptin 12.5 mg group: 54 cases, toleragliptin 25 mg group: 52 cases)

Number of examples Toleragliptin 50 mg group: 51 patients, toleragliptin 100 mg group: 55 patients
Toleragliptin 200 mg group: 54 patients, placebo group: 55 patients)
Trelagliptin succinate or placebo was orally administered once weekly for 12 weeks before breakfast.
Observation period Post-observation period

Treatment period (12 weeks)
(8 weeks) (1 week)
Toleragliptin 12.5 mg group (54 patients) Toleragliptin 12.5 mg
Administration method Toleragliptin 25 mg group (52 cases) Toleragliptin 25 mg
Toleragliptin 50 mg group (51 cases) Toleragliptin 50mg
Toleragliptin 100 mg group (55 cases) Toleragliptin 100mg
Toleragliptin 200 mg group (54 patients) Toleragliptin 200mg
Placebo group (55 cases) placebo
Primary endpoint Amount of change in HbA1c at the end of the treatment period [At the end of the treatment period-at the end of the observation
Secondary evaluation items period (0 week)] HbA1c, fasting blood glucose, blood glucose in the dietary load test
HbA1c: HbA1 ( c NGSP value) = 1.02 x HbA1 c( JDS value)Converted at +0.25.
1) Changes in HbA1c
The amount of change in HbA1c from the end of the control observation period (week 0) at the
end of the treatment period is as follows. There was no difference. There was a significant
decrease in HbA1c in all toleragliptin groups compared to the placebo group.
■ HbA1c change (at the end of the treatment period)
Trelagliptin
Administration group placebo
12.5mg 25mg 50mg 100mg 200mg
n 55 54 52 51 55 54
At the end of the observation period (0 week) 8.15 8.18 7.99 8.07 8.41 7.84
Measured valuea) (%) (0.946) (0.894) (0.770) (0.864) (0.965) (0.764)
At the end of the observation period (0 week) 0.35 --0.37 --0.32 --0.42 --0.54 --0.55
Amount of change fromb) (%) (0.068) (0.068) (0.070) (0.070) (0.068) (0.069)
--0.72 --0.67 --0.77 --0.90 --0.89
With placebo
― [-0.940, [-0.882, [-0.985, [-1.119, [-1.100,
Point estimation of difference between groups (%)
--0.510] --0.452] --0.556] --0.688] --0.687]
p-valuec) ― <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
a) Mean (standard deviation), b) Adjusted mean (standard error), c) p: vs placebo group, contrast test with analysis of covariance model [] is 95%
confidence interval on both sides
－ 17－
2) Side effects
The incidence of side effects was 7.4% (4/54 cases) in the toleragliptin 12.5 mg group, 9.6% (5/52 cases) in the 25 mg group,
11.8% (6/51 cases) in the 50 mg group, and 9.1% (5/55 cases) in the 100 mg group. ), 5.6% (3/54 cases) in the 200 mg group
and 3.6% (2/55 cases) in the placebo group. Of these, events with an incidence of 2% or more were anemia, diabetic
neuropathy, atrial fibrillation, hypertension, upper abdominal pain, liver dysfunction, increased alanine / aminotransferase,
increased aspartate aminotransferase, and blood in the 50 mg group. The increase in creatine phosphokinase and the
increase in γ-glucoltransferase were 2.0% (1/51 cases), respectively.

(4) Verification test
1) Effectiveness verification test
➀ Alogliptin-controlled double-blind comparative study (verification study)Five)
Alogliptin on the efficacy and safety of once-weekly administration of toleragliptin succinate

(100 mg as toleragliptin) in type 2 diabetic patients whose glycemic control is inadequate even
after diet and exercise therapy. Benzoate (25 mg as alogliptin) was used as a control.
Multicenter, double-blind, randomized, alogliptin control and placebo reference control, parallel group
Clinical trial design
comparison
Types of clinical trials Phase III, validation study, non-inferiority study
subject Japanese type 2 diabetic patients with insufficient glycemic control even after diet and exercise therapy
(1) HbA1 4 weeks after the start of the observation period ( c JDS value)Is 6.5% or more and less than 10.0%
(2) The difference in HbA1c between the start of the observation period and 4 weeks after the start of the observation period is 10% of HbA1c at the start of the observation period.
Main selection criteria Person within
(3) From 4 weeks before the start of the observation period to the end of the observation period, constant diet and exercise therapy (implemented)
If you are)
Diabetes treatment within 4 weeks before the start of the observation period and during the observation period (Including injection)Have been administered
Main exclusion criteria
Who has
243 cases (trelagliptin 100 mg group: 101 cases, alogliptin 25 mg group: 92 cases,
Number of examples
Placebo group: 50 patients)
Trelagliptin succinate or placebo was orally administered once weekly for 24 weeks before breakfast.
Alogliptin benzoate or placebo was orally administered once daily for 24 weeks before breakfast (double
dummy method).

(8 weeks) (1 week)
Administration method
Toleragliptin 100 mg group (101 patients) Trelagliptin 100mg once a week

Alogliptin 25 mg group (92 patients) Alogliptin 25mg once daily
Placebo group (reference control group) (50 patients) placebo
Primary endpoint Amount of change in HbA1c at the end of the treatment period [At the end of the treatment period-at the end of the observation
Secondary evaluation items period (0 week)] HbA1c, fasting blood glucose, blood glucose in the dietary load test
HbA1c: HbA1c (NGSP value) = 1.02 x HbA1c (JDS value) +0.25.
－ 18－
(A) Amount of change in HbA1c
Adjusted mean HbA1c changes at the end of the treatment period were -0.33% and -0.45% in the toleragliptin 100
mg and allogliptin 25 mg groups, respectively. The point estimate [between 95% confidence intervals on both sides]
of the adjusted mean difference in HbAlc changes at the end of the treatment period (trelagliptin 100 mg group-
alogliptin 25 mg group) was 0.11% [-0.054, 0.281]. The upper confidence limit of the bilateral 95% confidence interval
was below the preset tolerance of 0.40%, demonstrating non-inferiority of the toleragliptin 100 mg group to the
alogliptin 25 mg group.
■ HbA1c change (at the end of the treatment period)
Administration group Toleragliptin 100 mg Alogliptin 25 mg
n 101 92
At the end of the observation period (0 week)
7.73 (0.849) 7.87 (0.856)
Measured valuea) (%)
--0.33 (0.059) --0.45 (0.061)
Amount of change fromb) (%)
Alogliptin 25 mg group
0.11 [-0.054, 0.281] ―
Point estimate of difference between groups (%)
a) Mean (standard deviation) b) Adjusted mean (standard error), [ ] Is a 95% confidence interval on both sides
(B) HbA1c control index achievement rate
The proportion of subjects with HbA1c <7.0% at the end of the treatment period was as follows.
■ HbA1c control index (less than 7.0%) achievement rate (at the end of the treatment period)

n 89 83
HbA1c less than 7.0%
26 (29.2%) 30 (36.1%)
Number of achievements (achievement rate)
With alogliptin 25 mg group

--6.9 [-20.934, 7.072] ―
[] Is a 95% confidence interval on both sides
(C) Changes in fasting blood glucose
The changes in the fasting blood glucose levels of the toleragliptin 100 mg group and the alogliptin 25 mg group at the end of the treatment
period from the end of the observation period (week 0) were as follows.
■ Changes in fasting blood glucose (at the end of the treatment period)

n 101 92
157.3 (30.19) 165.9 (41.25)
Measured value (mg / dL)

--6.4 (21.20) --14.9 (27.04)
Amount of change from (mg / dL)
With alogliptin 25 mg group

8.6 [1.71, 15.45] ―
Point estimate of difference between groups (mg / dL)
Mean (standard deviation), [] is 95% confidence interval on both sides
－ 19－
(D) Changes in postprandial blood glucose 2-hour value in a dietary stress test
The 2-hour changes in postprandial blood glucose levels from the end of the observation period (week 0) at the end of the treatment period of
the toleragliptin 100 mg group and the alogliptin 25 mg group were as follows.
■ Amount of change in postprandial blood glucose 2-hour value in the dietary stress test (at the end of the treatment period)

n 101 92
239.7 (50.91) 251.4 (58.13)
Measured value (mg / dL)
n 97 90
--17.2 (47.65) --29.2 (42.24)
Amount of change from (mg / dL)
With alogliptin 25 mg group 12.1

―
Point estimate of difference between groups (mg / dL) [-0.94, 25.12]
(E) Side effects
The incidence of side effects was 5.0% (5/101 patients) in the toleragliptin 100 mg group, 7.6% (7/92 patients) in the alogliptin 25 mg
group, and 6.0% (3/50 patients) in the placebo group. Of these, the events with an incidence of 2% or more were dyslipidemia 2.0%
(2/101 cases) in the toleragliptin 100 mg group, and constipation, chest discomfort, pruritus, and hypertension in the placebo group
2.0% each (1/50). It was an example.
－ 20－
(2) Change test (comparative test) from DPP-4 inhibitor (administered once a day)6)
DPP-4 inhibitor in addition to diet and exercise therapy*The effect of changing to once-weekly administration of
toleragliptin succinate (100 mg as toleragliptin) on blood glucose in type 2 diabetic patients who receive once-daily
administration of succinate, and its efficacy and efficacy The safety was examined exploratively.
Clinical trial design Single facility, open-label
Types of clinical trials Phase III, general clinical trials
DPP-4 inhibitor in addition to diet and exercise therapy*Japanese type 2 diabetic patients receiving once
subject
daily
(1) HbA1 at the start of the observation period ( c JDS value)5.8% or more and less than 8.0%
(2) The difference between HbA1c before the start of the observation period and HbA1c at the start of the observation period is that of HbA1c before the start of the observation period.
Those within 5.0%
Main selection criteria (3) Those who have been receiving a certain diet and exercise therapy (if any) from 10 weeks before the start of the observation period
to the end of the observation period
(Four)
DPP-4 inhibitor continuously from 10 weeks before the start of the observation period to the end of the observation period Those who donate *
once a day
(1) Those whose fasting blood glucose level at the start of the observation period is less than 70 mg / dL or 250 mg / dL or more Main exclusion criteria (2) DPP-4
inhibitor within 10 weeks before the start of the observation period and during the observation period*Other diabetes treatments (injections)
Those who have received administration of)
Number of examples 14 cases
Toleragliptin succinate was orally administered once a week for 12 weeks before breakfast.
Post-observation period
Observation period (2 weeks) Treatment period (12 weeks)
(1 week)
DPP-4 inhibitor* Toleragliptin 100 mg

Once a day Once a week
The start date of administration of the investigational drug was calculated as the first day
Primary endpoint (Day 1). Blood glucose in a dietary stress test
Other
HbA1c, fasting blood glucose, adverse events, etc.
Evaluation item

*: DPP-4 inhibitor administered once daily (1 specific domestically approved drug administered at regular dose)
- twenty one-
(A) Changes in blood glucose in a dietary stress test
In the dietary stress test conducted in the hospital, the amount of change in blood glucose level from the day before the start of administration of
toleragliptin (Day-1) was as follows.
■ Amount of change in blood glucose level in the dietary load test
Change before After change
measured value Amount of change from Day-1
At the time of evaluation Day-1 Day1 Day2 Day3 Day7

n 14 14 14 14 14
140.9 --0.4 (6.71) --6.2 (5.42) --3.0 (7.98) --1.7 (13.21)
Before breakfast (mg / dL)
(23.70) [-4.23, 3.52] [-9.35, -3.08] [-7.61, 1.61] [-9.34, 5.91]
2 hours after breakfast starts 202.1 --4.4 (17.88) --1.6 (30.78) 7.0 (31.93) --8.7 (25.38)
(Mg / dL) (38.30) [-14.75, 5.89] [-19.41, 16.13] [-11.43, 25.43] [-23.37, 5.94]
139.9 --3.7 (22.33) 0.4 (17.98) --4.1 (12.99)
Before lunch (mg / dL) ―
(39.19) [-16.61, 9.18] [-9.95, 10.81] [-11.57, 3.43]
2 hours after lunch starts 217.4 --10.6 (18.13) --36.4 (24.81) --28.1 (27.58)
―
(Mg / dL) (49.07) [-21.11, -0.17] [-50.68, -22.03] [-44.07, -12.22]
141.2 --4.6 (19.76) ―― 10.4 (25.41) 3.4 (23.71)
Before dinner (mg / dL) ―
(40.82) [-15.98, 6.84] [-25.10, 4.24] [-10.33, 17.04]
2 hours after the start of dinner 229.1 12.1 (17.67) ―― 16.4 (26.89) ―― 13.2 (35.11)
―
(Mg / dL) (55.70) [1.87, 22.27] [-31.95, -0.90] [-33.49, 7.06]
Mean (standard deviation), [ ] Is a 95% confidence interval on both sides
(B) Changes in HbA1c and fasting blood glucose at the end of the treatment period
The amount of change in HbA1c and the amount of change in fasting blood glucose from Day 1 at the end of the treatment period were as follows.
■ Changes in HbA1c and fasting blood glucose levels (at the end of the treatment period)
Before change (Day 1) After change (at the end of the treatment period)
measured value Amount of change from Day 1
n 14 14
HbA1 c( %) 7.06 (0.493) 0.04 (0.359)[-0.164, 0.250]
Fasting blood glucose level (mg / dL) 140.5 (23.25) --1.6 (13.93)[-9.61, 6.47]
(C) Side effects
The incidence of side effects was 7.1% (1/14 cases), and the increase in lipase was 7.1% (1/14 cases).
- twenty two-
➂ Type 2 diabetes mellitus with severe renal dysfunction or end-stage renal disease (validation / long-term administration test)7)
Severe renal dysfunction or end-stage renal disease with insufficient glycemic control even after diet
and exercise therapy (if any), or administration of one diabetes treatment in addition to diet and
exercise therapy We will examine the efficacy and safety of once-weekly administration of
Purpose of clinical trial toleragliptin succinate (25 mg as toleragliptin) in patients with type 2 diabetes mellitus (Phasebo I).
Period).
In addition, the safety and efficacy of long-term administration of toleragliptin 25 mg once a week in the same
patient will be investigated (treatment stage II).
Clinical trial design Multicenter, randomized (Phase I: Double-blind, Phase II: Open-label) Phase III,
Types of clinical trials Phase I: Verification study, Phase II: Long-term administration test
Advanced kidney with inadequate glycemic control even after diet and exercise therapy (if implemented), or
subject administration of one diabetes treatment in addition to diet and exercise therapy (if implemented) Type 2 diabetic
patients with dysfunction or end-stage renal disease
(1) Observation period-2 weeks HbA1c is 7.0% or more and less than 10.0%. However, if you are undergoing hemodialysis
In the case of patients with end-stage renal disease, HbA1c at the observation period-2 weeks was less than 7.0%, but
glycoalbumin was 20% or more.
(2) (-6 weeks) creatinine clearance
At the start of the observation period Hemodialysis with (Ccr) less than 30 mL / min
Main selection criteria
Persons with severe renal dysfunction who have not undergone analysis or peritoneal dialysis, or end-stage renal disease who has undergone
hemodialysis
(3) At the start of the observation period Those who have been on a certain diet and exercise therapy (if any) for 6 weeks or
more before (-6 weeks)
If you are using one diabetes drug, use two or more other diabetes drugs 6 weeks before the start of the observation period
Main exclusion criteria
(-6 weeks) (43 days before the start of the observation period). Those who are
107 cases
Number of examples Toleragliptin (25 mg / toleragliptin 25 mg) group: 55 patients Placebo

(placebo / toleragliptin 25 mg) group: 52 patients
In Phase I, 25 mg of toleragliptin was orally administered once a week (toleragliptin group) or placebo
(placebo group) at random, and either toleragliptin 25 mg or placebo was given once a week, 1 tablet per
week. The dose was orally administered for 12 weeks before breakfast. In stage II of treatment, patients
assigned to the toleragliptin group in stage I of treatment continued to be changed to toleragliptin 25 mg,
and patients assigned to the placebo group in stage I of treatment were changed to toleragliptin 25 mg
once. Tablets were orally administered once a week for 40 weeks before breakfast.
Administration method Observation period Phase I Phase II Post-observation period
*
(6 weeks) (Double blind) (Unblind) (2 weeks)
(12 weeks) (40 weeks)
Trelagliptin group
Trelagliptin 25mg once a week
(55 cases)
Placebo group placebo Trelagliptin
(52 cases) Once a week 25mg once a week
* The double-blind period will continue until the end of this treatment.
Efficacy endpoint: HbA1c change at the end of treatment phase I [end of treatment phase I-end of observation phase
Primary endpoint At the end (0 week)]
Safety endpoint: Adverse event
Secondary evaluation items Efficacy endpoints: HbA1c, fasting blood glucose, glycoalbumin
HbA1c used the NGSP value.
- twenty three-
(A) Amount of change in HbA1c
The adjusted mean (standard error) of the change in HbA1c from the end of the observation period (week 0) at the end of the double-blind
period was -0.71 (0.087)% and 0.01 (standard error) in the toleragliptin group and placebo group, respectively. 0.089)%, the point estimate of
the difference between the adjusted mean values [95% confidence interval on both sides] was -0.72% [-0.966, -0.473], verifying the superiority
of the trellaglycin group over the placebo group. Was done (p <0.0001).
■ Change in HbA1c (at the end of the double-blind period)
Administration group Trelagliptin group Placebo group
n 55 52
The amount of change from the end of the observation period (week 0)
--0.71 (0.087) 0.01 (0.089)
Adjusted average value (standard error) (%)
Adjusted mean value with placebo group

--0.72 [-0.966, -0.473] -
p-valuea) <0.0001 -
c (NGSP
a) HbA1 before administration value)Test of difference in population mean based on analysis of covariance model
HbA1c measurements at the end of the open-label period and at the end of the observation period (Week 0)The amount of change from was as follows.
■ Change in HbA1c (at the end of the open-label period)
n 55 52
Measured value at the end of the observation period (week 0) 7.57 (0.849) 7.74 (1.049)
n 55 48
Measurements at the end of the open-label period 6.81 (0.877) 6.91 (1.044)
n 55 48
At the end of the observation period at the end of the open-label period
--0.76 (0.824) --0.74 (0.843)
Amount of change from (0 week)
Mean (standard deviation) (%)
The changes in HbA1c from the end of observation (week 0) analyzed according to the presence or absence of hemodialysis are as
follows, and the HbA1c tended to decrease in the toleragliptin group compared to the placebo group.
■ Change in HbA1c with or without hemodialysis (at the end of the double-blind period)
n 40 39
Hemodialysis available
--0.71 (0.580) --0.04 (0.782)
(End-stage renal failure)
n 15 13
No hemodialysis
--0.68 (0.500) 0.10 (0.564)
(Severe renal dysfunction)
- twenty four-
(B) HbA1c control target achievement rate
The HbA1c control target achievement rate at the end of the double-blind period was as follows.
■ HbA1c control target achievement rate (at the end of the double-blind period)
Trelagliptin group Placebo group

HbA1c control target achievement rate
n = 55 n = 52
HbA1c less than 6.0% n = 53 n = 50

Number of cases (achievement rate) 3 (5.7%) 2 (4.0%)
Point estimate of difference between groups 1.7 [-6.598, 9.919] -
Point estimate of difference between groups 32.9 [14.194, 51.660] -
Point estimate of difference between groups 45.6 [15.528, 75.700] -
The HbA1c control target achievement rate at the end of the open-label period was as follows.
■ HbA1c control target achievement rate (at the end of the open-label period)
Trelagliptin group Placebo group

HbA1c control target achievement rate
n = 55 n = 52



(C) Changes in fasting blood glucose
The measured values of fasting blood glucose at the end of the double-blind period and the amount of change from the end of the observation period (week 0) were as
follows.
■ Changes in fasting blood glucose (at the end of the double-blind period)
n 55 52
n 55 52
Measurements at the end of the double-blind period 128.3 (26.64) 151.9 (45.21)
n 55 52
At the end of the observation period at the end of the double-blind period
Amount of change from (0 week) --14.8 (31.51) 0.8 (25.50)

Point estimate of difference between groups --15.6 [-26.67, -4.62] -
Mean (standard deviation) (mg / dL), [ ] Is a 95% confidence interval on both sides
- twenty five-
(Week 0)The amount of change from was as follows.
Fasting blood glucose measurements at the end of the open-label period and at the end of the observation period
■ Changes in fasting blood glucose (at the end of the open-label period)
n 55 52
n 55 48
n 55 48
--14.3 (37.48) --7.3 (34.31)
Mean (standard deviation) (mg / dL)
(D) Change in glycoalbumin

The measured values of glycoalbumin at the end of the double-blind period and the amount of change from the end of the observation period (week 0) were
as follows.
■ Changes in glycoalbumin (at the end of the double-blind period)
n 55 52
n 55 52
Measurements at the end of the double-blind period 20.40 (2.885) 24.15 (4.837)
n 55 52
At the end of the observation period at the end of the double-blind period
Amount of change from (0 week) --2.81 (2.401) --0.15 (2.537)

Point estimate of difference between groups --2.66 [-3.608, -1.715] -
Mean (standard deviation) (%), [] is 95% confidence interval on both sides
Glycoalbumin measurements at the end of the open-label period and at the end of the observation period The amount of change from (0 weeks) is as follows.
It was.
■ Changes in glycoalbumin (at the end of the open-label period)
n 55 52
n 55 48
n 55 48
--3.12 (2.580) --3.06 (2.604)
－ 26－
(E) Side effects
The frequency of adverse drug reactions that occurred during the double-blind period was 18.2% (10/55 cases) and 7.7% (4/52
cases) in the toleragliptin group and placebo group, respectively, and the incidence was slightly higher in the toleragliptin
group. .. The side effect with an incidence of 2.0% or higher was hypoglycemia in 12.7% (7/55 cases) in the toleragliptin group.
In the placebo group, hypoglycemia was 5.8% (3/52 cases) and ECG QT prolongation was 3.8% (2/52 cases). The side effect of
the toleragliptin group, which was more than 5.0% more frequent than the placebo group, was hypoglycemia. All events were
mild.
The frequency of adverse drug reactions that occurred by the end of the open-label period was 23.6% (13/55 cases) and 12.5% (6/48 cases) in the
toleragliptin group (continuous administration group) and placebo group (switching group), respectively. rice field.
The side effects with an incidence of 2.0% or higher were hypoglycemia in 18.2% (10/55 cases) in the toleragliptin group (continuous administration
group). In the placebo group (switching group), hypoglycemia was 10.4% (5/48 cases), electrocardiogram QT prolongation was 4.2% (2/48 cases),
and altered state of consciousness was 2.1% (1/48 cases). One patient with ECG QT prolongation in the placebo group (switching group) had high
severity, while other events were mild or moderate.
(F) Safety with or without hemodialysis
We evaluated the presence or absence of hemodialysis [presence (end-stage renal failure), absence (severe renal dysfunction)] as an intrinsic
factor.
At the end of the double-blind period, the incidence of adverse events in subjects with hemodialysis (end-stage renal disease) was
70.0% (28/40) and 66.7% (26 / 26 /), respectively, in the trelagliptin and placebo groups. 39 cases). The incidence of adverse events in
subjects without hemodialysis (severe renal dysfunction) was 80.0% (12/15) and 46.2% (6/13) in the toleragliptin and placebo groups,
respectively. The number of cases was small in the group without hemodialysis (severe renal dysfunction) and evaluation was difficult,
but in the group with hemodialysis (end-stage renal failure), there was no significant difference between the administration groups.
At the end of the open-label period, the frequency of adverse events in subjects with hemodialysis (end-stage renal failure) was
It was 98.7% (76/77 cases). The incidence of adverse events in subjects without hemodialysis (severe renal dysfunction)
was 100.0% (26/26 cases).
Note: Adverse events include events for which a causal relationship with the investigational drug is unknown.
(Precautions for use Revision material: September 2019)
－ 27－
2) Safety test
➀ Long-term administration test (single administration or combined administration)8)
<Example of long-term administration alone>
Safety and efficacy of long-term weekly administration of toleragliptin succinate (100 mg as

toleragliptin) to patients with type 2 diabetes who have insufficient glycemic control even after diet
and exercise therapy It was investigated.
Purpose of clinical trial <Example of long-term combined administration>
Basic diabetes treatment drug for type 2 diabetic patients whose glycemic control is insufficient even if any one of the
existing oral hypoglycemic agents (hereinafter referred to as basal diabetes treatment drug) is administered in addition to
diet and exercise therapy. In addition, the safety and efficacy of long-term administration of toleragliptin succinate (100 mg
as toleragliptin) once a week were investigated.
Clinical trial design Multi-institutional joint, open-label
Types of clinical trials Phase III, long-term administration study
Type 2 diabetic patients with inadequate glycemic control even after diet and exercise therapy <Long-term
subject combined administration>

Type 2 diabetic patients with inadequate glycemic control even after administration of basic diabetes treatments in addition to diet and
exercise therapy
<Common>
c (JDS
(1) HbA1 at the start of the observation period value)Is 6.5% or more and less than 10.0%
(2) From 10 weeks before the start of the observation period to the end of the observation period, constant diet and exercise therapy (implemented)
If you have)
<Example of long-term combined administration>
Main selection criteria (1) 10 weeks before the start of the observation period (in the case of long-term administration of thiazolidinediones, before the start of the observation period 14
Those who are using basal diabetes treatment at a certain dosage and administration from (before the week) to the end of the observation
period
(2) At the beginning of the observation period, sufficient effects have not been obtained by treatment with basal diabetes drugs.
However, the investigator or the investigator has determined that increasing the dose of the basic diabetes drug is
inappropriate.
Diabetes treatment within 10 weeks before the start of the observation period and during the observation period (Including injection)Have been administered
Who has
Main exclusion criteria <Example of long-term combined administration>
(In the
Within 10 weeks before the start of the observation period case of long-term administration of thiazolidinediones, within 14 weeks after the start of the observation period) And
Diabetes treatments other than basic diabetes treatments during the observation period (Including injection)Have been administered
Who has
680 patients (trelagliptin alone group) : 248 cases

Sulfonylurea combination group : 158 cases
Fast-acting insulin secretagogue combination group : 67 cases
Number of examples
α-Glucosidase inhibitor combination group : 65 cases
Biguanide drug combination group : 70 cases
Thiazolidine-based drug combination group : 72 cases)
－ 28－
<Common>
Toleragliptin succinate was orally administered once weekly for 52 weeks before breakfast.

(2 weeks) (1 week)
Toleragliptin alone group (248 patients)
Sulfonylurea combination group (158 patients)
Fast-acting insulin secretagogue combination group (67 cases) Toleragliptin 100 mg
α-Glucosidase inhibitor combination group (65 cases) Once a week
Biguanide drug combination group (70 cases)
Thiazolidine-based drug combination group (72 cases)

The same drug was administered for the treatment of basal diabetes during the study period, and the dosage and administration at the start of the observation
period were continuously administered.
List of existing oral hypoglycemic agents that can be used in combination as basal diabetes treatments in this clinical trial
kinds Drug name (generic name)
Sulfonylurea drugs Glibenclamide, gliclazide, glimepiride

Fast-acting insulin secretagogue Nateglinide, mitiglinide calcium hydrate
α-Glucosidase inhibitor Acarbose, miglitol, voglibose
Biguanide drugs Metformin hydrochloride, buformin hydrochloride
Thiazolidine drugs Pioglitazone hydrochloride
<Common>
Adverse events, etc.
Primary endpoint
<Combined use of sulfonylurea drugs>
Blood glucose by self-monitoring of blood glucose
Secondary evaluation items HbA1c, fasting blood glucose
(A) Changes in HbA1c and fasting blood glucose levels
At the end of the observation period at each evaluation point of the treatment period The changes in HbA1c and fasting blood glucose levels from (week 0) are as follows.
It was as it was.
■ Change in HbA1c (at the end of the treatment period)
Combination group
Trelagrip Fast-acting ins

Administration group
Chin alone group
Sulfonyl α-Glucosy Biguanide Thiazolidine
Phosphorus secretion
Rare drugs Dase inhibitor Drugs Drugs
Accelerator
n 248 158 67 65 70 72
Measured value (%) (0.871) (0.837) (0.778) (0.975) (0.943) (0.959)
n 248 158 66 65 70 72
At the end of the treatment period 7.30 7.72 7.61 7.40 7.51 7.18
Measured value (%) (0.940) (1.098) (1.168) (0.968) (1.356) (0.913)
--0.57 --0.37 --0.25 --0.67 --0.31 --0.74

(0.883) (0.902) (0.784) (0.739) (0.816) (0.654)
Of the amount of change from
[-0.679, [-0.511, [-0.446, [-0.849, [-0.502, [-0.891,
Point estimate (%)
--0.458] --0.228] --0.060] --0.483] --0.113] --0.584]
－ 29－
■ Change in fasting blood glucose level (at the end of the treatment period)
Combination group
Trelagrip Fast-acting ins

Chin alone group Sulfonyl c α-Glucosy Biguanide Thiazolidine
Phosphorus secretion
Rare drugs Dase inhibitor Drugs Drugs
Accelerator
n 248 158 67 65 70 72
Measured value (mg / dL) (35.56) (33.07) (33.64) (37.74) (36.13) (34.92)
n 248 158 66 65 70 72
At the end of the treatment period 150.6 167.6 167.7 156.9 155.4 147.2
Measured value (mg / dL) (33.39) (41.52) (42.21) (35.92) (39.00) (32.11)
--10.0 --0.8 --4.8 ―― 13.5 --2.4 ―― 10.6

(31.17) (35.53) (33.38) (31.39) (29.32) (22.65)
Of the amount of change from
[-13.88, [-6.42, [-13.01, [-21.27, [-9.39, [-15.91,
Point estimate (mg / dL)
--6.99] 4.75] 3.40] --5.71] 4.59] --5.26]
(B) Side effects
The incidence of side effects was 15.7% (39/248 cases). Of these, the event with an incidence of 2% or more was
nasopharyngitis in 3.2% (8/248 cases).
The frequency of side effects was 10.8% (17/158 cases) in the sulfonylurea combination group, 11.9% (8/67 cases) in the fast-
acting insulin stimulant combination group, and 6.2% in the α-glucosidase inhibitor combination group. (4/65 cases), 11.4%
(8/70 cases) in the biguanide combination group, and 13.9% (10/72 cases) in the thiazolidine combination group. Of these,
events with an incidence of 2% or more were hypoglycemia 3.2% (5/158 cases) in the sulfonylurea combination group, eczema
3.0% (2/67 cases) in the fast-acting insulin secretagogue combination group, and thiazolidine. In the drug combination group,
the increase in alanine aminotransferase and the increase in aspartate aminotransferase were 2.8% (2/72 cases), respectively.
－ 30－
(2) Insulin preparation (validation / long-term administration test)9)
(A) Double-blind period
In addition to diet and exercise therapy, insulin preparation [mixed type (fast-acting or super-fast-acting insulin content is 30% or less),
intermediate type, long-acting type dissolving alone, daily dose is 8 units or more and 40 units or less, in principle, do not change
throughout the double-blind period] 100 mg of toleragliptin (once a week before breakfast) is administered for 12 weeks to patients
with type 2 diabetes who have insufficient glycemic control. bottom. The results are shown in the following table. The mean (standard
deviation) of HbA1c (NGSP value) before administration was 8.42 (0.68)% in the toleragliptin 100 mg combination group and 8.50
(0.68)% in the insulin preparation alone group.
*
HbA1 (c NGSP value) Fasting blood glucose※※ Postprandial blood glucose 2 hour value※※
(%) (Mg / dL) (Mg / dL)

From before administration Insulin preparation From before administration Insulin preparation From before administration Insulin preparation
change amount Change amount difference from alone Difference change amount from alone Difference from alone
Insulin preparation 0.07 0.8 2.3

Alone (n = 124) (0.07) --0.63# (42.4) --3.6. (59.9) ―― 32.2
Trelagliptin --0.56 [-0.83, -0.44] --2.8 [-14.0, 6.9] ―― 29.9 [-48.5, -15.9]
Combined use of 100 mg (n = 116) (0.07) (39.4) (42.2)
*: HbA1 before administrationc( NGSP value)Adjusted mean value after adjusting with, () is standard error, [] is 95% confidence interval on both sides
* *: Average value, () is standard deviation, [] is 95% confidence interval on both sides
#: p <0.0001 (HbA1 before administrationc( NGSP value)Test of difference in population mean based on analysis of covariance model with covariance)
n: Number of examples of the analysis target population
(B) Continuous open-label long-term administration period
After the end of the double-blind period, stable glycemic control was obtained for 52 weeks with continuous administration of 100 mg
of toleragliptin, including the group switching from insulin preparation alone to combined use of toleragliptin 100 mg. HbA1 at the end
of the continuous open-label long-term administration period c NGSP value) average value (standard) of change from before administration
The quasi-deviation) was -0.43 (0.83)% in the toleragliptin 100 mg continuous combination group and -0.60 (0.83)% in the switching
group.
The incidence of hypoglycemic side effects until the end of the continuous open-label long-term administration period was 12.9% (15/116) in the
toleragliptin 100 mg continuous combination group and 10.9% (13/119) in the switching group.
(In-house data: Post-marketing clinical trial results)
➂ Type 2 diabetes mellitus with severe renal dysfunction or end-stage renal disease (validation / long-term administration test)7)
(A) Double-blind period
Advanced renal function with inadequate glycemic control even with diet and exercise therapy, or with fast-acting insulin
secretagogues, α-glucosidase inhibitors or insulin preparations in addition to diet and exercise therapy Trearagliptin 25 mg
(once a week before breakfast) was administered to patients with type 2 diabetes mellitus with disability or end-stage renal
disease for 12 weeks. The results are shown in the following table. The mean (standard deviation) of HbA1c (NGSP value) before
administration was 7.57 (0.85)% in the toleragliptin 25 mg group and 7.74 (1.05)% in the placebo group.
HbA1c (NGSP value) (%)

Amount of change from before administration Difference from placebo
Placebo (n = 52) 0.01 (0.09)

--0.72#[-0.97, -0.47]
Toleragliptin 25 mg (n = 55) --0.71 (0.09)
Adjusted mean value adjusted for HbA1c (NGSP value) before administration, () is standard error, [] is bilateral 95% confidence interval #: p <0.0001 (covariance of
HbA1c (NGSP value) before administration) Test of difference in population mean based on the analysis of covariance model) n: Number of cases in the analysis
target population
－ 31－
(B) Continuous open-label long-term administration period
After the double-blind period, stable glycemic control was obtained for 52 weeks with continuous administration of 25 mg of
toleragliptin, including the group switching from placebo to 25 mg of toleragliptin. The mean (standard deviation) of the change in
HbA1c (NGSP value) at the end of the continuous open-label long-term administration period was -0.76 (0.82)% in the toleragliptin 25
mg continuous administration group and -0.74 in the switching group. It was (0.84)%. The incidence of hypoglycemic side effects until
the end of the continuous open-label long-term administration period was 18.2% (10/55) in the toleragliptin 25 mg continuous
administration group and 10.4% (5/48) in the switching group.
－ 32－
(5) Patient / pathological examination
Not applicable
(6) Therapeutic use
1) Use-results survey (general use-results survey, specific use-results survey, use-results comparison survey), post-marketing database
Survey, post-marketing clinical trial content
It is in the reexamination period.
2) Contents scheduled to be implemented as approval conditions or outline of surveys / tests conducted
Formulate a drug risk management plan and implement it appropriately.
(7) Others
Not applicable
－ 33－
VI. Items related to medicinal pharmacology
1. 1. Pharmacologically related compounds or compounds
Dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor)
Note: Refer to the latest package insert for the indications or effects of related compounds.
2. Pharmacological action
(1) Site of action / mechanism of action
GLP by inhibiting the activity of dipeptidyl peptidase-4 (DPP-4), which inactivates glucagon-like peptide-1 (GLP-1) secreted into
the blood from the intestinal tract by stimulating oral intake of food. Increases blood concentration of -1 and promotes insulin
secretion from the pancreas in a glucose concentration-dependent manner11)..
(2) Test results to support the medicinal effect
1) Inhibitory action on DPP-4

➀ Inhibitory activity against DPP-4 (in vitro)It showed inhibitory activity against human DPP-4 of human colon adenocarcinoma-derived
cells and plasma DPP-4 of humans, dogs, and rats.
■ Inhibitory activity against DPP-4
Enzyme source I cFiveBoth

0 [[ sides 95% confidence interval] (nmol / L)
Human colon adenocarcinoma-derived cells 5.4 [5.2, 5.7]
Human 4.2 [4.1, 4.3]
plasma Dog 6.2 [6.0, 6.4]
Rat 9.7 [8.0, 11.8]
[Test method]
The DPP-4 fraction obtained by partially purifying the crude cell extract derived from human colon adenocarcinoma or human, dog, or rat plasma was used as an enzyme source. Gly-Pro-
pNA · Tos was used as a substrate, and the enzyme activity was measured using the absorbance (405 nm) 1 hour after the reaction as an index. I c50The value was calculated using a logistic
curve.
➁ Inhibitory activity against related enzymes (in vitro)The inhibitory activity of DPP-4 on related enzymes (DPP-
II, DPP-8, DPP-9, PEP, FAPα) was low.
■ Inhibitory activity against DPP-4 related enzymes
Related enzymes I cFive

0 nmol
( / L)
DPP-II > 100,000
DPP-8 > 100,000
DPP-9 > 100,000
PEP > 100,000
FAPα > 100,000
e Proline
PEP: protease (prolyl endopeptidas) Endopeptidase)
FAPα: fibroblast activation protein α (Fibroblast activation protein α)
[Test method]
DPP-II activity was measured using the active fraction of rat kidney extract as an enzyme source and H-Lys-Ala-pNA · 2HCl as a substrate. PEP activity was measured using
the active fraction obtained from the rat brain as an enzyme source and Suc-Ala-Pro-pNA as a substrate. DPP-8, DPP-9 and FAPα use the active fraction obtained by partially
purifying the human gene expression cell extract as an enzyme source, and DPP-8 and DPP-9 use Gly-Pro-pNA / Tos. For FAPα, the enzyme activity was measured using H-
Ala-Pro-pNA / HCl as a substrate. In each case, the enzyme activity was measured using the absorbance (405 nm) as an index. I c50The value was calculated using a logistic
curve.
－ 34－
➂ Plasma DPP-4 inhibition rate (healthy adults)1)
Maximum plasma DPP-4 inhibition rate (E) when a single dose of 100 mg of toleragliptinmax) And TmaxWas
as follows.
■ Parameters related to plasma DPP-4 inhibition rate
Administration group placebo Toleragliptin 100 mg
n 18 8
Ema(x %) 7.1 (2.90) 99.3 (0.14)
Tma(x h) 114.3 (57.36) 1.2 (0.37)
Mean value (standard deviation)
[Test method]
Target: Healthy adults (26 cases)
Administration method: 100 mg of toleragliptin or placebo was orally administered as a single dose 30 minutes before breakfast.
➃ DPP-4 inhibition rate 1 week after the final administration (type 2 diabetic patients)Four)
When 100 mg of toleragliptin was administered once a week for 12 weeks, the plasma DPP-4 inhibition rate was 77.4% 1 week after the
final administration.
■ Plasma DPP-4 inhibition rate 1 week after final administration
(%)
100
77.4 (11.53)
80
DPP-4 inhibition rate
60
40
20
2.4 (15.46)
0
placebo Trelagliptin
100mg
(40) (41)

, Numbers in parentheses below the figure
[Test method]
Subjects: Type 2 diabetic patients with insufficient glycemic control even after diet and exercise therapy (110 patients) Administration
method: 100 mg of toleragliptin or placebo was orally administered once a week for 12 weeks before breakfast.
－ 35－
➄ Plasma DPP-4 inhibition rate after long-term administration (type 2 diabetic patients)8)
When toleragliptin 100 mg was administered once a week for 52 weeks alone or in combination, the plasma DPP-4 inhibition rate at the
end of the treatment period was as follows: toleragliptin alone group, sulfonylurea drug combination group, fast-acting insulin
secretagogue combination group, α- The glucosidase inhibitor combination group, biguanide drug combination group, and
thiazolidine drug combination group were 79.0%, 76.5%, 78.9%, 78.3%, 76.6%, and 79.6%, respectively.
■ Changes in plasma DPP-4 inhibition rate
(%)
120
100
80
60
40
Toleragliptin alone(N = 248) Combined use with sulfonylurea drugs(N = 158)
20 Combined use of fast-acting insulin secretagogue (N = 65) Combined use of α-glucosidase inhibitor (N = 65)
Combined with biguanide drugs(N = 70) (N = 72)
Combined use with thiazolidine drugs
0
0 2 Four 12 twenty four 36 52 At the end of the treatment period
Administration period (week)
[Test method]
Target: Type 2 diabetic patients (680 patients) whose glycemic control is insufficient even if basal diabetes treatment drug is administered in addition to diet therapy and exercise therapy.
Administration method: 100 mg of toleragliptin in addition to basal diabetes treatment drug once a week for breakfast It was orally administered for 52 weeks before.
－ 36－
2) Comparison with DPP-4 inhibitor (administered once a day)
➀ in vitroComparison of DPP-4 inhibitory activity in12)

Toleragliptin succinate, It showed stronger DPP-4 inhibitory activity than alogliptin benzoate.
■ IC of human DPP-4 inhibitory activity50value
Trelagliptin Alogliptin
Succinate Benzoate
I cFive0 95%
[[ confidence interval] (nmol / L) 1.3 [1.1, 1.5] 5.3 [5.0, 5.7]
[Test method]
Recombinant human DPP-4 protein was used as the enzyme source. The reaction was carried out for 15 minutes using Gly-Pro-AMC as a substrate, and the enzyme activity
was measured using the fluorescence intensity (Ex: 380 nm / Em: 460 nm) of the produced AMC (7-amino-4-methylcoumarin) as an index. I c50The value was calculated using a
logistic curve.
(2) Comparison of plasma DPP-4 inhibition rate (type 2 diabetic patients)2)
The changes in the plasma DPP-4 inhibition rate when 100 mg of toleragliptin was administered once a week or 25 mg of alogliptin was
administered once a day for 24 weeks were as follows.
■ Changes in plasma DPP-4 inhibition rate
(%)
140
120
100
80
60 placebo(N = 50)
40 Trelagliptin 100mg once a week (N = 101)
20 Alogliptin 25mg once daily (N = 92)
0
―― 20
0 2 Four 8 12 16 20 twenty four Treatment period
When finished
Administration period (week)
[Test method]
Subjects: Type 2 diabetic patients with inadequate glycemic control even after diet and exercise therapy (243 patients) Administration method: 100 mg of
toleragliptin or placebo once a week, 25 mg of alogliptin or placebo once a day, It was orally administered for 24 weeks before breakfast.
－ 37－
➂ Dietary stress test (type 2 diabetic patients)Four)
Changes in active GLP-1 concentration, insulin concentration and blood glucose level in the toleragliptin 100 mg group in the dietary
stress test, and AUC at the end of each treatment period (12 weeks)0-2The amount of change was as follows.
■ Changes in active GLP-1 concentration ■ Active GLP-1 AUC0-2Amount of change (at the
end of the treatment period (12 weeks))

(Pmol / L) Toleragliptin 100 mg (0 week)
16
Toleragliptin 100 mg (12 weeks))
(At the end of the treatment period
pmol ・ h / L)
14 Five
Active GLP-1 AUC0-2Amount of change

12 3.40
Active GLP-1 concentration
Four (4.71)
Ten
8 3
6
2
Four
2 1 0.33
(2.79)
0
0 0.5 1 2
0
0 week (55) (55) (55) (55) Trelagliptin placebo
12 weeks (54) (54) (54) (54)
100mg
Time after meal load (h) (54) (53)
■ Changes in insulin concentration ■ Insulin AUC0-2Amount of change (at the
(ΜU / mL) Toleragliptin 100 mg (0 week) end of the treatment period (12 weeks))
80
(At the end of the treatment period μU ・ h / mL)
8
5.06
60
stomach
Insulin AUC0-2Amount of change 6 (18.08)
Hmm
vinegar
Ri Four
Hmm40
Rich 2
Every time
0
20
―― 2 --0.51
(12.70)
0 - Four
0 0.5 1 2
0 week (55) (55) (55) (55)
12 weeks (53) (54) (54) (54) Trelagliptin placebo
100mg
Time after meal load (h)
(54) (50)
■ Changes in blood sugar level ■ Blood sugar AUC0-2Amount of change
(Mg / dL) Toleragliptin 100 mg (0 week) (At the end of the treatment period (12 weeks))
350
(At the end of the treatment period mg · h / dL)
60
300 28.0
40 (83.12)
Blood sugar AUC0-2Amount of change
Blood 250
20
sugar
value 0
200 ―― 20
―― 40
150
―― 44.1
―― 60
(51.93)
100 --80
0 0.5 1 2
0 week (55) (55) (55) (55)
12 weeks (54) (54) (54) (54) Trelagliptin placebo
100mg
Time after meal load (h)
(54) (53)

, Numbers in parentheses below the figure
[Test method]
Subjects: Type 2 diabetic patients with insufficient glycemic control even after diet and exercise therapy (110 patients) Administration method: 100 mg of toleragliptin or
placebo was administered once a week for 12 weeks before breakfast. At the end of the control observation period (week 0)
A dietary stress test was conducted at the end of the treatment period (12 weeks).
－ 38－
➃ Glucose tolerance improving effect in non-obese type 2 diabetes / insulin secretagogue model (rat)11)
(A) Suppressing DPP-4 activity in plasma and increasing active GLP-1
Administration of toleragliptin resulted in a dose-dependent decrease in plasma DPP-4 activity and a dose-dependent increase
in active GLP-1 concentration.
■ 30 minutes after glucose loading ■ Up to 10 minutes after glucose loading
Plasma DPP-4 activity Plasma active GLP-1 concentration
(% Of (Pmol / L)
Control) *
120 12
Plasma active GLP-1 concentration 0-10 min

100 Ten
*
Plasma DPP-4 activity
80 8
*
60 6
* Four
40
* 2
20
0 0
Control 0.01 0.03 0.1 0.3 Control 0.01 0.03 0.1 0.3
Toleragliptin (mg / kg) Toleragliptin (mg / kg)
Mean value (standard deviation) (N = 6)

*: P≤0.025 (vs Control group, one side Shirley-
Williams test)
(B) Plasma glucose lowering and plasma insulin concentration increasing action
By administration of toleragliptin, the plasma glucose increase area after glucose loading was significantly decreased at 0.1 mg / kg or more, and
the plasma insulin concentration 10 minutes after glucose loading was significantly increased at 0.03 mg / kg or more.
■ Plasma glucose concentration AUC0-120min ■ Plasma insulin concentration 10 minutes after glucose loading
(Mg / dL ･ min) (Ng / mL)

30000 2.5 *
*
Plasma insulin concentration (10 minutes after loading)
*
Plasma glucose concentration (AUC0-120min)
25000 *
* 2.0
20000
1.5
15000
1.0
10000
0.5
5000
0 0
Control 0.01 0.03 0.1 0.3 Control 0.01 0.03 0.1 0.3
(N = 6)
*: P≤0.025 (vs Control group, one-sided Williams test) *: P≤0.025 (vs Control group, one-sided Shirley-Williams test)
[Test method]
After fasting overnight, 26-week-old male N-STZ-1,5 rats (6 patients in each group) were orally administered 0.01, 0.03, 0.1 and 0.3 mg / kg of trellaglycin as a single dose,
and 1 g / 1 hour after administration. kg of glucose was orally administered.
Plasma DPP-4 activity was measured 30 minutes after glucose loading. In addition, the amount of increase in plasma active GLP-1 concentration from before glucose
loading to 10 minutes after loading was calculated.
Blood was collected before glucose loading and 10, 30, 60 and 120 minutes after loading, and plasma glucose and plasma insulin concentrations were measured.
－ 39－
➄ Glucose tolerance improving effect in obesity type 2 diabetes / insulin resistance model (rat)11)
(A) Plasma DPP-4 activity inhibitory effect
Dose-dependent reduction in plasma DPP-4 activity was observed with the administration of toleragliptin.
■ Plasma DPP-4 activity
(% Of
Control)
120
100
Plasma DPP-4 activity
80
60
40
20
0
Control 0.01 0.03 0.1 0.3
Toleragliptin (mg / kg)
(B) Plasma glucose lowering action and plasma insulin concentration increasing action
AUC of plasma glucose concentration after glucose loading by administration of toleragliptin0-60minDecreased significantly
above 0.03 mg / kg, and plasma insulin concentration 10 minutes after glucose loading increased significantly above 0.1 mg /
kg.
■ Plasma Plasma glucose concentration AUC0-60min ■ Plasma insulin concentration 10 minutes after glucose loading
(Mg / dL ･ min) (Ng / mL)

15000 70
*
Plasma insulin concentration (10 minutes after loading)
Plasma glucose concentration (AUC0-60min)
12500 * 60
*
* * 50
10000
40
7500
30
5000
20
2500 Ten
0 0
Control 0.01 0.03 0.1 0.3 Control 0.01 0.03 0.1 0.3
Mean value (standard deviation) (N = 6) Mean value (standard deviation) (N = 6)

*: P≤0.025 (vs Control group, one-sided Williams test) *: P≤0.025 (vs Control group, one-sided Williams test)
[Test method]
12-week-old female Wister fatty rats (6 patients in each group) were fasted overnight, followed by a single dose of 0.01, 0.03, 0.1 and 0.3 mg / kg as toleragliptin, and 1 g / kg of glucose was
orally administered 1 hour after administration. It was administered.
Plasma DPP-4 activity was measured 40 minutes after administration of toleragliptin. Blood was collected before and 10 minutes, 30 and 60 minutes after the
glucose loading, and the plasma glucose and plasma insulin concentrations were measured.
－ 40－
➅ Diabetes improving effect (mouse)
Administration of toleragliptin reduced glycated hemoglobin by 0.9% in the 0.03% group, and plasma insulin
A 1.9-fold increase and a 1.8-fold increase in insulin content were observed.
■ Amount of saccharified hemoglobin
(%)
9.0
*
8.0 8.0
7.0 7.0
sugar
To 6.0 6.0
He
Mo 5.0
Gu
B 4.0
Bi
Hmm3.0
2.0
1.0
0
Control 0.003 0.03 Normal control
mouse
Trelagliptin (%)
ob / ob mouse
■ Plasma insulin concentration ■ Pancreatic insulin content
ng / mL) (Ng / mg)

70 400
* *
60 350
blood
300
Syrup 50 Pancreas
stomach
stomach
Hmm250
Hmm
40 vinegar
vinegar
Ri 200
Ri Hmm
Hmm30
Rich 150
Including
amount
Every time
20
100
Ten 50
0 0
Control 0.003 0.03 Normal control Control 0.003 0.03 Normal control
mouse mouse
Trelagliptin (%) Trelagliptin (%)
ob / ob mouse ob / ob mouse
(Ob
Mean value (standard deviation) / ob mouse: n = 8, normal control mouse: n = 5)
*: p≤0.025 (vs Control group, one-sided Williams test)
[Test method]
Seven-week-old male ob / ob mice (8 in each group) and normal control mice (5) were used. Toleragliptin of 0.003 and 0.03% (dose equivalent to 5.7 and 51.9 mg / kg / day)
was fed for 4 weeks. Blood was collected in the morning after 4-week mixed diet administration, and plasma parameters under non-fasting conditions were measured.
Then, after an overnight fast, the pancreas was isolated and the insulin content in the pancreas was measured.
(3) Onset time / duration of action
The plasma DPP-4 inhibition rate peaked after 1.2 (0.4) hours, and the DPP-4 inhibition activity was sustained until 1 week after
administration (mean (standard deviation)).1)..
－ 41－
VII. Items related to pharmacokinetics
1. 1. Changes in blood concentration
(1) Therapeutically effective blood concentration
"VII.1 (. 2) Blood concentration confirmed in clinical trialsSee section
(2) Blood concentration confirmed in clinical trials
1) Single dose 1)
When 50 mg or 100 mg of toleragliptin was administered as a single dose to healthy adults (16 patients) 30 minutes before
the start of breakfast, the changes in plasma concentration and pharmacokinetic parameters were as follows. The mean
plasma concentration 168 hours after administration in the toleragliptin 100 mg group was 2.1 ng / mL.
■ Changes in plasma concentration of toleragliptin after a single dose
(Ng / mL)
800
Toleragliptin 50mg (n = 8)
600
blood
Syrup
During ~ 400
Rich
Every time
200
0
0 twenty four 48 72 96 120 144 168
Time after administration (h)
■ Pharmacokinetic parameters
Dose n Cma(x ng / mL) Tma(x h) AUC0-in(f ng ･ h / mL) T1/2 (0-72))(h) T1/2 (0-168() h)
50mg 8 268.3 (88.8) 1.5 (0.7) 3106.7 (329.3) 20.0 (2.6) 53.9 (6.6)
100mg 8 619.4 (77.3) 1.3 (0.4) 6601.7 (845.4) 18.5 (1.9) 54.3 (7.9)
－ 42－
2) Repeated administration 2)
In healthy adults (9 patients), 100 mg of toleragliptin was administered as a single dose 30 minutes before the start of breakfast (1st day), and
then once daily from the 4th day to the 14th day for 11 consecutive days. .. The changes in plasma concentration and pharmacokinetic
parameters on the 1st and 14th days of administration were as follows, and it was considered that the patient had reached a nearly steady state
by the 14th day of administration.
■ Changes in plasma concentration of toleragliptin during repeated administration
(Ng / mL)
800
700
600
500
blood
Syrup
During ~ 400
Rich
Every time
300
200
100
0
0 24 48 72 96 120 144 168 192 216 264 312 336 360 384 480
Dose n Date of administration Cma(x ng / mL) Tma(x h) AUC0-inf(* ng ･ h / mL) T1/2 (0-72))(h)
First day 544.3 (122.0) 1.3 (0.5) 5572.3 (793.2) 17.9 (2.1)
100mg 8
14th day 602.6 (149.5) 1.5 (0.8) 5292.9 (613.8) 17.6 (1.3)
Average value (standard deviation), * AUC on the 14th day0-tau
■ Cumulative coefficient (R) and accumulation evaluation (AI)
a) b) c) d)
Dose n R (AUC) R (Cmax) A I( AUC) A IT
( 1/2)
100mg 8 1.321 (0.1056) 1.141 (0.3153) 0.953 (0.0734) 0.994 (0.1198)
a) R (AUC) = AUC0-ta( u Day 14) / AUC0-2( Four Day 1) b) R (Cmax) = Cmax (14th day) / Cma(x First day)
c) A I( AUC) = AUC0-ta( u Day 14) / AUC0-in( f Day 1) d) A ( IT1/2) = T1 /( 2 14th day) / T1 /( 2 First day)
－ 43－
3) Kinetic parameters of active metabolites
The pharmacokinetic parameters of metabolite M-I when a single dose of 100 mg of toleragliptin was administered to healthy
adults (8 patients) 30 minutes before breakfast were as follows.
n Cma(x ng / mL) Tmax(a) h) AUC0-in(f ng ･ h / mL) T 1/2

a( ) h)
Metabolite M-I 8 0.7 (0.5) 1.6 (0.5) 21.9 (13.7) 22.1 (5.7)
Mean (standard deviation), a) n = 7
(3) Poisoning area
Not applicable
(4) Effects of diet and combination drugs
1) Effect of diet 13)

When 100 mg of toleragliptin was administered as a single dose to healthy adults (12 patients) by the crossover method under breakfast fasting or 30
minutes after the start of breakfast, the changes in plasma concentration and pharmacokinetic parameters were as follows. there were. Administration 30
minutes after the start of breakfast is C compared to administration under breakfast fasting.maxIncreased by 16.8%, AUC0-infDecreased by 2.5%.
■ Changes in plasma concentration of toleragliptin under fasting and after a single dose after meals
(Ng / mL)
800
600
blood
Syrup
(N = 12)
Under breakfast fasting
Medium 400
Rich 30 minutes after breakfast starts (N = 12)
Every time
200
0
0 twenty four 48 72 96 120 144 168
Administration conditions n Cma(x ng / mL) Tma(x h) AUC0-in(f ng ･ h / mL) T1/2 (0-168() h)
Under breakfast fasting 12 640.1 (189.0) 1.3 (0.9) 6047.5 (634.1) 56.4 (6.7)
30 minutes after breakfast starts 12 734.3 (159.0) 1.6 (0.5) 5890.0 (553.8) 53.4 (6.1)
－ 44－
2) Drug-drug interactions
➀ Glimepiride*, Metformin[Foreigner data]14) 15)

When toleragliptin was used in combination with glimepiride or metformin, no clear effect was observed on the
pharmacokinetics of toleragliptin and these concomitant drugs.
When 200 mg of toleragliptin was repeatedly administered to healthy adults (12 patients) once daily for 11 days, and when glimepiride
1 mg was administered in combination on the 11th day of administration, there was no change in toleragliptin and glimepiride
compared to the single administration. Body AUC0-infAnd CmaxThe point estimates of the ratio of the adjusted mean values [90%
confidence intervals on both sides] were 99.6% [97.0, 102.3] and 104.3% [94.5, 115.1] for trellagriptin and 103.5% [99.1,] for glimepiride
unchanged. It was 108.1] and 121.5% [109.6, 134.8].
When 100 mg of toleragliptin was repeatedly administered once daily and 1,000 mg of metformin twice daily for 12 days (crossover
study) to healthy adults (48 patients), the amount of toleragliptin and metformin was compared with that of single administration. AUC
0-tauAnd CmaxThe point estimates of the ratio of the adjusted mean values [90% confidence intervals on both sides] are 105.0% [102.3,
107.8] and 108.5% [100.6, 117.0], respectively, for toleragliptin. , Metformin 90.4% [84.1,
97.2] and 73.3% [66.6, 80.6].
* Glimepiride is Japanese data
➁ Caffeine, tolbutamide, dextromethorphan, midazolam[Foreigner data]16)

When toleragliptin was used in combination with caffeine, tolbutamide, dextromethorphan or midazolam, no clear
effect was observed on the pharmacokinetics of these concomitant drugs.
Single dose of cytochrome P-450 substrate (caffeine 200 mg, tolbutamide 500 mg, dextromethorphan 30 mg and
midazolam 4 mg) to healthy adults (18 patients) on days 4-14 (11 days) 100 mg of toleragliptin was repeatedly
administered once a day, and on the 14th day, a single combination of cytochrome P-450 substrate was administered.
AUC of caffeine, tolbutamide, midazolam and each metabolite0-tlqc, AUC0-infAnd CmaxThe bilateral 90% confidence interval for the
adjusted average ratio (combination / single administration) was in the range of 80-125%. Dextromethorphan AUC0-tlqcAnd Cmax
The point estimates of the ratio of the adjusted mean values [90% confidence intervals on both sides] were 117.9% [98.8,
140.7] and 111.3% [95.5, 129.8], respectively, but the metabolite dextorphan AUC.0-tlqc, AUC0-infAnd CmaxThe 90% confidence
intervals on both sides of the adjusted mean ratio of were in the range of 80-125%.
－ 45－
2. Drug kinetic parameters
(1) Analysis method
Analysis not based on a compartment model (non-compartment model)
(2) Absorption rate constant
Not applicable
(3) Disappearance rate constant
When a single dose of 100 mg of toleragliptin was administered to healthy adults (16 patients), the rate of disappearance of the apparent disappearance
phase was 0.0129 (0.00196) h, which was administered 30 minutes before breakfast.-1, Breakfast fasted administration 0.0115 (0.00120) h-1Was (average value
(standard deviation))1)..
(4) Clearance
When a single dose of 100 mg of toleragliptin was administered to healthy adults (16 patients), the apparent systemic
clarity was 15.35 (1.743) L / h 30 minutes before breakfast and 15.38 (1.203) L / h under fasting breakfast. It was h.
Renal clearance was 11.63 (1.357) L / h 30 minutes before breakfast and 12.07 (0.982) L / h after breakfast fasting
(mean (standard deviation)).1)..

(5) Volume of distribution
[Foreigner data]
In healthy adults (31 patients), the apparent volume of distribution in the disappearance phase when 50 mg of
toleragliptin was orally administered was 689.32 to 1334.46 L (mean).17) 18)..

(6) Others
Not applicable
3. 3. Population analysis
(1) Analysis method
(2) Parameter fluctuation factors
Population pharmacokinetic analysis was performed by merging the plasma concentrations of toleragliptin measured in the phase II dose-ranging
study, phase III single long-term administration or combined long-term administration study, and phase I single-dose study conducted in Japan. As
a result, it was shown that the plasma concentration of toleragliptin tended to increase due to creatinine clearance, decrease in body surface area,
or increase in LDH.
－ 46－
Four. absorption
■ Absorption rate
(reference)[Rat, dog]
[[14C] From the AUC ratio of total radioactivity when orally and intravenously administered toleragliptin succinate to rats
and dogs, the absorption rates were 67.1% and 96.1%, respectively.
■ Absorption site / absorption route
(reference)[Rat]
In rats, most of the toleragliptin succinate administered into the gastrointestinal tract was considered to
be absorbed from the portal vein as toleragliptin. It was also considered that toleragliptin succinate was
hardly absorbed via the lymph.
■ Bioavailability
The bioavailability determined from the AUC ratio after oral and intravenous administration was 50.3 (8.2)% in rats and
129.8 (37.6)% in dogs (mean (standard deviation)).

Five. distribution
(1) Blood-brain barrier crossing
"VII.5 (. 5) Migration to other organizationsSee section
(2) Blood-placental barrier crossing
(reference)[Rat]
In rats on the 18th day of gestation [14C] When toleragliptin succinate (3 mg / kg as toleragliptin) is orally administered, the
concentration is low, but toleragliptin and some of its derived components are transferred to fetal plasma, and the main
component in fetal plasma is toleragliptin. It was considered.
■ Transition to the foetation
Concentration (μg / mL, toleragliptin equivalent)

sample Compound
1 hour 4 hours 8 hours 24 hours 48 hours
0.168 (0.016) 0.197 (0.038) 0.082 (0.009) 0.006 (0.001) 0.002 (0.000)
Total radioactivity
[100.0] [100.0] [100.0]
0.137 0.157 0.063
Trelagliptin ― ―
[81.5] [79.7] [76.8]
Maternal plasma
Metabolites 0.008 0.009 <LOQ
― ―
MI [4.8] [4.6] [0.0]
0.023 0.031 0.019
others ― ―
[13.7] [15.7] [23.2]
placentaa) Total radioactivity 0.590 (0.039) 0.833 (0.100) 0.571 (0.009) 0.051 (0.004) 0.017 (0.006)
Amniotic fluid Total radioactivity 0.012 (0.003) 0.045 (0.014) 0.065 (0.006) 0.010 (0.002) <LOQ
0.042 (0.003) 0.057 (0.010) 0.033 (0.001)
Total radioactivity <LOQ <LOQ
[100.0] [100.0] [100.0]
0.037 0.049 0.029
Trelagliptin ― ―
[88.1] [86.0] [87.9]
Fetal plasma
Metabolites <LOQ <LOQ <LOQ
― ―
MI [0.0] [0.0] [0.0]
0.005 0.008 0.004
others ― ―
[11.9] [14.0] [12.1]
Foetationa) Total radioactivity 0.125 (0.007) 0.166 (0.025) 0.108 (0.002) 0.014 (0.001) 0.006 (0.001)
Total radioactivity is mean (standard deviation) (n = 3), toleragliptin and metabolites are pool sample values (n = 3)
LOQ: lower limit of quantification,-: not measured,% of radioactivity in []
a) μg / mL
－ 47－
(3) Transferability to milk
(reference)[Rat]
For lactating rats on the 14th day of delivery [14C] When toleragliptin succinate (3 mg / kg as toleragliptin) was orally
administered, some of the components derived from toleragliptin were transferred to milk, and it was considered that the
main component in milk was toleragliptin.
■ Transition to milk
Concentration (μg / mL, toleragliptin equivalent)

sample Compound
1 hour 4 hours 24 hours 48 hours
0.307 (0.049) 0.284 (0.042) 0.008 (0.001) 0.003 (0.001)

Total radioactivity
[100.0] [100.0] [100.0]
0.278 0.244 0.005

Trelagliptin ―
[90.6] [85.9] [62.5]
plasma
―
MI [1.6] [3.5] [0.0]
0.024 0.030 0.003
others ―
[7.8] [10.6] [37.5]
0.373 (0.057) 0.298 (0.060) 0.017 (0.008) 0.002 (0.001)
Total radioactivity
[100.0] [100.0] [100.0]
0.339 0.229 0.006

Trelagliptin ―
[90.9] [76.8] [35.3]
milk
―
MI [4.3] [13.8] [0.0]
0.018 0.028 0.011
others ―
[4.8] [9.4] [64.7]
Total radioactivity is mean (standard deviation) (n = 4), toleragliptin and metabolites are pool sample values (n = 4)
LOQ: lower limit of quantification,-: not measured, [] is for total radioactivity %
(4) Translocation to cerebrospinal fluid
Not applicable
－ 48－
(5) Migration to other organizations
(reference)[Rat]
To the rat[[14C] When toleragliptin succinate (3 mg / kg as toleragliptin) was orally administered, the tissue concentration of total
radioactivity reached the maximum 1 hour or 6 hours after administration in all tissues. The total tissue radioactivity concentration 1
hour after administration was higher than plasma in the intestinal wall, kidney, stomach wall, liver, lung, pituitary gland, submandibular
gland, adrenal gland, bladder, pancreas, and spleen. On the other hand, it was lower than plasma in the testis, brain and spinal cord.
■ Migration to each organization
Radioactivity concentration (μg / g, toleragliptin

Organization
15 minutes equivalent) 1 hour 6 hours 24 hours 72 hours 168 hours
blooda) 0.049 (0.013) 0.099 (0.004) 0.091 (0.019) 0.006 (0.001) 0.002 (0.000) 0.001 (0.001) 0.056
plasmaa) (0.011) 0.114 (0.005) 0.104 (0.021) 0.007 (0.001) 0.002 (0.001) <LOQ
brain 0.005 (0.001) 0.017 (0.004) 0.022 (0.001) 0.003 (0.001) 0.001 (0.000) 0.000 (0.001) 0.005
Spinal cord (0.001) 0.011 (0.002) 0.018 (0.002) 0.004 (0.001) <LOQ <LOQ
Pituitary 0.091 (0.083) 0.648 (0.112) 1.331 (0.140) 0.098 (0.047) 0.017 (0.002)<LOQ
0.071 <LOQ
Eyeball (0.011) 0.125 (0.015) 0.008 (0.002) 0.001 (0.001) <LOQ
Harder gland 0.071 (0.012) 0.371 (0.028) 0.649 (0.088) 0.018 (0.005) 0.008 (0.002) 0.002 (0.001)
Submandibular gland 0.181 (0.029) 0.637 (0.064) 0.891 (0.210) 0.034 (0.004) 0.006 (0.000) 0.003 (0.001) 0.154
Thyroid (0.042) 0.432 (0.096) 0.402 (0.075) 0.021 (0.037) <LOQ <LOQ
Thymus 0.044 (0.009) 0.203 (0.014) 0.287 (0.024) 0.050 (0.005) 0.007 (0.002) 0.001 (0.000) 0.119
heart (0.011) 0.268 (0.021) 0.273 (0.067) 0.024 (0.002) 0.009 (0.002) 0.005 (0.001) 0.496 ( 0.045)
lung 0.907 (0.067) 1.366 (0.165) 0.279 (0.032) 0.108 (0.010) 0.051 (0.008) 0.886 (0.234) 1.895
liver (0.314) 1.572 (0.291) 0.204 (0.007) 0.037 (0.002) 0.010 (0.001) 0.207 (0.037) 0.537 (0.066)
spleen 0.534 (0.083) 0.081 (0.003) 0.013 (0.002) 0.005 (0.002) 0.173 (0.028) 0.567 (0.059) 0.654
pancreas (0.112) 0.035 (0.003) 0.011 (0.001) 0.004 (0.002) 0.257 (0.055) 0.635 ( 0.061) 0.500 (0.085)
Adrenal glands 0.060 (0.013) 0.004 (0.008) <LOQ
kidney 1.075 (0.178) 2.725 (0.258) 3.125 (0.086) 1.561 (0.104) 0.523 (0.046) 0.065 (0.027) 0.008
Testes (0.002) 0.046 (0.006) 0.270 (0.059) 0.186 (0.041) 0.037 (0.005) 0.003 (0.000) 0.023 ( 0.003)
Skeletal muscle 0.118 (0.013) 0.170 (0.025) 0.004 (0.001) 0.001 (0.000) <LOQ
Skin 0.039 (0.010) 0.135 (0.016) 0.167 (0.031) 0.025 (0.002) 0.009 (0.000) 0.003 (0.001) 0.007
White fat (0.006) 0.056 (0.019) 0.070 (0.025) <LOQ <LOQ <LOQ
Femur 0.015 (0.008) 0.068 (0.021) 0.067 (0.022) 0.004 (0.003) 0.103 (0.013)<LOQ <LOQ
0.376 (0.040) 0.405
Bone marrow (0.050) 0.042 (0.004) 0.005 (0.004) 0.068 (0.013) 0.588 (0.200) 0.477 (0.062) 0.120 ( <LOQ
0.014)
bladder 0.091 (0.005) 0.080 (0.008)
Stomach wall 1.804 (0.173) 2.044 (0.163) 0.613 (0.146) 0.022 (0.004) 0.007 (0.001) 0.004 (0.001)
Intestinal wall 1.256 (0.422) 3.253 (0.865) 1.274 (0.049) 0.068 (0.004) 0.028 (0.006) 0.021 (0.004)
Mean (standard deviation) (n = 3), LOQ: Lower limit of quantification
a) μg / mL
－ 49－
(6) Plasma protein binding rate
[Foreigner data]
When a single dose of 50 mg of toleragliptin was administered to healthy adults (24 patients), the proportion of non-
protein-bound toleragliptin in plasma was 0.76 to 0.79.17)..

(reference)[[in vitro] In rat, dog and human plasma [14C] When trellaglycin succinate was added, the
plasma protein binding rate was as follows.19)..
Trelagliptin Plasma protein binding rate (%)
Plasma concentration (μg / mL) Rat Dog Human
0.1 54.7 25.2 27.6

1 42.6 22.8 26.5
Ten 24.1 22.9 22.1
Average value of 3 measurements
6. metabolism
(1) Metabolic site and metabolic pathway
Toleragliptin succinate is in vivoN-It was considered that it was produced by demethylation and metabolized to M-I, which has
pharmacological activity.
■ Estimated metabolic pathway
Toleragliptin succinate M-I

(2) Molecular species and contribution rate of enzymes involved in metabolism (CYP, etc.)
(reference)[[in vitro]20)
(1) As a result of metabolic tests using various human CYP molecular species expression microsomes, metabolites M-I are mainly CYP2D6,
Several other metabolites were produced primarily by CYP3A4. (2) As a result of investigating the inhibitory effect on various CYP
molecular species using human liver microsomes, topoisomerase
Topoisomerase showed no inhibitory action on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 (direct inhibitory
action and metabolism-derived inhibitory action IC)50Value: 100 μmol / L or more). It showed weak inhibitory activity
against CYP3A4 / 5 [direct inhibitory action IC50Value: 100 μmol / L or more, metabolism inhibitory action IC50Value: 12
μmol / L (midazolam 1' --Hydroxide activity) and 28 μmol / L (testosterone 6)

β-hydroxyl activity)].
(3) As a result of investigating the inducing action on various CYP molecular species using human primary hepatocytes, the
inducing action of toleragliptin on CYP1A2, CYP2B6 and CYP3A4 was not observed.
－ 50－
(3) Presence / absence of first pass effect and its ratio
It was presumed that the first pass effect was difficult to receive.
(4) Presence / absence of activity of metabolites, activity ratio, abundance ratio
The active metabolite M-1 in human plasma was less than 1% of the unchanged form of toleragliptin.Ten)..
(reference)[Rat]
IC of metabolite M-I50The value was 6.9 nmol / L.

7. 7. excretion
Excretion site and route
Mainly excreted in urine1)..

Excretion rate
When 100 mg of toleragliptin was orally administered to healthy adults (12 patients) under breakfast fasting or 30 minutes after the start
of breakfast, the cumulative urinary excretion rate of toleragliptin up to 168 hours after administration was 76.6%, respectively.
Was 76.1%13)..
■ Changes in the cumulative urinary excretion rate of toleragliptin
(% Of Dose)
100
80
Kasane
Product 60
urine
During ~
Exclusion
Excretion
Rate 40
(N = 12)
Under breakfast fasting
20
30 minutes after breakfast starts (N = 12)
0
0 twenty four 48 72 96 120 144 168
8. 8. Information about transporters
(reference)[[in vitro]twenty one)
(1) A P-gp substrate for investigating the P-glycoprotein (P-gp) inhibitory effect of topoisomerase succinate.
[[3H] The effect of digoxin on Caco-2 cell permeation was investigated. Toleragliptin is [3H] Slightly inhibited
the transport of digoxin (IC50Value: 500 μmol / L or more). (2) The inhibitory effects on BCRP, OATP1B1,
OATP1B3, OAT1, OAT3 and OCT2 were investigated. door
Relagliptin showed an inhibitory effect on the uptake of metformin, a substrate for the organic
cation transporter OCT2 (IC).50Value: 55.9 μmol / L).
－ 51－
9. Removal rate by dialysis etc.
Hemodialysis[Foreigner data]
In patients with end-stage renal disease (6 patients), a single dose of 50 mg of toleragliptin removed
9.2% (mean, n = 4) of the dose by 4-hour hemodialysis.17)..
Ten. Patients with a specific background
(1) Examination in patients with renal dysfunction[Foreigner data]17)
Patients with mild renal dysfunction (Ccr: 50≤ ~ <80mL / min) , Patients with moderate renal dysfunction (Ccr: 30≤ ~ <50mL / min) ,
Patients with severe renal dysfunction (Ccr: <30mL / min) , Patients with end-stage renal disease and age, gender, race and weight
Healthy adult(6 cases each)When 50 mg of toleragliptin was administered as a single dose under fasting, the plasma
concentration transition and pharmacokinetic parameters were as follows.
AUC0-tlqcAnd Cmax55.7% increase, 36.3% increase in patients with mild renal dysfunction, 105.7% increase, 12.9% increase in patients with moderate renal
dysfunction, 201.4% increase, 9.1% increase in patients with severe renal dysfunction, compared to healthy adults. It increased by 268.1% and decreased by
13.8% in patients with end-stage renal disease.
■ Changes in plasma concentration of toleragliptin in patients with renal dysfunction
(Ng / mL) (Ng / mL)

250 250
200 Patients with mild renal dysfunction 200 Patients with moderate renal dysfunction
blood blood
Serpent 150 Serpent 150
During ~ During ~
Rich Rich
Degree 100 Degree 100
Patients with mild renal dysfunction (N = 6) Patients with moderate renal dysfunction (N = 6)
Healthy adult (N = 6) Healthy adult (N = 6)
50 50
0 0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 0 24 48 72 96 120 144 168 192 216 240 264 288 312
Time after administration (h) Time after administration (h)
(Ng / mL) (Ng / mL)

250 250
200 Patients with severe renal dysfunction

200 Patients with end-stage renal disease
blood blood
Serpent 150 Serpent 150
During ~ During ~
Rich Rich
Degree 100 Degree 100
Patients with severe renal dysfunction (N = 6) (N = 5)
Patients with end-stage renal disease
Healthy adult (N = 6) Healthy adult (N = 6)

50 50
0 0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 0 24 48 72 96 120 144 168 192 216 240 264 288 312
Time after administration (h) Time after administration (h)
Average value
－ 52－
Of renal dysfunction Terminal stage

Mild Healthy adult Moderate degree Healthy adult Altitude Healthy adult Healthy adult
degree kidney failure
n 6 6 6 6 6 6 Five 6
Cma(x ng / mL) 236.36 173.36 264.35 234.07 240.62 220.55 154.24 178.89
a)
Tma(x h) 3.25 2.75 1.75 2.00 3.00 2.25 6.00 2.50
AUC0-tlqc
4807.22 3087.08 7209.65 3505.31 10344.81 3431.79 10837.04 2944.16
(Ng ･ h / mL)
b)
T1/2 (0-312))(h) 67.82 55.56 82.60 64.68 88.45 56.43 107.97 56.75
Adjusted mean, a) median, b) mean

(2) Examination in patients with hepatic dysfunction[Foreigner data]18)
Patients with moderate hepatic dysfunction (Child-Pugh)*Scores 7-9, 8) and age, gender, race, smoking history, and
body weight-corresponding healthy adults (8) with a single dose of 50 mg of toleragliptin under fasting,
pharmacokinetics. The target parameters were as follows.
AUC in patients with moderate hepatic dysfunction compared to healthy adults0-infIncreased by 5.1%, CmaxDecreased 4.3%.
* Bilirubin, albumin, PT (prothrombin time) , Hepatic

Or INR (international standard ratio) encephalopathy, Ascites status to score
Tma(x h))a AUC0-in(f ng ･ h / mL)

b)
n Cma(x ng / mL) T1/2 (0-72))(h)
Patients with moderate hepatic dysfunction 8 148.83 2.00 2596.14 24.92
Healthy adult 7 155.50 3.00 2471.04 22.60
Adjusted mean, a) median, b) mean

11. others
Not applicable
－ 53－
VIII. Items related to safety (precautions for use, etc.)
1. 1. Warning content and reason
Not set
2. Contraindications and their reasons
2. Contraindications (do not administer to the following patients)
2.1 Patients with severe ketosis, diabetic coma or precoma, type 1 diabetes [Infusion, rapid correction of hyperglycemia
with insulin is essential, so administration of this drug is not suitable. ]
2.2 Patients with severe infections, before and after surgery, and with serious trauma [Because insulin injection is desired for glycemic control,
administration of this drug is not suitable. ]
2.3 Patients with a history of hypersensitivity to the ingredients of this drug
<Commentary>
2.1 This is a common precaution for oral diabetes drugs.
Insulin therapy is an absolute indication for acute ataxic conditions such as severe ketosis, diabetic
coma or precoma, and type 1 diabetes is not an indication of this drug.
Patients with severe ketosis, diabetic coma or precoma must be corrected for their basic pathological
conditions: intracellular and extracellular dehydration, ketoacidosis, electrolyte loss, and hyperglycemia. For
reference, it is necessary to actively administer appropriate insulin and replenish water and electrolytes.
2.2 This is a common precaution for oral diabetes drugs.
In diabetes with severe infectious diseases, the blood glucose level rises remarkably due to an increase in
insulin resistance due to infection, which may lead to diabetic coma, and accurate blood glucose control by
insulin injection is desired. In patients before and after surgery, changes in glycemic control status due to
mental stress, physical stress due to surgical invasion, postoperative infections, etc. are possible. Good
blood sugar control is desired.
In patients with severe trauma, changes in glycemic control status due to physical and mental stress
due to trauma may occur, so accurate glycemic control by insulin injection is desired.
2.3 This is a general precaution for pharmaceutical products. Since hypersensitivity is likely to recur in such patients,
administration of this drug should be avoided in patients who develop hypersensitivity due to this drug.
3. 3. Precautions and reasons related to efficacy or effect
"V. 2. Precautions related to efficacy or effectSee.
Four. Precautions and reasons related to usage and dosage
"V. 4. Precautions related to usage or dosageSee.
－ 54－
Five. Important basic notes and why
8. Important basic notes
8.1 Since hypoglycemia may occur, patients should be fully informed of hypoglycemic symptoms and
how to deal with them before using this drug. [Refer to 9.1.1 and 11.1.1]
8.2. 8.2 Acute pancreatitis may occur. If initial symptoms such as persistent severe abdominal pain or
vomiting appear, instruct the patient to see a doctor immediately. [Refer to 11.1.3]
8.3 This drug is orally administered once a week, and its action continues even after discontinuation of administration. Therefore, pay close attention to
blood glucose levels and the occurrence of side effects.
In addition, when using other diabetic drugs after discontinuation of administration of this drug, the timing and dose of administration
should be examined based on the blood glucose control status. [See 16.1.1, 16.1.2, 18.2.2]
8.4 During administration of this drug, blood glucose should be checked regularly and the course should be carefully monitored. If
the effect of this drug for 2 to 3 months is insufficient, the treatment may be more appropriate. Consider changes.
8.5 Be careful when administering to patients who are engaged in aerial work, driving a car, etc., as they may cause
hypoglycemic symptoms. [Refer to 11.1.1]
8.6 Both this drug and the GLP-1 receptor agonist have a GLP-1 receptor-mediated hypoglycemic effect. There are no clinical trial
results when both drugs are used in combination, and the efficacy and safety have not been confirmed.
<Commentary>
8.1 Hypoglycemia is an important and basic precaution in the treatment of diabetes with diabetes drugs. Explain
hypoglycemic symptoms to patients and how to deal with them.

8.2. 8.2 This is described because cases of acute pancreatitis have been reported in post-marketing surveillance. Instruct
patients to seek medical attention immediately if they have initial symptoms such as persistent severe abdominal pain or
vomiting.
8.3 This drug is taken once a week. When 50 mg or 100 mg of toleragliptin was orally administered to healthy adults in
Japan 30 minutes before breakfast, the average plasma concentrations 168 hours after administration were 1.2
ng / mL and 2.1 ng / mL, respectively. Met. (""VII.1 ( . 2) Blood concentration confirmed in clinical trialsSee section)
In addition, when 100 mg of toleragliptin was orally administered once a week for 12 weeks before breakfast to patients with type
2 diabetes in Japan, the average plasma DPP-4 inhibition rate 7 days after the final administration of toleragliptin was 77.4%. .. (""
VI.2 ( . 2) Test results to support the medicinal effect 1) See section ➃)
Therefore, since the plasma DPP-4 inhibition rate is maintained 7 days after administration of this drug, sufficient attention should be paid
to the blood glucose level and the occurrence of side effects. When discontinuing this drug and using other diabetic drugs, consider the
timing, dosage and administration of the next drug, taking into consideration the patient's glycemic control status.
8.4 Generally, when changing the treatment of diabetes, it is necessary to observe the course for about 2 to 3 months, and if the effect is
insufficient, consider other treatment methods including concomitant use with other drugs. ..
8.5 This is a common precaution for diabetes drugs.
Since hypoglycemic symptoms may occur, pay attention to the patient's physical condition and living conditions, and instruct
them to be careful when driving a car, operating machinery, or working at heights.
[Notice of Chief of Safety Measures Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labor and Welfare (January 7, 2014)]
8.6 DPP-4 inhibitors including this drug and GLP-1 receptor agonists have the same GLP-1 receptor-mediated hypoglycemic effect.
There are no clinical results regarding the combined use of this drug and a GLP-1 receptor agonist, and its efficacy and safety
have not been confirmed.
－ 55－
6. Precautions regarding patients with specific backgrounds
(1) Patients with complications / medical history
9.1 Patients with complications / medical history
9.1.1 The following patients or conditions that may cause hypoglycemia
・ Pituitary dysfunction or adrenal dysfunction
・ Malnutrition, starvation, irregular dietary intake, lack of dietary intake or weakness ・
Vigorous muscle exercise
・ Excessive alcohol intake

[Refer to 8.1 and 11.1.1]
9.1.2 Patients with a history of abdominal surgery or intestinal
obstructionMay cause intestinal obstruction. [Refer to 11.1.4]
<Commentary>
9.1.1 This is a common precaution for diabetes drugs.
These patients or conditions may cause hypoglycemia. (""VIII. 5.
Important basic precautions and their reasons 8.1 "and"VIII.8

. 1)( Serious side effects and early symptoms 11.1.1 ”section
reference)
9.1.2 Patients with a history of abdominal surgery or intestinal obstruction may have intestinal obstruction and should be
given with caution.
(2) Patients with renal dysfunction
9.2 Patients with renal dysfunction
9.2.1 Patients with moderate or higher renal dysfunction
Reduce the dose and carefully observe the patient's condition. The blood concentration of this drug increases due to delayed excretion
depending on the degree of renal function. [Refer to 7.1 and 16.6.1]
<Commentary>
Since this drug is mainly excreted from the kidney as an unchanged form, excretion is delayed when administered to patients with
moderate or higher renal dysfunction or patients with end-stage renal disease on dialysis, and the exposure dose of this drug. May
increase. In order to use this drug safely, the dose should be adjusted based on the degree of renal dysfunction, such as measuring the
serum creatinine level of the patient and calculating the creatinine clearance from the values of sex, age, and body weight. "V. 4.
Precautions related to usage and dosage"as well as"VII.10. Patients with a specific background(1) ”)
(3) Patients with hepatic dysfunction
Not set
(4) Those who have fertility
Not set
－ 56－
(5) Pregnant women
9.5 Pregnant woman
Administer to pregnant or potentially pregnant women only if the therapeutic benefit

outweighs the risks. Placental passage has been reported in animal studies (rats).
<Commentary>
It has not been used in pregnant women or women who may be pregnant, and the safety of administration during pregnancy
in humans has not been established. If pregnancy is confirmed during administration of this drug, discontinue administration
and consider dietary management or switching to insulin therapy.
Labeled body of this drug (14C-Toleragliptin) was orally administered (3 mg / kg) to rats on the 18th day of gestation, and the transfer of
toleragliptin and its derived components to the placenta and foetation was examined. The placenta showed the highest radioactivity
concentration at the time of collection. The total radioactivity concentration in amniotic fluid and fetal plasma was lower than that in
maternal plasma, but the total radioactivity concentration in fetal homogenate was almost the same as the concentration in maternal
blood serum. From this, it is considered that toleragliptin and some of its derived components are transferred from maternal blood to
the foetation.
(6) Lactating women
9.6 Lactating women
Consider continuing or discontinuing breastfeeding, taking into account the therapeutic benefits and benefits of breastfeeding. It has
been reported in animal studies (rats) that it is transferred into milk.
<Commentary>
In lactating rats, it has been confirmed that some of the components derived from toleragliptin are transferred to milk.
(""VII.5 ( . 3) Transfer to milkSee section)
(7) Children, etc.
9.7 Children, etc.
No clinical trials have been conducted for children.
<Commentary>
In low birth weight infants, newborns, infants, toddlers or children, no studies have been conducted to examine the efficacy and safety
of this drug.
(8) Elderly people
9.8 Elderly
Carefully administer the drug while paying attention to the occurrence of side effects and carefully observing the course. In general, renal
function is often impaired. [Refer to 7.1 and 16.6.1]
<Commentary>
In general, elderly people often have decreased physiological functions such as renal function and liver function, and it is possible that side
effects of pharmaceutical products are likely to occur.
This drug is a renal excretion type drug, and when it is administered to the elderly, it is necessary to pay attention to renal function and
administer it carefully. Adjust the dose according to the degree of renal dysfunction, such as calculating creatinine clearance. (""V. 4.
Precautions related to usage and dosageSee section)
－ 57－
[Results of domestic clinical trials]
In a combined analysis of domestic clinical trials in type 2 diabetic patients up to the time of initial approval (100 mg tablets and 50 mg tablets)
(administration period 12 to 52 weeks), non-elderly people under 65 years old and elderly people over 65 years old The table below shows the
incidence of adverse events when 50 mg or 100 mg of toleragliptin was administered to patients.
■ Frequency of adverse events by age in domestic clinical trials up to the time of initial approval (combined analysis)
Toleragliptin 50mg Toleragliptin 100 mg

n = 51 n = 850
31 572
Under 65
13 (41.9) 434 (75.9)
20 278
7 (35.0) 214 (77.0)
65 years of age or older
Top: Number of cases in category, Bottom: Number of cases (%)
[Pharmacokinetics in the elderly]
Population pharmacokinetics of plasma levels of toleragliptin measured in a domestic clinical study (100 mg of toleragliptin
administered for 12 to 52 weeks) in type 2 diabetic patients up to the time of initial approval (100 mg and 50 mg tablets) Analysis was
performed and the AUC of toleragliptin under steady state in patients with type 2 diabetes(0–168)And CmaxAs a result of estimating the
ratio of elderly people (65 years old and over) to non-elderly people (under 65 years old), they were about 1.2 to 1.4 times and about
1.1 to 1.3 times, respectively.
－ 58－
7. 7. Interaction
(1) Contraindications for combined use and their reasons
Not set
(2) Precautions for combined use and the reason
10.2 Precautions for combined use (Be careful for combined use)
Drug name, etc. Clinical symptoms / measures Mechanism / risk factors
Diabetes drug May develop hypoglycemia Hypoglycemic effect when used in combination
Sulfonylurea There is. In particular, Sulfoni There is a risk that the usage will increase
Fast-acting insulin secretagogue Lurea or Insuri be.

α-Glucosidase inhibitor When used in combination with the drug
Biguanide drugs Increased risk of hypoglycemia

Thiazolidine drugs Because of these drugs
GLP-1 receptor agonist Consider weight loss.
SGLT2 inhibitor
Insulin preparation
[Refer to 11.1.1]
Drugs that enhance the hypoglycemic effect of diabetic drugs Blood sugar may drop
β-blocker be.
Salicylic acid preparation
Monoamine oxidase inhibitor

Fibrates for the treatment of hyperlipidemia
etc
Drugs that reduce the hypoglycemic effect of diabetic drugs Blood sugar may rise Hypoglycemic effect when used in combination
Adrenaline be. There is a risk that the usage will be diminished
Corticosteroids be.
Thyroid hormone, etc.
<Commentary>
In patients who are also taking other diabetic drugs, in addition to the action of this drug, the hypoglycemic action of the
diabetic drug used in combination may act additively to cause hypoglycemia. ..
Side effects of hypoglycemia have also been reported in a combination study of this drug with a sulfonylurea drug, a
fast-acting insulin secretagogue, a biguanide drug, and a thiazolidinedione drug in Japan. In particular, severe
hypoglycemia has been reported with other DPP-4 inhibitors in combination with sulfonylureas or insulin
preparations. When used in combination with these drugs, consider reducing the dose of sulfonylureas or insulin
preparations. (""VIII.8 ( . 1) Serious side effects and early symptoms 11.1.1 ”)
If hypoglycemic symptoms are observed in combination with an α-glucosidase inhibitor, even if sucrose is administered, it is not
decomposed into glucose by the action of the α-glucosidase inhibitor and is not absorbed, so it is suitable for the treatment of
hypoglycemic symptoms. Administer glucose.
Although the interaction between the drugs illustrated in this section and this drug has not been investigated, the drugs on the left are known to
enhance or attenuate the hypoglycemic effect of diabetic drugs. When administering this drug in addition to the drug on the left, it is necessary
to pay sufficient attention to the hypoglycemic effect of this drug on the action of the drug on the left, and to be careful not to cause
hypoglycemia or deterioration of glycemic control. There is.
－ 59－
[Mechanism that is thought to enhance the hypoglycemic effect]
β-blockers:
Non-specific β-blockers suppress gluconeogenesis in the liver and are thought to delay or prolong recovery
from hypoglycemia.
Salicylic acid preparation:
Since the salicylic acid preparation itself has hypoglycemic properties, it may enhance the hypoglycemic
effect of this drug.
Monoamine oxidase inhibitor:
Although the mechanism is unknown, it has been reported that administration alone causes hypoglycemia. It is speculated
that this is due to its direct action on the pancreas and promotion of insulin secretion.
Fibrates for hyperlipidemia:

Although the mechanism is unknown, fibrates for the treatment of hyperlipidemia are known to have a hypoglycemic
effect and improve glucose tolerance.
[Mechanism that is thought to diminish the hypoglycemic effect]
Adrenaline:
It suppresses glucose uptake in peripheral tissues, promotes gluconeogenesis in the liver, and may increase blood glucose levels. Insulin
secretion suppression may also be considered.
Corticosteroids:
As known as steroid-induced diabetes, it is known to increase blood glucose and induce diabetes, which may diminish
the effect of this drug.
Thyroid hormone:
Since there are reports showing an increase in blood glucose, the effect of this drug may be diminished.
(Stockley's Drug interactions 8th ed,: The Pharmaceutical Press, London, 2008.)
About drug interaction tests examined so far with this drug"
VII.1. (4) Effect of diet and combination drugs 2) ”
About metabolism of this drug
"VII. 6. MetabolismSee section
－ 60－
8. 8. Side effects
11. Side effects
The following side effects may occur, so observe carefully and take appropriate measures such as discontinuing the
administration if any abnormalities are observed.
(1) Serious side effects and initial symptoms
11.1 Serious side effects
(0.1-5%)
11.1.1 Hypoglycemia
Hypoglycemia may occur. It has been reported that severe hypoglycemic symptoms occur when used in combination with a
sulfonylurea agent or an insulin preparation, resulting in loss of consciousness. If hypoglycemic symptoms are observed, take
appropriate measures such as ingesting foods containing sugar. However, when used in combination with an α-glucosidase
inhibitor, glucose should be administered. [See 8.1, 8.5, 9.1.1, 10.2, 17.1, 17.2]
11.1.2 Pemphigoid(Frequency unknown)
If blisters or erosions appear, consult a dermatologist and take appropriate measures such as discontinuing
administration.
11.1.3 Acute pancreatitis(Frequency unknown)
If abnormalities such as persistent severe abdominal pain and vomiting are observed, administration should be discontinued and appropriate measures should be
taken. [Refer to 8.2]
11.1.4 Intestinal obstruction(Frequency unknown)
If abnormalities such as severe constipation, abdominal distension, persistent abdominal pain, and vomiting are observed, administration should be discontinued
and appropriate measures should be taken. [Refer to 9.1.2]
<Commentary>
11.1.1 In a phase III long-term administration study (100 mg of toleragliptin, once a week, administration period 52 weeks) in Japanese patients
with type 2 diabetes, this drug was administered alone, sulfonylurea was used in combination, and fast-acting insulin secretion-
promoting agent was used in combination. Hypoglycemia in 9 patients, including biguanide drugs and thiazolidinedione drugs
(Side effects) are occurring. No hypoglycemia (side effect) was observed in any of the other clinical
studies in Japan up to the time of approval. In addition, the reported degree of hypoglycemia (side effects)
was judged to be mild, and all cases recovered within the day of onset.
■ Number of cases of hypoglycemia (side effects) in domestic phase III long-term administration studies
Administration example Number of cases (%)
(N = 248)
Example of single administration 1 (0.4%)
Example of combined use of sulfonylurea (n = 158) 5 (3.2%)
Example of combined use of fast-acting insulin secretagogue (n = 67) 1 (1.5%)
Example of combined use of biguanide drug (n = 70) 1 (1.4%)
Example of combined use of thiazolidine-based drug (n = 72) 1 (1.4%)
Example of combined use of α-glucosidase inhibitor (n = 65) 0
If hypoglycemia develops, take the following general measures against hypoglycemia, including guidance to
the patient.
1) When this drug is administered alone or when a diabetic drug other than an α-glucosidase inhibitor is used in combination:
Ingest sucrose (20 g of sugar).

2) If you are also using an α-glucosidase inhibitor: Take glucose (10 g).
－ 61－
3) Suspend or reduce the dose of this drug or the diabetic drug used in combination.
In addition, when dealing with a patient suspected of having hypoglycemia with impaired consciousness, first immediately measure
the blood glucose level (simple method) to confirm that the patient has hypoglycemia, and then perform 50% glucose injection 20
mL (20). 40 mL for% glucose) should be administered intravenously. Measure blood glucose again, confirm recovery of
consciousness and increase in blood glucose level, and recommend oral carbohydrate intake to patients.
(Partially quoted from Diabetes Treatment Guide 2014-2015, p.70, 2014 Bunkodo, edited by Japan Diabetes Foundation)
We have created a medication precaution that can be used for patient guidance at the time of prescription, so please
contact our staff if necessary.
In combination with a sulfonylurea agent or an insulin preparation, serious hypoglycemia has been reported
with other DPP-4 inhibitors. When used in combination with these drugs, consider reducing the dose of
sulfonylureas or insulin preparations.
A similar alert has been issued by the Commission on the Proper Use of Incretins (GLP-1 Receptor agonists and DPP-4
Inhibitors). For details, refer to the Japan Diabetes Foundation website (http://www.jds.or.jp/) or the Japan Association
for Diabetes Association website (http://www.nittokyo.or.jp/). (""VIII. 5. Important basic precautions and their
reasons"as well as"VIII. 7. InteractionSee section)
11.1.2 Cases of pemphigoid, including severe cases, have been reported with this drug.
11.1.3 If any abnormalities such as persistent abdominal pain or vomiting are observed during administration of this drug, the onset of acute pancreatitis is
suspected and administration of this drug should be discontinued. In addition, serum amylase, serum lipase, amylase fraction, etc. should be
measured, and a definitive diagnosis should be made by abdominal ultrasonography or imaging tests such as abdominal CT. After diagnosing
acute pancreatitis, monitor the state of consciousness, blood pressure, pulse rate, respiratory rate, body temperature, urine volume, and oxygen
saturation over time, and take appropriate measures such as infusion of a sufficient amount. matter.
11.1.4 If any abnormalities such as severe constipation, abdominal distension, persistent abdominal pain, or vomiting are observed during administration of this drug,
administration of this drug should be discontinued. In addition, make a definitive diagnosis by abdominal X-ray examination or abdominal CT examination. If
intestinal obstruction is diagnosed, appropriate measures such as fasting, fasting, fluid replacement, administration of intestinal motility improving drug, and
general conservative treatment such as gastric tube insertion should be taken.
In domestic clinical studies up to the time of initial approval of this drug (100 mg tablets and 50 mg tablets), moderate ileus and
intestinal obstruction (side effects) were observed in 1 patient each. All of these cases were reported in a phase III long-term
administration study (100 mg of toleragliptin once a week for 52 weeks), and were cases in which a fast-acting insulin secretagogue was
used in combination.
As a result of close examination of cases with ileus, lower anterior resection was performed because of peripheral rectal cancer and
multiple liver metastases. Administration of this drug was discontinued, and recovery was achieved by decompression of the intestinal
tract by inserting an ileus tube. In addition, rectal cancer is considered to have been complicated before the start of the study, so a
causal relationship with the study drug has been ruled out.
In addition, patients with intestinal obstruction were diagnosed with intestinal obstruction on the first
day after administration of this drug, but no hospitalization treatment was performed.
－ 62－
(2) Other side effects
11.2 Other side effects
0.1-5%
Hypersensitivity Rash, pruritus
Cardiovascular Atrial fibrillation
liver ALT rise, AST rise, γ-GTP rise

others Elevated blood amylase, elevated lipase, elevated CK, positive urinary occult blood, nasopharyngitis
<Commentary>
Eczema 6 cases (0.7%), rash 4 cases (0.4%), pruritus, skin ulcer and urticaria 2 cases each (0.2%), erythema, papules,
generalized pruritus and addictive pruritus 1 case each (0.1%) side effects have been reported.
Eczema in 3 cases, rash in 1 case, and skin ulcer in 1 case were moderate, but the others were mild. In addition, there were some cases
in which administration of this drug had to be discontinued, but all cases have recovered. The period from the start of administration to
the onset ranged from those that developed within 2 weeks to those that developed after more than 10 months.
Adverse reactions have been reported in 3 cases (0.3%) of atrial fibrillation and 1 case (0.1%) of palpitation. The period from the start of
administration to the onset ranged from those that developed within 2 weeks to those that developed over 5 months. The severity was mild in
both cases, and the outcome was unrecovered in 2 cases of atrial fibrillation, but no case required a change in administration of this drug.
Adverse reactions were reported in 4 cases (0.4%) with abnormal liver function, 3 cases (0.3%) with increased ALT and 3 cases with increased AST, 2 cases (0.2%) with
increased γ–GTP, and 1 case (0.1%) with abnormal liver function test. There is.
One case of hepatic dysfunction developed 1 week after the end of the administration period of this drug, and the degree was
reported to be moderate. Other than that, the degree was mild, and there were no cases requiring change of administration of
this drug. All cases recovered without treatment with drugs.
Blood amylase increased in 3 cases (0.3%), lipase increased in 8 cases(0.9%), increased pancreatic enzyme in 2 cases (0.2%), abnormal pancreatic enzyme 1
Adverse reactions have been reported in 1 patient (0.1%), 5 patients with elevated CK (0.6%), 3 patients with positive urinary occult blood (0.3%),
and 9 patients with nasopharyngitis (1.0%). In both cases, the degree was reported to be mild, and the outcome was unrecovered in 2 cases with
positive urinary occult blood, but recovered in all other cases.
－ 63－
■ List of side effect occurrence frequency and laboratory test value abnormalities by item Side effect
occurrence status [at the time of initial approval (100 mg tablet and 50 mg tablet)]
Number of cases to be analyzed 901

Number of side effects 103
Number of side effects 151
Frequency of side effects (%) 11.4
Types of side effects Number of cases of expression (%) Types of side effects Number of cases of expression (%)
Infectious diseases and parasites 11 (1.2) Colorectal polyps 1 (0.1)

Nasopharyngitis 9 (1.0) nausea 1 (0.1)
bronchitis 1 (0.1) Pancreatic enzyme abnormality 1 (0.1)
Cellulitis 1 (0.1) Hepatobiliary system disorder 8 (0.9)
Bacterial vaginitis 1 (0.1) Liver dysfunction 4 (0.4)
Vulva inflammation 1 (0.1) Cholecystitis 1 (0.1)
Wound infection 1 (0.1) Cholelithiasis 1 (0.1)
Benign, malignant and unspecified newborns Fatty liver 1 (0.1)
2 (0.2)
Things (including cysts and polyps) Hyperbilirubinemia 1 (0.1)
Adrenal neoplasm 1 (0.1) Skin and subcutaneous tissue disorders 16 (1.8)
Bladder cancer 1 (0.1) eczema 6 (0.7)
Plasma cell myeloma 1 (0.1) rash 4 (0.4)
Blood and lymphatic system disorders 2 (0.2) Pruritus 2 (0.2)
anemia 2 (0.2) Skin ulcer 2 (0.2)
Endocrine disorders 1 (0.1) hives 2 (0.2)
Thyroid cyst 1 (0.1) Alopecia areata 1 (0.1)
Metabolic and nutritional disorders 12 (1.3) Erythema 1 (0.1)
Hypoglycemia 9 (1.0) Papules 1 (0.1)
Dyslipidemia 2 (0.2) Generalized pruritus 1 (0.1)
Hyperkalemia 1 (0.1) Addictive rash 1 (0.1)
Nervous system disorders 1 (0.1) Musculoskeletal and connective tissue disorders 3 (0.3)
Diabetic Neuropathy 1 (0.1) Muscle spasticity 1 (0.1)
Eye disorders 3 (0.3) Limb pain 1 (0.1)
Dry eye 2 (0.2) Polyarthritis 1 (0.1)
Diabetic retinopathy 1 (0.1) Renal and urinary tract disorders 1 (0.1)
Heart damage 4 (0.4) Ureter stones 1 (0.1)
Atrial fibrillation 3 (0.3) Reproductive system and breast disorders 2 (0.2)
Palpitations 1 (0.1) Benign prostatic hyperplasia 1 (0.1)
Angiopathy 1 (0.1) Hematospermia 1 (0.1)
High blood pressure 1 (0.1) General / systemic disorders and the condition of the administration site 1 (0.1)
Respiratory, thoracic and mediastinal disorders 2 (0.2) Thirst 1 (0.1)
Oropharyngitis 2 (0.2) Laboratory test 32 (3.6)
Gastrointestinal disorders 18 (2.0) Increased lipase 8 (0.9)
constipation 5 (0.6) Increased blood creatine phosphokinase 5 (0.6)
Gastric polyp 2 (0.2) Increased alanine aminotransferase 3 (0.3)
stomach ache 1 (0.1) Increased amylase 3 (0.3)
Upper abdominal pain 1 (0.1) Increased aspartate aminotransferase 3 (0.3)
diarrhea 1 (0.1) Urine blood positive 3 (0.3)
Indigestion 1 (0.1) Increased γ-glutamyl transferase 2 (0.2)
gastritis 1 (0.1) Increased pancreatic enzymes 2 (0.2)
Erosive gastritis 1 (0.1) Increased blood creatinine 1 (0.1)
hemorrhoid 1 (0.1) Increased blood glucagon 1 (0.1)
Ileus 1 (0.1) Decrease in blood glucose 1 (0.1)
Intestinal obstruction 1 (0.1) Increased blood glucose 1 (0.1)
－ 64-
Types of side effects Number of cases of expression (%) Types of side effects Number of cases of expression (%)
Increased blood triglyceride 1 (0.1) Platelet count reduction 1 (0.1)

Increased blood uric acid 1 (0.1) Increased platelet count 1 (0.1)
Liver function test abnormalities 1 (0.1) Urine protein positive 1 (0.1)
This table is the Japanese version of the ICH International Pharmaceutical Glossary (MedDRA / J Ver.16.0) Terms listed in (Preferred Term) It is displayed with.
When the same event occurs multiple times in the same case, the number of adverse drug reactions (number of cases) is counted as one case. In addition, the total number
of adverse drug reactions is counted.
(Aggregation at the time of initial approval: March 2015)
(Reference) Frequency of adverse drug reactions in daily administration test of toleragliptin[Overseas data]Ten)
Toleragliptin 100 mg, daily preparation for type 2 diabetic patients* 1Alternatively, when placebo was administered once daily
for 12 weeks, the side effects with an incidence of 2% or more in either group were as follows. Hypoglycemia* 2The expression
rate was 0% (0/65 cases) in the toleragliptin 100 mg group, daily preparation.* 1Although it was 1.6% (1/61 cases) in the group,
the amount of change in fasting blood glucose level* 3Is a toleragliptin 100 mg group-20.5 (-99.0, 131.0; 166.6) mg / dL, daily
preparation* 1The group was -16.6 (-160.0, 141.0; 167.7) mg / dL.

*1 DPP-4 inhibitor administered once daily
*2 The onset of hypoglycemia was defined as a blood glucose level of less than 60 mg / dL and a blood glucose level of less than 50 mg / dL regardless of the presence or absence of hypoglycemic symptoms. Amount of change
*3 from before administration: Indicates the least squares average value (Min, Max; pre-administration value (average value)).
■ Side effects with an incidence of 2% or more in any group
Toleragliptin 100 mg daily formulation placebo
Number of cases investigated 65 61 63

Number of cases with adverse drug reactions (%) 14( 21.5) 16 (26.2) 8 (12.7)
Gastrointestinal disorders
diarrhea 2 (3.3) 5 (7.9)
nausea (1 1.5) 1 (1.6) 4 (6.3)
Systemic disorders and local mode of administration
fatigue (2 3.1)
Nervous system disorders
headache 2 (3.3) 1 (1.6)
Skin and subcutaneous tissue disorders
rash (3 4.6)
Only toleragliptin 100 mg, daily preparation and placebo are shown in the table. MedDRA / J ver.10.0
[Test method]
Subjects: Type 2 diabetic patients with inadequate glycemic control even after lifestyle improvement (diet / exercise therapy) or metformin monotherapy (385
patients)
Administration method: 3.125 mg, 12.5 mg, 50 mg, 100 mg of toleragliptin, daily preparation (DPP-4 inhibitor administered once daily) or placebo once daily
for 12 weeks before the first meal of the day It was administered.
9. Impact on laboratory test results
Not set
－ 65－
Ten. Overdose
13. Overdose
13.1 Treatment
It is considered that removal of this drug by hemodialysis is not useful. [Refer to 16.6.1]
<Commentary>
For the removal rate of this drug by dialysis, etc.VII. 9. Removal rate by dialysis, etc.See section.
11. Precautions for application
14. Precautions for application
14.1 Precautions when delivering drugs
Instruct them to take the drug in the PTP package from the PTP sheet and take it. Accidental ingestion of the PTP sheet
may cause a hard sharp corner to pierce the esophageal mucosa and cause perforation, resulting in serious
complications such as mediastinitis.
<Commentary>
This is a common precaution for drugs that use PTP sheets. Accidents have been reported in which patients accidentally take PTP sheets. Accidental ingestion
of PTP sheets can have serious consequences such as gastrointestinal tears and perforations, and has been alerted by the Ministry of Health, Labor and
Welfare, the National Consumer Affairs Center of Japan, the Japanese Nursing Association, and the Japan Council for Quality Health Care.
Accidental ingestion of the PTP sheet occurs both in the hospital and at home, so when giving medicine in the
hospital, take out the drug from the PTP sheet and hand it over. Be careful, such as explaining that the PTP sheet
should not be separated, but should be taken out of the sheet and taken internally.
(Medical Administration Total Issue 0915 No. 2, Yaksik Total Issue 0915 No. 5, Yaksik Safety Issue 0915 No. 1 dated September 15, 2010)
12. Other notes

(1) Information based on clinical use
15.1 Information based on clinical use
800 mg as toleragliptin in overseas clinical trialsnote)QT prolongation has been reported with a single
dose of. [Refer to 17.3.1]
Note) The approved dosage and administration of this drug is usually 100 mg of toleragliptin orally administered once
a week.
<Commentary>
"V.5. (2) Clinical pharmacology study 2) ”. In the domestic phase III study (100 mg of toleragliptin, 795 patients, administration period 12
to 52 weeks), each clinical trial institution conducted a more objective and accurate ECG evaluation. Evaluation was performed using the
results of measurement with the same electrocardiograph and rereading the measurement results at the Central Reading Center
(central measurement institution outside the hospital). As a result, no concerns were found regarding each parameter, including
arrhythmia-related adverse events associated with QT / QTc interval prolongation and the ECG QTcF interval.Note b..
Note b Negative in the QT / QTc evaluation test based on the ICH E14 guidelines means that the upper limit of the 90% confidence interval on both sides of the QTc prolongation effect is 10 msec.
It is defined to refer to cases below.
(2) Information based on non-clinical studies
Not set
－ 66－
IX. Items related to non-clinical trials
1. 1. Pharmacological test
(1) Pharmacological test
"VI. Items related to medicinal pharmacologySee section
(2) Safety pharmacology test
Actions on general symptoms and behavior in rats (comprehensive evaluation method for functional observation), actions on the
respiratory system in rats (whole body plethysmography method), actions on hERG current (whole cell clamp method), and blood
(Telemetry
pressure and heart rate in unanesthetized dogs Effect on numbers and electrocardiogram method) was examined
As a result, toleragliptin succinate or toleragliptin trifluoroacetatein vitroIn the test, the hERG
current was slightly inhibited, butin vivoNo relevant changes were found in the study.
(3) Other pharmacological tests
For the purpose of investigating the possibility of pharmacological action due to activities other than DPP-4 inhibition, it is
intended for inhibitory activity against various enzymes, receptors, ion channels and transporters.in vitroThe action was
examined. Toleragliptin succinate showed no more than 50% inhibition at a concentration of 10 μmol / L for all assessed
enzymes, receptors, ion channels and transporters.

2. Toxicity test
(1) Single-dose toxicity test
Animal species Route of administration Dosea) (Mg / kg / day) Approximate lethal dosea) (Mg / kg / day)
Rat Oral 0, 600, 2000 > 2000
Dog Oral 30 → 300 → 2000 (gradual increase) > 2000
a) As toleragliptin
－ 67－
(2) Repeated dose toxicity test
Animal species Administration period Route of administration Dosea) (Mg / kg / day) NOAELa) (Mg / kg / day)
4 weeks 0, 50, 250, 1000 250

Rat 13 weeks Oral 0, 80, 250, 750, 1500 0, 250
26 weeks + 8 weeks recovery 25, 75, 250, 750 250
4 weeks 0, 25, 75, 200 75
13 weeks 0, 10, 30, 100, 300 100
Dog Oral
0, 15, 50, 150/100 (weight loss
39 weeks + 13 weeks recovery 100
from 150 to 100 on Day15)
a) As toleragliptin
1) rat
In a 4-week study, hair contamination, neutrophil count, high lymphocyte count (male) and white blood cell count (male), increased
urinary protein (male), total cholesterol, inorganic phosphorus and ALP at 1000 mg / kg / day High levels of sodium, chloride, albumin
and total protein, high liver weight and lobular central hepatocyte hypertrophy, low thymic weight and thymic cortical lymphocyte
depletion were observed. Both changes disappeared after a 2-week washout. In a 13-week study, hair contamination at 750 mg / kg /
day or higher, high levels of total cholesterol and ALP, vacuolarization of hepatocytes around the portal vein in the liver, suppression of
coarse hair and weight gain at 1500 mg / kg / day, γ- High GTP was found.
In the 26-week study, hypersalivation was observed at 75 mg / kg / day and above, and high water intake was observed at 250 mg / kg / day and
above. Hair contamination, suppression of weight gain (male), high feeding (female), red blood cell count, hemoglobin concentration, mildly low
hematocrit level, high ALP, calcium, inorganic phosphorus, and total cholesterol at 750 mg / kg / day (Female), low urine pH, high liver weight
(female), peristricular hepatocyte vacuolation and lobular central hepatocyte hypertrophy (female) were observed. All changes recovered after an
8-week washout.
2) dog
In a 4-week study, food intake decreased at 25 mg / kg / day or higher, auricle / periocular / nose / lip redness, hypersalivation (female),
hypersalivation (male) at 200 mg / kg / day or higher, 75 mg. Females at / kg / day and 200 mg / kg / day showed decreased locomotor activity,
facial swelling, decreased appetite and decreased feces, and 200 mg / kg / day showed weight loss, vomiting, slimming and decreased skin
elasticity. rice field. The change was also recovered by a 2-week washout.
In a 13-week study, severe food loss, extreme weight loss, salivation, yellowish watery stool / mucous stool, pinna / nose / periocular
redness or graying, locomotor activity at 300 mg / kg / day Decreased skin temperature, tremor and vomiting, periocular swelling
(female), red blood cell count, hematocrit, hemoglobin concentration, high monocyte count (male), low chloride, high albumin and urea
nitrogen There was a tendency, high levels of inorganic phosphorus (male) and low levels of potassium (female). At necropsy, the small
intestine turned red.
In the 39-week study, weight loss and food intake decreased after administration of 150 mg / kg / day, so the dose was reduced to 100 mg / kg /
day from the 15th day of administration. Facial swelling at 50 mg / kg / day (female) (1st week only), salivation at 150/100 mg / kg / day, facial
swelling (1st week only), red skin at 50 and 150/100 mg / kg / day The swelling was seen.
－ 68－
(3) Genotoxicity test
It was negative in all of the reversion mutation test using bacteria, the mouse phosphorform test, and the mouse
micronucleus test.
(4) Carcinogenicity test
As a result of conducting a 24-month forced oral administration carcinogenicity study in mice and rats, no carcinogenicity was
observed in any of the species.

(5) Reproductive developmental toxicity test
Dosea) NOAELa) (Mg / kg / day)

Test items Animal species Administration period
(Mg / kg / day) parent Embryo / foetation / birth
Male: 14 days before mating
Fertility and early stage autopsy 0, 100, 300, General toxicity: 300
Rat Embryo:≥1000
Embryogenesis Female: 14 days before mating 1000 Fertility:≥1000
7 days pregnant
0, 100, 300,
Rat 6-17 days pregnant 300 Embryo / foetation: 300
1000
Embryogen / fetal development
0, 25, 80,
rabbit 6-18 days pregnant 80 Embryo / foetation:≥250
250
0, 100, 300,
Occurs before and after birth Rat 6 days pregnant to 20 days breastfeeding 300 Birth: 300
1000
a) Orally administered as toleragliptin
1) Tests on fertility and early embryonic development
In rats, weight gain suppression and low food intake were observed in males and females in the 1000 mg / kg / day group.
2) Tests for embryo / fetal development
In rats, maternal animals in the 1000 mg / kg / day group had low body weight and food intake, and the foetation had
low body weight and associated delayed ossification.
In rabbits, maternal animals in the 250 mg / kg / day group showed death, miscarriage, suppression of weight gain, and low food intake.
3) Prenatal and postnatal tests

In rats, maternal animals in the 1000 mg / kg / day group showed death, suppression of weight gain and low values, and low food intake, and for offspring,
high stillbirth rate, survival rate, weaning rate, and number of surviving babies. And low weight of surviving infants, delayed auricular opening and delayed
foreskin separation of the glans penis were observed.
(6) Topical irritation test
Not applicable
(7) Other special toxicity
1) Phototoxicity test
With a hairless mousein vivoAs a result of conducting a phototoxicity test, the phototoxicity was negative.
2) Monkey skin toxicity test
Since the development of necrotic lesions was reported in monkey skin with a similar drug having a DPP-4 inhibitory effect, the possibility of
inducing monkey skin toxicity was investigated. No abnormalities were found in the macroscopic observation of the skin or histopathological
examination.
－ 69－
X. Items related to management matters
1. 1. Regulation classification
Made Agent: Zafatec Tablets 100mg / 50mg / 25mg

Prescription drugs (Caution-Use according to the prescription of a doctor,
etc.) Active ingredient: Toleragliptin succinate Not applicable
2. Validity period
Validity period: Zafatec Tablets 100mg: 4 years
Zafatec Tablets 50mg :3 years
Zafatec Tablets 25mg :3 years
3. 3. How to store in the package
Store at room temperature
Four. Handling precautions
Not set
Five. Materials for patients
Patient Drug Guide: Yes

Medicine bookmark: Yes
Other patient materials:
・ For patients taking Zafatec tablets (Patient medication precautions: hypoglycemia)
(Materials created to minimize the risk of RMP) -For patients taking Zafatec tablets (Patient medication
precautions: Events related to overdose / overdose) (Created to minimize the risk of RMP) Materials)
"Ⅰ.4. Characteristics that should be known regarding proper useSee section
6. Same ingredient / same effect
Same ingredient drug: None
Efficacy: sitagliptin, vildagliptin, alogliptin, linagliptin, etc.
7. 7. International date of birth
March 26, 2015 (Japan)
8. 8. Manufacturing and marketing approval date and approval number, drug price standard listing date, sales start date
Manufacture and sale Drug price standard

Brand name Approval number Sales start date
Approval date Date of listing
Zafatec lock
22700AMX00643
100mg
March 26, 2015 May 20, 2015 May 28, 2015
Zafatec lock
22700AMX00642
50mg
Zafatec lock
August 21, 2019 30100AMX00217 November 27, 2019 December 3, 2019
25mg
－ 70－
9. Date and contents of indication or addition of effect, usage and dose change addition, etc.
Not applicable
Ten. Re-examination result, re-evaluation result publication date and contents
During the reexamination period
11. Reexamination period
Zafatec Tablets 100mg, Zafatec Tablets 50mg 8

years: March 26, 2015-March 25, 2023
Zafatec Tablets 25mg

Remaining period above: August 21, 2019-March 25, 2023
12. Information on dosing period restrictions
There are no restrictions on the duration of medication (or administration) for this drug.
13. Various codes
Individual drug code

Ministry of Health, Labor and Welfare drug price standard Receipt computer processing
Brand name HOT (9 digits) number
Listed drug code (YJ code) System code
Zafatec lock
3969024F2024 3969024F2024 124155601 622415501
100mg
Zafatec lock
3969024F1028 3969024F1028 124154901 622415401
50mg
Zafatec lock
3969024F3020 3969024F3020 126995601 622699501
25mg
14. Precautions for insurance benefits
Not applicable
－ 71－
Ⅺ. Literature
1. 1. Citations
1) Toleragliptin pharmacokinetic test results ➀ (Approved March 26, 2015: CTD 2.7.6.3) 2)
Toleragliptin pharmacokinetic test results ➁ (Approved March 26, 2015: CTD 2.7.6.4) 3)
Toleragliptin Examination of QT / QTc interval (approved on March 26, 2015: CTD 2.7.6.7) 4) Clinical
trial results of toleragliptin ➁ (approved on March 26, 2015: CTD 2.7.6.13) 5) Clinical trial results of
toleragliptin ➂ (Approved on March 26, 2015: CTD 2.7.6.16) 6) Clinical trial results of toleragliptin
➄ (Approved on March 26, 2015: CTD 2.7.6.18) 7) Clinical trial results of toleragliptin ➅ (August 21,
2019) Date Approval: CTD 2.7.6.2) 8) Clinical trial results of toleragliptin ➃ (Approved on March 26,
2015: CTD 2.7.6.17) 9) In-house data: Post-marketing clinical trial results of toleragliptin
10) Clinical test results of toleragliptin ➀ (approved on March 26, 2015: CTD 2.7.2.1) 11) Examination of the glucose
tolerance improving effect of toleragliptin (approved on March 26, 2015: CTD 2.6.2.2) 12) Examination of enzyme
inhibitory activity (approved on March 26, 2015: CTD 2.6.2.2) 13) Pharmacokinetic test results of toleragliptin ➂
(approved on March 26, 2015: CTD 2.7.6.1) 14) Mutual drug-to-drug with glymepyrid Action test results (March 26,
2015 approval: CTD 2.7.6.10) 15) Drug-drug interaction test results with metformin (March 26, 2015 approval: CTD
2.7.6.11) 16) Caffeine, tolbutamide, dext Results of drug-drug interaction test with Rometrphan and Midazolam
(Approved on March 26, 2015: CTD 2.7.6.12) 17) Pharmacokinetic test results in patients with renal
dysfunction (Approved on March 26, 2015: CTD 2.7.6.8) 18) Pharmacokinetic test results in patients with
hepatic dysfunction (Approved March 26, 2015: CTD 2.7.6.9) 19) Examination of protein binding of
toleragliptin (Approved March 26, 2015: CTD 2.6.4.4) 20) Examination of metabolism of toleragliptin
(March 26, 2015) Approval: CTD 2.6.4.5) 21) Examination of excretion of toleragliptin (Approved on March
26, 2015: CTD 2.7.2.2)
2. Other references
Not applicable
－ 72－
Ⅻ. Reference material
1. 1. Sales status in major foreign countries
Not sold overseas
2. Overseas clinical support information
Not applicable
－ 73－
XIII. remarks
1. 1. Reference information for making clinical decisions regarding dispensing and medication support
Note on information in this section: This section contains information about unapproved quality. It includes contents for
which the test method has not been established, and the results obtained by the described test method are presented as
facts. It is reference information for medical professionals to consider clinical application, and does not indicate the
possibility of processing.
(1) Crushing
Stability after crushing
The stability of Zafatec tablets 25 mg, 50 mg and 100 mg after pulverization were as follows, respectively.
■ Storage conditions: 25 ℃ / 75% RH, indoor scattered light (glass bottle, opening)
Zafatec Tablets 25mg (Lot No.58102201)

Measurement item initial 0.5 months 1 month 2 months 3 months 100 days
Fine band yellowish white

Appearance (color / shape) No change No change No change No change No change
Powder
Related substances (total amount) (%) 0.42 0.42 0.40 0.40 0.39 0.39
content(%) 98.8 98.9 98.5 98.3 98.0 98.1
[Residual rate in parentheses] (100.0) (100.1) (99.7) (99.5) (99.2) (99.3)
Dry weight loss (%) 1.6 3.9 3.7 3.8 3.8 3.7
Quantitative limit Quantitative limit Quantitative limit Quantitative limit Quantitative limit Quantitative limit
Enantiomer (%)
Less than Less than Less than Less than Less than Less than
■ Storage conditions: 25 ° C / 75% RH, white fluorescent lamp (500lx x 24h = 12000lx ・ h / day) (test container, opening)

Fine band yellowish white

Powder
content(%) 100.1 99.5 100.2 99.4 99.3 98.8
Dry weight loss (%) 1.6 3.5 3.4 3.4 3.6 3.8 3.8
Enantiomer (%)

Fine band reddish white

Powder
content(%) 100.0 98.7 99.0 99.1 98.9 98.7
Dry weight loss (%) 1.2 3.4 3.4 3.3 3.6 3.6 3.6
Enantiomer (%)
－ 74－
■ Storage conditions: 40 ° C, dark place (glass bottle, tight plug)

Measurement item initial 0.5 months 1 month 2 months 3 months
Microband yellowish white

Appearance (color / shape) No change No change No change No change
Powder
Related substances (total amount) (%) 0.42 0.42 0.41 0.48 0.50
content(%) 98.8 98.4 98.0 98.2 97.5
Dry weight loss (%) 1.6 3.4 3.4 4.1 4.7 5.0
Enantiomer (%) less than quantification limit Less than the quantification limit Less than the quantification limit Less than the quantification limit Less than the quantification limit
■ Storage conditions: 40 ° C, dark place (test container, tight plug)

Microband yellowish white

Powder
content(%) 100.1 98.8 99.8 99.4 99.1
Dry weight loss (%) 1.6 1.9 2.0 2.0 2.0

Fine band reddish white

Powder
content(%) 100.0 98.9 100.0 99.2 99.7
[Residual rate in ()] (100.0) (98.9) (100.0) (99.2) (99.7)
Dry weight loss (%) 1.2 1.7 1.7 1.9 1.9 1.8 1.8
(2) Disintegration / suspension and passability of tube administration tube
1) Disintegration and passage through the suspension

Suspension conditions: Add 20 mL of water at 55 ° C to one tablet, leave at 37 ° C, and shake gently after 5 and 10 minutes to disintegrate.
After observing the condition, the test was performed.
Destruction operation: With coating destruction operation
Results: Disintegration was confirmed after 5 minutes, and there was no problem with the passage of the tube
administration tube. Zafatec Tablets 25mg (Lot No.58102201)
Measurement item after 5 minutes 10 minutes later Test results
Nasal tube
Completely collapsed Completely collapsed There was no problem with passability
(8Fr.)
Gastro button
Feeding tube Completely collapsed Completely collapsed There was no problem with passability
(18Fr.)
－ 75－
Zafatec Tablets 50mg / Zafatec Tablets 100mg
Suspension conditions: Add 20 mL of water at 55 ° C to one tablet, leave at room temperature, and shake gently after 5 and 10 minutes to disintegrate.
After observing the condition, the test was performed. (Syringe)
Destruction operation: With coating destruction operation
Result: Disintegration was confirmed after 10 minutes with Zafatec Tablets 50 mg (depending on the test results, after 5 minutes.
Collapsed). Disintegration was confirmed after 10 minutes with Zafatec Tablets 100 mg. In each case, there was no problem
with the passability of the tube throwing tube.
Zafatec Tablets 50 mg (Lot No.002) and Zafatec Tablets 100 mg (Lot No.001)
Measurement item after 5 minutes 10 minutes later Test results
Some small chunks For passability

Zafatec Tablets 50mg Tube tube (8Fr.) Completely collapsed
Was left There was no problem
Some small chunks For passability

Zafatec Tablets 100mg Tube tube (8Fr.) Completely collapsed
Was left There was no problem
Gastro button For passability

Zafatec Tablets 50mg Completely collapsed ―
Feeding tube (18Fr.) There was no problem
Gastro button Some small chunks For passability

Zafatec Tablets 100mg Completely collapsed
Feeding tube (18Fr.) It was left There was no problem
2) Suspension stability

The state was observed.
Storage conditions: 25 ° C (glass bottle, tight stopper)
Results: Even after 4 hours, no particular problematic changes were observed in the content.
Measurement item initial Half an hour 1 hour 2 hours 4 hours
content(%) 99.0 98.8 99.0 99.3 99.8
[Residual rate in ()] (100.0) (99.8) (100.0) (100.3) (100.8)
Zafatec Tablets 50mg / Zafatec Tablets 100mg

The state was observed.
Storage conditions: 25 ° C (test container, tight plug)
Results: No particular problematic changes were observed in the content, etc., even after 4 hours.
content(%) 97.8 97.9 99.9 97.6 97.5
[Residual rate in ()] (100.0) (100.1) (102.1) (99.8) (99.7)

content(%) 97.8 98.8 99.3 96.9 96.0
[Residual rate in ()] (100.0) (101.0) (101.5) (99.1) (98.2)
－ 76－
2. Other related materials
Materials for healthcare professionals:
For patients taking Zafatec tablets (Patient explanatory material: events related to overdose / overdose)
(Material created to minimize the risk of RMP)
"Ⅰ.4. Characteristics that should be known regarding proper useSee section
－ 77－
12 (1)

Pharmaceutical Interview Form: One Name

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Pharmaceutical Interview Form: One Name

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Translated from Japanese to English - www.onlinedoctranslator.

Pharmaceutical interview form

Persistent Selective DPP-4 Inhibitor-Therapeutic Agent for Type 2 Diabetes-

Toleragliptin succinate tablets

100mg: Film-coated lock with double-sided

Japanese name: Toleragliptin succinate (JAN)

100mg, 50mg 25mg

Manufacture, sale, approval

Sales start date May 28, 2015 December 3, 2019

Manufacture, sale (import),

Contact information for medical representatives

Takeda Pharmaceutical Company Limited Medicine Counseling Room

Inquiry window mouth Toll free number 0120-566-587

(Revised in April 2020)

1. 1. Background of creating the drug interview form

Information Committee revised the IF description guidelines.

by companies involved in the manufacture, sale or sale of

Medical Devices Information Search page before using IF.

Four. Points to keep in mind when using

I. Items related to the overview

(1) Approval conditions (2) For distribution and use Restrictions on 2

II. Items related to names

(1) Japanese name 3

(1) Japanese name (nomenclature) (2) Western name (Nomenclature) 3

III. Items related to active ingredients

(1) Appearance / properties Four

Ⅳ. Items related to pharmaceutical products

V. Items related to treatment

(1) Clinical data package 14 (2) Clinical pharmacology study 15

Patient / pathological examination 33 (6) Therapeutic use

VI. Items related to medicinal pharmacology

1. 1. Pharmacologically related compounds or groups of compounds 34 2. Pharmacological

VII. Items related to pharmacokinetics

(1) Therapeutically effective blood concentration 42 (2) Confirmed in clinical trials

(1) Analysis method 46 (2) Absorption rate constant

(1) Analysis method 46 (2)

(1) Blood-brain barrier crossing 47 (2) Blood-placental barrier Passability

(4) Translocation to cerebrospinal fluid

(5) Migration to other organizations 49

VIII. Items related to safety (precautions for use, etc.)

(1) Patients with complications / medical history 56 56 56

(3) Patients with hepatic dysfunction

(4) Those who have fertility 56

(8) Elderly people

(1) Contraindications for combined use and their reasons 59 59

(1) Serious side effects and initial symptoms 61

IX. Items related to non-clinical trials

(1) Pharmacological drug efficacy test 67 (2) Safety pharmacological test

(1) Single-dose toxicity test 67 68

(3) Genotoxicity test 69 69

(5) Reproductive developmental toxicity test 69

X. Items related to management matters

1. 1. Sales status in major foreign countries 73 2. Overseas clinical support information

Toleragliptin succinate is a dipeptidyl peptidase-4 (DPP-4) inhibitor created by Takeda California,

administration once a week.

2. Therapeutic properties of the product

showed an excellent hypoglycemic effect when administered once a week.

(""VI.2. (2) Tests to support drug efficacy 1) and 2) ”)

(""VIII. 8. (1) Serious side effects and initial symptomsSee section)

3. 3. Pharmaceutical properties of the product

Four. Characteristics that should be known regarding proper use

For patients taking Zafatec tablets (Patient medication precautions: overdose

Events related to giving / overdose)