Attachment 2 - Trelagliptin Succinate - Reference of Japanese IF File

2016 Year 6 month revised (5th edition)
Pharmaceutical interview forms

Persistent selective DPP-4 inhibitor
-2 diabetes treatment－
Japan Hospital Pharmacists of IF according to the guidelines in 2013 prepared in accordance with the
Japan Standard commodity classification numbers:873969
Agent
Form
100mg: double-sided secant get Film-coated tablets
50 mg :film-coated tablets
Made by agents of the regulatory divisions
Note－doctors, etc., prescription for use by the
Regulations
Rating ・
Including
Amount
1 tablet in the report, alogliptin as 100 mg and 50 mg contain
One
General
Name
Japanese name:plus alogliptin succinic acid salt (JAN)
ocean name: Trelagliptin Succinate(JAN)
Manufacturing sales approval date
drug prices based on the quasi-fit mounting
・ Emits sale Year Month Day
Manufacturing sales approval date: 2015 Year 3 month 26 day
drug prices based on the quasi-fit mounting day month year: 2015 Year 5 month 20 day
totals sold date: 2015 Year 5 month 28 day
Development, production and distribution (import)･
Alliance ･ sale company name:
Manufacture and sale of original Takeda Pharmaceutical Co., Ltd.
Pharmaceutical information contact
Contact window mouth
Takeda Pharmaceutical Co., Ltd. the consultation
toll 0120-566-587
hours: 9: 00 ~ 17:30(weekends and holidays･our holiday except)
medical personnel for the home page http://www.takedamed.com/
This IF the 2016 6 on the revision of the attachments listed are based on.
For the latest package insert information,National Institute for pharmaceuticals and Medical Devices Agency home page"Drug
Information"
http://www.pmda.go.jp/safety/info-services/drugs/0001.html please check the.
IF the use of guide overview

－Japan hospital pharmacists－
1. Pharmaceutical interview forms create history
Pharmaceuticals basic summary information as prescription drugs attachment (the attachment abbreviated as)is
your.
In medical practice, doctors, pharmacists and other healthcare professionals in their day-to-day job required of
rational drug use information to use when
, and attachment information confirms that the additional information may be required.
In medical practice, the pharmaceutical industry, pharmaceutical companies, medical personnel, etc. information
add request or questions using
the information complementary to deal with that. This information needed to comprehensively obtain the
information for the list
and the interview form was born.
Showa era 63 year in Japan of hospital pharmacists(hereinafter, day, disease, drug and abbreviated) academic No.
2 Subcommittee is" pharmaceutical interview
forms"(or less, IF substantially all)of the position and IF according to the style developed. Then, for healthcare
professionals
and patients for the drug information needs change, receive, Ltd., 10 years and 9 months to the day of disease
pharmaceutical technology, 3rd Subcommittee and
as IF the stated terms and conditions of the revision is made.
Even 10 years have passed, and Drug Information of the products in the pharmaceutical industry, use hand and in
the medical field, pharmacist, capital
and Regulatory Affairs・medical environment is changing, the Heisei 20 years and 9 months to the day of disease
medicine pharmaceutical information Committee
meetings IF according to the manner 2008 was formulated.
IF according to the manner in 2008, IF a printed booklet that provides a method from PDF, etc. of
electromagnetic data, and
providing (e-IF) is the principle was. This changes,attachments, and"indications of the chase
in","warning・contraindications・important fundamental note of the revision, such as"revision if there was a
revision of the basis of the data up
in the latest version of e-IF it is provided with.
The latest version of e-IF,(Germany) pharmaceuticals and Medical Devices Agency of medicines information
home page(http://www.
info. pmda. go. jp/)from bulk, available now. Japan hospital pharmacists, the e-IF posting to
the pharmaceutical provision of information on the home page is a public site that in consideration, the date of
listing in the Nhi reimbursement price to your e-
IF the information that you consider your organization to be installed as an individual IF you are attachments to
complement the appropriate use of information as appropriate
for the screening and examination to be decided.
In 2008, more than 4 times a year of the interview form an investigative Commission was held in that matters to
reevaluate,
pharmaceutical companies, doctors, pharmacists, etc. and also efficiency, a good source of that thought. It
is we,IF according to the manner of some revise IF the stated guidelines 2013 as published and.
2. IF and is
IF" attachment information such as complement, pharmacists and other healthcare professionals in their daily
work necessary, medicines
for quality control of information,the formulation for the design of the information, and dispensing information
for pharmaceuticals for the appropriate use of
information,pharmaceutical patient care information is aggregated comprehensive individual drug Handbook, the
day the
disease, the medicine according to the guidelines formulated, pharmacists, etc., for the pharmaceutical
pharmaceutical companies to create and offer to ask about
academic material"is being positioned as.
However, the Pharmaceutical Affairs Law, the pharmaceutical company confidential, etc. related to
pharmaceutical formulation efforts to disable and drugs,
agents and masters of their evaluation and judgment・the offer of certain matters is IF the contents are not. In
other words, the pharmaceutical company
business provided IF pharmacists of their evaluation and decision・clinical indications and the necessary
complement to that
of Take That.
[IF the style of]
① standard A4 size, horizontal and,as a Rule 9 or more points of Face(Charts excluded) shown,one color printing
In the left-hand column of said table. However, the attachments in the red frame・deficit in the case of using
electronic media in this follow
that.
②IF, wherein the instructions are based on each item name is the Gothic listed.
③ Cover the description of the unified,the cover to continue the day's disease drugs to create "IF the use of the
manual, you can find an overview of" the full text of the described
Of the 2 pages together.
[IF create
①IF principle, formulation, route of administration to another(residual information that will remain within our
databases and other records, and injectables,topical agents) to be created.
② IF according to the items and an array is the day the disease the drug is formulated IF the stated guidelines to
comply with.
③ The attachment of the content that complements and IF the spirit of along the required information is stated.
④ Pharmaceutical companies of the confidential information relates to pharmaceutical formulations effort to
disable and pharmacists for
Medical personnel of their evaluation and judgment・the offer should be matters not described.
⑤ "Pharmaceutical interview forms according to guidelines 2013"(hereinafter, the" IF according to guidelines
2013" and abbreviated) to make
Made IF the electronic media, of providing basic and necessary, pharmacists electronic(PDF)from the sign
- printing and use. Companies of binding is not mandatory.
[IF the issuance of]
① "IF according to guidelines 2013"is Heisei 25 years 10 months since the approval of a new drug from the rules
that apply.
② Other drugs," IF according to guidelines 2013" by Create・offer forced to
No.
③ Precautions for use of the revision,review results or revaluation results(clinical revaluation)is published at the
time and adapted to the
Disease of the expansion will be indicated altered significantly if the IF is to be revised.
3. IF using
"IF the stated guidelines 2013"in a PDF file and electronic media in the provision of basic as that. Information
to include your full name and the e-mail address you used to the pharmacist,electronic media, print from the EP:
the EPO has been informed by WIPO that EP was designated in this principle.
Electronic form of the IF, the pharmaceuticals and Medical Devices Agency of the pharmaceutical and medical
device information on the home page
location has been set.
Pharmaceutical company" pharmaceutical interview forms of the manuals in accordance with the"Create・offer,
IF the original
point, given the medical field is missing information or IF the creation time listed in the hard information about
pharmaceutical companies of
MR, etc. to the interview by pharmacists, etc., from their courses IF have to enhance.
Also, from time to time been revised to precautions concerning matters,IF revision in between the
the pharmaceutical pharmaceutical companies to provide attachments and documents, etc., or pharmaceutical
and medical device information delivery
services such as pharmacists, etc., their service, and IF you have the latest package insert for
the pharmaceutical and medical device information on the home page to check.
Incidentally, the proper use and safety of the points listed from" clinical performance"and" the main foreign at
the launch of"the situation
concerning the items, etc. is approval matters relating to this,the handling of it is enough should be noted.
4. Use of notes
IF pharmacists, etc., of the daily operations to essential medicines as a source of information and to use it for.
However, the Pharmaceutical Affairs Act and the prescription drug promotion code, etc., by regulations,
pharmaceutical companies are drug information
can be offered as to the extent of their limitations. IF November's disease drug according to instructions received,
the drug of the pharmaceutical
industry to create・and you mentioned,・to Express the constraints would recognize that
needed to be made.
For pharmaceutical companies,IF there are attachments to complement the information, the materials, and the
Internet in publishing
, etc., based on the Pharmaceutical Affairs Law on the advertising regulations be created with the understanding
that the information utilized
for the need.
(2013 年 4 月 revised)
The
ⅰ . Summary about the item
1. History of development
1
2. Products of a therapeutic formulation composition characteristics
1
II. Name of related items
1. Product name
1-1 Japanese name
2
1-2 Western name
2
1-3 names of origin
2
2. Common name
2-1 Japanese name(nomenclature)
2
2-2 Western names (nomenclature)
2
2-3 system (stem)
2
3. Structural formula or shows sexual expression
2
4. Molecular formula and molecular weight
2
5. Chemical name(nomenclature)
2
6. 慣用名, alias, abbreviations,symbols, numbers
2
7. CAS registry number
2
III. The active ingredient related items
1. Physicochemical properties
1-1 appearance・properties
3
1-2 solubility
3
1-3 hygroscopic
3
1-4 melting point (decomposition point),the boiling point,freezing point
3
1-5 acid-base dissociation constant
3
1-6 distribution coefficient
3
1-7 other main 示性値
3
2. The active ingredient of various conditions on the stability under
3
3. The active ingredient of the confirmatory test method
3
4. The active ingredient of the quantitative method
3
IV. Formulation related items
1. Dosage form
1-1 dosage form of distinction, the appearance and properties
4
1-2 physical properties of the formulation
4
1-3 identification code
4
1-4 pH, osmotic pressure ratio, viscosity, specific gravity, aseptic effect and the stable pH range, etc.
4
2. The formulation of the composition
2-1 active ingredient(active ingredient)of the content
4
2-2 additives
4
2-3 other
4
3. Suspensions, emulsion dispersion for attention
4
4. Formulation of various conditions on the stability under
5
5. Preparation and dissolution after the stability of the
5
6. Other agents and formulation changes(physical and chemical changes)
5
7. Dissolution
5
8. Biological test method
5
9. The formulation of the active ingredient of the confirmatory test method
5
10. Active ingredients in the formulation of quantitative method
5
11. Titer
5
12. Mixed with the possibility of contaminants
5
13. Caution container・appearance is a special container information
5
14. Other
5
V. Items related to treatment
1. Potency or effect
6
2. Usage and dosage
6
3. Clinical performance
3-1 clinical data package
8
3-2 clinical effect
9
3-3 Clinical Pharmacology
10
3-4 exploratory testing
11
3-5 verification studies
13
3-6 therapeutic use
20
VI. Medicinal pharmacology related fields
1. Pharmacologically relevant compound or group of compounds
21
2. Pharmacological action
2-1 site of action・mechanism of action
21
2-2 medicinal supporting test results
21
2-3 effect of the expression of time・duration
28
VII. Pharmacokinetics related items
1. The blood concentration of the transition and measurement
1-1 therapeutically effective blood concentration
29
1-2 the highest blood concentration time
29
1-3 clinical trials confirmed the blood concentration
29
1-4 addiction region
32
1-5 meal・the combination of the drugs effects
32
1-6 population (variation)analysis revealed drug pharmacokinetics variability factors
33
2. Drug kinetic parameters
2-1 analysis methods
34
2-2 absorption rate constant
34
2-3 bioavailability
34
2-4 elimination rate constant
34
2-5 clearance
34
2-6 volume of distribution
34
2-7 plasma protein binding rate
34
3. Absorption
35
4. Distribution
4-1 blood－brain barrier through sex
35
4-2 blood－placenta barrier through sex
35
4-3 milk to migration
36
4-4 cerebrospinal fluid to migration
36
4-5 other organizations to migration
37
5. Metabolism
5-1 metabolic site and metabolic pathways
38
5-2 involved in the metabolism enzymes (CYP450, etc.) of the molecular species
38
5-3 first-pass effect of presence and proportion of
38
5-4 metabolites of the active presence and ratio
38
5-5 active metabolite of kinetic parameters
38
6. Excretion
6-1 excretory sites and pathways
39
6-2 excretion rate
39
6-3 excretion rate
39
7. Transport information
39
8. Dialysis, such as removal rate
39
VIII. Safety (precautions, etc.) relating to the items
1. Warning the contents and why
40
2. Contraindications content and why
40
3. Indications associated with the precautions for use and why
41
4. Usage and dosage associated with the precautions for use and why
41
5. Cautious administration of content and why
41
6. Important fundamental note and its reasons and treatment methods
42
7. Interaction
7-1 combination of contraindications and why
45
7-2 used with caution and why
45
8. Side effects
8-1 side effects overview
47
8-2 significant side effects and symptoms
47
8-3 other side effects
49
8-4 itemized side effect frequency and laboratory abnormalities list
51
8-5 underlying disease,complications, severity and surgery, the presence or absence of the background another
side effect frequency
52
8-6 Allergy medication for attention and test methods
52
9. Elderly administration to
52
10. Pregnant women, nursing mothers,lactation, etc. to the administration of
53
11. Childhood etc. to the administration of
54
12. Laboratory test results on the impact of
54
13. Overdosage
54
14. Application precautions
54
15. Other notes
55
16. Other
55
IX. Non-clinical studies concerning the item
1. Pharmacology
1-1 medicinal pharmacology test ("VI. Medicinal pharmacology related items"section).
56
1-2 secondary pharmacology
56
1-3 safety pharmacology studies
56
1-4 other pharmacology
56
2. Toxicity test
2-1 single dose toxicity test
56
2-2 repeated dose toxicity studies
57
2-3 reproductive and developmental toxicity testing
58
2-4 other special toxicity
58
X. Administrative matters relating to the item
1. Regulatory classification
59
2. Period of validity or expiration date
59
3. Storage method・storage conditions
59
4. Drug handling considerations
4-1 pharmacy in handling matters of note
59
4-2 preparing drugs at about the handling of(patient, etc. should be borne in mind requirements, etc.)
59
4-3 dispensing at key points
59
5. The approval conditions, etc.
59
6. Packaging
59
7. Container material
59
8. The same ingredient・medications with the same
59
9. International birth date
59
10. Approval date and the approval number
59
11. Date of listing in the Nhi reimbursement price date
60
12. Potency or effect add, usage and dosage changes, such as adding the date and contents
60
13. The re-examination results,revaluation results announced date and contents
60
14. The re-examination period
60
15. Dosing period limit drug information
60
16. Various codes
60
17. Insurance benefits on the note
60
ⅺ . Literature
1. References
61
2. Other references
61
ⅻ . References
1. The main foreign release status
62
2. Overseas clinical support information
62
. Remarks
Other related materials
63
－1－
ⅰ. Summary about the item
1. History of development
Plus alogliptin succinic acid salt,Takeda California Inc. developed by dipeptidyl team
peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1(GLP-1) concentrations rise through blood sugar
depends on
if the resistance of the insulin secretagogue action of having Type 2 diabetes treatment. This agent is administered
by the DPP-4 inhibitory
activity lasts for 1 Week and national clinical results confirmed,1 time per week by the administration dosing
frequency reduction and
good medication adherence is expected.
This drug, diet, exercise regimen may be conducted in Type 2 diabetic patients with uncontrolled blood glucose
went on the Internet Sina tablets (up alogliptin benzoate)for non-inferiority trials, including in clinical trials
that the efficacy and safety are reviewed in 2015, 3 month"Type 2 diabetes"of the indications in the manufacturing
and marketing approval
obtained.
2. Products of a therapeutic formulation composition characteristics
(1) the world's first 1 time per week administration of oral hypoglycemic drugs.
(2) 1 time per week administration of excellent hypoglycemic effect was shown. (9, 11 ~ 15 pages)
(3) Week 1 times in the administration of potent DPP-4 inhibitory activity was shown. (22 ~ 24 pages)
(4) side effects
Approval of domestic clinical trials, 901 example in 103 patients (11.4%)in the clinical laboratory value
abnormalities, including the Deputy made
for was observed. The main thing is hypoglycemia, nasopharyngitis,lipase increase, etc. were. (51, 52 pages).
serious side effects as a low glycemic be aware. Also, acute pancreatitis, intestinal obstruction is
made that is similar drugs have been reported.
This material, and HbA1c(NGSP value) = 1.02 ×HbA1c(JDS value) + 0.25 in the exchange rate.
－2－
II. Name of related items
1. Product name
1-1 Japanese name
User file system
®
Tablet 100 mg
User file system
®
Tablets 50mg
1-2 Western name
Zafatek
®
Tablets 100mg.
Zafatek
®
Tablets 50mg.
1-3 names of origin
An oral diabetes medicine which is the first 1 Week 1 dose formulation since it is The first technology
of weekly DPP-4i derives from that.
2. Common name
2-1 Japanese name(nomenclature)
Plus alogliptin succinic acid salt (JAN)
2-2 Western names (nomenclature)
Trelagliptin Succinate(JAN),trelagliptin(r-INN)
2-3 system (stem)
DPP–4 inhibitors:-gliptin
3. Structural formula or shows sexual expression
4. Molecular formula and molecular weight
Molecular formula:C
18
H
20
FN
5
O
2
・C
4
H
6
O
4
Molecular weight: 475.47

5. Chemical name(nomenclature)
2-（｛ 6-［（3
R)-3-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1 (2
H)-yl }methyl)-4-fluorobenzonitrile monosuccinate
6. 慣用名, alias, abbreviations,symbols, numbers
Development code:SYR-472
7. CAS registry number
1029877-94-8
－3－
III. The active ingredient related items
1. Physicochemical properties
1-1 appearance・properties
White~almost white crystals or crystalline powder.
(Takeda・Institute)
1-2 solubility
Water or dimethyl sulfoxide to dissolve easily, methanol and dissolves in ethanol (99.5),
Tetrahydrofuran or diethyl Amine dissolved in the acetonitrile or 2-propanol
is extremely soluble.
1-3 hygroscopic
No (25℃ / 75% RH for 7 days saved)
1 － 4 melting point (decomposition point),the boiling point,freezing point
Melting point: 187.1℃
1-5 acid-base dissociation constant
pKa: 8.6(titration method)
1-6 distribution coefficient
■ 1-octanol and various pH aqueous solution and of the distribution coefficient (25℃)
pH
The distribution coefficient, log P (log Co/Cw)
a)
3.0
－ 2.6
5.0
－ 1.9
7.0
－ 0.99
9.0
0.55
11.0
0.75
a) Co/Cw = 1-octanol phase of the program, alogliptin succinic acid salt concentration/water phase of the program, alogliptin
succinic acid salt
1-7 other main 示性値
Specific rotation〔α〕
20
D
:+ 16.7°
(0.25 g, dimethyl sulfoxide,25 ml,100 mm)
2. The active ingredient of various conditions on the stability under
Test
Storage conditions
Save form
Age
Results
Temperature
Humidity
Long-term storage test
25℃
60% RH
Polyethylene bag(sealed)
36 months
No change
3. The active ingredient of the confirmatory test method
(1) UV-visible absorbance measurement method,
(2) infrared absorption spectrum measurement(potassium bromide tablet Method)
(3) qualitative reaction(succinic acid salt)
4. The active ingredient of the quantitative method
Liquid chromatography
－4－
IV. Formulation related items
1. Dosage form
1-1 dosage form of distinction, the appearance and properties
The tech tablets 100mg
Dosage form
Double-sided secant get Film-coated tablets
Film-coated tablets
Tablet color
Pale red
Pale 黄赤色
Shape
Top view
The lower surface of the
Side
Diameter(mm)
11.0
8.2
Short diameter(mm)
5.6
4.7
Thickness (mm)
About 3. 8
About 3. 1
Mass(mg)
About 187
About 93
1-2 physical properties of the formulation
1-3 identification code
Tablets 100 mg:
◯D389
Tablets 50mg :
◯D388
1-4 pH, osmotic pressure ratio, viscosity, specific gravity, aseptic effect and the stable pH range, etc.
Not applicable
2. The formulation of the composition
2-1 active ingredient(active ingredient)of the content
Tablets 100 mg: 1 tablet in the report, alogliptin succinic acid salt as 133mg(plus alogliptin as 100mg)
Containing
Tablets 50 mg : 1 tablet in the report, alogliptin succinic acid salt as 66. 5mg(plus alogliptin as 50mg)
Containing
2-2 additives
D-mannitol, microcrystalline cellulose,croscarmellose sodium,hydroxypropyl cell
process, sodium stearyl fumarate,hypromellose, macrogol 6000, titanium oxide,
ferric oxide (or more, all formulations containing),yellow ferric oxide(tablets 50mg containing only)
2-3 other
Not applicable
3. Suspensions, emulsion dispersion for attention
Not applicable
－5－
4. Formulation of various conditions on the stability under
The tech tablets 100mg and 50mg of stability both were following the.
Test
Storage conditions
Save form
Age
Results
Temperature
Humidity
Light
Long-term storage test
25℃
60% RH
―
PTP+paper box
36 months
No change
Photostability testing
―
―
D65 light source
(2500lx) without packaging:Greece
120 million lx･h
No change
5. Preparation and dissolution after the stability of the
Not applicable
6. Other agents and formulation changes(physical and chemical changes)
Applicable materials without
7. Dissolution
Dissolution test method and paddle method
8. Biological test method
Not applicable
9. The formulation of the active ingredient of the confirmatory test method
Ultraviolet-visible absorbance measurement
10. Active ingredients in the formulation of quantitative method
Liquid chromatography
11. Titer
Not applicable
12. Mixed with the possibility of contaminants
13. Caution container・appearance is a special container information
Not applicable
14. Other
Not applicable
－6－
V. Items related to treatment
1. Potency or effect
Type 2 diabetes
2. Usage and dosage
Usually, for adults, plus alogliptin as 100 mg
1 week to 1 times of oral administration.
<Dosage and administration related to the usage note>
(1)
Moderate renal impairment patients, the excretion of delay by the drug concentration in the blood will rise to the
following table
for reference
The dose of this. (【Pharmacokinetics】of the section).
Moderate renal impairment patients the dose
Serum creatinine
(mg/dL)
※
Creatinine clearance
(Ccr,mL/min)
Dosage
Moderate renal impairment patients
Male: 1.4<~
≤2.4
30
≤~ < 50
50 mg,1 time per week
Woman: 1.2<~
≤2.0
※:Ccr corresponding to the conversion rate (age 60 Years, Weight 65kg)
(2) the following to the patient guidance can.
1) the agent is
Week 1 times in the medications you take, and the same day of the week to take this.
2) this drug to take if you have forgotten, I noticed at the time
For a dose of only taking, then you
Given the day to take that.
<Remarks>
(1) overseas renal dysfunction to the subject, and alogliptin as 50mg single dose of
Pharmacokinetics were studied as a result, mild renal dysfunction(50<Ccr ≦80mL/min),moderate renal
dysfunction
(30≦Ccr≦50 ml/min),advanced renal dysfunction (Ccr<30 mL/min) and end-stage renal disease patients (blood
transparent
Analysis required for the patient)
(Each group consisting of 6 cases), and gender, age(±10 Years), Weight(±20%) and race to match
For health than adults, and alogliptin unchanged form of the dose(AUC(0－tlqc)
Note a
)Each approximately
1.56-fold,2.06-fold,3. 01-fold and 3. 68-fold. ("VII. 1-3 clinical trials confirmed in the blood concentration,
(3) in Chapter")
From this, moderate renal dysfunction for healthy adults with the same degree of exposure amount for the
normal dose (100mg) of half (50 mg)can. Advanced renal dysfunction and end-stage renal disease for patients with
this agent is contraindicated as that.

Also, mild renal dysfunction, for drug dosage adjustment is not necessary and considered.
Incidentally, in Type 2 diabetes patients domestic clinical trials of combined analysis(plus alogliptin as 50mg
51 examples and 100mg 850 example,the administration period 12 ~ 52-week)safety in the effect of renal
impairment, we examined the effects
as a result of moderate to severe renal impairment (Ccr<50 ml/min)The number of patients from a very
small(plus
alogliptin as 50mg 0 examples and 100mg 16 cases), renal dysfunction (Ccr different) Specific adverse events and
the expression frequency obvious trend was not observed.
Note a 0 hour last from a lower limit of quantification exceeded the concentrations measured time of the plasma area under the concentration-
time curve
－7－
Reference: creatinine clearance(Ccr)
by the following equation creatinine clearance, serum creatinine, gender, age and body weight from approximately
calculation that you can(execution engine－Gault formula).

Ccr(mL/min)=
(140－age)×body weight (kg)
Serum creatinine(mg/dL)×72
The above formula is for men and women this value to 0. 85 multiplied.
(2) this agent is Week 1 times in the medications you take every day to take the drug or not. Weekly on the same
day of the week to take this
And,also, for doses exceeding the taking of such guidance can. If the directions for
the amount of mistake or consultation with you,the following guidance can.
① Agent for the taking if you forget
noticed at the time determined from the dose, and then is given the day of the week to take
To. The following after the date if you have noticed,noticed, and 1 tablet of, and later planned to take
so that the guidance can. Absolutely 2 tablets and not taking.
② The next date before taking, or or 2 tablets at the same time taking you
anxious symptoms if your doctor immediately and consult a pharmacist so that guidance can. Next
From scheduled this was due to the fact that the days of the week taking.
And abroad, and this drug daily administration for safety information,"VIII . 13. Overdose throw
Given in Chapter".
This drug is an oral diabetes medicines for the first time in Week 1 times to take the drug. The patient with
enough medication guidance to do
this.
Patient teaching for underlay and medication notes to prepare, and which can help produce new insights well
beyond what can be achieved when our
company representative for assistance.
－8－
3. Clinical performance
3-1 clinical data package
Rating
reference
Implementation of
regional phase
The purpose of the test
Subject
Study design
◎
Domestic I. single-dose study
Healthy adult male (110 cases)
A double-blind,random assignment, the
placebo control, parallel-group comparison
◎
Repeated administration exam
Healthy adult male(24 examples)
◎
II dosage test
Type 2 diabetic patients(321 example)
◎
Center of drug mutual
action of the test
Healthy adult men's(12 cases)
Open-label, parallel -
◎
III alone long-term administration, or combination of long-term
Administration of the test
Type 2 diabetic patients(680 example)
◎
Validation testing
Type 2 diabetic patients(243 cases)
A double-blind,random assignment, and
log application and check the control and
the reference contrast, parallel-group compared to
comparison
◎
Open label study design
◎
Bioequivalence and food of
the impact test
Healthy adult male
( Bioequivalence testing: 24 example
The influence of diet on test: 12 examples)
Open-label, parallel-random assignment,2×2
crossover
◎
Australia I. QT/QTc assessment test
Healthy adults (260 cases)
Double blind(positive control except for
some), stratified random assignment,the program
set Button and the positive control, parallel-group
comparison
○
United States
Renal impairment in patients with
clinical pharmacology
patients with impaired renal function(24 examples)
Open-label, parallel -, parallel-group comparison
○
Liver dysfunction in patients with
clinical pharmacology
liver dysfunction patients (8 cases)
Open-label, parallel -, parallel-group comparison
○
Metformin drug mutual
action of the test
Healthy adult male (48 examples)
Open-label, parallel-random assignment,2×2
crossover
○
Caffeine, your
address,dextromethorphan
, and midazolam drug phase
interaction test
○
The United States､
Amerika
Serikat
II dose setting test (daily administration)
A double-blind, stratified random assignment
with placebo and the real medicine for the
light, parallel-group comparison
◎
:
Assessment materials,○
:
References
－9－
3-2 clinical effect
HbA1c(NGSP value) = 1.02 ×HbA1c(JDS value) + 0.25 in the exchange rate.
(1) double-blind comparison test(set dose test)
1)
Diet and exercise regimen may be conducted in Type 2 diabetic patients with uncontrolled blood glucose in-
tolerance
, alogliptin as 100 mg(Week 1 times before Breakfast)for 12 weeks was administered a placebo-controlled double-
blind parallel-group comparison
results of the test are as follows was.
The completion of the treatment period, HbA1c(NGSP value) from the previous administration, the amount of
change of the adjusted mean(standard error)and
error alogliptin 100 mg group-0.54(0.068)%,placebo 0 in. 35(0.068)%, and tray green check
design 100 mg group and the placebo group compared with the significant HbA1c reduction was observed (before
Administration of HbA1c(NGSP value) of the
covariate for the analysis of covariance model, based on the comparison test by paired comparison:p < 0.0001).
Also, each evaluation
item of the mean(standard deviation) that are listed in the following table you want. And,before Administration of
HbA1c(NGSP value)of the mean(target
semi-deviation) are tolerant, alogliptin 100 mg group 8. 41(0.97)%,in the placebo group 8. 15(0.95) percent.
Administration Group
HbA1c(NGSP value)
(%)
Fasting glucose
(mg/dL)
Postprandial 2-hour value
(mg/dL)
From the previous administration
The amount of change in the
Placebo
The difference between the
Placebo
Placebo
Placebo (n=55)
0.35
(0.63)
-0.90
[-1.12, -0.69]
9.8
(20.7)
-21.4
[-29.5, -13.2]
16.0
(48.6)
-48.5
[-64.9, -32.0]
Plus alogliptin
100 mg (n=55)
-0.55
(0.50)
-11.5
(22.6)
-32.4
(36.6)
The mean(standard deviation), [] is a two-sided 95% confidence interval
(2) double-blind comparison test(verification test)
2)
Diet and exercise regimen may be conducted in Type 2 diabetic patients with uncontrolled blood glucose in-
tolerance
, alogliptin as 100 mg(Week 1 times before Breakfast), and alogliptin as 25mg (1 Days 1 times before Breakfast)to
24 weeks
multilateral given to local alogliptin contrast, double-blind, parallel-group comparison of the test results are listed
in the following table, the cure,
the treatment period at the end and HbA1c(NGSP value) Before the administration of the amount of change from
the adjusted mean between-group difference in
all, and alogliptin 100 mg group of alogliptin 25 mg group for non-inferiority (tolerance limit: 0.40%)
were tested. And,before Administration of HbA1c(NGSP value)of the mean(standard deviation) are tolerant,
alogliptin
100 mg group, 7.73(0.85)%, and alogliptin 25 mg group, 7.87(0.86)%, respectively.
HbA1c(NGSP value)
※
(%)
Fasting glucose
※※
(mg/dL)
Postprandial 2-hour value
※※
(mg/dL)
Program memory type
Program memory type
Program memory type
Program memory type
25mg (n=92)
-0.45
(0.06)
0.11
[-0.05, 0.28]
-14.9
(27.0)
8.6
[1.7, 15.5]
-29.2
(42.2)
12.1
[-0.9, 25.1]
Plus alogliptin
100 mg (n=101)
-0.33
(0.06)
-6.4
(21.2)
-17.2
(47.7)
※Before the administration of HbA1c(NGSP value)was adjusted on the adjusted mean(standard error), [] is a two-sided 95% confidence interval
※※the mean(standard deviation), [] is a two-sided 95% confidence interval
－ 10 －
(3) long-term administration exam
3)
Diet, therapeutic exercise only,or diet and exercise therapy in addition to oral hypoglycemic agents may be used in
combination with blood glucose
control in Type 2 diabetic patients with uncontrolled plus alogliptin as 100 mg(Week 1 times before Breakfast)
to 52 weeks was administered and the results are listed in the following table you want.
HbA1c(NGSP value) (%)
Pre-dose value
From the previous administration of change
Single administration of cases (n=248)
7.87(0.87)
-0.57(0.88)
Sulfonyl high-dose combination of cases (n=158)
8.09(0.84)
-0.37(0.90)
Rapid-acting insulin secretagogue combination of cases (n=67)
7.87(0.78)
-0.25(0.78)
α-glucosidase inhibitors in combination examples (n=65)
8.07(0.98)
-0.67(0.74)
Biguanides-based drug combination example (n=70)
7.82(0.94)
-0.31(0.82)
Thiazolidine-based drug combination example (n=72)
7.91(0.96)
-0.74(0.65)
The mean(standard deviation)
(4) the DPP-4 inhibitor (1 Day 1 dose)from the change of the exam
4)
Diets, exercise regimens in addition to the existing DPP-4 inhibitor 1 Day 1 times administered to type 2 diabetic
patients(14 cases)
to the subject, and alogliptin as 100 mg(Week 1 times before Breakfast)change after 12 weeks of administration,
the results of the following table
, and there was.
Before the change value
Before the change amount of change from the
After Breakfast blood sugar 2 time value(mg/dL)
202.1(38.3)
-8.7(25.4)
※
Fasting glucose(mg/dL)
140.5 (23.3)
-1.6(13.9)
HbA1c(NGSP value) (%)
7.06(0.49)
0.04(0.36)
The mean(standard deviation) ※tolerant alogliptin change in 7 days after
3-3 Clinical Pharmacology
(1) tolerability test
1) a single dose test
5)
Healthy adult men (110 cases) to the subject, and alogliptin as 3.125 mg, 6.25 mg, 12.5 mg, 25mg,
50mg,100mg, 200mg,400mg,800mg or placebo Breakfast starts 30 minutes before or Breakfast fast under a single
oral administration. 1 or more adverse events expressed subject, the 200mg group in 1/8 patients (12.5%), 100 mg
(morning
food fast under administration) Group in 1/8 patients (12.5%), and clinical and causation is denied. The
other group of adverse events was not observed.
(Approved 時資 fee: 2015 Year 3 month)
Note: This drug's dosage and administration
Usually, for adults, plus alogliptin as 100mg 1 week to 1 times of oral administration.
2) repeated administration exam
6)
Healthy adult men(24 examples)to the subject, and alogliptin as 100mg, 200mg or placebo for Breakfast't Open,
beginning 30 minutes before a single administration (Day 1), and from Day 3 after Breakfast and 30 minutes
before the start of 1 Day 1 times in 11 days repeated administration (4
day~ 14 day) was. Adverse events expressed subjects,the placebo group in 1/6 patients (16.7%), 200mg group
in 1/9 patients (11.1%), and 100 mg group did not. Clinical and causality is undeniable
adverse events were rash is 1 example(200mg group) was.
－ 11 －
(2) the QT/QTc assessment test[overseas]
7)
Healthy adults (260 cases) to the subject, and alogliptin as 200mg,800mg,placebo or positive control
as moxifloxacin 400mg Breakfast intake of 1 to 1.5 hours after single oral administration.
QTcF interval of time-matched baseline from the amount of change of the adjusted mean between-group
difference (plus
alogliptin 200mg group－placebo group)on both sides of the 90% confidence interval upper limit of, any of the
assessment also 10msec
not exceed, the maximum dose 6 hours after 5.85 msec was.
difference (training
program alogliptin 800mg group－placebo group)on both sides of the 90% confidence interval upper limit of the
administration of 1.5 to 8 hours after the
10msec exceed,the maximum is 2 hours after administration of 13.77 msec was.
difference (model
system of the 400mg group－placebo group)on both sides of the 90% confidence interval lower bound of the
administered 2 to 6 hours after
5msec beyond,this study is the analysis sensitivity is shown to be.
3-4 exploratory testing
Double-blind comparison test(set dose test)
1)
Clinical trial purposes

Diet and exercise regimen may be conducted in Type 2 diabetic patients with uncontrolled blood glucose, and
tolerant alogliptin of clinical doses to consider, and alogliptin as 12. 5mg,25mg,
50mg,100mg, 200mg 1 time per week was administered at the efficacy and safety of placebo versus
light and a random assignment, double-blind, parallel-group comparison method was investigated.
Clinical study design multicenter,double-blind,random assignment,placebo-controlled, parallel-group comparison
Trial type
In Phase II, dose-setting the test
Subject
Diet and exercise regimen may be conducted glycemic control is inadequate with Type 2 diabetes
Main selection criteria
(1) the control of the observation period starting 4 weeks after(-4 weeks) HbA1c(JDS value) 6. 5% more than 10. 0% less than the
WHO
(2) the control of the observation period at the beginning (8 weeks) and a control observation period starting 4 weeks after(-4 weeks)
of the HbA1c difference, in contrast to the view
Observation period at the beginning (8 weeks)of HbA1c values within 10% of those who
(3) the control of the observation period at the beginning (8 weeks)in the past 4 weeks or more, a constant diet, exercise
regimen(carried out
If you are)that implement those
The main exclusion criteria for the control of the observation period at the beginning (8 weeks)in the past 4 weeks and contrast of the
observation period during diabetes treatment to medication for those who
Number of cases
321 example( plus alogliptin 12. 5mg group: 54 patients, and alogliptin 25 mg group: 52 for example,
Plus alogliptin 50 mg groups:51 cases, and alogliptin 100 mg group: 55 examples,
plus alogliptin 200mg group: 54 patients,placebo:55 examples)
Method of administration
Plus alogliptin succinic acid or a salt or a placebo to 1 time a week, before Breakfast for 12 weeks was administered orally.
Observation period
(8 weeks)
The treatment phase (12 weeks)
After the observation period
(1 Week)
Plus alogliptin 12.5 mg group (54 cases)
Plus alogliptin 12.5 mg
Plus alogliptin 25 mg group (52 cases)
Plus alogliptin 25mg
Plus alogliptin 50 mg
Plus alogliptin 200mg group (54 cases)
Plus alogliptin 200mg
Placebo group
(55 cases)
Placebo
The main evaluation items, the completion of the treatment period, HbA1c variation〔at the completion of the treatment phase－
observation period at the end(Week 0)〕
a secondary evaluation items HbA1c, fasting blood glucose, meal tolerance test blood glucose
HbA1c:HbA1c(NGSP value) = 1.02×HbA1c(JDS value) + 0.25 in the exchange rate.
－ 12 －
(1) HbA1c change
At the completion of the treatment phase contrast observation period at the end(0 per week)from HbA1c variation
is as shown below,almost the administration
in accordance with the amount of HbA1c reduction from the 100mg group of the HbA1c change 200mg group and
the big difference is
you. All report alogliptin group in the placebo group as compared with the significant HbA1c reduction was
observed.
■ HbA1c change(at the completion of the treatment phase)
Placebo
Plus alogliptin
12.5 mg
25mg
50mg
100mg
200mg
n
55
54
52
51
55
54
Observation period at the end(Week 0)
Measurements
a)
(%)
8.15
(0.946)
8.18
(0.894)
7.99
(0.770)
8.07
(0.864)
8.41
(0.965)
7.84
(0.764)
The amount of change from the
b)
(%)
0.35
(0.068)
-0.37
(0.068)
-0.32
(0.070)
-0.42
(0.070)
-0.54
(0.068)
-0.55
(0.069)
Placebo and
Between-group differences of the point estimate(%)
―
-0.72
[-0.940,
-0.510]
-0.67
[-0.882,
-0.452]
-0.77
[-0.985,
-0.556]
-0.90
[-1.119,
-0.688]
-0.89
[-1.100,
-0.687]
p-value
c)
―
< 0.0001
< 0.0001
< 0.0001
< 0.0001
< 0.0001
a) the mean(standard deviation), b)adjusted mean(standard error), [] is a two-sided 95% confidence interval
c) the p-value for:vs the placebo group,analysis of covariance model was applied to the contrast test
(2) side effects
Side effects the expression of the frequency, and alogliptin 12.5 mg group, 7.4%(4/54 example),25mg group
9.6%(5/52 example),
50mg Group 11. 8% (6/51 cases), 100 mg group 9. 1% (5/55 cases), 200mg Group 5. 6% (3/54 patients) and the
placebo group 3. 6%
(2/55 example)was. This expression frequency of 2% or more of the events,the 50 mg group, anemia, diabetic
menu
Parameter Qi, atrial fibrillation, hypertension, upper abdominal pain,liver function abnormalities, alanine・
amino transferase
increased,aspartate aminotransferase increased,blood creatine phosphokinase increased, and
and γ-polyglutamic the transferase increased each 2.0%(1/51 example)was.
－ 13 －
3-5 verification studies
(1) double-blind comparison test(verification test)
2)

Diet and exercise regimen may be conducted in Type 2 diabetic patients with uncontrolled blood glucose, and
tolerant alogliptin succinic acid salt (plus alogliptin as 100 mg) 1 time per week administration of
efficacy and safety to property, alogliptin benzoate(up alogliptin as 25mg) contrast test to
avenge you.
Clinical trial design
Multicenter,double-blind,random assignment, and alogliptin control and placebo in reference to the control,parallel
between-group comparison
Trial type
Phase III,validation testing,non-inferiority trial
Subject
Diet and exercise regimen may be conducted glycemic control is inadequate for Japanese Type 2 diabetic patients
(1) observation period starting after 4-weeks of HbA1c(JDS value) 6. 5% more than 10. 0% less than the WHO
(2) the observation period at the start and the observation period starting 4 weeks after the HbA1c difference between the
observation period at the start of HbA1c of 10%
Within those
(3) observation period before the start 4 weeks before the completion of the observation period at a constant diet, exercise
regimen(carried out
The main exclusion criteria
Observation period before the start of the 4 weeks and observed during diabetes treatment(injections containing)received a dose of
the
Lord
Number of cases
243 example( plus alogliptin 100 mg group: 101 examples and alogliptin 25 mg group: 92 for example,
Placebo:50 examples)
Plus alogliptin succinic acid or a salt or a placebo to Week 1 times before Breakfast, 24-week oral administration.
Application alogliptin benzoate or placebo for 1 Day 1 times before Breakfast, 24 weeks was administered orally(double -
dummy law).
Observation period
(8 weeks)
The treatment phase(24 weeks)
(1 Week)
Plus alogliptin 100 mg 1 time per week
Application alogliptin 25 mg group (92 cases)
Application alogliptin 25mg 1 Day 1 times
The placebo group (reference control group)(50 examples)
Placebo
The main evaluation items, the completion of the treatment period, HbA1c variation〔at the completion of the treatment phase－
observation period at the end(Week 0)〕
a secondary evaluation items HbA1c, fasting blood glucose, meal tolerance test blood glucose
1) HbA1c change
The completion of the treatment period, HbA1c variation of the adjusted average, and alogliptin 100 mg group
and the program memory
Type 25 mg group, respectively-0.33%and 0.45%, respectively. At the completion of the treatment period HbAlc
change the adjustment of
only the mean of The between-group difference (plus alogliptin 100 mg group－the alogliptin 25 mg group) of the
point estimates[on both sides
95% confidence interval], and 0.11% [-0.054,0.281], and two-sided 95% confidence interval of the upper
confidence limit is pre -
set tolerance limit value is 0.40%fell below this, and alogliptin 100 mg group of
alogliptin 25 mg group for non-inferiority were tested.
■ HbA1c change(at the completion of the treatment phase)
Application alogliptin 25mg
n
101
92
Measurements
a)
(%)
7.73(0.849)
7.87(0.856)
The amount of change from the
b)
(%)
-0.33(0.059)
-0.45(0.061)
Application alogliptin 25 mg group
And of between-group differences of the point estimate(%)
0.11[-0.054,0.281]
―
a) the mean(standard deviation) b)adjusted mean(standard error), [] is a two-sided 95% confidence interval
－ 14 －
2) HbA1c control of the indicators of achievement
The treatment period at the end of HbA1c is 7.0%less than was the proportion of subjects are the following: I.
■ HbA1c control of indicators (7.0% less)achievement (at the completion of the treatment phase)
n
89
83
HbA1c7. 0%less than
Achieved a number of cases(percentage)
26(29.2%)
30(36.1%)
Application alogliptin 25 mg group and of the
Between-group differences of the point estimate(%)
-6.9[-20.934, 7.072]
―
[] Is a two-sided 95% confidence interval
3) fasting blood glucose changes
Plus alogliptin 100 mg group and alogliptin 25 mg group, the treatment period at the end of the fasting blood
glucose levels of the observation
period at the end(Week 0)from the variation of the I.
■ Fasting blood glucose variation (at the completion of the treatment phase)
n
101
92
Measurements(mg/dL)
157.3(30.19)
165.9(41.25)
From the amount of change(mg/dL)
-6.4(21.20)
-14.9(27.04)
Between-group difference in the point estimate of(mg/dL)
8.6[1.71, 15.45]
―
4) meal tolerance test 2-hour post-meal blood glucose values change
Plus alogliptin 100 mg group and alogliptin 25 mg group at the completion of the treatment phase of postprandial
blood glucose level of the observation period
at the end(Week 0)from the 2-hour value variation are as follows I.
■ The meal tolerance test 2-hour post-meal blood glucose value of the change amount(at the completion of the
treatment phase)
n
101
92
Measurements(mg/dL)
239.7(50.91)
251.4(58.13)
n
97
90
From the amount of change(mg/dL)
-17.2(47.65)
-29.2(42.24)
Between-group difference in the point estimate of(mg/dL)
12.1
[-0.94, 25.12]
―
－ 15 －
5) side effects
Side effects the expression of the frequency, and alogliptin 100 mg group 5. 0%(5/101 example) and alogliptin 25
mg group 7. 6%
(7/92 example) and the placebo group 6.0%(3/50 example)was. This expression frequency of 2% or more of the
events, the
Level alogliptin 100 mg group dyslipidemia 2.0%(2/101 example),placebo in constipation, chest discomfort, 瘙
itching disease and high blood pressure are each 2.0%(1/50 example)was.
(2) safety testing
1) long-term administration exam(administered alone or combined administration)
3)

<Alone long-term administration example >
diet, exercise therapy may be conducted in Type 2 diabetic patients with uncontrolled blood glucose, and
tolerant alogliptin succinic acid salt (plus alogliptin as 100 mg) 1 time per week long-term administration
of safety and efficacy were examined.
< Combined with long-term administration example >
diet, exercise regimen, in addition to the existing oral hypoglycemic agents(hereinafter, the Foundation Diabetes Drug)any of
from 1 agent to be administered in Type 2 diabetic patients with uncontrolled blood glucose, on the basis of diabetes
treatment, in addition to tolerance, alogliptin succinic acid salt (plus alogliptin as 100 mg) 1 time per week long
- term administration of safety and efficacy were studied.
Clinical study design multicenter,open-label, parallel -
Trial type
Phase III,long-term administration exam
Subject
diet, exercise therapy may be conducted glycemic control is inadequate with Type 2 diabetes
<a concomitant long-term administration example >
diet, exercise regimen in addition to basic diabetes drugs may be administered if blood glucose control is inadequate
without Type 2 diabetes
<Common >
(1) observation period at the start of HbA1c(JDS value) 6. More than 5%, 10.0% less than the WHO
(2) observation period before the start of the 10 weeks before the completion of the observation period at a constant diet, exercise
regimen(carried out
<Concomitant long-term administration example >
(1) observation period before the start of the 10 week earlier (thiazolidine-based drug combination of long-term administration, for
example, if the observation period before the start of the
14 week earlier) from the completion of the observation period at the Foundation, diabetes treatment to a certain dosage and
administration, use in
persons
(2) observation period at the start, the basic therapeutic agent for diabetes treatment by a sufficient effect is obtained as
Also,the investigator or clinical trials-sharing medical doctor is the basis of diabetes treatment of bulking is inappropriate and the
court
refused for those
observation period before the start of the 10 weeks and observed during diabetes treatment(injections) that contains the
administration received
his
<a concomitant long-term administration example >
observation period before the start of the 10 weeks(thiazolidine-based drug long-term administration, for example, if the observation
period starting 14 weeks) and
and observation during the period basic therapeutic agent for diabetes other than diabetic medications(injections containing)received
a dose of the
Lord
Number of cases
680 example( plus alogliptin alone group
:248 example
Sulfonyl high-dose combination group
:158 examples
rapid-acting insulin secretagogue in the combination group : 67 example
α-glucosidase inhibitors in the combination group
: 65 examples
Biguanides-based drug combination group
: 70 examples
Thiazolidine-based drug combination group
: 72 example)
－ 16 －
<Common >
array alogliptin succinic acid salt to 1 time a week before Breakfast, 52 weeks was administered orally.
Observation period
(2 weeks)
The treatment period (52 weeks)
(1 Week)
Plus alogliptin alone group(248 cases)
1 time per week
Sulfonyl high-dose combination group(158 cases)
rapid-acting insulin secretagogue in the combination group(67 cases)
α-glucosidase inhibitors in the combination group(65 cases)
biguanides-based drug combination group(70 cases)
thiazolidine-based drug combination group(72 cases)
<Concomitant long-term administration examples>
basics Diabetes Therapeutics Clinical Trials during the period,the same drugs are administered, the observation period at the start of
the dosage and administration took over
last administration.
本治 test on the basis of diabetes treatment can be combined with existing oral hypoglycemic drugs list
Type
Drug name (generic name)
Sulfonyl urea-based drugs
Dark,gliclazide,with
a rapid-acting insulin secretagogue nateglinide,check the green calcium hydrate
α-glucosidase inhibitors
You, a list box, the program ribose
Biguanides-based drugs
Metformin hydrochloride, brand hormones hydrochloride
Thiazolidine-based drugs
Pioglitazone hydrochloride
The main evaluation items
<Common >
adverse events, etc.
<sulfonyl high-dose combination>
blood glucose self-measurement of blood glucose
Secondary endpoints HbA1c,fasting blood glucose
①HbA1c and fasting blood glucose levels of change
The treatment period for each evaluation point in the observation period at the end(0 per week)from HbA1c and
fasting blood glucose levels change,or
under your.
■HbA1c change(at the completion of the treatment phase)
Training program application
Check-alone group
Combination group
Sulfonyl download
High-dose
Fast-acting type line
Link secretion
Promoter
desirable
Peptidase inhibitor
Biguanides
System agents
Thiazolidine
System agents
n
248
158
67
65
70
72
Measurements(%)
7.87
(0.871)
8.09
(0.837)
7.87
(0.778)
8.07
(0.975)
7.82
(0.943)
7.91
(0.959)
n
248
158
66
65
70
72
the treatment period at the end
of readings(%)
7.30
(0.940)
7.72
(1.098)
7.61
(1.168)
7.40
(0.968)
7.51
(1.356)
7.18
(0.913)
From the variation of the
Point estimate(%)
-0.57
(0.883)
[-0.679,
-0.458]
-0.37
(0.902)
[-0.511,
-0.228]
-0.25
(0.784)
[-0.446,
-0.060]
-0.67
(0.739)
[-0.849,
-0.483]
-0.31
(0.816)
[-0.502,
-0.113]
-0.74
(0.654)
[-0.891,
-0.584]
－ 17 －
■Fasting blood glucose levels of variation(at the completion of the treatment phase)
Training program application
Check-alone group
Combination group
Sulfonyl download
High-dose
Fast-acting type line
Link secretion
Promoter
desirable
Peptidase inhibitor
Biguanides
System agents
Thiazolidine
System agents
n
248
158
67
65
70
72
Measurements(mg/dL)
160.5
(35.56)
168.5
(33.07)
173.1
(33.64)
170.4
(37.74)
157.8
(36.13)
157.8
(34.92)
n
248
158
66
65
70
72
At the completion of the treatment phase
Measurements(mg/dL)
150.6
(33.39)
167.6
(41.52)
167.7
(42.21)
156.9
(35.92)
155.4
(39.00)
147.2
(32.11)
From the variation of the
Point estimates(mg/dL)
-10.0
(31.17)
[-13.88,
-6.09]
-0.8
(35.53)
[-6.42,
4.75]
-4.8
(33.38)
[-13.01,
3.40]
-13.5
(31.39)
[-21.27,
-5.71]
-2.4
(29.32)
[-9.39,
4.59]
-10.6
(22.65)
[-15.91,
-5.26]
② Side effects
side effects of expression frequency,15.7%(39/248 example)was. This expression frequency of 2% or more of the
events,
nasopharyngitis 3.2%(8/248 example)was in the.
< Combined with long-term administration example >
side effects of expression frequency,sulfonyl high-dose combination group in 10.8%(17/158 example),a rapid-
acting insulin
- secreting promoter combination group in 11.9%(8/67 example), α-glucosidase inhibitors in the combination
group and in 6.2%(4/65 example),
biguanides-based drug combination group at 11.4%(8/70 example),thiazolidine-based drug combination group in
13.9%(10/72 example)
was. This expression frequency of 2% or more of the events,sulfonyl high-dose combination group hypoglycemia
3.2%(5/158 example),a rapid-acting insulin secretagogue in the combination group eczema 3.0%(2/67
example),thiazolidine
- based drug combination group in alanine amino transferase increased and aspartate amino TRANS
Blowjob presence of increased each 2.8%(2/72 example)was.
－ 18 －
2) the DPP-4 inhibitor (1 Day 1 dose)from the change of the exam
4)

Diets, exercise regimens in addition to DPP-4 inhibitors
*
1 Day 1 times administered to type 2 diabetic patients to

target, and alogliptin succinic acid salt (plus alogliptin as 100 mg)1 time per week administration of change
even when the blood sugar to investigate the effect and efficacy and safety exploratory study
was.
Clinical study design single-center, open-label, parallel -
Trial type
Phase III,General clinical trials
Subject
Diets, exercise regimens in addition to DPP-4 inhibitors
*
1 Day 1 dose in Japan with Type 2 diabetes

Patients
(1) observation period at the start of HbA1c(JDS value) is 5. 8% or 8. 0% less than the WHO
(2) observation period before the start of HbA1c and observation period at the start of the HbA1c difference between the observation
period before the start of HbA1c of
5.0%within party
(3) observation period before the start of the 10 weeks before the completion of the observation period at a constant diet, exercise
regimen(carried out
(4) observation period before the start of the 10 weeks before the observation period until the end and continue to DPP-4 inhibitors
*
1 Day 1 times
Administration who
(1) observation period at the start of the fasting blood glucose level is 70mg/dL or less than 250mg/dL or more persons
(2) observation period before the start of the 10 weeks and observed during the period DPP-4 inhibitors
*
Other diabetes medications(injections

Including)received a dose of you who
Number of cases
14 example
Plus alogliptin succinic acid salt to 1 time a week, before Breakfast for 12 weeks was administered orally.
Observation period (2 weeks)
The treatment phase (12 weeks)
(1 Week)
DPP-4 inhibitors
*
1 Days 1 times
1 time per week
Clinical administration of the start date 1 day(Day1)and counted.
The main evaluation items in the meal tolerance test blood glucose
Other
evaluation items
HbA1c, fasting blood glucose, adverse events, etc.
*: 1 Day 1 dose of the DPP-4 inhibitor (certain domestic approval Drug 1 agent to the drug administered)
－ 19 －
① The meal tolerance test, and blood sugar changes
Hospitalization was carried out under a meal tolerance test and report alogliptin administration started the day
before (Day-1)from the blood sugar levels of
variation were following the.
■The meal tolerance test, the blood glucose level of variation
Before the change
After the change
Measurements
Day-1 the amount of change from the
Assessment
Day-1
Day1
Day2
Day3
Day7
n
14
14
14
14
14
Before Breakfast(mg/dL)
140.9
(23.70)
-0.4(6.71)
[-4.23, 3.52]
-6.2(5.42)
[-9.35, -3.08]
-3.0(7.98)
[-7.61, 1.61]
-1.7(13.21)
[-9.34, 5.91]
Breakfast 2 hours after the start of the
(mg/dL)
202.1
(38.30)
-4.4(17.88)
[-14.75, 5.89]
-1.6(30.78)
[-19.41, 16.13]
7.0(31.93)
[-11.43, 25.43]
-8.7(25.38)
[-23.37, 5.94]
Before lunch(mg/dL)
139.9
(39.19)
-3.7(22.33)
[-16.61, 9.18]
0.4(17.98)
[-9.95, 10.81]
-4.1(12.99)
[-11.57, 3.43]
―
Lunch 2 hours after the start of the
(mg/dL)
217.4
(49.07)
-10.6(18.13)
[-21.11, -0.17]
-36.4(24.81)
[-50.68,
-22.03]
-28.1(27.58)
[-44.07,
-12.22]
―
Before dinner(mg/dL)
141.2
(40.82)
-4.6(19.76)
[-15.98, 6.84]
-10.4(25.41)
[-25.10, 4.24]
3.4(23.71)
[-10.33, 17.04]
―
Dinner 2 hours after the start of the
(mg/dL)
229.1
(55.70)
12.1(17.67)
[1.87, 22.27]
-16.4(26.89)
[-31.95, -0.90]
-13.2(35.11)
[-33.49, 7.06]
―
② The completion of the treatment period, HbA1c and fasting blood glucose variation
At the completion of the treatment phase Day1 from HbA1c change and changes in fasting blood glucose is below
and I.
■HbA1c and fasting blood glucose levels of variation(at the completion of the treatment phase)
Before the change(Day1)
After the change(at the completion of the treatment phase)
Measurements
Day1 amount of change from the
n
14
14
HbA1c(%)
7.06(0.493)
0.04(0.359)
[-0.164, 0.250]
Fasting glucose(mg/dL)
140.5(23.25)
-1.6(13.93)
[-9.61, 6.47]
③ Side effects
Side effects of the expression frequency is 7.1%(1/14 example), and lipase increased 7.1%(1/14 example)was.
－ 20 －
(3) (reference) plus alogliptin daily administration in the Test side effects the expression of the frequency[overseas]
8)
In Type 2 diabetes patients to, and alogliptin 100 mg,daily formulation

※1
Or placebo for 1 Day 1 times 12 weeks
Administration of either group, the expression frequency of 2% or more of the side effects are as follows was.
Incidentally, hypoglycemia
※2
The expression rate, and alogliptin 100 mg group, 0%(0/65 cases), daily formulation
※1
Group 1. 6% (1/61 example)
Oh, and fasting blood glucose levels of variation
※3
Is, and alogliptin 100 mg group-20.5(-99.0,131.0;166.6)
mg/dL,daily formulation
※1
Group-16.6(-160.0,141.0;167.7) mg/dL was.
※1 1 Day 1 dose of the DPP-4 inhibitor
※2 of hypoglycemia expression,glucose 60 mg/dL in less than hypoglycemia symptoms if you have symptoms regardless of the presence of glucose
50 mg/dL
And.
※3 from the previous administration of Change:least-squares mean(Min, Max;pre-dose (mean) value)is shown.
■One of the groups in the expression frequency of 2% or more of the side effects
daily formulation
Placebo
The number of cases investigated
65
61
63
Side effects the expression of the number of cases(%)
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)
disorders and administration topical aspect
fatigue
2 (3.1)
nervous system disorders
headache
2 (3.3)
1 (1.6)
skin and subcutaneous tissue disorders
rash
3 (4.6)
Plus alogliptin 100 mg,daily formulation,placebo only shown in the table.
MedDRA/J ver. 10. 0
[Test method]
Target:improve your lifestyle(diet/exercise therapy) or Metformin monotherapy carried out glucose control is inadequate in Type 2 diabetes
patients (385 cases)
and method of Administration:report alogliptin as 3.125 mg, 12.5 mg, 50 mg,100 mg,daily preparation (1 Day 1 dose of the DPP-4 inhibitor) or
placebo for 1 Day 1 Times, 1 days of the first before meals for 12 weeks was administered orally.
3-6 therapeutic use
(1) Use results survey・specific use results survey (Special Investigation) and post・marketing surveillance study
(post-marketing clinical trial)
The re-examination period.
(2) approval conditions as scheduled for the content or implementation exam overview
Pharmaceutical risk management plan on the right to implement this.
－ 21 －
VI. Medicinal pharmacology related fields
1. Pharmacologically relevant compound or group of compounds
Dipeptidyl peptidase-4 inhibitors(DPP-4 inhibitors)
2. Pharmacological action
2-1 site of action・mechanism of action
This drug is supplementation of the diet by a stimulus from the intestinal tract into the blood secreted glucagon-
like peptide-1(GLP-
1), which inactivates the dipeptidyl peptidase-4 (DPP-4) activity by inhibiting GLP-1
blood levels increases the sugar concentration-dependent manner from the pancreas of insulin secretion to
promote
9)
.
2-2 medicinal supporting test results
(1) the DPP-4 inhibitory effect on
1) the DPP-4 inhibitory activity against(
the in vitro)
human colon adenocarcinoma-derived cell lines of human type DPP-4 and human, dog, rat plasma DPP-4 against
the inhibitory
activity was shown.
■ DPP-4 inhibitory activity against
Enzyme source
IC
50
[Two-sided 95% confidence interval] (nmol/L)

Human colon adenocarcinoma-derived cells
5.4 [5.2, 5.7]
Plasma
Human
4.2 [4.1, 4.3]
Dogs
6.2 [6.0, 6.4]
Rat
9.7 [8.0, 11.8]
[Test method]
Human colon adenocarcinoma-derived cell crude extract was partially purified obtained by DPP-4 fractions or human,dog, rat plasma enzymes
as a source for
your. As the substrate Gly-Pro-pNA・Tos, the reaction after 1 hour of absorbance(405nm)indicator enzyme activity was measured. IC
50
The value is
Logistic curve was calculated using.
2) Affinity enzyme inhibitory activity against(
the in vitro)
DPP-4 affinity of the enzyme (DPP-II,DPP-8, DPP-9, PEP,FAPα)inhibitory activity against both
was low.
■ DPP-4 affinity enzyme inhibitory activity against
Affinity enzyme
IC
50
(nmol/L)
DPP-II
>100,000
DPP-8
>100,000
DPP-9
>100,000
PEP
>100,000
FAPα
>100,000
PEP:prolyl endopeptidase(Proline endopeptidase)
FAPα: fibroblast activation protein α (fibroblast activation protein α)
[Test method]
DPP-II activity in rat kidney extract activity of the fractions of the enzyme source,the H-Lys-Ala-pNA・2HCl as a substrate was measured. PEP
use
, the rat brain obtained from the active fractions of the enzyme source,Suc-Ala-Pro-pNA as a substrate was measured. DPP-8, DPP-9 and
and FAPα human-type gene expression in the cell-free extract was partially purified obtained by the active fractions of the enzyme as the source
of DPP-8 and DPP-9 is Gly-
Pro-pNA・Tos, and FAPα is H-Ala-Pro-pNA・HCl as a substrate, and enzyme activity was measured. Both absorbance(405nm)refers to
target the enzyme activity was measured. IC
50
The value is the logistic curve was calculated using.

－ 22 －
3) the plasma DPP-4 inhibition rate(healthy adult)
5)
Plus alogliptin 100 mg single dose, the maximum plasma DPP-4 inhibition rate(Emax) and the Tmax is
as follows: I.
■ Plasma DPP-4 inhibition rate parameter related to the
Placebo
n
18
8
Emax(%)
7.1(2.90)
99.3(0.14)
Tmax(h)
114.3(57.36)
1.2(0.37)
[Test method]
Subjects: healthy adults (26 cases)
and method of Administration:report alogliptin as 100 mg or placebo for Breakfast 30 minutes before a single oral administration.
4) the final Administration 1 week after DPP-4 inhibition rate(type 2 diabetics)
1)
Plus alogliptin 100 mg 1 time a week, 12 weeks, and the final Administration 1 week after the plasma DPP-4
inhibition
harm rate of 77.4 percent.
■ The final Administration 1 week after the plasma DPP-4 inhibition rate
2.4(15.46)
77.4(11.53)
(%)
0
100
80
60
40
20
DPP
-4 inhibition rate
Placebo
(40)
(41)
Plus alogliptin
100mg
The mean(standard deviation), in the figure below (in brackets) the number of cases
[Test method]
Subject:diet, exercise therapy may be conducted glycemic control is inadequate with Type 2 diabetes (110 cases)
and method of Administration:report alogliptin as 100 mg or placebo to 1 time a week, before Breakfast for 12 weeks was administered orally.
－ 23 －
5) long-term administration at the time of plasma DPP-4 inhibition rate(type 2 diabetics)
3)
Plus alogliptin 100 mg 1 time a week, 52 weeks alone or in combination were administered when,at the completion
of the treatment period, the plasma
DPP-4 inhibition rate plus alogliptin alone group,sulfonyl high-dose combination Group,a rapid-acting insulin
- secreting promoter combination Group,an α-glucosidase inhibitor in the combination group,biguanides-based
drug combination group and check
exotic lysine-based drug combination group, respectively 79.0％、76.5％、78.9％、78.3％、76.6％and 79.6
percent.
■ Plasma DPP-4 inhibition rate of
0
20
40
60
80
100
120
(%)
DPP-4 inhibition rate
The administration period(weeks)
024
12
24
36
52
At the completion of the treatment phase
Plus alogliptin alone (n=248)
Rapid-acting insulin secretagogue combination (n=65)
Biguanides-based drug combination (n=70)
Sulfonyl high-dose combination (n=158)
α-glucosidase inhibitors in combination (n=65)
Thiazolidine-based drug combination (n=72)
[Test method]
Subject:diets, exercise regimens in addition to the basic treatment of diabetes drugs to be administered glucose control is inadequate with Type 2
diabetes(680 example)
and method of administration:the Foundation of diabetes treatment, in addition to tolerance, alogliptin as 100 mg 1 time a week before
Breakfast, 52 weeks was administered orally.
－ 24 －
(2) the DPP-4 inhibitors (1 Day 1 dose)compared with
1)
in vitro DPP-4 inhibitory activity of comparison
10)
Plus alogliptin succinic acid salt, and alogliptin benzoate as compared with the strong DPP-4 inhibitory activity
was shown.
■ Human DPP-4 inhibitory activity of IC
50
Value
Plus alogliptin
Succinic acid salt
Program memory type
Benzoate
IC
50
[95% confidence interval] (nmol/L)

1.3[1.1, 1.5]
5.3 [5.0, 5.7]
[Test method]
Recombinant human DPP-4 protein enzyme source was used. Gly-Pro-AMC as a substrate for 15 minutes, the reaction was carried out to
generate,
AMC(7-amino-4-methylcoumarin)of the fluorescence intensity(Ex:380nm/Em:460nm)indicator enzyme activity was measured. IC
50
The value is the

Stick curve was calculated using.
2) the plasma DPP-4 inhibition rate comparison (type 2 diabetics)
2)
Plus alogliptin 100 mg 1 time a week or property, alogliptin 25 mg for 1 Day 1 times, 24 weeks Administration of
plasma DPP-4 inhibition rate of the I.
■ Plasma DPP-4 inhibition rate of
024
8
12
16
20
24
The treatment period
At the end
-20
0
20
40
60
80
100
120
140
(%)
DPP-4 inhibition rate
The administration period(weeks)
Placebo (n=50)
Plus alogliptin 100 mg 1 time a week (n=101)
Application alogliptin 25mg 1 Day 1 times (n=92)
[Test method]
Subject:diet, exercise therapy may be conducted glycemic control is inadequate with Type 2 diabetes(243 cases)
and method of Administration:report alogliptin as 100 mg or placebo to Week 1 times and alogliptin as 25mg or placebo for 1 Day 1 times,
Breakfast before 24 weeks was administered orally.
－ 25 －
(3) the meal tolerance test(type 2 diabetics)
1)
The meal tolerance test report alogliptin 100 mg group of active GLP-1 concentration, insulin concentration and
blood
glucose values remained and each of the completion of the treatment period (12 weeks)of the AUC
0-2
The amount of change, and there was.
■Active GLP-1 concentrations remained
0
0.5
1
2
(54)
(55)
12 weeks
Week 0
(54)
(55)
(54)
(55)
(54)
(55)
Meals after the load time(h)
0
2
4
6
8
10
12
14
16
(pmol/L)
Active GLP-1 concentration
Plus alogliptin 100 mg(Week 0)
report alogliptin 100 mg(at the completion of the treatment phase (12 weeks))
■ Active GLP-1 AUC

0-2
Change
(At the completion of the treatment phase(12 weeks))
0.33
(2.79)
0
5
4
3
2
1
The active form of GLP
-1 AUC
0-2
Change
Placebo
(53)
(pmol * h/L)
3.40
(4.71)
(54)
Plus alogliptin
100mg
■Insulin concentration remained
0
0.5
1
2
(53)
(55)
12 weeks
Week 0
(54)
(55)
(54)
(55)
(54)
(55)
0
20
40
60
80
(μU/mL)
Insulin concentration
■ Insulin AUC
0-2
Change
(At the completion of the treatment phase (12 weeks))
-0.51
(12.70)
4
6
8
-2
-4
Insulin AUC
0-2
Change
Placebo
(50)
(μU・h/mL)
(54)
Plus alogliptin
100mg
5.06
(18.08)
■Changes in blood glucose level

0
0.5
1
2
(54)
(55)
12 weeks
Week 0
(54)
(55)
(54)
(55)
(54)
(55)
100
150
200
250
300
350
(mg/dL)
Blood sugar levels
■ Blood glucose AUC

0-2
Change
(At the completion of the treatment phase (12 weeks))
0
40
20
60
-20
-40
-60
-80
The blood glucose AUC
0-2
Change
Placebo
(53)
(mg * h/dL)
(54)
Plus alogliptin
100mg
28.0
(83.12)
-44.1
(51.93)
The mean(standard deviation), in the figure below (in brackets) the number of cases
[Test method]
Subject:diet, exercise therapy may be conducted glycemic control is inadequate with Type 2 diabetes (110 cases)
and method of Administration: report alogliptin as 100 mg or placebo to Week 1 times before Breakfast, was administered for 12 weeks. Contrast
observation period at the end(Week 0)
And at the completion of the treatment phase (12 weeks)in a meal tolerance test was performed.
－ 26 －
(4) non-obese type 2 diabetes/insulin secretion reduced model of glucose tolerance Improvement Act (rat)
9)
1) plasma DPP-4 activity suppression and active GLP-1 increase in action

Plus alogliptin administration,plasma DPP-4 activity in a dose-dependent decrease,and active GLP-1
concentration
degree of dose-dependent increase was observed.
■ The glucose load after 30 minutes of
Plasma DPP-4 activity
0
120
100
80
60
40
20
(%of
Control)
Control
0.01
0.03
0.1
0.3
Plus alogliptin (mg/kg)
*
*
*
Blood
Plasma
In D
PP
-4
Activities
Sex
The mean(standard deviation) (n= 6)
*: p
≤0.025 (vs the Control group,one side of Shirley-
Williams test)
■ Glucose load after 10 minutes of
Plasma active GLP-1 concentration
0
12
10
8
6
4
2
(pmol/L)
Control
0.01
0.03
0.1
0.3
*
*
Blood
Plasma
In
Activities
Sex
Type
G
LP
-1
Dark
Degrees
0
-1
0m
in
*: p
≤0.025 (vs the Control group,one side of Shirley-
Williams test)
2) plasma glucose decreased and plasma insulin concentration increased effect
Plus alogliptin administered by,after the glucose load plasma glucose increased area is 0. 1mg/kg or more
significantly reduced glucose load after 10 minutes of plasma insulin concentration is 0. 03mg/kg or more
significantly increased.
■ Plasma glucose concentration, AUC
0-120min
0
Control
0.01
0.03
0.1
0.3
*
*
30000
(mg/dL * min)
Blood
Plasma
Tags
The
The
User
Status
Dark
Degrees (
A
U
C
0
-12
0m
in
)
25000
20000
15000
10000
5000
*:p
≤0.025 (vs the Control group,one-sided Williams test)
■ Glucose load after 10 minutes of plasma insulin concentration
0
Control
0.01
0.03
0.1
0.3
*
*
*
2.5
(ng/mL)
Blood
Plasma
Size
Download
Status
Link
Download
Concentration
(
Negative
Packing
10 minutes
After
)
2.0
1.5
1.0
0.5
*:p
≤0.025 (vs the Control group,one side of Shirley-Williams test)
[Test method]
26-week-old male N-STZ-1,5 rats (each group consisting of 6 cases) were fasted overnight and then, and alogliptin as 0.01, 0.03,0.1 and 0.3 mg/kg
single oral dose,administered 1 hour after 1 g/kg of glucose was orally administered.
After the glucose load and 30 minutes to the plasma DPP-4 activity was measured. Moreover, the glucose load before the load after 10 minutes in
the plasma of the activities of
resistance-type GLP-1 concentration, the amount of increase was calculated.
The glucose load before and after the load 10, 30, 60 and 120 minutes to draw blood, and plasma glucose and plasma insulin concentrations were
measured.
－ 27 －
(5) obesity, Type 2 diabetes/insulin resistance model in glucose tolerance Improvement Act (rat)
9)
1) plasma DPP-4 activity inhibitory action

Plus alogliptin administered, in a dose-dependent plasma DPP-4 activity decline was observed.
■ Plasma DPP-4 activity
0
120
100
80
60
40
20
(%of
Control)
Control
0.01
0.03
0.1
0.3
Blood
Plasma
In D
PP
-4
Activities
Sex
2) plasma glucose lowering effect and the plasma insulin concentration increased effect
Plus alogliptin administered by,after the glucose load plasma glucose concentration, AUC
0-60min
Is
0.03 mg/kg or more significantly reduced glucose load after 10 minutes of plasma insulin concentration is 0.1
mg/kg or more
on the significantly increased.
■ Plasma plasma glucose concentration, AUC
0-60min
0
15000
10000
5000
12500
7500
2500
(mg/dL * min)
Control
0.01
0.03
0.1
0.3
*
*
*
Blood
Plasma
Tags
The
The
User
Status
Dark
Degrees (
A
U
C
0
-6
0mi
n
)
*:p
■ Glucose load after 10 minutes of plasma insulin concentration
0
70
60
50
40
30
20
10
(ng/mL)
Control
0.01
0.03
0.1
0.3
*
*
Blood
Plasma
Size
Download
Status
Link
Download
Concentration
(
Negative
Packing
10 minutes
After
)
*:p
[Test method]
12-week-old female Wister fatty rats (each group consisting of 6 cases) were fasted overnight and then, and alogliptin as 0.01, 0.03,0.1 and 0.3
mg/kg
single dose, and Administration 1 hour after 1 g/kg of glucose was orally administered.
Plus alogliptin administered after 40 minutes after the lapse of plasma DPP-4 activity was measured.
The glucose load before and after the load 10, 30 and 60 minutes to draw blood, and plasma glucose and plasma insulin concentrations were
measured.
－ 28 －
(6) diabetes improvement action(mouse)
Plus alogliptin administered by 0.03%in the group administered 0.9%of glycated hemoglobin, lowering of the
plasma device
of 1.9 times, and the insulin content of 1.8 fold increase was observed.
■ Glycated hemoglobin amount
0
9.0
6.0
7.0
8.0
5.0
4.0
3.0
2.0
1.0
(%)
Control
0.003
0.03
Normal control
Mouse
Plus alogliptin (%)
ob/ob mice.
*
Glycated hemoglobin
■Plasma insulin concentration

0
70
60
50
40
30
20
10
(ng/mL)
Control
0.003
0.03
Normal control
Mouse
Plus alogliptin (%)
ob/ob mice.
*
Plasma insulin concentration
■Pancreatic insulin content

0
400
350
300
250
200
150
100
50
(ng/mg)
Control
0.003
0.03
Normal control
Mouse
Plus alogliptin (%)
ob/ob mice.
*
Pancreatic insulin content
The mean(standard deviation) (
ob/ob mice:n=8,normal control mice:n=5)
*:p
[Test method]
7-week-old male
ob/ob mice(each group consisting of 8 cases) and normal control mice (5 cases) was used. Plus alogliptin as 0. 003 and 0. 03%
(investment
given the amount of 5.7 and 51.9 mg/kg/day or equivalent) for 4 weeks mixed feeding was administered. 4 weeks mixture of feed administered in
the morning after blood sampling, non-fasting conditions,
plasma parameters were measured. Then fasted overnight after pancreas isolated pancreas in insulin content were measured.
2-3 effect of the expression of time・duration
Plasma DPP-4 inhibition rate is 1.2(0.4)hours after the peak,administered 1 week after the DPP-4 inhibitory
activity of
persistence was observed (mean(standard deviation))
5)
.
－ 29 －
VII. Pharmacokinetics related items
1. The blood concentration of the transition and measurement
1-1 therapeutically effective blood concentration
" 1 -3 clinical trials confirmed the blood concentration"section reference
1-2 the highest blood concentration time
" 1 -3 clinical trials confirmed the blood concentration"section reference
1-3 clinical trials confirmed the blood concentration
(1) a single dose of study
5)
Healthy adults (16 cases)to the subject, and alogliptin as 50mg or 100mg Breakfast 30 minutes before the start of
the single
dose, the plasma concentration transition and the pharmacokinetic parameters were following the.
Plus alogliptin 100 mg in the control group were administered to 168 hours after the plasma concentrations of the
average value of 2.1 ng/mL
I.
■ A single dose at the time of the report, alogliptin of the plasma concentration transition
0
24
48
72
96
120
144
168
200
400
600
800
(ng/mL)
0
Plus alogliptin 50 mg (n=8)
Hours after administration(h)
Plasma concentration
■Pharmacokinetic parameters
Dosage
n
Cmax(ng/mL)
Tmax(h) AUC
0-inf
(ng･h/mL) T
1/2 (0-72)
(h) T
1/2 (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)
－ 30 －
(2) repeated administration in consideration of
6)
Healthy adults (9 cases)to the subject, and alogliptin as 100mg Breakfast 30 minutes before the start of the Single
Dose (Day 1)
after Day 4 and day 14 in 1 Days 1 times,11 consecutive days was administered. Administered on Day 1 and
administered 14 days of
the plasma concentration transition and the pharmacokinetic parameters are as follows,administered 14 days
nearly steady
state is reached as it is.
■ Repeated dose at the time of the report, alogliptin of the plasma concentration transition
200
100
300
400
500
600
700
800
(ng/mL)
0
0
24 48 72 96 120 144 168 192 216
264
480
384
360
312 336
Dosage
n
Administration Day
Cmax(ng/mL)
Tmax(h)
AUC
0-inf
※
(ng･h/mL)
T
1/2 (0-72)
(h)
100mg
8
1 day
544.3(122.0)
1.3(0.5)
5572.3(793.2)
17.9 (2.1)
14 day
602.6(149.5)
1.5 (0.8)
5292.9(613.8)
17.6(1.3)
The mean(standard deviation),※14 day AUC
0-tau
■Cumulative coefficient(R) and the accumulation and evaluation(AI)

Dosage
n
R(AUC)
a)
R(Cmax)
b)
AI (AUC)
c)
AI (T
1/2
)
d)
100mg
8
1.321(0.1056)
1.141(0.3153)
0.953(0.0734)
0.994(0.1198)
a) R(AUC)=AUC
0-tau
(14 day)/ AUC
0-24
(Day 1)
b)R(Cmax)=Cmax(day 14)/ Cmax (Day 1)
c)AI (AUC)=AUC
0-tau
(14 day)/ AUC
0-inf
(Day 1)
d)AI (T
1/2
)=T
1/2
(14 day) / T
1/2
(Day 1)
－ 31 －
(3) in patients with impaired renal function examination of the[foreign data]
11)
Light degrees of renal function impairment patients (Ccr:50 ≤ ~ <80mL/min), in the equal degrees of renal
function impairment patients (Ccr:30≤ ~
< 50mL/min),advanced patients with impaired renal function (Ccr:< 30mL/min),end-stage renal disease patients
and age, sex,
race and body weight for healthy adults (each 6 for an example) To the subject, and alogliptin as 50mg fast
under a single administration, the plasma concentration transition and the pharmacokinetic parameters were
following the.
AUC
0-tlqc
And Cmax in healthy subjects as compared with mild impairment of renal function in patients with
55.7% and 36.3%increase,in
such degrees in patients with impaired renal function 105.7% and 12.9% in advanced renal failure patients
201.4%increase,9.1%
, increase in end-stage renal failure in patients with 268.1% and 13.8%lower.
■ Patients with impaired renal function that alogliptin of the plasma concentration transition
Mild renal impairment patients (n=6) and
healthy adults (n=6)
312
288
0 24 48 72 96 120 144 168 192 216 240 264
250
0
50
100
150
200
(ng/mL)
Advanced renal failure patients (n=6) and
312
288
0 24 48 72 96 120 144 168 192 216 240 264
250
0
50
100
150
200
(ng/mL)
Moderate renal impairment patients (n=6) and
312
288
0 24 48 72 96 120 144 168 192 216 240 264
250
0
50
100
150
200
(ng/mL)
End-stage renal failure patients (n=5)
312
288
0 24 48 72 96 120 144 168 192 216 240 264
250
0
50
100
150
200
(ng/mL)
Mild renal impairment patients
Advanced renal failure patients
Moderate renal impairment patients
End-stage renal disease patients
Average
Renal impairment
About
Mild
Healthy adults
Moderate
Healthy adults
Advanced
Healthy adults
The end
Renal failure
Healthy adults
n
6
6
6
6
6
6
5
6
Cmax(ng/mL) 236.36
173.36
264.35
234.07
240.62
220.55
154.24
178.89
Tmax(h)
a)
3.25
2.75
1.75
2.00
3.00
2.25
6.00
2.50
AUC
0-tlqc
(ng･h/mL)
4807.22
3087.08
7209.65
3505.31 10344.81 3431.79 10837.04 2944.16
T
1/2 (0-312)
(h)
b)
67.82
55.56
82.60
64.68
88.45
56.43
107.97
56.75
The adjusted mean, a) median b)mean
－ 32 －
(4) liver dysfunction in patients with consideration of the[foreign data]
12)
Moderate stunned dysfunction patients (Child-Pugh

※
Score 7 ~ 9, 8 cases) and age, gender, race, Smoking history, and body
weight for healthy adults (8 cases)to the subject report, alogliptin as 50mg fast under a single administration
, the pharmacokinetic parameters were following the.
Healthy adults, compared with moderate stunned dysfunction in patients with AUC
0-inf
Is 5. 1% increase in Cmax is 4. 3% declined.
※Bilirubin, albumin, PT (prothrombin time) or INR(international normalized ratio),hepatic encephalopathy,ascites, from the state of the model
classification
n
Cmax(ng/mL) Tmax(h)
a)
AUC
0-inf
(ng･h/mL) T
1/2 (0-72)
(h)
b)
Moderate stunned dysfunction in patients with

8
148.83
2.00
2596.14
24.92
Healthy adults
7
155.50
3.00
2471.04
22.60
The adjusted mean, a) median b)mean
1-4 addiction region
1-5 meal・the combination of the drugs effects
(1) the influence of diet on
13)
Healthy adults (12 cases)to the subject, and alogliptin as the 100mg version of the law in Breakfast fast under
or Breakfast starts 30 minutes after a single dose, the plasma concentration of the transition and the
pharmacokinetic parameters
were following the. Breakfast starts 30 minutes after the administration,Breakfast fast under administration, as
compared to the Cmax is 16.8%
increase in AUC
0-inf
A 2.5% decline.
■Fast down and postprandial single dose at the time of the report, alogliptin of the plasma concentration
transition
0
200
400
600
800
(ng/mL)
0
24
48
72
96
120
144
168
Breakfast fast under(n=12)
Breakfast starts 30 minutes later(n=12)
Administration conditions
n
Cmax(ng/mL)
Tmax(h) AUC
0-inf
(ng･h/mL) T
1/2 (0-168)
(h)
Breakfast fast under
12
640.1(189.0)
1.3(0.9)
6047.5(634.1)
56.4(6.7)
Breakfast starts 30 minutes later
12
734.3(159.0)
1.6(0.5)
5890.0(553.8)
53.4 (6.1)
－ 33 －
(2) drug interactions
1) Center
14)
Healthy adults (12 cases)for 1 day with 1 mg single dose,3 to 13 eyes (11 days) by
level alogliptin as 200mg 1 Day 1 times repeated administration,13 days with 1 mg single combined administration
was.
Center of AUC
0-inf
And Cmax of the average value of the ratio (combined administration/administered alone)is a point estimate
of[both sides 90%
Confidence interval], respectively 103.5％［99.1，108.1］、121.5％［109.6，134.8］was.
2) Metformin[foreign data]
15)
Healthy adults (48 cases)to the subject,crossover method in class alogliptin as 100 mg for 1 Day 1 times 12 days
between repeated administration,or report alogliptin as 100 mg for 1 Day 1 times and Metformin as 1,000 mg
1 to 2 times a day for 12 days iterative combination was administered.
Plus alogliptin AUC
0-tau
And Cmax of the adjusted average of the ratio (combined administration/single

administration)of the point estimate
value [both sides 90% confidence interval], respectively 105.0％［102.3，107.8］、108.5％［100.6，117.0］was.
Metformin AUC
0-tau
And Cmax of the adjusted average of the ratio of the point estimates[both sides 90% confidence interval] is
Each 90.4％［84.1，97.2］、73.3％［66.6，80.6］was.
3) caffeine, your,dextromethorphan,midazolam[foreign data]
16)
Healthy adults (18 cases)for 1 day to cytochrome P-450 substrates(caffeine 200mg,your

guide 500mg,dextromethorphan 30 mg and midazolam 4 mg) in a single dose,4 ~ 14 days(11 days)
to report alogliptin as 100 mg for 1 Day 1 times repeated administration,14 day to cytochrome P-450 substrates
just
around the concomitant administration.
Caffeine, your,midazolam and each metabolite AUC
0-tlqc
AUC
0-inf
And Cmax of adjusting

only the average value of the ratio (combined administration/administered alone)on both sides of the 90%
confidence interval of 80 to 125%was in the range of.
Dextromethorphan AUC
0-tlqc
And Cmax of the adjusted average of the ratio of the point

estimates[both sides 90%that
rely on the interval], respectively 117.9％［98.8，140.7］、111.3％［95.5，129.8］Oh, and metabolite data
storage fan of AUC
0-tlqc
AUC
0-inf
And Cmax of the adjusted average of the ratio of the sides of the 90% confidence interval is
80 ~ 125%was in the range of.
1-6 population (variation)analysis revealed drug pharmacokinetics variability factors
In Japan conducted a Phase II dose-setting trials,phase III alone long-term administration, or combination of
long-term administration of the test and the Phase I single -
dose trials in the measured plus alogliptin plasma concentrations of annexation, the population pharmacokinetic
analysis was performed
as a result,creatinine clearance,body surface area decrease,or LDH due to the increase of training programs the
application
of the plasma concentration tends to rise indicated.
－ 34 －
2. Drug kinetic parameters
2-1 analysis methods
Compartment model by analysis of(non-compartment model)
2-2 absorption rate constant
2-3 bioavailability
(Reference) [rat, and dog]
Oral and intravenous administration at the time of the AUC ratio was determined from the bioavailability is at
50.3(8.2)%,
in dogs 129.8(37.6) % for (mean(standard deviation)).
2-4 elimination rate constant
Healthy adults (16 cases)to the subject, and alogliptin as a 100 mg single dose, and only cancel a
lost phase of the elimination rate is Breakfast 30 minutes before Administration 0.0129(0.00196)h
-1
Breakfast fast under the administration of 0.0115(0.00120)h

-1
Was (mean(standard deviation))

5)
.
2-5 clearance
Healthy adults (16 cases)to the subject, and alogliptin as a 100 mg single dose, and only of the systemic
clearance,Breakfast 30 minutes before Administration 15.35(1.743)L/h,Breakfast fast under the administration of
15.38(1.203)L/h was.
Renal clearance Breakfast, 30 minutes before Administration 11.63(1.357)L/h,Breakfast fast under the
administration of 12.07(0.982)L/h, there
was (mean(standard deviation))
5)
.
2-6 volume of distribution
[Foreign data]
Healthy adults (31 cases)to the subject, and alogliptin as 50mg was administered orally at the disappearance of the
phase and
the apparent volume of distribution is 689.32 ~ 1334.46 L was (mean)
11) 12)
.
2-7 plasma protein binding rate
[Foreign data]
Healthy adults (24 examples)to the subject, and alogliptin as 50mg single dose, and it can be a single type
of blood plasma protein Unbound type of ratio is 0.76 ~ 0.79 was
11)
.
(Reference) [
in vitro]
Rat, dog and human plasma[
14
C] Plus alogliptin succinic acid salt was added, the plasma proteins
The binding rate were following the
17)
.
Plus alogliptin
Plasma concentration(µg/mL)
The plasma protein binding rate(%)
Rat
Dogs
Human
0.1
54.7
25.2
27.6
1
42.6
22.8
26.5
10
24.1
22.9
22.1
3 times the average value of the measurements
－ 35 －
3. Absorption
■Absorption rate
(reference) [rat, and dog]
[
14
C] Plus alogliptin succinic acid salt rats and dogs, the oral and intravenous administration of total radiation
performance of the AUC from the ratio of the absorption rate each of 67.1% and 96.1%, respectively.
■ Site of absorption・the absorption path
(Reference) [rat]
Rats in the digestive tract when administered tolerant alogliptin succinic acid salt is the most tolerant group
options, and from the portal vein to be absorbed and thought. We do not sell, trade, or rent La alogliptin succinic
acid salt lymph
through almost not absorbed was considered.
4. Distribution
4-1 blood－brain barrier through sex
" 4 -5 other tissues of migration"section of the reference
4-2 blood－placenta barrier through sex
(Reference) [rat]
Pregnancy day 18 of rats[
14
C] Plus alogliptin succinic acid salt (plus alogliptin as 3mg/kg)
was orally administered, the concentration is low tolerance alogliptin and the origin of some of the ingredients
fetal plasma transferred to
the fetal plasma is the main component tolerance, alogliptin was considered to be.
■ Fetus migration
Sample
Compound
Concentration (µg/mL, and alogliptin conversion value)
1 hour
4 hours
8 hours
24 hours
48 hours
Maternal plasma
Total radioactivity
0.168 (0.016)
[100.0]
0.197(0.038)
[100.0]
0.082(0.009)
[100.0]
0.006(0.001) 0.002(0.000)
Plus alogliptin
0.137
[81.5]
0.157
[79.7]
0.063
[76.8]
―
―
Metabolite
M-I
0.008
[4.8]
0.009
[4.6]
<LOQ
[0.0]
―
―
Other
0.023
[13.7]
0.031
[15.7]
0.019
[23.2]
―
―
Placenta
a)
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
Fetal plasma
Total radioactivity
0.042(0.003)
[100.0]
0.057(0.010)
[100.0]
0.033(0.001)
[100.0]
<LOQ
<LOQ
Plus alogliptin
0.037
[88.1]
0.049
[86.0]
0.029
[87.9]
―
―
Metabolite
M-I
<LOQ
[0.0]
<LOQ
[0.0]
<LOQ
[0.0]
―
―
Other
0.005
[11.9]
0.008
[14.0]
0.004
[12.1]
―
―
Fetus
a)
Total radioactivity
0.125（0.007） 0.166（0.025） 0.108（0.002） 0.014（0.001） 0.006（0.001）
The total radioactivity is the mean(standard deviation) (n=3), and alogliptin and metabolite pools of the sample values (n=3)
LOQ:lower limit of quantification values,―: without measure, in [] is the radiation%
a) µg/g
－ 36 －
4-3 milk to migration
(Reference) [rat]
Birth day 14 of lactation in rats[
14
C] Plus alogliptin succinic acid salt (plus alogliptin as

3mg/kg) when administered orally, and alogliptin-derived ingredients part of the milk to the migration, and milk
in
a major component of the report, alogliptin was considered to be.
■ Milk to migration
Sample
Compound
Concentration (µg/mL, and alogliptin conversion value)
1 hour
4 hours
24 hours
48 hours
Plasma
Total radioactivity
0.307(0.049)
[100.0]
0.284(0.042)
[100.0]
0.008(0.001)
[100.0]
0.003(0.001)
Plus alogliptin
0.278
[90.6]
0.244
[85.9]
0.005
[62.5]
―
Metabolite
M-I
0.005
[1.6]
0.010
[3.5]
<LOQ
[0.0]
―
Other
0.024
[7.8]
0.030
[10.6]
0.003
[37.5]
―
Milk
Total radioactivity
0.373(0.057)
[100.0]
0.298(0.060)
[100.0]
0.017(0.008)
[100.0]
0.002(0.001)
Plus alogliptin
0.339
[90.9]
0.229
[76.8]
0.006
[35.3]
―
Metabolite
M-I
0.016
[4.3]
0.041
[13.8]
<LOQ
[0.0]
―
Other
0.018
[4.8]
0.028
[9.4]
0.011
[64.7]
―
The total radioactivity is the mean(standard deviation) (n=4), and alogliptin and metabolite pools of the sample values (n=4)
LOQ:lower limit of quantification values,―: without measure, in [] is the total radiation%
4-4 cerebrospinal fluid to migration
－ 37 －
4-5 other organizations to migration
(Reference) [rat]
Rats[
14
C] Plus alogliptin succinic acid salt (plus alogliptin as 3mg/kg) was orally administered
, the total radioactivity in the organization of the concentration of all tissues and after administration for 1 hour
or 6 hours the maximum value shown.
After administration of 1 hour and in the organization of the total radioactivity concentration in the intestinal
wall, kidneys, stomach wall, liver, lung, pituitary gland,submandibular glands,
adrenal glands, bladder, pancreas, spleen and plasma were higher than. On the other hand, testis, brain, spinal
cord plasma than
was low.
■ Each organization for Migration
Organization
Radioactivity concentration (µg/g, and alogliptin conversion value)
15 minutes
1 hour
6 hours
24 hours
72 hours
168 hours
Blood
a)
0.049（0.013） 0.099（0.004） 0.091（0.019） 0.006（0.001） 0.002（0.000） 0.001（0.001）

Plasma
a)
0.056（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）
Spinal cord
0.005（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）
<LOQ
<LOQ
Eyeball
0.017（0.002） 0.071（0.011） 0.125（0.015） 0.008（0.002） 0.001（0.001）
<LOQ
Hard glands 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 glands
0.181（0.029） 0.637（0.064） 0.891（0.210） 0.034（0.004） 0.006（0.000） 0.003（0.001）
Thyroid
0.154（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）
Heart
0.119（0.011） 0.268（0.021） 0.273（0.067） 0.024（0.002） 0.009（0.002） 0.005（0.001）
Lung
0.496（0.045） 0.907（0.067） 1.366（0.165） 0.279（0.032） 0.108（0.010） 0.051（0.008）
Liver
0.886（0.234） 1.895（0.314） 1.572（0.291） 0.204（0.007） 0.037（0.002） 0.010（0.001）
Spleen
0.207（0.037） 0.537（0.066） 0.534（0.083） 0.081（0.003） 0.013（0.002） 0.005（0.002）
Pancreas
0.173（0.028） 0.567（0.059） 0.654（0.112） 0.035（0.003） 0.011（0.001） 0.004（0.002）
Adrenal glands
0.257（0.055） 0.635（0.061） 0.500（0.085） 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）
Testis
0.008（0.002） 0.046（0.006） 0.270（0.059） 0.186（0.041） 0.037（0.005） 0.003（0.000）
Skeletal muscle
0.023（0.003） 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）
White fat
0.007（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）
<LOQ
<LOQ
Bone marrow
0.103（0.013） 0.376（0.040） 0.405（0.050） 0.042（0.004） 0.005（0.004）
<LOQ
Bladder
0.068（0.013） 0.588（0.200） 0.477（0.062） 0.120（0.014） 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）
The mean(standard deviation) (n=3), LOQ:quantitative lower limit value
a) µg/mL
－ 38 －
5. Metabolism
5-1 metabolic site and metabolic pathways
Plus alogliptin succinic acid salt Vivo
N-demethylation produced by the pharmacological activity
having
M-I metabolism was considered.
■ The estimated metabolic pathways
H
5-2 involved in the metabolism enzymes (CYP450, etc.) of the molecular species
(Reference) [in vitro]
18)
(1) various human CYP species and the expression of microsomal for the metabolism of the test results,the
metabolite M-I is mainly
CYP2D6,several other metabolites are mainly CYP3A4 produced by.
(2) human liver microsomes using various CYP species, the inhibitory effect on the results of a study, a green
process
Is CYP1A2,CYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP2D6, whereas an inhibitory effect
did not show(acting by direct inhibition and metabolic-derived inhibitory effect IC
50
Value:100μmol/L or more).
CYP3A4/5 for weak inhibitory activity showed[direct inhibitory effect IC
50
Value:100μmol/L or more, and metabolism

Derived from the inhibitory effect IC
50
Value:12μmol/L(midazolam 1’-hydroxylation activity) and 28μmol/L(testosterone

Online 6β-hydroxylation activity)].
(3) human primary hepatocytes using various CYP molecular species with respect to the induced action of the
investigated results, and alogliptin
Of CYP1A2,CYP2B6 and CYP3A4 to the induction effect was observed.
5-3 first-pass effect of presence and proportion of
The first pass effect is less susceptible was presumed.
5-4 metabolites of the active presence and ratio
(Reference) [rat]
Metabolites M-I IC
50
Value 6.9 nmol/L was in.

5-5 active metabolite of kinetic parameters
Healthy adults (8 cases)to the subject report, alogliptin as 100mg Breakfast 30 minutes before a single dose at the
time of the metabolic
composition of M-I and pharmacokinetic parameters were following the.
n
Cmax(ng/mL)
Tmax
a)
(h) AUC
0-inf
(ng･h/mL)
T
1/2
a)
(h)
Metabolites M-I
8
0.7(0.5)
1.6(0.5)
21.9(13.7)
22.1(5.7)
The mean(standard deviation), a) n=7
Plus alogliptin succinic acid salt
M-I
－ 39 －
6. Excretion
6-1 excretory sites and pathways
Mainly excreted in the urine
5)
.
6-2 excretion rate
Healthy adults (12 cases)to the subject, and alogliptin as 100mg Breakfast fast or Breakfast starts 30 minutes later
by a single oral dose, when administered to 168 hours after that alogliptin of the cumulative urinary excretion rate
of each of
these 76.6%,76.1%were
13)
.
■Tolerant alogliptin of the cumulative urinary excretion rate of
20
0
40
60
80
100
(%of Dose)
0
24
48
72
96
120
144
168
Cumulative urinary excretion rate
Breakfast fast under(n=12)
Breakfast starts 30 minutes later(n=12)
6-3 excretion rate
7. Transport information
(Reference) [in vitro]
19)
(1) tolerance alogliptin succinic acid salt of P-glycoprotein(P-gp) inhibition to consider the P-gp substrate
[
3
H]road of the Caco-2 cell permeation impact was studied. Plus alogliptin is[
3
H] the goal
Of transportation to slightly inhibited (IC
50
Value:500μmol/L or more).
(2) BCRP,OATP1B1,OATP1B3,OAT1,OAT3 and OCT2 to the inhibitory effect was studied.
Plus alogliptin is an organic cation Transporter OCT2 substrate of Metformin takes
only against the inhibitory effect was shown (IC
50
Value:55.9 µmol/L).
8. Dialysis, such as removal rate
Hemodialysis[foreign data]
End-stage renal failure patients (6 cases)to the subject, and alogliptin as 50mg single dose, and 4 hours of blood
fluid dialysis at a dose of 9. 2% (mean, n=4) has been removed
11)
.
－ 40 －
1. Warning the contents and why
Not applicable
2. Contraindications content and why
(1) severe ketosis, diabetic coma or pre-coma, type 1 diabetes patients[infusion, insulin and
Rapid correction of hyperglycemia is essential to book in the administration of the agent are not suitable.]
(2) severe infection,before and after surgery,severe trauma patients[insulin injections and blood sugar
management is desirable
In this administration of the agent are not suitable.]
(3) the advanced patients with impaired renal function or dialysis in ESRD patients[this drug is primarily
excreted by the kidneys to
For excretion by the delay of this drug blood levels could rise.]
(
【Pharmacokinetics】of the section).
(4) this drug is a component of hypersensitivity to patients with a history of
<Remarks>
(1) oral diabetes medicines for common operating procedures or conditions and can be avoided by taking proper
precautions as you.
Severe ketosis, diabetic coma or pre-coma-like acute metabolic imbalance against the state, or
online therapy is absolute indication, and Type 1 diabetes, this drug's efficacy is not.
Severe ketosis, diabetic coma or pre-coma patients, the basic condition of the cell and out of
dehydration, ketoacidosis, electrolyte loss, high blood sugar for correction while aging
in obtained test results,the appropriate insulin administration,water and electrolyte supplementation positively
by time.
(2) oral diabetes medicines for common operating procedures or conditions and can be avoided by taking proper
precautions as you.
Severe infections are merged in diabetes, infection and insulin resistance increase due to the blood glucose level is
markedly elevated, diabetic coma due to insulin injections and proper blood sugar management is
desired.
Before and after surgery in patients with mental stress, surgery, invasive physical stress, postoperative infections
, such as glycemic control of the situation changes from being a stable blood glucose level is obtained
in the insulin injections and proper blood sugar management is desired.
Severe trauma patients in the trauma by physical and mental stress, blood sugar control
the change in the situation considered,insulin injections and proper blood sugar management is desired.
(3) this drug is mainly from the kidneys to the first changes in the body and excreted as for renal dysfunction when
administered to,excretion
Delay,the drug exposure amount may increase.
Overseas clinical studies, mild to advanced renal dysfunction and end-stage renal disease patients (hemodialysis
cost to
the patient)to the subject of this agent when administered in advanced renal dysfunction and end-stage renal
failure patients, healthy
adults when administered, compared to the book agents of the AUC and 3 times higher than the Rose.
("V. "Items related to treatment of the section).
VIII. Safety (precautions, etc.) relating to the items
－ 41 －
(4) Pharmaceuticals in the General notes in.
Such patients with hypersensitivity relapse likely to be considered for this agent by hypersensitivity
is expressed patients, the administration of the agent to avoid.
3. Indications associated with the precautions for use and why
Not applicable
4. Usage and dosage associated with the precautions for use and why
" V. Treatment related items"section of the reference
5. Cautious administration of content and why
The following patient or state
(1) moderate patients with impaired renal function(
<Dosage and administration related to the cautions＞,【pharmacokinetics】
Of the section).
(2) sulfonyl urea agents or insulin formulation administered in patients with the other DPP-4 inhibitors,in
combination with
More severe hypoglycemia has been reported.] ("Important basic attention","interaction","critical sub -
effect"of the section).
(3) pituitary insufficiency or adrenal insufficiency[low blood sugar cause it is.]
(4) malnourishment,starvation, irregular dietary intake, food intake, lack of or debilitated state [low blood sugar
Could be.]
(5) intense muscle exercise[low blood sugar cause it is.]
(6) excessive alcohol intake who[low blood sugar cause it is.]
<Remarks>
(1) this drug is mainly from the kidneys to the first changes in the body and excreted as for renal dysfunction when
administered to,excretion
Delay,the drug exposure amount may increase. This drug is safe for use, the patient's serum, click
creatinine value measured, gender, age, weight from the values of creatinine clearance to calculate, etc.,
the degree of renal dysfunction based on the dose adjusting. ("V. Items related to treatment"and"7. Mutual
action of the Chapter")
(2) medicines for diabetes the diabetes cure low blood sugar, is an important basic precautions should. Other
sugars
Urine disease for the drug combination in patients,this drug action, in addition to a combination of medicines for
diabetes and blood
sugar lowering effect will additively acting,low blood sugar may cause. Especially sulfonyl urea agents or
insulin formulation in combination with other DPP－4 inhibitors in severe hypoglycemia has been reported.
These drugs when used in combination with a sulfonyl urea agents or insulin preparations weight loss consider
that. ("6. Important fundamental note and its reasons and treatment methods","7. Interaction"and"8-2. Serious
side effects and symptoms"of the section).
－ 42 －
(3) diabetes medicines for common operating procedures or conditions and can be avoided by taking proper
precautions as you.
Pituitary insufficiency or adrenal insufficiency as a result of the merger in patients,glucocorticoid secretion
deficiency
due to blood sugar level is lowered when a sufficient blood glucose level of recovery can low blood sugar cause to
think
that.
precautions as you.
Food intake is irregular, if blood glucose control is poor and more likely to hypoglycemia
could be. Also, malnourishment,starvation,food intake, lack of or weakness in the state
in the liver of glucose storage is enough to make one,book agents such as medicines for diabetes by the action of
the blood glucose level is
decreased when the blood glucose level to recover only glucose can produce is likely to be low blood sugar
cause is considered likely.
precautions as you.
Muscle movement during muscle glucose utilization in the liver from glucose release outweigh the reduced blood
glucose levels and hypoglycemia
leading to the possibility. Also, exercise consumed by the muscles of the liver of glycogen times
recovery for glycogen synthesis post-exercise 12 to 24 hours sustained enhancement for the delay
as low blood sugar can be considered.
precautions as you.
Alcohol and its breakdown product of insulin secretion, suppress peripheral tissue insulin sensitivity
and decreases on the other hand,in the liver, gluconeogenesis, to suppress the action, because excessive alcohol
intake
, who is this agent or other medicines for diabetes lowers blood glucose by when enough glucose, you can generate
one
to hypoglycemia that is considered.
6. Important fundamental note and its reasons and treatment methods
(1) the agent or other medicines for diabetes when used in combination with hypoglycemia could be in these pills
Agent and in combination with sometimes for patients with hypoglycemia symptoms and how to deal with them
thoroughly described,attention
, stimulating. Especially sulfonyl urea agents or insulin preparations when used in combination with,hypoglycemia
increases the risk and it is. Sulfonyl urea agents or insulin preparations by hypoglycemia
to reduce the risk of these drugs when used in combination with a sulfonyl urea agent or
insulin formulations for weight loss in this study. ("Careful administration","interaction","significant adverse
effects"
of the section).
(2) this agent is 1 week to 1 times the oral dose of the drug, the administration cancelled after effects persist in
blood sugar
Value and side effects of expression about enough to be noted. (
【Pharmacokinetics】and【medicinal pharmacology] of
Section).
moreover, the agent is administered after discontinuation of other medicines for diabetes when you use blood
sugar management situation, considering
that the start of the administration period and dose in this study.
(3) diagnosis of diabetes is established patients only applied to consider. Diabetes and other glucose tolerance
Abnormal・urine glucose-positive, such as diabetes similar symptoms (renal resistance, diabetes, thyroid
dysfunction, etc.) having a disease is
to be noted that that.
－ 43 －
(4) the agent application for diabetes treatment is the basis of diet, exercise regimen, well made
The effect is insufficient to take into account as far as possible.
(5) this drug during administration of blood sugar regularly inspect and,after enough observation,this drug is 2 ~
3 months
The administration even if the effect is insufficient, and as a treatment to consider changes to the.
(6) Administration for the duration of, the administration of the need for the patient's 不養生,infection of
Also due to ineffective or insufficient, when the dietary intake, blood glucose,
and the presence of infections, etc., in mind, and always administered in continuation, the drug of choice, etc.,
should be noted.
(7) hypoglycemia symptoms may occur, aerial work platforms,driving, etc., which is engaged in the patients
When administered to note that. ("Serious side effects"section of the reference)
(8) insulin formulation in combination with one of the clinical efficacy and safety have not been studied.
(9) the agent and the GLP-1 receptor agonists are both GLP-1 receptor-mediated hypoglycemic effect has
To. Both agents combined use of clinical trial results, the efficacy and safety has not been confirmed.
<Remarks>
(1) medicines for diabetes the diabetes cure low blood sugar, is an important basic precautions should. Other
sugars
Urine disease for the drug combination in patients,this drug action, in addition to a combination of medicines for
diabetes and
hypoglycemic action is additively acting,low blood sugar may cause. Especially sulfonyl urea agents
or insulin formulation in combination with other DPP－4 inhibitors in severe hypoglycemia has been reported
that. These drugs when used in combination with a sulfonyl urea agents or insulin formulations for weight loss
in this study.
And, as well as raise awareness of the"incretin(GLP－1 receptor agonists and DPP－4 inhibitors) for the proper
use of
the Committee on the"issued to. Details for Japan Diabetes Society on the home page(http://www.jds.
or. jp/) or the Japan Diabetes Association home page(http://www.nittokyo.or.jp/) to see. ("5. Cautious
administration of content and why","7. Interaction"and"8-2. Serious side effects and symptoms"of the section).
(2) this agent is 1 time a week to take the drug. Domestic healthy adults, the report alogliptin as 50mg or
Is 100mg Breakfast 30 minutes before a single oral dose, when administered to 168 hours after the plasma
concentrations of the average value, and
for each 1. 2ng/mL and 2. 1ng/mL. ("VII. Pharmacokinetic-related items, 1-3 (1)"of Section).
Also, the domestic type 2 diabetes patients to, and alogliptin as 100 mg,1 time a week before Breakfast
for 12 weeks when administered orally, and alogliptin final dose after 7 days the average plasma DPP－4
inhibition rate of
77.4 percent. ("VI. Medicinal pharmacology related fields, 2-2 (1) 4)"terms of reference)
from this, the drug is administered 7 days later if the plasma DPP－4 inhibition rate maintain blood sugar levels,
side effects
for the expression be careful about that. This agent to stop other medicines for diabetes when you use the patient
's blood glucose management on the administration of the drug start time and dosage and administration, such as
in this study.
precautions as you.
This administration of the agent to be considered before the diagnosis of diabetes mellitus should be established.
precautions as you.
Diet and exercise regimen is the treatment of diabetes mellitus is the basis of this agent administered in any way
through this.
－ 44 －
(5) in General the treatment of diabetes of the approximately 2 ~ 3 months after the observation, the effect is
insufficient
If the other agent, including a combination of other treatments should be considered.
(6) General precautions at you.
This drug treatment, and diabetes of the basic treatment diet, exercise regimen is sufficiently carried out
by the patient, the pathogenesis of this agent, including the drug treatment is unnecessary State improved to be
even
that. Also, patients 不養生(diet turbulence, exercise regimen is insufficient, etc.), the diabetes
of the basic treatment is not done enough, the glycemic control is disturbed, and this
by this drug effect was insufficient, and it is also expected that. Therefore, this drug by
drug therapy, including treatment of diabetes mellitus if you have done is always the patient's dietary intake
status, weight, thrust,
move, blood sugar, infection, or other condition of the check out the book while administration of the agent,
continue the advisability of including the cure,
health policies need to consider.
precautions as you.
Hypoglycemia symptoms may occur, the patient's condition and life situation, such as noted,drive a car,
operate machinery, or work in high places, etc., be careful so that the guidance can.
[Ministry of Health, Labour and welfare pharmaceutical and Food Safety Bureau safety Manager notification (as of 26 years 1 month 7 dates)]
(8) insulin formulation in combination with one or clinical performance, and the clinical effect and safety are
confirmed
Not.
(9) book agents including DPP－4 inhibitors and GLP－1 receptor agonists is the same GLP－1 receptor-
mediated hypoglycemic make
For to have. Book agents and GLP－1 receptor agonists in combination with one or clinical performance, and the
effectiveness
and safety has not been confirmed.
7. Interaction
This drug is mainly from the kidneys to the first changes in the body and excreted, and excretion of a normal
glomerular filtration urinary excretion
can be estimated. (
<Commentary>
array alogliptin excretion of about
domestic health adult male to the subject report, alogliptin as 50 mg or 100 mg single dose(in each group, 8
cases)or
when administered to 168 hours after that alogliptin of the urinary excretion rate of the mean, respectively, 71.
45% and
75.96% for.
Overseas health adults to report alogliptin as 50 mg or 100 mg single dose(each group consisting of 6 for
example)and
you, and alogliptin administered 72 hours after of the urinary excretion rate of the mean, respectively, 55. 71%
and
57.75%and is mainly excreted by the kidneys were considered. We do not sell, trade, or rent La alogliptin of renal
clearance
, the average glomerular filtration rate〔125mL/min (7.5 L/hr)] and the big difference is normal glomerular
would
spend in the urine excreted was considered.
Renal dysfunction to administration when"2. Contraindications content and why"and"V. Treatment related
items"section of the reference.
－ 45 －
7-1 combination of contraindications and why
Not applicable
7-2 used with caution and why
Drug name, etc.
Clinical manifestations・measures・how to
mechanisms such as
medicines for diabetes
sulfonyl urea agent
With,the,gliclazide,
Assembly code, etc.
Rapid-acting insulin secretagogue
Nateglinide,check the green calcium hydrate,green
α - glucosidase inhibitors
Button, green button, and you, a list
Biguanides-based drugs
Metformin hydrochloride, brand hormones hydrochloride
Thiazolidine-based drugs
Pioglitazone hydrochloride
GLP-1 receptor agonist
Note 2)
Round green check,the original check, the system Center team

SGLT2 inhibitors
Ipragliflozin L - Proline,
Empagliflozin propylene glycol hydrate,
White glyph Rosin hydrate,process video full version hydrate, etc.
Insulin preparations
Note 3)
・On the left of medicines for diabetes and concomitant use when
Hypoglycemia expression may be
carefully administered. Especially
sulfonyl urea agent, or the license
application preparation and when used in combination with a low blood
sugar increase the risk of it is
you. These drugs lower blood
sugars to reduce the risk of a
sulfonyl urea agents or insulin
content of the formulation weight loss in this study.
・α - glucosidase inhibitor and the combination of
For more hypoglycemia symptoms is observed
when sucrose is a way to drive
out the sugar administering.
Hypoglycemic effect augmented or attenuated by the drug combination if you're
○ medicines for diabetes of the hypoglycemic effect of enhancing the drug
beta - blockers, salicylic acid preparations, monoamine oxidase inhibitors,
fibrate of medications for the treatment of hyperlipidemia, etc.
○Medicines for diabetes of the hypoglycemic effect of attenuating drugs
Epinephrine,adrenocortical hormone,thyroid hormone, etc.
On the left of the drug when used in combination with a
book agent of the insulin secretagogue action is
to effect enough to note
if any revision is not acceptable to you, your only recourse is to cease that.
Note 2)"is an important basic attention (9)"Chapter
Note 3)"important basic attention (8)"Chapter
<Commentary>
other diabetes medicines for use in patients,this drug action, in addition to a combination of medicines for
diabetes and blood
sugar lowering effect will additively acting,low blood sugar cause is considered likely.
Domestic this drug and sulfonyl urea agent,a rapid-acting insulin secretagogue,biguanides system drugs,
agents and thiazolidine-based drug testing, low-glycemic side effects have been reported.
In particular, the sulfonyl urea agents or insulin formulation in combination with other DPP－4 inhibitors weight
Atsushi no hypoglycemia has been reported. These drugs when used in combination with a sulfonyl urea agents or
insulin formulations for weight loss in this study. ("5. Cautious administration of content and why","6. Important
basic attention with
its reasons and treatment methods"and"8-2. Serious side effects and symptoms"of the section).
α－glucosidase inhibitors in combination with hypoglycemia symptoms was observed when sucrose was
administered, the
α－glucosidase inhibitor of the action of the glucose decomposed into one not absorbed because of hypoglycemia
symptoms treatment
on glucose administered.
－ 46 －
This section illustrated that the drug and this drug interaction have not been studied, and left drugs for diabetes
drugs, hypoglycemic effect enhance or attenuate known to be. Left the drugs in addition to this drug, when
administered to
the left of the drug to the action of this drug hypoglycemic effect by the addition of enough note,hypoglycemia and
glycemic control
of worse to come in you need to keep in mind.
【Hypoglycemic effect of enhancing the considered mechanisms】
beta－blockers:
non-specific β－blockers in the liver for gluconeogenesis, to suppress hypoglycemia and a delay in recovery from a
persistent be
considered.
Salicylic formulation:
salicylic formulation is itself a hypoglycemic properties from this agent hypoglycemic action to
strengthen and it is.
Monoamine oxidase inhibitors:
mechanism is unknown, alone administered hypoglycemic reported to cause that. This is the the pancreas
pancreas to direct action, and insulin secretion by promoting it has been speculated.
Fibrate of medications for the treatment of hyperlipidemia:
the mechanism is unknown, the fibrate of medications for the treatment of hyperlipidemia is itself a hypoglycemic
effect has
and glucose tolerance improved in this study.
【Hypoglycemic effect of attenuating that and the probable mechanism】
Adrenaline:
peripheral tissue glucose uptake, suppressing hepatic gluconeogenesis, promotes the blood glucose level may rise
, you. Also, insulin secretion inhibition is also considered.
Corticosteroids:
steroid diabetes known as blood sugar rises, the diabetes-induced is known and this drug effect
results in attenuation and it is.
Thyroid hormone:
the blood sugar rise that indicates there is a report that this drug effect of attenuated and there you have it.
(Stockley’
s Drug interactions 8th ed : The Pharmaceutical Press , London, 2008.)
This drug can consider drug interactions when testing
"VII. Pharmacokinetic-related items,1 － 5 (2)"Chapter
This drug metabolism and about
"VII. Pharmacokinetic-related items,5"Section reference
－ 47 －
8. Side effects
8-1 side effects overview
Approval of domestic clinical trials, 901 example in 103 patients (11.4%)in the clinical laboratory value
abnormalities, including Deputy
effects were observed. The main thing is,hypoglycemia, nasopharyngitis,lipase increase, etc. were.
<Remarks>
the time of approval of the national clinical trials, and alogliptin as 50 mg or 100 mg 1 time per week
administered in patients with side effects of expression indicating the status. ("8-4. Itemized side effects the
expression of the frequency and clinical test
results value anomaly list"of the section).
・ Type 2 diabetes patients, this agent of a clinical dose to consider,Week 1 dose at the time of effectiveness
And to study the safety of the test(plus alogliptin 50 mg dose group 51 examples and 100mg dose group 55 for
example,
the administration period of 12 weeks)
・ In patients with Type 2 diabetes, and alogliptin as 100 mg 1 time per week dosing and effectiveness, and
Safety and alogliptin contrast to study for exams(101 example, the administration period of 24 weeks)
・ In patients with Type 2 diabetes, and alogliptin as 100 mg 1 time a week, long-term administration of effective
Resistance and safety were examined test (680 example, administration period and 52-week)
・ Other DPP－4 inhibitors day administered in patients with Type 2 diabetes, and alogliptin as
100 mg 1 time a week the administration was changed,efficacy and safety study for the exam(14 cases, the
administration period
between 12 weeks)
Domestic clinical trials, 901 example in 103 patients (11.4%)in laboratory values, including abnormalities in side
effects was observed.
This degree is advanced and it is determined that the case was not.
The main side effect is hypoglycemia 9 cases(1.0%), nasopharyngitis 9 cases(1.0%), lipase increase in 8 patients
(0.9%), and there
was.
8-2 significant side effects and symptoms
Hypoglycemia (0.1 ~ 5% or less) be aware of the condition of the patient, fully observing the toss,
given that.
Other DPP-4 inhibitors,sulfonyl urea agent and in combination with severe hypoglycemia
symptoms is
a loss of consciousness comes to cases that have been reported from the sulfonyl urea agents used in conjunction
with a place to
meet, a sulfonyl urea agent of weight loss in this study. Also, this drug by the administration of hypoglycemia
symptoms
was observed in the case usually sucrose administration is,
α-glucosidase inhibitors in combination with
The hypoglycemia symptoms was observed when glucose is administered.
<Commentary>
domestic type 2 diabetes patients in the Phase 3 long-term administration trial (plus alogliptin as 100 mg,1 / Week,
administration period and 52-week), this agent is administered alone for example,sulfonyl urea-drug combination
for example,a rapid-acting insulin minutes
secretion promoter combination with e.g., biguanides-based drug combination examples and thiazolidine-based
drug combination example 9 example hypoglycemia
(Side effects)are expressed. Otherwise, at the time of approval of the domestic clinical trials, either hypoglycemia
Symptoms(side effects)is not permitted. Also, the reported hypoglycemia(side effects)the degree of all the mild and
stamp
set,one of the cases also expressed the day of the event during the recovery.
－ 48 －
■ Domestic Phase 3 long-term administration test hypoglycemia(side effects) expression in a number of cases
Administration examples
Number of cases (%)
Single administration of cases (n=248)
1 (0.4%)
Sulfonyl urea-drug combination example (n=158)
5 (3.2%)
Rapid-acting insulin secretagogue combination of cases (n=67)
1 (1.5%)
Biguanides-based drug combination example (n=70)
1 (1.4%)
Thiazolidine-based drug combination example (n=72)
1 (1.4%)
α－glucosidase inhibitors in combination examples (n=65)
0
Hypoglycemia is expressed in the case,the patient guidance, including the hypoglycemic response to
do this.
1) this drug is administered alone or α－glucosidase inhibitors, other medicines for diabetes may be used in
combination if:
Sucrose (sugar 20g)to consume.
2) α－glucosidase inhibitors may be used in combination if:glucose(10g)to consume.
3) this agent is used for diabetes medications temporarily to discontinue,or to lose weight.
Moreover, disturbance of consciousness resulting in hypoglycemia and patients suspected when responding to the
first, immediately the blood glucose level
measurement (simple method), and hypoglycemia to make sure that your,50% glucose injection
20mL(20%glucose
in the case 40mL) administered intravenously can. For measuring the blood sugar level, and awareness of recovery
of blood glucose
to rise, confirming the carbohydrate intake to encourage the patient to this.
(The Japan Diabetes Society and edited Diabetes Treatment Guide 2014－2015, p. 70 in 2014, 文光 Hall and some of the quotes)
Prescription of the patients at the time of the guidance to use medication reminder to create all necessary, at our
request, please ask your server for today's selection.
Incidentally, the sulfonyl urea agents or insulin formulation in combination with other DPP－4 inhibitors weight
Atsushi no hypoglycemia has been reported. These drugs when used in combination with a sulfonyl urea agents or
insulin formulations for weight loss in this study.
As well as raise awareness of the"incretin(GLP－1 receptor agonists and DPP－4 inhibitors) regarding the
appropriate usage of that Committee
Committee"issued to. Details for Japan Diabetes Society on the home page(http://www.jds.or.jp/) or
the Japan Diabetes Association home page(http://www.nittokyo.or.jp/) to see. ("5. Cautious administration of
content and it makes sense
why","6. Important fundamental note and its reasons and treatment methods"and"7. Interaction"of the section).
－ 49 －
(Similar drugs)
(1)
Acute pancreatitis be aware of and to observe carefully,persistent severe abdominal pain, vomiting
abnormal if the administration should be discontinued and appropriate treatment to do.
(2)
Ileus be aware of and to observe carefully, advanced constipation, bloating, sustained
to abdominal pain, vomiting abnormal if the administration should be discontinued and appropriate treatment to
do.
<Remarks>
(1) the other DPP－4 inhibitors in acute pancreatitis expression of examples have been reported.
This drug during administration,lasting abdominal pain, vomiting abnormal if there is, acute pancreatitis, an
expression of doubt,
this administration of the agent should be discontinued. Also, serum amylase, serum lipase or amylase fractions
such as measuring,abdominal ultrasound and abdominal CT scans and other imaging tests to confirm the
diagnosis is to do. Acute pancreatitis
is diagnosed, the state of consciousness, blood pressure, pulse rate, respiratory rate, body temperature, urine
output, oxygen saturation over time remote
monitoring, conduct a sufficient amount of fluids such as performing appropriate procedures.
This agent of domestic clinical trials 901 example, acute pancreatitis(side effects)of the expression for example is
not reported.
(2) this agent during the administration of advanced constipation, bloating, persistent abdominal pain, vomiting,
etc. no abnormalities were observed in the case
This administration of the agent should be discontinued. Also, abdominal X-ray and abdominal CT examination
to confirm the diagnosis is to do
with. Intestinal obstruction was diagnosed if you constantly drink,fast,fluid,bowel movement and improve the
administration of drugs,stomach tube insertion, such as
the common conservative treatment such as performing appropriate procedures.
Incidentally, this drug at the time of approval of the domestic clinical trials, moderate ileus and intestinal
obstruction(side effects)for each 1
for an example only. None of the 3-Phase long-term administration trial (plus alogliptin as 100 mg 1 time a week,
52
weeks) in the reported cases, and a rapid-acting insulin secretagogue used with example by.
The expression for example, scrutiny result,the whole circumference of the rectal cancer and multiple liver
metastases was observed
for low anterior resection was enforced. This drug is administered, discontinue ileus tube insertion by intestinal
decompression
by the enforcement recovered. Incidentally, rectal cancer, the clinical trials started before the merger had been
considered
from the clinical and causation is denied.
Also, intestinal obstruction, the expression for example is this drug after administration on Day 1, bowel
obstruction, and the diagnosis has been admitted, the treatment is
not performed, the drug is administered, discontinue bowel movement and improved drugs and fluid, etc., by the
administration of recovery.
8-3 other side effects
The following side effects if the symptoms according to the appropriate procedures.
0.1 ~ 5% less than
1)
Hypersensitivity
Rash, 瘙 itchy
2)
Cardiovascular
Atrial fibrillation
3)
Liver
ALT(GPT), elevated AST(GOT)rise, γ-GTP rise
4)
Other
Blood amylase increase,lipase increase,CK(CPK)increase, urine occult blood positivity,nasopharyngitis
<Commentary>
eczema in 6 cases (0.7%), rash in 4 cases(0.4%), pruritus,skin ulcers and urticaria each 2 cases (0.2%), erythema
Hill,
maculopapular rash, generalized pruritus and addictive rash each 1 case (0.1%) of side effects have been reported.
Eczema 3 for example, rash 1 Examples and skin ulcers 1 for example, the moderate was, it was mild.
－ 50 －
Moreover, the administration of the agent, discontinue the necessary cases, there were none of the cases have
recovered. Administration starting from
the current period, and within 2 weeks was expressed from 10 months after the expression was.
Atrial fibrillation in 3 cases (0.3%) and palpitations 1 case (0.1%) of side effects have been reported. From the
start of the administration, the expression of
a period, and within 2 weeks was expressed from 5 months to more than the expression was. Either as
degrees are mild, and atrial fibrillation of 2 cases the outcome is not the recovery, the Drug Administration of
change took cases
did not.
Liver function abnormalities in 4 cases(0.4%), ALT(GPT) rise and AST(GOT)the rise each 3 cases (0.3%), γ－
GTP rising
2 cases (0.2%) and abnormal liver function tests 1 case (0.1%) of side effects have been reported.
Liver function abnormalities 1 for example, the book agent of the end of the administration period from 1 week
after the expression and the degree in
such degrees and reported. It is highly recommended that you review all the data for accuracy, and the degree is
mild, and the Drug Administration of change took syndrome
example was not. Either of these cases, drug treatment is performed to recover.
Blood amylase increase in 3 cases (0.3%), lipase increase in 8 cases(0.9%), pancreatic enzymes increased in 2 cases
(0.2%), pancreatic enzyme abnormalities in
1 case (0.1%), CK(CPK)increase in 5 cases (0.6%), urine occult blood-positive in 3 cases (0.3%) and
nasopharyngitis 9 cases(1.0%)of the Deputy
effect has been reported. One degree is mild and reported, and urine occult blood-positive in 2 cases the outcome
is
yet to recover, the other cases are either recovering.
－ 51 －
8-4 itemized side effect frequency and laboratory abnormalities list
■Side effects of expression situation
Analysis number of cases
901
Side effects the expression of a number of cases
103
Side effects, expression number
151
Side effect frequency(%)
11.4
Different types of side effects
Expression number of cases(%)
Infections and infestations
11 (1.2)
Nasopharyngitis
9 (1.0)
Bronchitis
1 (0.1)
Cellulitis
1 (0.1)
Bacterial vaginal flame
1 (0.1)
Vulva flame
1 (0.1)
Wound infection
1 (0.1)
benign, malignant and unspecified of the nascent
ones(cysts and polyps included)
2 (0.2)
Adrenal gland neoplasms
1 (0.1)
Bladder cancer
1 (0.1)
Plasma cell myeloma
1 (0.1)
Blood and lymphatic system disorders
2 (0.2)
Anemia
2 (0.2)
Endocrine disorders
1 (0.1)
Thyroid cysts
1 (0.1)
Metabolism and nutrition disorders
12 (1.3)
Hypoglycemia
9 (1.0)
Dyslipidemia
2 (0.2)
Hyperkalemia
1 (0.1)
Nervous system disorders
1 (0.1)
Diabetic neuropathy
1 (0.1)
Eye disorders
3 (0.3)
Eye dryness
2 (0.2)
Diabetic retinopathy
1 (0.1)
Heart failure
4 (0.4)
Atrial fibrillation
3 (0.3)
Palpitations
1 (0.1)
Vascular disorders
1 (0.1)
High blood pressure
1 (0.1)
Respiratory, thoracic and mediastinal disorders
2 (0.2)
Oropharyngeal pain
2 (0.2)
Gastrointestinal disorders
18 (2.0)
Constipation
5 (0.6)
Stomach polyps
2 (0.2)
Abdominal pain
1 (0.1)
Upper abdominal pain
1 (0.1)
Diarrhea
1 (0.1)
Indigestion
1 (0.1)
Gastritis
1 (0.1)
Erosive gastritis
1 (0.1)
Hemorrhoids
1 (0.1)
Ileus
1 (0.1)
Intestinal obstruction
1 (0.1)
Colon polyps
1 (0.1)
Nausea
1 (0.1)
Pancreatic enzyme abnormalities
1 (0.1)
Hepatobiliary disorders
8 ( 0.9)
Abnormal liver function
4 (0.4)
Cholecystitis
1 (0.1)
Cholelithiasis
1 (0.1)
Fatty liver
1 (0.1)
Hyperbilirubinemia
1 (0.1)
Skin and subcutaneous tissue disorders
16 (1.8)
Eczema
6 (0.7)
Rash
4 (0.4)
瘙 itchy disease
2 (0.2)
Skin ulcers
2 (0.2)
Urticaria
2 (0.2)
Alopecia areata
1 (0.1)
Erythema
1 (0.1)
Pimples
1 (0.1)
Systemic 瘙 itchy disease
1 (0.1)
Addictive rash
1 (0.1)
Musculoskeletal and connective tissue disorders
3 (0.3)
Muscle spasticity
1 (0.1)
Limb pain
1 (0.1)
Polyarthritis
1 (0.1)
Renal and urinary disorders
1 (0.1)
Ureteral stone
1 (0.1)
Reproductive system and breast disorders
2 (0.2)
Benign prostatic hyperplasia
1 (0.1)
Blood semen syndrome
1 (0.1)
General disorders and Administration site conditions
1 (0.1)
Dry mouth
1 (0.1)
Laboratory tests
32 (3.6)
Lipase increased
8 ( 0.9)
Blood creatine phosphokinase increased
5 (0.6)
Alanine aminotransferase increased
3 (0.3)
Amylase increased
3 (0.3)
Aspartate aminotransferase increased
3 (0.3)
Urine and blood positive
3 (0.3)
－ 52 －
This is the ICH international pharmaceutical Glossary English(MedDRA/J Ver. 16. 0)which are listed in the Term(Preferred Term: basic)show
that.
The same cases in the same event multiple times for the manifestation of side effects, the expression of a number(the expression number)is 1 for
example an aggregate to. Also, side effects, expression
number is the total number of aggregates that.
(Approval summary: 2015 Year 3 month)
Blood triglycerides increased
1 (0.1)
Blood uric acid increased
1 (0.1)
Abnormal liver function tests
1 (0.1)
Platelet count decreased
1 (0.1)
Platelet count increased
1 (0.1)
The urine protein-positive
1 (0.1)
γ-polyglutamic the transferase increased
2 (0.2)
Pancreatic enzyme increase
2 (0.2)
Blood creatinine increased
1 (0.1)
Blood glucagon increased
1 (0.1)
Blood glucose decreased
1 (0.1)
Blood glucose increased
1 (0.1)
8-5 underlying disease,complications, severity and surgery, the presence or absence of the background another
side effect frequency
8-6 Allergy medication for attention and test methods
【Contraindications】
(4) this drug is a component of hypersensitivity to patients with a history of
Other side effects
the following side effects if the symptoms according to the appropriate procedures.
0.1 ~ 5% less than
1)
Hypersensitivity
Rash, 瘙 itchy
9. Elderly administration to
In General in the elderly have poor kidney function can often effects the expression of the mind, the course of ten
minutes to observe them carefully administered. (
<Dosage and administration-related precautions>," carefully
Administration"and
<Remarks>
In General in the elderly renal function and liver function and other physiological functions are often decreases,
drug side effects is
expressed and is considered likely.
This drug is renal excretion of the drug type, the elderly administration if kidney function note carefully
administered to
you. Creatinine clearance calculation, etc. (the calculation formula is"V. Treatment related items"section), and
the degree of renal dysfunction, depending on the dose adjusting. ("V. Items related to treatment","5. Carefully
administered in the
content and why"and"7. Interaction"of the section).
－ 53 －
【Domestic clinical trial results]
In Type 2 diabetes patients domestic clinical trials of combined analysis(administration period 12 ~ 52 weeks), the
65-year-old first
meeting of the non-elderly and 65 years of age or older to drive alogliptin as 50 mg or 100 mg was administered
and
adverse events expressed the situation below was.
■ Domestic clinical trials age-specific adverse event frequency(combined analysis)
n=51
n=850
65 years old
31
13(41.9)
572
434(75.9)
65 years old
20
7(35.0)
278
214 (77.0)
Top categories: number,bottom:number of cases(%)
【Elderly pharmacokinetics】
In Type 2 diabetes patients domestic clinical trials(plus alogliptin as 100 mg of between 12 and 52 weeks)
in the measured plus alogliptin of the plasma concentration in the population pharmacokinetic analysis conducted
in Type 2 sugar
urine disease patients in steady state under the tolerant alogliptin of AUC(0-168) and Cmax of the non-
elderly(aged 65 years
or less) for the elderly(65 years old) compared to the estimated result,each approximately 1. 2 ~ 1. 4-fold and
approximately 1. 1 ~ 1.3
- fold.
10. Pregnant women, nursing mothers,lactation, etc. to the administration of
(1) a pregnant woman or a pregnant lady who might be a therapeutic benefit risk on that
It is determined only when administered. [Pregnancy administration regarding the safety of the drug have not
been established.
Animal studies (rats), the placenta passes have been reported.]
(2) lactating women administered to avoid unavoidably, when administered to breast-feeding discontinue this
And. [Animal experiments (rats) in milk during the transition to it has been reported.]
<Remarks>
(1) a pregnant woman or a pregnant lady who might be used in relation to the experience, not human pregnancy
administration
Safety has not been established. If this drug is administered during pregnancy has been confirmed, if the
administration
discontinued the diet by management or insulin therapy switching in this study.
This agent signs the body(
14
C－Plus alogliptin) on pregnancy day 18 rats by Oral Administration(3 mg/kg) as the placenta
and the fetus tolerant alogliptin and its derived components of the migration study,maternal plasma for
in organizations,all collected at the time the placenta is the highest radioactivity concentration was shown.
Amniotic fluid and fetal blood
plasma in total radioactivity concentration in the maternal plasma concentration compared to low, the fetal
homogenates in the
total radioactivity concentration in the maternal plasma concentration was almost equal. From this, and
alogliptin
and the origin of some of the ingredients in maternal plasma from the fetus to migrate and considered.
(2) nursing a rat, and alogliptin origin of some of the ingredients are milk migrate to confirm that
It. ("VII. Pharmacokinetic-related items,4-3 in Chapter")
－ 54 －
11. Childhood etc. to the administration of
Low birth weight infants,newborns,infants, toddlers or children, for the safety of the drug have not been
established(in-use experience is
not).
<Commentary>
low birth weight infants,newborns,infants, toddlers or children of any agent of efficacy and safety to consider the
untested.
12. Laboratory test results on the impact of
13. Overdosage
Overdose at the safety information is fully integrated, you can have intervention of diet and exercise or Metformin
alone therapy may be conducted and in Type 2 diabetic patients with uncontrolled blood glucose, and this drug is
100 mg to 12 weeks of daily oral administration of overseas clinical trials of this drug daily administration
recognized the Deputy
effect,the placebo group was similar
8)
.
<Remarks>
this drug 1 time per week to take the drug. Taking the correct guidance so that you can. ("V. Treatment regarding
to the items, 3-5 (3)"terms of reference)

14. Application precautions
The drug delivery time: PTP packaging of pharmaceutical PTP sheet is taken out from the take that guidance
can.
[PTP sheet of accidental ingestion by a hard, sharp edge portion of the esophagus mucous membrane insertion,
and further drilling and
The mediastinal sinus flames and other serious complications that have been reported.]
<Remarks>
PTP sheet using a drug that common operating procedures or conditions and can be avoided by taking proper
precautions as you.
PTP sheet for patients accidentally taking as an accident has been reported. PTP sheet of accidental ingestion, the
digestive
tube laceration and perforation, such as serious consequences from the Ministry of Health, Labour and welfare
and the National Life Center, the Japanese Nursing Association, and the
Japan medical functional evaluation mechanism from the attention of being.
PTP sheet of the accidental ingestion is in the hospital or at home going inside the hospital to give the drug when
the PTP
sheet from drug to take out the pass, or at home, oral medical treatment and leave the hospital, even if you're PTP
system
cut away, the sheet is taken out from etiology to explain that, like that.
(April 22 years, 9 month 15 date health policy the total emitted 0915 No. 2,drug and food total emitted 0915 No. 5, medicine 食安 development
0915 No. 1)
－ 55 －
15. Other notes
Overseas clinical trials and tolerant alogliptin as 800mg single dose and QT prolongation reported
it. (
(The approval dosage is usually, and alogliptin as 100mg 1 Week 1 orally administered once a
In.)
<Remarks>
"V. Items related to treatment, 3-3 (2)"Chapter
In Japan, a Phase 3(plus alogliptin as 100mg, 795 example,the administration period 12 ~ 52 weeks), the
more objectively accurate ECG assessment for each clinical trial conducted medical institutions in the same
electrocardiogram measurement,
and the measurement results to a Central data center (outside of the Central Metrology Authority) in re the result
of
using evaluated. As a result, the QT/QTc interval prolongation accompanied by Entertainment arrhythmia-
related adverse events and ECG
figure of the QTcF interval containing for each parameter, the concern that matters is not permitted
Note b
.
Note b ICH E14 guidelines based on the QT/QTc assessment test negative, the QTc prolongation effect on both sides of the 90%confidence
interval upper limit of 10msec
Below you pointing and defined.
16. Other
Not applicable
－ 56 －
1. Pharmacology
1-1 medicinal pharmacology test ("VI. Medicinal pharmacology related items"section).
1-2 secondary pharmacology
DPP-4 inhibition and other activity attributed to the pharmacological action of the possibility to consider
purpose,a variety of enzymes for the
inhibitory activity,receptors, ion channels and transporters for
the in vitro effects were examined. Training
program
application check succinic acid salt was evaluated for all of the enzymes, receptors, ion channels and transporters
for
10 µmol/L concentration of more than 50% inhibition did not show.
1-3 safety pharmacology studies
Rat and General symptoms and behavior. action(function observation assessment method), in the rat respiratory
system effects (Hall body pleth method),hERG current with respect to the action(whole-cell
clamp method) and no anesthesia in dogs blood pressure,heart rate and ECG for action(telemetry method)
We examined the results, and alogliptin succinic acid salt or report alogliptin trifluoroacetic acid
salt
in vitro studies on hERG current mild inhibition, and in vivo testing and The Associated changes in the
They did not.
1-4 other pharmacology
2. Toxicity test
2-1 single dose toxicity test
Species
Route of administration
Dosage
a)
(mg/kg/day)
A schematic of a lethal dose
a)
(mg/kg/day)
Rat
Oral
0, 600, 2000
>2000
Dogs
Oral
30→300→2000(titration)
>2000
a) report alogliptin as
IX. Non-clinical studies concerning the item

－ 57 －
2-2 repeated dose toxicity studies
Species
Administration period
Route of administration
Dosage
a)
(mg/kg/day)
Non-toxic amount of
a)
(mg/kg/day)
Rat
4 weeks
Oral
0,50, 250, 1000
250
13 weeks
0、80、250、750、1500
250
26 weeks + 8 weeks of recovery
0、25、75、250、750
250
Dogs
4 weeks
Oral
0, 25, 75, 200
75
13 weeks
0、10、30、100、300
100
39 weeks+the 13-week recovery
0, 15, 50, 150/100(Day15
to 150 from 100 to weight loss)
100
a) report alogliptin as
(1) rat
4 weeks Test, 1000mg/kg/day coat pollution, neutrophil count,lymphocyte count (male) and white blood cell count
high (male),
urine protein increased (male),total cholesterol, inorganic phosphorus and ALP highs, sodium, local,
albumin and Total Protein of low value,the liver weight of the highs and lobular centrilobular hepatic
hypertrophy, thymus weight of low
value and thymic cortical lymphocytes, a decrease was observed. One of the changes 2 weeks of withdrawal by the
disappeared.
13 weeks Test 750mg/kg/day or more in fur pollution, total cholesterol and ALP highs, the liver and
the portal vein around the resistance of hepatocytes with vacuolated,1500mg/kg/day in 粗毛 and weight gain
suppression, γ-GTP highs of
them.
26 weeks Test, 75mg/kg/day or more in salivation, 250mg/kg/day or more in water intake highs of them.
750mg/kg/day coat pollution, suppression of body weight gain(males),food intake high (female),red blood cell
count, hemoglobin concentration,
hematocrit value of mild low value,ALP, calcium, inorganic phosphorus,total cholesterol highs (female),
urine pH, low value, liver weight, high (female), portal vein around the resistance of hepatocytes with vacuolated
and lobular centrilobular hepatic hypertrophy (female)
was observed. Any change after 8 weeks of withdrawal and recovery.
(2) Dog
4 weeks Test, 25mg/kg/day or more in food intake, lowering of the auricular/ocular around/on the nose/lips
reddening,salivation
(female),200mg/kg/day or more in salivation (male),75mg/kg/day for females and 200 mg/kg/day in locomotor
activity, reduced Face
Surface swelling, reduced appetite and feces decrease in the amount of 200mg/kg/day in weight loss, vomiting, cut
thin and skin elasticity decline
was observed. One of the changes 2 weeks of withdrawal and recovery.
13 weeks Test, 300mg/kg/day in severe food intake decrease, extreme weight loss, salivation, yellow watery/sticky
liquid stool,ear/nose/eye around the perimeter of reddening or gray,locomotor activity, decreased skin
temperature decreased,tremor, and
vomiting, the eyeball and the surrounding swelling (female),red blood cell count,hematocrit value, hemoglobin
concentration, monocyte count (male) of the
high, of low value, albumin and urea nitrogen high trend,inorganic phosphorus highs (male) The American
system of low value (in females) was observed. Autopsy in the small intestine of the reddening was observed.
39 weeks Test, 150mg/kg/day administered in weight loss and food intake decrease was observed for dosing on Day
15
and 100 mg/kg/day to lose weight. 50mg/kg/day(females) facial swelling (1 Week only), 150/100mg/kg/day in
salivation, facial swelling (1 Week only), 50 and 150/100mg/kg/day in skin reddening was observed.
－ 58 －
2-3 reproductive and developmental toxicity testing
Test items
Species
Administration period
Dosage
a)
(mg/kg/day)
Non-toxic amount of
a)
(mg/kg/day)
Parent
Embryo･fetus･babies
Fertility and early
embryonic development
Rat
Male:mating before the 14th -
autopsy
female:the mating before 14 days to
pregnant 7 days
0, 100, 300,
1000
General toxicity:300
fertility:
≥1000
Embryo:
≥1000
Embryo・fetal occurrence
Rat pregnancy 6 to 17
0, 100, 300,
1000
300
Embryo・fetal:300
Rabbit pregnancy 6 to 18
0, 25, 80,
250
80
Embryo・fetal:
≥250
Birth before and after the occurrence
Rat gestation Day 6~Nursing 20 days
0, 100, 300,
1000
300
Live birth:300
a) report alogliptin as,either orally
(1) fertility and early embryonic development study
In rats,1000 mg/kg/day group males and females in the suppression of body weight gain and food intake of the low
value was observed.
(2) the embryo・fetus and the occurrence of trials
In rats,1000 mg/kg/day group, the mother of the animal body weight and food intake of low value, and fetal weight
on a low value,
and it is thought to be related to ossification delay was observed.
Rabbit,250mg/kg/day group, the mother of the animals died in a miscarriage, suppression of body weight gain and
food intake of the low value was observed.
(3) birth before and after the occurrence of trials
In rats,1000 mg/kg/day group, the mother of the animals died,suppression of body weight gain and the lower the
value,the food intake of low value, and
birth children about the stillbirth rate is high, the survival rate,weaning rate, survival olds and in the number of
living children with the body weight of low value,auricular open exhibition
and the glans penis prepuce separation of delay was observed.
2-4 other special toxicity
(1) genotoxicity test
The bacteria using the reverse mutation test,mouse lymphoma test and the mouse micronucleus test and
all were negative.
(2) Carcinogenicity test
Mice and rats for 24 months gavage Carcinogenicity study was conducted as a result, any of these species and
also, Carcinogenicity was not observed.
(3) phototoxicity test
Hairless mouse using
in vivo phototoxicity test was carried out as a result, light and toxicity were negative.
(4) of the skin toxicity test
DPP-4 inhibitory action type drugs and the skin in the necrotic lesions of the expression have been reported from
the
site of skin toxicity may induce investigated. The skin of naked eye observation and histopathological examination
abnormality
was observed.
－ 59 －
1. Regulatory classification
Made agent: user software tech tablets 100mg・50mg attention－e.g. doctor's prescription to use and
the active ingredient:plus alogliptin succinic acid salt not applicable
2. Period of validity or expiration date
3 years(the outer box to the expiration date displayed in even after opening to what used to be.)
3. Storage method・storage conditions
Stored at room temperature
4. Drug handling considerations
4-1 pharmacy in handling matters of note
Not applicable
4-2 preparing drugs at about the handling of(patient, etc. should be borne in mind requirements, etc.)
(1)" VIII. 6. Most attention and why, and treatment method"of Paragraph (1), (7) reference
(2)" VIII. 14. Apply precautions"section for reference
4-3 dispensing at key points
Not applicable
5. The approval conditions, etc.
Pharmaceutical risk management plan on the right to implement this.
6. Packaging
Patients for the package with the PTP
off the tech tablets 100mg :20 tablets(2 tablets sheet× 10)
Safe tech tablets 50mg :20 tablets(2 tablets sheet× 10)
7. Container material
PTP sheet, paper box
8. The same ingredient・medications with the same
The same ingredient medications: no
medications with the same:sitagliptin,Builder, alogliptin and alogliptin, Lina, alogliptin, etc.
9. International birth date
2015 Year 3 month 26 day (national development)
10. Approval date and the approval number
Product name
Approval date
Approval number
2015 Year 3 month 26 day
22700AMX00643
22700AMX00642
X. Administrative matters relating to the item

－ 60 －
11. Date of listing in the Nhi reimbursement price date
2015 Year 5 month 20 day
12. Potency or effect add, usage and dosage changes, such as adding the date and contents
Not applicable
13. The re-examination results,revaluation results announced date and contents
The re-examination period
14. The re-examination period
8 year: 2015 Year 3 month 26 day~ 2023 years 3 months 25 days
15. Dosing period limit drug information
This drug is a medication (or administration) with respect to the period limits have not been established for.
16. Various codes
Product name
HOT (9 digits) number
Ministry of Health, Labour and welfare drug price standard fit
Mounting drug code
Record operation code
124155601
3969024F2024
622415501
124154901
3969024F1028
622415401
17. Insurance benefits on the note
Not applicable
－ 61 －
1. References
1) tolerance alogliptin of clinical trial results ② (Phase II dose setting test) (internal documents)
[HB15D299]
2) tolerant alogliptin of clinical trial results ③ (Phase III confirmatory studies)(internal documents)
[HB15D281]
3) tolerance alogliptin of clinical trial results ④ (Phase III alone or in combination with long-term administration
exam)
(Internal document)
[HB15D287]
4) plus alogliptin of clinical trial results ⑤ (Phase III Phase 1 Day 1 dose changes from Test)
(Internal document)
[HB15D288]
5) Plus alogliptin pharmacokinetics of the test results ① (single dose test) (internal documents)
[HB15D289]
6) Plus alogliptin pharmacokinetics of the test results ② (repeated dose test) (internal documents)
[HB15D290]
7) Plus alogliptin of QT/QTc study(internal documents)
[HB15D291]
8) Plus alogliptin of clinical trial results ① (Phase II daily administration exam,overseas)
(Internal document)
[HB15D284]
9) plus alogliptin of glucose tolerance improvement action study(internal documents)
[HB15D283]
10) plus alogliptin enzyme inhibitory activity relating to the study (internal documents)
[HB15D286]
11) patients with impaired renal function on the pharmacokinetics test results (internal documents)
[HB15D282]
12) liver dysfunction in patients with pharmacokinetic studies grades(internal documents)
[HB15D297]
13) plus alogliptin of the influence of diet on test results (internal documents)
[HB15D298]
14) gourmet recipes and drug interactions test results (internal documents)
[HB15D292]
15) Metformin drug interactions between test results (internal documents)
[HB15D293]
16) caffeine, your,dextromethorphan,midazolam and
Drug interactions between test results (internal documents)
[HB15D294]
17) plus alogliptin of protein binding study(internal documents)
[HB15D285]
18)plus alogliptin of the metabolic study(internal documents)
[HB15D295]
19) plus alogliptin pharmacokinetics of the test results ③ (P-gp inhibition,various transporters
The inhibitory effect on review) (internal documents)
[HB15D296]
2. Other references
Not applicable
ⅹⅰ . Literature
－ 62 －
1. The main foreign release status
Overseas been released.
2. Overseas clinical support information
Not applicable
ⅹⅱ . References
－ 63 －
Other related materials
Not applicable
ⅹⅲ . Room ideas
5 (1)

Attachment 2 - Trelagliptin Succinate - Reference of Japanese IF File

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Attachment 2 - Trelagliptin Succinate - Reference of Japanese IF File

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2016 Year 6 month revised (5th edition)

Pharmaceutical interview forms

IF the use of guide overview

Molecular weight: 475.47

this agent is contraindicated as that.

calculation that you can(execution engine－Gault formula).

Clinical trial purposes

observation period at the end(Week 0)〕

Clinical trial purposes

Clinical trial purposes

Clinical trial purposes

1 Day 1 times administered to type 2 diabetic patients to

1 Day 1 dose in Japan with Type 2 diabetes

Other diabetes medications(injections

In Type 2 diabetes patients to, and alogliptin 100 mg,daily formulation

disorders and administration topical aspect

nervous system disorders

skin and subcutaneous tissue disorders

[Two-sided 95% confidence interval] (nmol/L)

The value is the logistic curve was calculated using.

[95% confidence interval] (nmol/L)

The value is the

■ Active GLP-1 AUC

■Changes in blood glucose level

■ Blood glucose AUC

1) plasma DPP-4 activity suppression and active GLP-1 increase in action

1) plasma DPP-4 activity inhibitory action

■Plasma insulin concentration

■Pancreatic insulin content

■Cumulative coefficient(R) and the accumulation and evaluation(AI)

Moderate stunned dysfunction patients (Child-Pugh

Moderate stunned dysfunction in patients with

And Cmax of the adjusted average of the ratio (combined administration/single

Healthy adults (18 cases)for 1 day to cytochrome P-450 substrates(caffeine 200mg,your

And Cmax of adjusting

And Cmax of the adjusted average of the ratio of the point

Breakfast fast under the administration of 0.0115(0.00120)h

Was (mean(standard deviation))

C] Plus alogliptin succinic acid salt (plus alogliptin as

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（0.011） 0.114（0.005） 0.104（0.021） 0.007（0.001） 0.002（0.001）

Value:100μmol/L or more, and metabolism

Value:12μmol/L(midazolam 1’-hydroxylation activity) and 28μmol/L(testosterone

Value 6.9 nmol/L was in.

Round green check,the original check, the system Center team

to the items, 3-5 (3)"terms of reference)

IX. Non-clinical studies concerning the item

X. Administrative matters relating to the item

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