VIBERZI Film-coated tablet Ref.[27436] Active ingredients: Eluxadoline

Cardiac Electrophysiology

At a dose 10 times the maximum recommended dose (100 mg), VIBERZI does not prolong the QT interval to any clinically relevant extent.

Following oral administration of 100 mg VIBERZI in healthy subjects, the C_max of eluxadoline was approximately 2 to 4 ng/mL and AUC was 12 to 22 ng.h/mL. Eluxadoline has approximately linear pharmacokinetics with no accumulation upon repeated twice daily dosing. The variability of eluxadoline pharmacokinetic parameters ranges from 51% to 98%.

Absorption

Absolute bioavailability of eluxadoline has not been determined.

Effect of Food

The median T_max value was 1.5 hours (range: 1 to 8 hours) under fed conditions and 2 hours (range: 0.5 to 6 hours) under fasting conditions [see Dosage and Administration (2)].

The administration of VIBERZI with a high fat meal that contained approximately 800 to 1000 total calories, with 50% of calories being derived from fat content decreased the C_max of eluxadoline by 50% and AUC by 60%.

Distribution

Plasma protein binding of eluxadoline was 81%.

Elimination

The mean plasma elimination half-life of eluxadoline ranged from 3.7 hours to 6 hours.

Metabolism

Cytochrome P450 (CYP) and UGT pathways have minimal involvement in the metabolism of eluxadoline. It is unlikely that metabolism of eluxadoline by these enzymes has a clinically meaningful impact on systemic exposure.

Excretion

Following a single oral dose of 300 mg [¹⁴C] eluxadoline in healthy male subjects, 82.2% of the total radioactivity was recovered in feces within 336 hours and less than 1% was recovered in urine within 192 hours.

Specific Populations

Patients with Hepatic Impairment

Following a single oral 100–mg dose in subjects with varying degrees of liver impairment and healthy subjects, mean eluxadoline plasma exposure was 6-fold, 4-fold, and 16-fold higher in mild, moderate, and severe hepatically impaired subjects (Child Pugh Class A, B, C), respectively, compared to the subjects with normal liver function [see Dosage and Administration (2), Contraindications (4), Use in Specific Populations (8.6)].

Patients with Renal Impairment

Following a single oral 100 mg dose, the mean eluxadoline C_max and AUC_0-t were 3.7-fold and 4.7-fold higher, respectively, in subjects with severe renal impairment (eGFR 15 to 30 mL/min/1.73 m², n=2) and 2.4-fold and 5.9-fold higher, respectively, in subjects with ESRD not yet on dialysis (eGFR less than 15 mL/min/1.73 m², n=6) compared to healthy subjects with normal renal function (n=6) [see Dosage and Administration (2), Use in Specific Populations (8.7)].

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

In vitro studies indicate that eluxadoline is neither an inducer of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant systemic concentrations. Although CYP2E1 was slightly inhibited by eluxadoline (IC₅₀ of approximately 20 micromolar [11 mcg/mL]), clinically meaningful interactions are unlikely. Despite mechanism-based inhibition of CYP3A4 in vitro, eluxadoline did not have a clinically meaningful drug-drug interaction with the CYP3A4 substrate midazolam.

In vitro studies suggest that eluxadoline is a substrate for OAT3, OATP1B1, BSEP and MRP2, but not for OCT1, OCT2, OAT1, OATP1B3, P-gp and BCRP. Based on the in vitro studies, clinically meaningful interaction via inhibition of OCT1, OCT2, OAT1, OAT3, OATP1B3, BSEP and MRP2 by eluxadoline is unlikely.

In Vivo Assessment of Drug Interactions

The following drug interactions were studied in healthy subjects:

Oral Contraceptives:

Coadministration of multiple doses of 100 mg VIBERZI with multiple dose administration of an oral contraceptive (norethindrone 0.5 mg/ethinyl estradiol 0.035 mg) does not change the exposure of either drug.

Cyclosporine:

Coadministration of a single dose of 100 mg VIBERZI with a single dose of 600 mg cyclosporine resulted in 4.4-fold and 6.2-fold increase in AUC and C_max of eluxadoline, respectively, compared to administration of VIBERZI alone [see Drug Interactions (7)].

Probenecid:

Coadministration of a single dose of 100 mg VIBERZI with a single dose of 500 mg probenecid resulted in a 35% and 31% increase in eluxadoline AUC and C_max, respectively, compared to administration of VIBERZI alone. This change in eluxadoline exposures is not expected to be clinically meaningful.

Rosuvastatin:

Coadministration of multiple doses of 100 mg VIBERZI twice daily with a single dose 20 mg rosuvastatin resulted in an increase in the AUC (40%) and C_max (18%) of rosuvastatin compared to administration of rosuvastatin alone. Similar results were observed with the active, major metabolite, n-desmethyl rosuvastatin [see Drug Interactions (7)].

Midazolam:

Coadministration of multiple doses of 100 mg VIBERZI twice daily with single dose administration of 4 mg midazolam did not affect midazolam pharmacokinetics in humans, suggesting that eluxadoline will not affect the exposure of concomitantly administered CYP3A4 substrates.

Carcinogenesis

Two-year oral carcinogenicity studies have been conducted with eluxadoline in CD-1 mice at doses up to 1500 mg/kg/day (about 14 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) and in Sprague Dawley rats at oral doses up to 1500 mg/kg/day (about 36 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Oral administration of eluxadoline for 104 weeks did not produce tumors in mice and rats.

Mutagenesis

Eluxadoline was negative in the Ames test, chromosome aberration test in human lymphocytes, in the mouse lymphoma cell (L5178Y/TK^+/-) forward mutation test and in the in vivo rat bone marrow micronucleus test.

Impairment of Fertility

Eluxadoline at oral doses up to 1000 mg/kg/day (about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

The efficacy and safety of VIBERZI in IBS-D patients was established in two randomized, multi-center, multi-national, double-blind, placebo-controlled trials (Studies 1 and 2). A total of 1281 patients in Study 1 and 1145 patients in Study 2 received treatment with VIBERZI 75 mg, VIBERZI 100 mg or placebo twice daily [overall, patients had a mean age of 45 years (range 18 to 80 years with 10% at least 65 years of age or older), 66% female, 86% white, 11% black, and 27% Hispanic].

All patients met Rome III criteria for IBS-D (loose [mushy] or watery stools ≥25% and hard or lumpy stools <25% of bowel movements) and were required to meet both of the following criteria:

• an average of worst abdominal pain scores in the past 24 hours of >3.0 on a 0 to 10 scale over the week prior to randomization.
• an average daily stool consistency score (Bristol Stool Scale or BSS) of ≥5.5 and at least 5 days with a BSS score ≥5 on a 1 to 7 scale over the week prior to randomization.

Pertinent exclusion criteria included: prior pancreatitis, alcohol abuse, cholecystitis prior 6 months, sphincter of Oddi dysfunction, inflammatory bowel disease, intestinal obstruction, gastrointestinal infection or diverticulitis within prior 3 months, lipase greater than 2 xULN, ALT or AST greater than 3 xULN.

Study 1 and Study 2 included identical 26-week double-blind, placebo-controlled treatment periods. Study 1 continued double-blinded for an additional 26 weeks for long-term safety (total of 52 weeks of treatment), followed by a 2-week follow-up. Study 2 included a 4-week single-blinded, placebo-withdrawal period upon completion of the 26-week treatment period. During the double-blind treatment phase and the single-blinded placebo withdrawal phase, patients were allowed to take loperamide rescue medication for the acute treatment of uncontrolled diarrhea, but were not allowed to take any other antidiarrheal, antispasmodic agent or rifaximin for their diarrhea. Additionally, patients were allowed to take aspirin-containing medications or nonsteroidal anti-inflammatory drugs, but no narcotic or opioid containing agents.

Efficacy of VIBERZI was assessed in both trials using an overall composite responder primary endpoint. The primary endpoint was defined by the simultaneous improvement in the daily worst abdominal pain score by ≥30% as compared to the baseline weekly average AND a reduction in the BSS to <5 on at least 50% of the days within a 12-week time interval. Improvement in daily worst abdominal pain in the absence of a concurrent bowel movement was also considered a response day. Results for endpoints were based on electronic daily diary entries by patients.

The proportion of composite responders over 12 weeks is shown in Table 4. In both trials, the proportion of patients who were composite responders to VIBERZI was statistically significantly higher than placebo for both doses. The proportion of patients who were composite responders to VIBERZI was similar for male and female patients in both trials.

Table 4. Efficacy Results in Randomized Clinical Trials:

¹ Composite = Simultaneous improvement of Worst Abdominal Pain (WAP) by ≥30% and Bristol Stool Score (BSS) <5 on the same day for ≥50% of days over the interval
² P<0.01
³ P<0.001
⁴ P<0.05

Additionally, the proportion of patients who were composite responders to VIBERZI at each 4-week interval was numerically higher than placebo for both doses as early as month 1 through month 6 demonstrating that efficacy is maintained throughout the course of treatment.

During the 4 week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose.