Goofice

Goofice

Manufacturer:

Eisai

Distributor:

DKSH
Full Prescribing Info
Contents
Elobixibat.
Description
Active ingredient: 5.13 mg of elobixibat hydrate (5 mg as elobixibat).
Nonproprietary name: Elobixibat hydrate (JAN).
Chemical name: [(2R)-2-(2-{[3,3-Dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamido)-2-phenylacetamido]acetic acid monohydrate.
Molecular formula: C36H45N3O7S2·H2O.
Molecular weight: 713.90.
Elobixibat hydrate occurs as a white powder. It is freely soluble in N,N-dimethylformamide, sparingly soluble in acetonitrile or methanol, slightly soluble in ethanol (99.5), and practically insoluble in water.
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.
Action
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.
Effects on Bile Acid Transporters in Transfected Cells: Elobixibat showed strong inhibitory effect on intracellular uptake of 14C-glycocholic acid (a substrate for bile acid transporters) on human IBAT with IC50 of 0.53 nmol/L in HEK293 cells transfected with human IBAT gene, while IC50 for human LBAT (liver bile acid transporter) was 240 nmol/L in HEK293 cells transfected with human LBAT gene. Elobixibat showed inhibitory effect on intracellular uptake of 14C-α-aminoisobutyric acid at the human neutral 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 to LBAT and neutral amino acid transporter.
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 acid absorption, 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 was shown to inhibit bile acid absorption in the ileum in mice.
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.
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 1.)

Click on icon to see table/diagram/image

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 2.)

Click on icon to see table/diagram/image

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%.
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 3.)

Click on icon to see table/diagram/image

Lacteal transfer in rat (See Precautions).
14C-Elobixibat was administered to male pigmented (Long Evans) rats at a single oral dose of 2.5 mg/kg, and then, whole-body autoradiograms were prepared. Distribution sites of radioactivity 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. Radioactivity was 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 after administration. No radioactivity was detected in the body 2 days after administration.
Metabolism: No metabolites were observed in plasma of healthy adult male subjects (n = 6) following a single oral dose of 14Celobixibat 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 AUC0-t and Cmax 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. AUC0-t and Cmax 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 AUC0-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. Cmax and AUC0-∞ under fed condition were approximately 20 to 30% of those under fasting one.
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.)

Click on icon to see table/diagram/image

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.)

Click on icon to see table/diagram/image
Indications/Uses
Chronic constipation (except for constipation associated with organic diseases).
Dosage/Direction for Use
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.
Overdosage
There is no data on overdose of the drug, do not exceed the dosing indicated of the drug. Actively monitor for timely response.
Contraindications
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.]
Special Precautions
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 withdrawal, 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, Operate Machinery: 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.
Use In Pregnancy & Lactation
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, breast feeding must be discontinued during treatment. [In an animal experiment (in rats) using 14C-elobixibat, transfer of radioactivity into milk has been reported.]
Adverse Reactions
Adverse reactions, including laboratory abnormalities, were reported 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 as follows, appropriate measures should be taken according to the patient's symptoms. (See Table 4.)

Click on icon to see table/diagram/image

Notify doctor or pharmacist immediately of adverse reactions occurred during use.
Drug Interactions
GOOFICE exerts its inhibitory effect on P-glycoprotein (See Pharmacology: Pharmacokinetics under Actions). (See Table 5.)

Click on icon to see table/diagram/image
Caution For Usage
Drug Compatibility: Because there are no studies on drug compatibility, do not mix this drug with other drugs.
Storage
Store at temperature below 30ºC. (Store protected from high temperature and moisture after opening the aluminum pouch.)
Shelf-Life: 36 months from manufacturing date.
ATC Classification
A06AX - Other drugs for constipation ; Used in the treatment of constipation.
Presentation/Packing
FC tab 5 mg (light-yellow, round-shaped with an identification code of 'EA1', weighing approx. 110.3 mg with a diameter of approx. 6.1 mm and a thickness of approx. 3.9 mm) x 100's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in