Goofice

GOOFICE is a light-yellow round-shaped film-coated tablet. (See Table 1.)

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Each film-coated tablet contains 5.13 mg of elobixibat hydrate (5 mg as elobixibat).
Excipients/Inactive Ingredients: Microcrystalline Cellulose, D-mannitol, Hypromellose, Croscarmellose Sodium, Light Anhydrous Silicic Acid, Magnesium Stearate, Macrogol 6000, Titanium Oxide, Yellow Ferric Oxide, and Carnauba Wax.

ATC code: A06AX09.
Pharmacology: Pharmacodynamics: Mechanism of action: Elobixibat inhibits bile acid reabsorption via ileal bile acid transporter (IBAT) expressed on the epithelial cells of the terminal ileum and thereby increases the amount of bile acid passing into the large intestinal lumen. Bile acid promotes the secretion of water and electrolytes into the large intestinal lumen and enhances the colonic motility. Therefore, GOOFICE induces the therapeutic effect on constipation.
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 improving constipation.
Clinical Studies: Phase III Double-blind, Placebo-controlled 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 the superiority of GOOFICE to the placebo (p <0.0001). (See Figure 1.)

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The frequency of adverse reactions was 30% (21/69 patients). Major adverse reactions included abdominal pain 19% (13/69 patients) and diarrhoea 13% (9/69 patients).
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, and maintained the similar level until Week 52. (See Figure 2.)

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The frequency of adverse reactions was 48% (163/340 patients). Major adverse reactions included abdominal pain 24% (82/340 patients), diarrhoea 15% (50/340 patients), abdominal pain lower 5% (17/340 patients), abdominal distension 3% (11/340 patients), nausea 3% (10/340 patients), liver function test abnormal 3% (10/340 patients), abdominal discomfort 2% (7/340 patients).
Pharmacokinetics: Absorption: A single oral dose of GOOFICE 5 mg, 10 mg or 15 mg was administered to patients with chronic constipation before breakfast and the pharmacokinetic parameters were noted as follows: See Table 2.

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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 as follows: See Table 3.

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Distribution: In vitro human plasma protein binding rate of elobixibat was in excess of 99% with human blood to plasma concentration ratio less than 5%.
Metabolism: No metabolites were observed in plasma of healthy adult male subjects (n = 6) following a single oral dose of 14C-elobixibat 5 mg (approx. 2.75 MBq). Unchanged and monohydroxy forms of elobixibat were found in feces pooled over 24 to 48 hours post-dose, while the percentages of radioactivity were 96.06% and 3.16%, respectively, indicating that the majority was unchanged form.
Excretion: When a single oral dose of GOOFICE was administered to patients with chronic constipation under fasting conditions, the cumulative 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.
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.
Drug-drug interactions: IC₅₀ of elobixibat towards digoxin (P-glycoprotein substrate) transport was 2.65 μmol/L in Caco-2 cells, indicating the inhibitory effect of elobixibat on P-glycoprotein.
In healthy adult male and female subjects (n = 25), GOOFICE 10 mg was orally administered once daily for 5 days with coadministration 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-glycoprotein substrate) were 1.17 fold greater (90% confidence interval: 1.00-1.36) 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. AUC_0-t and C_max of midazolam on Day 5 were 0.78-fold greater (90% confidence interval: 0.73-0.83) and 0.94-fold greater (90% confidence interval: 0.87-1.01), respectively, compared with those under monoadministration and the lower limit of 90% confidence intervals of AUC_0-t was below 0.80 as the reference value.
Food effects: In patients with chronic constipation (n = 60), the effect of food intake on pharmacokinetics was evaluated following a single oral dose of GOOFICE in a crossover design. C_max and AUC_0-∞ under fed condition were approximately 20 to 30% of those under fasting one.
Toxicology: Preclinical safety data: Serious toxicity or toxicity limiting the use of elobixibat to the intended indication was not observed in toxicological studies performed.
Single-dose toxicity: In single-dose toxicity studies in mice, rats, and dogs, elobixibat was well tolerated, and the approximate lethal dose was determined to be >2000 mg/kg in mice and rats and >140 mg/kg in dogs.
Repeat-dose toxicity: In a 13-week repeat-dose oral toxicity study in mice, there were treatment-related findings associated with the liver at a very high dose. Since these findings were observed at very high exposures compared with clinical exposure, there seems to be no concern about safety in clinical practice. The frequent vomiting observed in the 4- and 13-week oral toxicity studies in dogs was considered to be a toxic change. However, there was a reduction in the number of vomiting in the 52-week oral toxicity study, and there were no findings suggesting deterioration in general conditions. Thus, vomiting was not considered seriously toxic. A wide safety margin is supported by no observed adverse effect level (NOAEL), and there seems to be no concern about safety in clinical practice. All other findings are considered to be changes related to pharmacological effects of elobixibat, changes of no toxicological importance, or secondary effects associated with administration of elobixibat.
Genotoxicity and carcinogenicity: Elobixibat was not genotoxic or carcinogenic.
Reproductive and developmental toxicity: Evaluation of reproductive and developmental toxicity showed that elobixibat had no effect on fertility or embryo-fetal development. In the study for effects on pre- and postnatal development including maternal function, maternal toxicity and effects on survivability, growth, or development were observed in F1 pups at very high exposure. However, a wide safety margin is supported by NOAEL, and there seems to be no concern about safety in clinical practice.

Chronic constipation (except for constipation associated with organic diseases).

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.

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

Patients with medical history of hypersensitivity to the ingredients of GOOFICE.
Patients with a documented intestinal obstruction associated with a tumor or hernia or with the suspicion of such conditions. [Intestinal obstruction may be aggravated.]

Precaution concerning indication: No clinical experience of use in drug-induced and disease-induced constipations.
Precaution concerning dosage and administration: GOOFICE may cause abdominal pain or diarrhoea; dose reduction, drug interruption, or discontinuation should be considered depending on the patient's symptoms, and the need for continuing treatment with GOOFICE should be carefully evaluated on a regular basis to avoid continuing aimless administration.
Careful administration (GOOFICE should be administered with 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.]
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 taking drugs. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa causing perforation and resulting in serious complications, such as mediastinitis.]
Effects on ability to drive and use machines: There is no evidence of drug effects on the ability to drive or operate machinery.
Use in Children: Safety has not been established in low-birth-weight infants, neonates, nursing infants, infants, or pediatric patients (no clinical experience).
Use in the Elderly: Since the elderly generally have reduced physiological functions, cautions should be exercised, such as reducing the dose.

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 in animal studies (in rats) were observed in maternal toxicity (1000 mg/kg/day) and survival, growth and development of offspring (350 mg/kg/day and higher).]
It is advised that lactating women should avoid GOOFICE. If treatment with GOOFICE is essential, breastfeeding must be discontinued during treatment. [In an animal experiment (in rats) using ¹⁴C-elobixibat, transfer of radioactivity into milk has been reported.]

Any of the adverse reactions listed as follows may occur. Therefore, patients receiving GOOFICE treatment should be carefully monitored, and if any abnormalities are noted, appropriate measures should be taken including discontinuation of GOOFICE treatment.
Other adverse reactions: See Table 4.

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GOOFICE exerts its inhibitory effect on P-glycoprotein (see Pharmacology: Pharmacokinetics under Actions).
Precautions for Coadministration (GOOFICE should be administered with care when coadministered with the following drugs): See Table 5.

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Incompatibilities: Because there are no studies on drug compatibility, do not mix this drug with other drugs.

Do not store above 30°C. (Store protected from high temperature and moisture after opening the aluminum pouch.)
Shelf life: 36 months from manufacturing date.
6 months after opening aluminium bag.

Laxatives, Purgatives

A06AX09 - elobixibat ; Belongs to the class of other laxatives.