Ileal Bile Acid Transporter Inhibitor

GOOFICE®
<Elobixibat Hydrate Tablet>
Keep out of reach of children.
Read instructions carefully before use.
6.

[CONTRAINDICATIONS (GOOFICE® is contraindicatedto the following patients)]
1.

Patients with medical history of hypersensitivity to theingredients of GOOFICE®.
2. Patients with a documented intestinal obstruction associatedwith a tumor or hernia or with the suspicion of suchconditions. [Intestinal obstruction may be aggravated.]

Drugs[COMPOSITIONS AND PRODUCT DESCRIPTION,PHARMACEUTICAL DOSAGE FORM]
GOOFICE® is a light-yellow round-shaped ﬁlm-coated tablet.
Brand
nameGOOFICE®

Identiﬁcation
code

Appearance
FaceReverse

EA1

LateralDrug Interactions
GOOFICE ® exerts its inhibitory effect on P-glycoprotein (Seesection [PHARMACOKINETICS]).
Precautions for Coadministration (GOOFICE ® should be
administered with care when coadministered with the followingdrugs.)

Size
WeightDiameterapprox. 6.1 mm
Thickness
approx. 3.9 mm
Weightapprox. 110.3 mg

GOOFICE ® contains the following active ingredient andexcipients per tablet:
Active ingredient: 5.13 mg of elobixibat hydrate (5 mg aselobixibat)
Excipients: microcrystalline cellulose, D-mannitol, hypromellose,
croscarmellose sodium, light anhydrous silicic acid, magnesium
stearate, macrogol 6000, titanium oxide, yellow ferric oxide, andcarnauba wax[INDICATION]

The usual adult dose for oral use is 10 mg once daily as elobixibat
before meal. The dosage may be adjusted depending on the patient’s
symptoms but must not exceed the highest dose of 15 mg per day.

The inhibitory effectof GOOFICE® onileal bile acidtransporter (IBAT)
may interfere withreabsorption of bile
acid preparations.

Aluminum-containing
antacids
Sucralfate hydrate,
aldioxa, etc.

These drugs may
attenuate the effect of
GOOFICE®.

These drugs absorb
bile acids in thegastrointestinal tract
and may attenuate theeffect of GOOFICE®.

Cholestyramine,colestimide

These drugs may
attenuate the effect ofGOOFICE®.

These drugs absorb
bile acids and may
attenuate the effect of
GOOFICE®.

Digoxin, dabigatran
etexilatemethanesulfonate

The blood levels ofthese drugs mayelevate and possibly
enhance their effects.

Because of theinhibitory effect ofGOOFICE® on Pglycoprotein (Seesection[PHARMACOKINETICS]).

Midazolam

The blood level of
The mechanism is
midazolam mayunknown.
decrease, and theeffect of midazolam
may decrease (Seesection[PHARMACOKINETICS]).

[PRECAUTIONS]
1.

Precaution Concerning Indication
No clinical experience of use in drug-induced and disease-inducedconstipations.

2.

Precaution Concerning Dosage and Administration
GOOFICE ® may cause abdominal pain or diarrhoea; dose
reduction, drug withdrawal, or discontinuation should be considereddepending on the patient's symptoms, and the need for continuing
treatment with GOOFICE ® should be carefully evaluated on aregular basis to avoid continuing aimless administration.

3.

4.

5.

Careful Administration (GOOFICE® should be administeredwith care in the following patients.)
Patient with serious liver disorder. [GOOFICE® may fail to achieve
its expected efﬁcacy in patients with biliary obstruction or reduced
bile acid secretion, etc.]

Mechanism and Risk
Factors

Bile acid preparations The effects of these
Ursodeoxycholicdrugs may beacid,attenuated.
chenodeoxycholicacid

Chronic constipation (except for constipation associated withorganic diseases)[DOSAGE AND ADMINISTRATION]

Signs, Symptoms, andTreatment

7.

Drug Compatibility
Because there are no studies on drug compatibility, do not mix thisdrug with other drugs.

8.

Adverse Reactions
Adverse reactions, including laboratory abnormalities, werereported in 292/631 patients (46.3%) from clinical studies
conducted until the approval. Major adverse reactions included
abdominal pain in 120 patients (19.0%) and diarrhoea in 99 patients(15.7%).
Other Adverse Reactions
In the case of the adverse reactions below, appropriate measures
should be taken according to the patient's symptoms.

Precaution Concerning Use
Precaution Concerning the Dispensing of the Drug
Patients who are given drugs supplied in PTP package must be
instructed to remove the drugs from the PTP sheet before takingdrugs. [It has been reported that, if the PTP sheet is swallowed, thesharp corners of the sheet may puncture the esophageal mucosa
causing perforation and resulting in serious complications, such asmediastinitis.]≥5%
HepaticNote 1)

Effects on Ability to Drive, Operate Machinery
There is no evidence of drug effects on the ability to drive or
operate machinery.
11%≤ <5%
Liverfunction
test
abnormal(ALT(GPT)
increased,AST(GOT)
increased)<1%

Frequency
unknown≥5%1%≤ <5%

Headache,dizziness

Central andperipheral nervous
systemParameter

Cardiovascular
Gastrointestinal(2) A single oral dose of 14C-elobixibat 5 mg (approx. 2.75 MBq)
was administered to healthy adult male subjects (n = 6) before
breakfast and the pharmacokinetic parameters were noted asbelow.

Frequency
unknown<1%Hot ﬂush
Abdominal
pain(19.0%),
diarrhoea(15.7%),
abdominal
pain lower,
abdominal
distension

Nausea,abdominal
pain upper,
abdominal
discomfort,
faeces soft

Flatulence,
thirst,defaecation
urgency,
vomiting,
gastrointestinal sounds
abnormal,constipation,
stomatitis

HypersensitivityNote 2)

Urticaria,
rash

Hematologic

Eosinophilcountincreased,anaemia,vitamin E
increased

OthersCK (CPK)
increased

Dysmenorrhoea

Cmax (nmol/L)

0.5±0.3

AUC0-∞ (nmol•h/L)

1.2±0.4 (n = 3)

Tmax (h)*0.8 (0.5‒2.0)

t1/2 (h)0.8±0.2 (n = 3)
Mean ± S.D.
* Median (range)

2.

LDLdecreased,LDL/HDL
ratio
decreased

10. Use during Pregnancy, Delivery or Lactation(1) GOOFICE ® should be used in pregnant women and women
who may possibly be pregnant only if the expected therapeutic
benefits outweigh the possible risks associated with treatment.
[The influences of a high dose oral administration of drug inanimal studies (in rats) were observed in maternal toxicity(1000 mg/kg/day) and survival, growth and development ofoffspring (350 mg/kg/day and higher).](2) It is advised that lactating women should avoid GOOFICE®. Iftreatment with GOOFICE® is essential, breast feeding must bediscontinued during treatment. [In an animal experiment (in rats)
using 14C-elobixibat, transfer of radioactivity into milk has beenreported.]

12. Overdosage and Management
There is no data on overdose of the drug, do not exceed the dosing
indicated of the drug. Actively monitor for timely response.

[PHARMACOKINETICS]
Absorption(1) A single oral dose of GOOFICE® 5 mg, 10 mg or 15 mg wasadministered to patients with chronic constipation before
breakfast and the pharmacokinetic parameters were noted asbelow.
5 mg

10 mg

15 mg

101010Cmax (pg/mL)

186.8±87.1

386.4±215.4

389.7±103.6

AUC0-∞ (pg•h/mL)

837.8±572.9

1272.5±656.2

1632.2±475.8

Tmax (h)1.8±1.6

1.9±1.6

1.8±0.6

t1/2 (h)3.3±3.1

2.5±1.5

3.2±1.5

15 mg

n101010Vd/F (L/kg)

481.1±164.1

535.8±247.2

663.8±360.0

3.

Metabolism
No metabolites were observed in plasma of healthy adult malesubjects (n = 6) following a single oral dose of 14C-elobixibat 5 mg
(approx. 2.75 MBq). Unchanged and monohydroxy forms ofelobixibat were found in feces pooled over 24 to 48 hours postdose, while the percentages of radioactivity were 96.06% and 3.16%,
respectively, indicating that the majority was unchanged form.

4.

Excretion(1) When a single oral dose of GOOFICE® was administered topatients with chronic constipation under fasting conditions, thecumulative urine drug excretion rate up to 144 hours post-dose
was approximately 0.01% of the amount of dose, indicating that
drug excretion into urine was almost absent.
(2) When a single oral dose of 14C-elobixibat 5 mg (approx. 2.75 MBq)
was administered to healthy adult male subjects (n = 6), 103.1%
of radioactivity dosed was excreted in feces while 0.00 to 0.02%
excreted in urine up to 144 hours post-dose.

5.

Drug-Drug Interactions(1) IC50 of elobixibat towards digoxin (P-glycoprotein substrate)transport was 2.65 μmol/L in Caco-2 cells, indicating theinhibitory effect of elobixibat on P-glycoprotein.
(2) In healthy adult male and female subjects (n = 25), GOOFICE®
10 mg was orally administered once daily for 5 days withcoadministration of both dabigatran etexilate 150 mg/dose/day
on Day 1 and midazolam 2 mg/dose/day on Day 1 and Day 5
to compare with monoadministration of each drug. The results
showed that AUC 0-t and C max of dabigatran (P-glycoproteinsubstrate) were 1.17 fold greater (90% conﬁdence interval: 1.001.36) and 1.13 fold greater (90% conﬁdence interval: 0.96-1.33),
respectively, compared with those under monoadministration
and both the upper limit of 90% conﬁdence intervals were above
1.25 as the reference value. AUC0-t and Cmax of midazolam on
Day5 were 0.78-fold greater (90% confidence interval: 0.730.83) and 0.94-fold greater (90% conﬁdence interval: 0.87-1.01),

11. Pediatric Use
Safety has not been established in low-birth-weight infants,neonates, nursing infants, infants, or pediatric patients (no clinicalexperience).

Dose

10 mg

Mean ± S.D.

Use in the Elderly
Since the elderly generally have reduced physiological functions,cautions should be exercised, such as reducing the dose.

Number of patients

5 mg(3) Lacteal transfer in rat (See section [PRECAUTIONS] 10. (2))(4) 14C-Elobixibat was administered to male pigmented (LongEvans) rats at a single oral dose of 2.5 mg/kg, and then, wholebody autoradiograms were prepared. Distribution sites ofradioactivity after oral administration were limited, and most of
the radioactivity was observed in the gastric mucosa and in small
intestinal contents. Radioactivity concentrations in heart blood
were less than the detection limit at any time point. Radioactivitywas also found in bile, cecum contents, liver, renal cortex,
prostate gland, urine and skin by 4 hours after administration
but detected only in gastrointestinal contents 24 hours afteradministration. No radioactivity was detected in the body 2 days
after administration.

Notify doctor or pharmacist immediately of adverse reactions occurred
during use.

1.

Distribution(1) In vitro human plasma protein binding rate of elobixibat was inexcess of 99% with human blood to plasma concentration ratio
less than 5%.
(2) A single oral dose of GOOFICE® 5 mg, 10 mg or 15 mg wasadministered to patients with chronic constipation before
breakfast and the pharmacokinetic parameters were noted asbelow.
Parameter

Note 1) Patients should be carefully monitored for these symptoms and if any
abnormalities are observed, GOOFICE® should be discontinued.
Note 2) If these symptoms are observed, GOOFICE® should be discontinued.

9.

5 mg 14C-elobixibat

Mean ± S.D.

2

respectively, compared with those under monoadministration andthe lower limit of 90% conﬁdence intervals of AUC0-t was below
0.80 as the reference value.
6.

acid transporter) was 240 nmol/L in HEK293 cells transfectedwith human LBAT gene. Elobixibat showed inhibitory effect on
intracellular uptake of 14C-α-aminoisobutyric acid at the humanneutral amino acid transporter in HEK293 cells by 35%, 79%, and
93% at 3.125, 12.5, and 50 μmol/L, respectively. These studies
showed that elobixibat is a selective inhibitor for IBAT compared toLBAT and neutral amino acid transporter.

Food Effects
In patients with chronic constipation (n = 60), the effect of foodintake on pharmacokinetics was evaluated following a single oraldose of GOOFICE® in a crossover design. Cmax and AUC0-∞ underfed condition were approximately 20 to 30% of those under fasting
one.

3.

Effects on Bile Acid Absorption in Mice
Elobixibat was administered orally to ApoE gene knockout female
C57BL/6 mice thirty minutes before 75SeHCAT, a tracer of bile acidabsorption, was orally given. Twenty-four hours later, elobixibat
inhibited absorption of 75SeHCAT in a dose-dependent manner(ED50 = 0.274 mg/kg), indicating orally administered elobixibat wasshown to inhibit bile acid absorption in the ileum in mice.

4.

Effect on Constipation Induced by Loperamide in Rats
In rats of loperamide-induced constipation model, a single oral
administration of elobixibat demonstrated the effect of improvingconstipation.

[CLINICAL STUDIES]
1.

Phase III Double-blind, Placebo-controled Comparative Study
In patients with chronic constipation (n = 132), placebo or
GOOFICE ® 10 mg was orally administered once daily before
breakfast. The change from baseline in the spontaneous bowel
movement frequency on treatment period Week 1 with GOOFICE®
was significantly greater than that with placebo, confirming thesuperiority of GOOFICE® to the placebo (p < 0.0001).
(times/week)

p <0.0001

Mean±S.D.

[PHYSICOCHEMICAL PROPERTIES]

Change in the spontaneous bowel
movement frequency

12

Nonproprietary name: Elobixibat hydrate (JAN)
Chemical name: [(2R)-2-(2-{[3,3-Dibutyl-7-(methylsulfanyl)-1,1-dioxo5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin8-yl]oxy}acetamido)-2-phenylacetamido]acetic acidmonohydrate
Structural formula:

108
6.40
64CH31.73

2N
H 3C0Placebo
N = 63

SO OGOOFICE®
N = 67

Analysis of covariance was conducted with thespontaneous bowel movement frequency of baseline as acovariate

2.

OO HNH

CO2H ・H2O[SHELF-LIFE]
36 months from manufacturing date.

[STORAGE]
Store at temperature below 30ºC. (Store protected from high temperatureand moisture after opening the aluminum pouch.)(times/week)
10O

H
N

Molecular formula: C36H45N3O7S2•H2O
Molecular weight: 713.90
Description: Elobixibat hydrate occurs as a white powder. It is freely
soluble in N,N-dimethylformamide, sparingly soluble inacetonitrile or methanol, slightly soluble in ethanol (99.5),
and practically insoluble in water.

Long-term Treatment Study
In patients with chronic constipation (n = 340), GOOFICE® 10 mg
was orally administered once daily (adjusted in a range of 5 mg
to 15 mg depending on the patient’s symptoms) before breakfast
for 52 weeks. The mean weekly spontaneous bowel movement
frequency increased from baseline on treatment period Week 1, andmaintained the similar level until Week 52.

Mean weekly spontaneousbowel movement frequency

CH3S

Mean±S.D.

[PACKAGING]
A box of 10 blisters x 10 tablets in an aluminum pouch

8MANUFACTURER
EA Pharma Co., Ltd.
Head ofﬁce: 2-1-1, Irifune, Chuo-ku, Tokyo, Japan
Plant: Fukushima plant, 103-1, Shirasakaushishimizu, Shirakawa-shi,Fukushima, Japan

64

Imported into Thailand by:

20Baseline 4Eisai (Thailand) Marketing Co., Ltd. Bangkok
812162024 28(Weeks)

32

36

40

4448

52

[PHARMACOLOGY]
1.

Mechanism of Action
Elobixibat inhibits bile acid reabsorption via ileal bile acidtransporter (IBAT) expressed on the epithelial cells of the terminal
ileum and thereby increases the amount of bile acid passing into thelarge intestinal lumen. Bile acid promotes the secretion of water andelectrolytes into the large intestinal lumen and enhances the colonicmotility. Therefore, GOOFICE® induces the therapeutic effect onconstipation.

2.

Effects on Bile Acid Transporters in Transfected Cells
Elobixibat showed strong inhibitory effect on intracellular uptakeof 14C-glycocholic acid (a substrate for bile acid transporters) on
human IBAT with IC50 of 0.53 nmol/L in HEK293 cells transfectedwith human IBAT gene, while IC50 for human LBAT (liver bile

Manufactured byRevision: December, 2020

3

GOF-JP/01.20E