• Dosage and Administration
• Co-administration
• Clinical Effect
• Pharmacokinetics
• Pharmacology
• Patients with Specific Backgrounds
• Interactions
• Stability

Dosage and Administration

• Q. GOOFICE^Ⓡ is administered before meals. Why is it?

  A.

  It is to efficiently inhibit bile acid reabsorption in the intestine.
  This drug directly inhibits the transporter involved in bile acid reabsorption (IBAT) in the terminal ileum¹ (it does not move into blood to exert its effect), and inhibits reabsorption of bile acids,² thereby increasing the flow of bile acids into the large intestine.
  For this reason, it seems desirable for efficient onset of effects that this drug is administered before bile acids are released into the duodenum following stimulation with food.

  Since there is a report from healthy individuals (n=5)³ showing that bile acids are secreted under stimulation by breakfast, lunch, and dinner, it is considered that similar effects are exerted when the drug is administered before breakfast, lunch, and dinner, and the timing of administration of this drug is set to be administration before meals.

  Circadian variation in serum bile acid concentration by background
  
  
  CA: Cholic Acid, CDCA: Chenodeoxycholic Acid

   

  【Reference】
  1） EA Pharma Co., Ltd.: In-house data (effect on bile acid transporters)
  2） EA Pharma Co., Ltd.: In-house data (effect on bile acid absorption)
  3） Schalm SW, et al. Gut 1978; 19: 1006-14

  Prepared in November 2018

   

• Q. Is it acceptable to take GOOFICE^Ⓡ immediately before meals, after meals, between meals, at bedtime, or as needed?

  A.

  The approved dosage regimen of this drug is "oral administration once daily before meals." Administration with other dosage regimens is outside the approved dosage regimen, and there are no data on the efficacy and safety of this drug taken immediately before meals, after meals, between meals, at bedtime, or as needed.

  For efficient onset of the effects of this drug, it is desirable to administer this drug before bile acids are released into the duodenum after stimulation with meals, that is, "before meals." Therefore, the dosage regimen is specified as "administration before meals."
  The only investigation performed with the dosage regimen other than "once-daily oral administration before meals" was the investigation of the safety, pharmacokinetics, and effects of meals in the crossover study (Japanese phase 1 study)¹ of single-dose administration under fasting conditions and single-dose administration before breakfast in Japanese patients with chronic constipation.

  Excerpt from the package insert
  [Dosage and Administration]
  The usual adult dose is 10 mg of elobixibat administered orally once daily before meals. The dose may be adjusted appropriately according to symptoms; however, the maximum daily dose is 15 mg.

  Reference:
  In clinical studies for development, the drug was administered approximately 30 minutes before breakfast.

  【Reference】
  1） EA Pharma Co., Ltd.: In-house data (clinical pharmacology study in patients with chronic constipation)

  Prepared in November 2018

• Q. While GOOFICE^Ⓡ is to be administered before meals, which is the best timing, before breakfast, before lunch, or before dinner? Are there any data on comparisons?

  A.

  The approved dosage regimen of this drug is “The usual adult dose is 10 mg of elobixibat administered orally once daily before meals. The dose may be adjusted appropriately according to symptoms; however, the maximum daily dose is 15 mg.” Therefore, the drug can be taken either before breakfast, before lunch, or before dinner.
  Since there is a report from healthy individuals (n=5)¹ showing that bile acids are secreted under stimulation by breakfast, lunch, and dinner, it is considered that similar effects are exerted when the drug is administered before breakfast, lunch, and dinner.

  Therefore, set a time before breakfast, lunch, or dinner considering the patient's dosing compliance, and take the drug at that time.
  Because the Japanese phase 2 study, Japanese phase 3 study, and Japanese long-term administration study were all conducted with “administration before breakfast,” there are no data on the evaluation of differences in efficacy and safety among administration before breakfast, lunch, and dinner.

  Circadian variation in serum bile acid concentration by background

  CA: Cholic Acid, CDCA: Chenodeoxycholic Acid

  【Reference】

  1） Schalm SW, et al. Gut 1978; 19: 1006-14

  Prepared in November 2018

• Q. What should I do if I forgot to take GOOFICE^Ⓡ before a meal?

  A.

  If you forgot to take it before a meal, take it before the next meal.* Never take two doses at a time.

  The following is an excerpt from the instructions for patients "For patients taking GOOFICE^® Tablets 5 mg."

  • If you forgot to take the drug, take it before the next meal.
  • Do not take two doses at a time.

  From "Drug Information Sheet"
  “If you forgot to take the drug, take it before the next meal. Never take two doses at a time.”

  Reference:* Before meals ... In clinical studies for development, the drug was administered approximately 30 minutes before meals.

  Prepared in November 2018

Co-administration

• Q. What are the efficacy and safety of GOOFICE^Ⓡ when used in combination with other therapeutic agents for constipation?

  A.

  There are no sufficient data on the efficacy and safety of this drug used in combination with other therapeutic drugs for constipation.
  In the Japanese clinical studies, the use of bisacodyl suppository as rescue medication was allowed when there was no bowel movement for 72 consecutive hours or longer. The effect of this drug was maintained even in the patients who used rescue medication concomitantly, and the frequency of adverse events did not increase because of the concomitant use of the rescue medication.¹
  In the treatment of chronic constipation, multiple drugs are used in combination, and this drug is also assumed to be used in combination with other drugs because its mechanism of action is different from other drugs.
  Although it is assumed that this drug is used in combination with therapeutic agents for constipation with a different mechanism of action at the discretion of the prescribing physician, judgement on the insurance review will be made by the reviewing organization.

  【Reference】
  1） Review Report of Goofice^Ⓡ Tablets 5 mg

  Prepared in November 2018

Clinical Effect

• Q. What is the time to onset of the effect of GOOFICE^Ⓡ (time to onset of the first spontaneous bowel movement)?

  A.

  The time to onset of effect varies among patients. During development in Japan, the time from the start of administration of this drug to the onset of the first spontaneous bowel movement was generally several hours to several days.

  The time to the first spontaneous bowel movement during development is shown below.
  [1] The median time to occurrence of the first spontaneous bowel movement (estimate by the Kaplan-Meier method) was 5.2 hours (95% CI: 3.4-7.0) in the group treated with this drug in the Japanese phase 3 study (Placebo or 10 mg of this drug was orally administered once daily for 14 days, approximately 30 minutes before breakfast in Japanese patients with chronic constipation).¹ (n=69)
  25 percentile*, 2.4 hours; 75 percentile, 10.0 hours

  <Secondary endpoint> Time before first SBM
  
  

  [2] In the Japanese long-term administration study, this drug was orally administered once daily for 52 weeks, approximately 30 minutes before breakfast, in Japanese patients with chronic constipation. The daily dose was increased or decreased appropriately among 5 mg, 10 mg, and 15 mg depending on symptoms after 7 days from the start of this drug at a dose of 10 mg. The results showed that the median time to occurrence of the first spontaneous bowel movement (estimate by the Kaplan-Meier method) was 7.00 hours (95%CI: 5.67-7.75).² (n=340)
  25 percentile, 3.68 hours; 75 percentile, 27.93 hours
  

  Reference:
  * Percentile
  It is a unit that indicates the position in the whole by aligning the distribution of measured values (variation) from a small number to a large number and expressing them as percentages. The 50 percentile is the median. In other words, it is a numerical value that indicates the position of the number counted from the smallest number when the overall number is 100, and the "75 percentile" means that it is positioned at the 75th from the smallest number.

  【Reference】
  1） グーフィス錠5mg CTD 2.7.6.9 国内第Ⅲ相試験（AJG533/CT1）
  2） グーフィス錠5mg CTD 2.7.6.10 国内長期投与試験（AJG533/LT1）

  Prepared in November 2018

Pharmacokinetics

• Q. According to the section of the effect of meals in the package insert, the blood concentration (C_max and AUC) after administration of GOOFICE^Ⓡ before meals decreased to about 20 to 30% of the level after administration in a non-fed state (without meals).¹ Is there any possibility that administration between meals^* is more effective than administration before meals because blood concentration will be higher?

  A.

  This drug is absorbed into the body only slightly,* and it is not a drug that enters the blood to exert an effect to induce bowel movements. It directly inhibits the ileal bile acid transporter (IBAT) expressed in the epithelial cells of the terminal ileum from the luminal side,² and exerts an effect to induce bowel movements through inhibition of bile acid reabsorption.³
  Therefore, for efficient onset of the effects of this drug, it is considered desirable to administer this drug before bile acids are released into the duodenum by stimulation with meals, that is, "before meals." In clinical studies for development, the drug was administered approximately 30 minutes before meals.
  *: The unit of the blood concentration data (C_max) is pg/mL, which is 1/1000 of ng/mL, and absorption into the body is very small. It is not a drug that is transported into blood to show its efficacy, but it is presented as "reference data" for pharmacokinetics.

  Reference:
  *Between meals
  It refers to the time period between meals (approximately 2 hours after meals). It does not mean “during meals.”
  In clinical studies for development, the drug was administered approximately 30 minutes before meals.

  Excerpt from the package insert
  [Pharmacokinetics]
  6. Effect of Food
  After a single oral dose of this drug was administered to 60 Japanese patients with chronic constipation, the effect of food on pharmacokinetics was evaluated in a crossover manner. The C_max and AUC_0-∞ after administration before meals were approximately 20% to 30% of those after administration without meals.

  【Reference】
  1） EA Pharma Co., Ltd.: In-house data (clinical pharmacology study in patients with chronic constipation)
  2） EA Pharma Co., Ltd.: In-house data (effect on bile acid transporters)
  3） EA Pharma Co., Ltd.: In-house data (effect on bile acid absorption)

  Prepared in November 2018

Pharmacology

• Q. What is the mechanism of action of GOOFICE^Ⓡ?

  A.

  Elobixibat, the active ingredient of GOOFICE^Ⓡ, is minimally absorbed into the body, directly inhibits the ileal bile acid transporter (IBAT) expressed in the epithelial cells in the terminal ileum¹ (it does not move into blood to exert its effect), and inhibits reabsorption of bile acids,² thereby increasing the amount of bile acids flowing into the large intestinal lumen.
  Since bile acids induce secretion of fluid into the large intestinal lumen and promote gastrointestinal motility (dual action), elobixibat exerts its therapeutic effect on constipation.^3-5

  

   

  CFTR: Cystic fibrosis transmembrane conductance regulator, TGR5: Transmembrane G protein-coupled receptor, AC: Adenylate cyclase, ATP: Adenosine triphosphate, cAMP: cyclic adenosine monophosphate, PKA: Protein kinase A, 5-HT: Serotonin, IPAN: Intrinsic primary afferent neuron (It is thought to be the sensory nerve that is localized in the enteric plexus and detects mechanical and chemical stimuli to the gastrointestinal tract.), Ach: Acetylcholine, NO: Nitric oxide

  Editorial review: Professor Noriaki Manabe, Endoscopy and Ultrasound Center, Kawasaki Medical University
  

   

   

  【Reference】
  1） EA Pharma Co., Ltd.: In-house data (effect on bile acid transporters)
  2） EA Pharma Co., Ltd.: In-house data (effect on bile acid absorption)
  3） Acosta A, et al. Therap Adv Gastroenterol 2014; 7: 167-75
  4） Iser JH, et al. Drugs 1981; 21: 90-119
  5） Mitchell WD, et al. Gut 1973; 14: 348-53

  Prepared in November 2018

Patients with Specific Backgrounds

• Q. What are the efficacy and safety of GOOFICE^Ⓡ in patients with cholecystectomy?

  A.

  At the time of development in Japan, patients with cholecystectomy were excluded, and therefore there are no data on efficacy and safety.
  However, since the gallbladder is an organ where the bile generated in the liver is retained transiently, the bile flows out from the liver to the small intestine even after cholecystectomy, and it was reported that bile acids are secreted after dietary stimulation even in patients who have undergone cholecystectomy more than 6 months earlier (n=5).¹ Therefore, it is considered possible to expect the effect of this drug even in patients with cholecystectomy.

  Circadian variation in serum bile acid concentration by background
  
  

  【Reference】
  1） Schalm SW, et al. Gut 1978; 19: 1006-14

  Prepared in November 2018

• Q. What are the efficacy and safety of GOOFICE^Ⓡ in dialysis patients and patients with renal impairment?

  A.

  Patients on dialysis and patients with renal impairment are not subject to contraindications and careful administration, but patients with serious renal failure including dialysis patients were excluded from the subjects at the time of development in Japan, and consequently there are no data on efficacy and safety.
  The main route of excretion of this drug is feces. In a study in Japanese patients with chronic constipation, the cumulative urinary drug excretion rate up to 144 hours after administration of this drug was approximately 0.01% of the dose, showing almost no excretion of the drug in urine.¹ The results of safety pharmacology studies² also suggested that the drug was unlikely to have significant pharmacological effects on the kidneys. Therefore, patients with renal impairment are not included in careful administration, etc.

  【Reference】
  1） Interview form, VII. Pharmacokinetics, 6. Excretion
  2） Interview form, IX. Nonclinical studies, 1. Pharmacology studies, (3) Safety pharmacology study

  Prepared in November 2018

• Q. Can GOOFICE^Ⓡ be administered to pregnant women?

  A.

  Pregnant women are not subject to contraindications or careful administration, but no clinical studies have been conducted in pregnant women, and the safety has not been established. Therefore, this drug should be administered to women who are or may be pregnant only if the expected therapeutic benefits outweigh the possible risks associated with treatment.
  In animal studies (in rats), maternal toxicity (1000 mg/kg/day) and effects on survival, growth, and development of newborns (≥350 mg/kg/day) were observed after high-dose oral administration.¹

  Excerpt from the package insert
  [Precautions]
  5. Use during Pregnancy, Delivery or Lactation
  (1)This drug should be administered to women who are or may be pregnant only if the expected therapeutic benefits outweigh the possible risks associated with treatment. (In animal studies [in rats], maternal toxicity [1000 mg/kg/day] and effects on survival, growth, and development of newborns [≥350 mg/kg/day] were observed after high-dose oral administration.)

  【Reference】
  1） Interview form, IX. Nonclinical studies, 2. Toxicity study, (3) Reproduction toxicology study

  Prepared in November 2018

• Q. Can GOOFICE^Ⓡ be administered to lactating women?

  A.

  Lactating women are not subject to contraindications or careful administration, but no clinical studies have been conducted in lactating women, and the safety has not been established. Therefore, it is desirable to avoid administration to lactating women, but if administration is inevitable, breast-feeding should be avoided.
  When ¹⁴C-elobixibat was orally administered in a single dose at 50 mg/kg to female nursing rats 10 days after delivery, the plasma radioactivity concentration reached C_max (443 ng eq./mL) 2 hours after administration and decreased with t_1/2 of 11.3 hours.
  On the other hand, the radioactivity concentration in milk reached C_max (130 ng eq./mL) 8 hours after administration, then decreased with t_1/2 of 7.60 hours, and the radioactivity concentration in milk tended to increase more slowly than that in plasma. The radioactivity concentration in milk exceeded that in plasma only at 8 hours after administration (1.30 times higher than that in plasma), and the radioactivity concentration in milk did not greatly exceed that in plasma and radioactivity was eliminated with a similar change to that in plasma.¹

  【Reference】
  1） Interview form, VII. Pharmacokinetics, 4. Distribution, (3) Transfer into milk

  Prepared in November 2018

Interactions

• Q. What are the drug interactions of GOOFICE^Ⓡ?

  A.

  The following reports are available regarding drug interactions of this drug.
  From the section of “Drug Interactions” in Precautions
  This drug inhibits P-glycoprotein.1,2 (See the section of [Pharmacokinetics].)
  Precautions for Coadministration (This drug should be administered with care when coadministered with the following drugs.)

  Drug name, etc.	Clinical symptoms and measures	Mechanism and risk factors
  Bile acid preparations Ursodeoxycholic acid and chenodeoxycholic acid	The effects of these drugs may be reduced.	Reabsorption of bile acid preparations may be inhibited by the effect of this drug to inhibit ileal bile acid transporters (IBATs).
  Aluminum-containing antacids, sucralfate hydrate, aldioxa, etc.	The effect of this drug may be reduced.	Since these drugs adsorb bile acids in the gastrointestinal tract, the effects of this drug may be reduced.
  Cholestyramine and colestimide	The effect of this drug may be reduced.	Since these drugs adsorb bile acids, the effects of this drug may be reduced.
  Digoxin and dabigatran etexilate methanesulfonate	The blood concentrations of these drugs may increase and their effects may be enhanced.	This interaction occurs because of the inhibitory effect of this drug on P-glycoprotein. (See the section of [Pharmacokinetics].)
  Midazolam	The blood concentration of midazolam may decrease and its effect may be reduced. (See the section of [Pharmacokinetics].)	The mechanism is unknown.

  (1)Bile acid preparations (ursodeoxycholic acid and chenodeoxycholic acid)
  This drug is considered to inhibit IBAT, which is a transporter expressed in the terminal ileum and involved in reabsorption of bile acids, and to inhibit reabsorption of bile acids, thereby increasing the amount of bile acids flowing into the large intestine and promoting bowel movements.³ Bile acid preparations were specified as drugs that should be coadministered with care because this pharmacological action may inhibit reabsorption of bile acid preparations, and may attenuate their effects.

  (2)Aluminum-containing antacids (e.g., sucralfate hydrate, aldioxa)
  As described above, this drug inhibits IBAT and inhibits bile acid reabsorption, thereby increasing the amount of bile acids flowing into the lumen of the large intestine.³ On the other hand, aluminum-containing antacids have a characteristic to adsorb bile acids and therefore the action of this drug via bile acids may be reduced. Therefore, these drugs were specified as drugs that should be coadministered with care.

  (3)Cholestyramine and colestimide
  As described above, this drug inhibits IBAT and inhibits bile acid reabsorption, thereby increasing the amount of bile acids flowing into the lumen of the large intestine.³ On the other hand, cholestyramine and colestimide are anion exchange resins which absorb bile acids in the gastrointestinal tract and exert their therapeutic effects. Therefore, the effects of this drug mediated by bile acids may be reduced. Therefore, these drugs were specified as drugs that should be coadministered with care.

  (4)Digoxin and dabigatran etexilate methanesulfonate
  Elobixibat inhibited transportation of digoxin, which is a typical substrate for P-glycoprotein, in Caco-2 cells in an in vitro study. In addition, because it was considered impossible to rule out the possibility that this drug has a clinical inhibitory action against P-glycoprotein on the basis of a study on the drug-drug interaction (non-Japanese data) using dabigatran etexilate, a typical substrate of P-glycoprotein, digoxin and dabigatran etexilate methanesulfonate were specified as drugs that should be coadministered with care.^1,2

  (5)Midazolam
  Since this drug may decrease the plasma concentration of midazolam, this was specified as a drug that should be coadministered with care.²
  * From the section of [Pharmacokinetics] in the package insert.

  5.Drug Interactions

  (1)Elobixibat had an IC50 value of 2.65 μmol/L for transportation of digoxin, a substrate for P-glycoprotein, in Caco-2 cells, exhibiting an effect to inhibit P-glycoprotein.¹

  (2)To 25 non-Japanese healthy adult men and women, this drug at a dose of 10 mg was orally administered once daily for 5 days. Dabigatran etexilate, 150 mg/dose/day, was coadministered on Day 1, and midazolam, 2 mg/dose/day, was coadministered on Days 1 and 5. The findings were compared with those after each monotherapy. The results showed that AUC_0-t and C_max of dabigatran, a substrate of P-glycoprotein, were 1.17-fold (90% confidence interval: 1.00-1.36) and 1.13-fold (90% confidence interval: 0.96-1.33), respectively, of those after administration of dabigatran alone. For both, the upper limit of 90% confidence interval exceeded the reference value of 1.25. The AUC_0-t and C_max of midazolam were 0.78-fold (90% confidence interval: 0.73-0.83) and 0.94-fold (90% confidence interval: 0.87-1.01), respectively, of those after administration of midazolam alone, and the lower limit of the 90% confidence interval for AUC_0-t was below the reference value of 0.80.²

  
  

  【Reference】
  1） EA Pharma Co., Ltd.: In-house data (investigation on transporters)
  2） EA Pharma Co., Ltd.: In-house data (investigation on drug interactions)
  3） Acosta A, et al. Therap Adv Gastroenterol 2014; 7: 167-75

  Prepared in July 2019

Stability

• Q. Is there information on the stability of GOOFICE^Ⓡ in a crushed state, in a half-split state, in simple suspension, and in one-dose packaging (unpackaged)?

  A.

  We do not recommend administration in a crushed state, in a half-split state, in simple suspension, and in one-dose packaging (unpackaged).
  Since GOOFICE^Ⓡ Tablet 5 mg has been approved on the premise that it is taken as it is, the efficacy and safety of administration in a crushed state, in a half-split state, in simple suspension, and in one-dose packaging (unpackaged) have not been investigated.
  As reference information, data on stability in a crushed state, in simple suspension, and in one-dose packaging (unpackaged) are available. If necessary, please contact the Drug Information Office (0120-917-719).

  Prepared in July 2019