Summary Basis of Decision for Viberzi

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Viberzi is located below.

Recent Activity for Viberzi

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Viberzi

Updated:

2020-11-30

The following table describes post-authorization activity for Viberzi, a product which contains the medicinal ingredient eluxadoline. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Numbers (DINs):

  • DIN 02460890 - 75 mg, eluxadoline, tablet, oral
  • DIN 02460904 - 100 mg, eluxadoline, tablet, oral

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
Drug product (DIN 02460904) market notificationNot applicableDate of first sale:
2020-01-23
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02460890) market notificationNot applicableDate of first sale:
2020-01-17
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 2263602019-03-29Issued NOC
2019-04-29
Submission filed to change the name of the drug sponsor from Allergan Pharma Co. to Allergan Inc.
NC # 2225692018-11-30Issued NOL
2019-03-13
Submission filed as a Level II (120 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Action and Clinical Pharmacology, and Detailed Pharmacology sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 2162362018-05-11Issued NOL
2018-08-20
Submission filed as a Level II (90 day) Notifiable Change to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Serious Warnings and Precautions Box, Warnings and Precautions, Adverse Reactions, and Drug Interactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DINs 02460890, 02460904) market notificationNot applicableDate of first sale:
2017-04-24
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 1901622015-12-11Issued NOC
2017-01-26
Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Viberzi

Date SBD issued: 2017-03-01

The following information relates to the new drug submission for Viberzi.

Eluxadoline
75 mg and 100 mg tablets, oral

Drug Identification Number (DIN):

  • DIN 02460890 - 75 mg tablet
  • DIN 02460904 - 100 mg tablet

Allergan Pharma Co.

New Drug Submission Control Number: 190162

On January 26, 2016, Health Canada issued a Notice of Compliance to Allergan Pharma Co. for the drug product Viberzi.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Viberzi is favourable for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. In clinical trials, Viberzi improved abnormal stool consistency more prominently than abdominal pain.

1 What was approved?

Viberzi contains the medicinal ingredient eluxadoline which is a mixed mu opioid receptor (µOR) agonist and delta opioid receptor (δ OR) antagonist. Viberzi was authorized for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

In clinical trials, Viberzi improved abnormal stool consistency more prominently than abdominal pain.

Viberzi was not studied in patients 65 years and older in a specifically dedicated study. In the pivotal trials, 8% of patients were 65 years and older, and a higher proportion of elderly patients than younger patients experienced adverse reactions.

The safety and effectiveness of Viberzi in pediatric patients have not been established; therefore, use in children is not recommended.

Viberzi is contraindicated for patients with:

  • Hypersensitivity to eluxadoline or to any ingredient in the formulation or component of the container.
  • Known or suspected biliary duct obstruction; or sphincter of Oddi disease or dysfunction. These patients are at increased risk for sphincter of Oddi spasm.
  • Patients without a gallbladder. These patients are at increased risk for sphincter of Oddi spasm.
  • Alcoholism, alcohol abuse or alcohol addiction, or in patients who drink more than three alcoholic beverages per day. These patients are at increased risk for acute pancreatitis.
  • A history of pancreatitis; or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis.
  • Hepatic impairment (Child-Pugh Class A, B, and C). These patients are at risk for significantly increased plasma concentrations of eluxadoline.
  • A history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction. These patients may be at risk for severe complications of bowel obstruction.
  • Patients on concomitant treatment with potent inhibitors of organic anion transporting polypeptide 1B1 (OATP1B1; for example [e.g.], cyclosporine).

Viberzi was approved for use under the conditions stated in the Viberzi Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Viberzi (75 mg and 100 mg eluxadoline) is presented as a tablet. In addition to the medicinal ingredient, eluxadoline, the tablet core contains colloidal silica, crospovidone, mannitol, magnesium stearate, and silicified microcrystalline cellulose. The tablet coating contains iron oxide red, iron oxide yellow, polyethylene glycol, partially hydrolyzed polyvinyl alcohol, talc, and titanium dioxide.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Viberzi Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Viberzi approved?

Health Canada considers that the benefit/risk profile of Viberzi is favourable for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

Irritable bowel syndrome (IBS) is a chronic (relapsing) benign functional gastrointestinal disorder characterized by a group of symptoms with no evidence of damage/lesions or significant complications, but it may have an impact on the quality of life of patients. Symptoms include abdominal pain or discomfort relieved with bowel movement (BM), changes in BM patterns (frequency and/or stool consistency). The condition IBS-D is a subtype of IBS where diarrhea (that isi [i.e.], loose or watery stool ≥25% of BMs) is predominant. The prevalence of IBS has been estimated between 3% and 12% with higher prevalence in women (2/3 females, 1/3 males), and may account for approximately 1/3 of all IBS cases. The cause of IBS is unknown and may involve disturbance of bowel sensitivity, motility, and intestinal flora, and may be associated with psychological disorders. The diagnosis relies on the symptomatology described by the patient, and the exclusion of any other diagnosis. Management of IBS uses a stepwise approach and includes: first, non-pharmacological means; and second, non-prescription products e.g., loperamide, and probiotic supplements. Prescription drugs may be used when other means are insufficient to alleviate specific symptoms, such as diarrhea. There is no drug currently approved in Canada for both pain and diarrhea.

Viberzi has been shown to be efficacious in adult patients with IBS-D. The market authorization was based on two pivotal Phase III clinical studies (Studies 1 and 2). Both studies included identical 26-week double-blind, placebo-controlled treatment periods. Study 1 continued double-blinded treatment for an additional 26 weeks for a long-term safety assessment (total of 52 weeks of treatment), followed by a 2-week follow-up. Study 2 included a 4-week, single-blinded, placebo-withdrawal period after the 26-week treatment period. A total of 808 patients were treated with Viberzi 100 mg twice a day (BID), 808 with Viberzi 75 mg BID, and 809 with placebo.

The primary endpoint was the proportion of composite responders within the specified time interval. An overall composite responder 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 Bristol Stool Scale (BSS) to <5 on at least 50% of the days within a 12-week time interval. The composite responder endpoint was also evaluated over a 26-week time interval. Improvement in daily worst abdominal pain in the absence of a concurrent bowel movement was also considered a response day.

The rates of composite responders were statistically significantly greater with Viberzi as compared to placebo, with a difference of 10.3%, in the Week 1-12 analysis, and 11.5% in the Week 1-26 analysis. This is a modest to moderate benefit given the benign nature of the condition and the symptomatic nature of the treatment.

The analysis of the individual components of the primary endpoint showed that the benefit of Viberzi on the "stool consistency" component was significant (difference in rates of approx. 13% vs. placebo), but less so for the "abdominal pain" component (difference in rates of approximately 4.5%, and approximately 7.0% if a more stringent pain criterion was applied). This benefit is considered to be modest; hence, the following statement was added to the approved indication, "In clinical trials, Viberzi improved abnormal stool consistency more prominently than abdominal pain".

In patients 65 years of age and older, the efficacy of the 75 mg BID dose appeared to be greater than that obtained from 100 mg BID. This finding and the higher rates of adverse events in this subpopulation prompted a dose adjustment from 100 mg BID to 75 mg BID in elderly patients.

Serious adverse events of pancreatitis and sphincter of Oddi spasm were reported in 0.8% (8/1032) of patients with Viberzi (none with placebo). However, these events occurred almost exclusively in patients with no gallbladder. Given the moderate treatment benefit of Viberzi, a contraindication was added for patients without a gallbladder.

In patients with mild-to-moderate hepatic impairment, and in patients treated with organic anion-transporting polypeptide-P1B1 (OATP1B1) inhibitors, significant increases (4- to 6-fold) in systemic exposure to Viberzi were noted. Contraindications in patients with mild-to-moderate hepatic impairment, and in patients treated with potent OATP1B1 inhibitors were added. Furthermore, Viberzi is contraindicated in patients with biliary duct obstruction and sphincter of Oddi disease or dysfunction; patients without a gallbladder; with alcohol abuse or addiction; with a history of pancreatic conditions; with a history of chronic or severe constipation or sequelae from constipation, or patients with known or suspected mechanical gastrointestinal obstruction.

Abuse potential studies in humans and animals showed that the medicinal ingredient eluxadoline can produce psychological dependence. Viberzi tablets can be easily crushed, therefore, the potential for intravenous abuse of eluxadoline from crushed tablets in humans cannot be ruled out.

A Risk Management Plan (RMP) for Viberzi was submitted by Allergan Pharma Co. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Viberzi has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Viberzi therapy are considered to outweigh the potential risks. Viberzi has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Viberzi Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Viberzi?

Submission Milestones: Viberzi

Submission MilestoneDate
Pre-submission meeting:2015-06-16
Submission filed:2015-12-11
Screening
Screening Deficiency Notice issued:2016-01-28
Response filed:2016-02-12
Screening Acceptance Letter issued:2016-04-01
Review
Biopharmaceutics Evaluation complete:2017-01-23
Quality Evaluation complete:2017-01-16
Clinical Evaluation complete:2017-01-25
Labelling Review complete:2017-01-24
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2017-01-26

The Canadian regulatory decision on the non-clinical and clinical review of Viberzi was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

The medicinal ingredient of Viberzi, eluxadoline, is a mixed mu opioid receptor (µOR) agonist and, to a lesser extent, delta opioid receptor (δOR) antagonist. The binding affinity (Ki) to human µOR and δOR was 1.8 nM and 430 nM, respectively.

The binding affinity of eluxadoline for the human kappa opioid receptor has not been determined; however, the Ki for guinea pig cerebellum kappa opioid receptor was 55 nM. In animals, eluxadoline interacts with opioid receptors in the gut.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Viberzi for the specified indication.

In patients with mild to moderate hepatic impairment, a significant increase (4- to 6-fold) in systemic exposure to eluxadoline was associated with more frequent adverse events including nervous system disorders (dizziness, headaches, and nausea) but not in subjects with normal liver function. Consequently, a contraindication in patients with mild to moderate hepatic impairment was added to the Viberzi Product Monograph along with the existing contraindication for severe hepatic impairment.

Drug-drug interaction studies identified organic anion-transporting polypeptide-P1B1 (OATP1B1) inhibitors (e.g., cyclosporine) as leading to significant increases (4- to 6-fold) in systemic exposure to eluxadoline. Therefore, the sponsor was requested to add a contraindication for patients receiving treatment with potent OATP1B1 inhibitors. The following other interactions were also included in the Viberzi Product Monograph: OATP1B1 substrates (e.g., rosuvastatin) which increased the systemic exposure to rosuvastatin, constipation-inducing drugs (e.g., anticholinergics and opioids) which may potentiate the risk of constipation of Viberzi, and finally strong cytochrome P450 (CYP) inhibitors (e.g., ciprofloxacin, clarithromycin) which may potentially increase the systemic exposure to eluxadoline.

The submitted bioavailability studies support the statements in the labelling recommending patients take Viberzi with food. The labelling was revised to explain that Viberzi is taken with food to maximize the drug's therapeutic effect locally in the gastrointestinal tract.

Overall, the data from the submitted clinical pharmacology studies are considered sufficient and there are no major concerns to prevent the market authorization of Viberzi for the specified indication.

For further details, please refer to the Viberzi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Viberzi (eluxadoline) in adult patients with irritable bowel syndrome with diarrhea (IBS-D) was primarily supported by two Phase III, randomized, multicentre, double-blind, placebo-controlled studies, Study 1 and Study 2. Both studies were similar in design (efficacy assessment through a 12-week treatment period, and a 26-week treatment period), except that Study 1 had an additional 26-week treatment period to allow for a long-term safety assessment (total of 52 weeks of treatment), while Study 2 included a 4-week single-blinded withdrawal period to assess rebound effects. The overall design of the studies was acceptable for the study objectives, and the dose selection was based on a dose-ranging 12-week efficacy/safety study where 100 mg eluxadoline had the best benefit/safety profile.

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

There were a large number of exclusion criteria, most of which were appropriately aimed at excluding patients with a history of significant gastrointestinal (GI) conditions. Exclusion criteria included: prior pancreatitis, alcohol abuse, cholecystitis in the prior 6 months, sphincter of Oddi dysfunction, inflammatory bowel disease, intestinal obstruction, GI infection or diverticulitis within the prior 3 months, levels of lipase greater than 2 times the upper limit of normal (x ULN), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 x ULN, or total bilirubin >3 mg/dL (>51.3 mmoL/L). Patients with history of cholecystectomy with any history of post cholecystectomy biliary tract pain were also excluded (successful cholecystectomy with no biliary pain were acceptable). Overall, the selection criteria were reasonable and are in line with the intended target patient population.

During the study, patients were allowed to take only loperamide rescue medication for diarrhea, and aspirin or nonsteroidal anti-inflammatory drugs for abdominal pain, but not narcotic or opioid agents.

A total of 808 patients were treated with Viberzi 100 mg twice a day (BID), 808 patients with Viberzi 75 mg BID, and 809 patients with placebo. Two-thirds of the patients were female. Fifty-two percent were 41 to 64 years old, 37% were 18 to 40 years old, and 10% were ≥65 years old. Demographic characteristics were not significantly different across treatment groups.

The primary endpoint was adequately selected and was in line with IBS-D recommendations based on accepted regulatory guidance documents. The primary efficacy endpoint itself was the composite response within a 12-week interval and 26-week interval. A composite responder was defined by a simultaneous improvement in the daily worst abdominal pain score by ≥30% compared to the baseline weekly average, and a reduction in the BSS to <5 on at least 50% of the days within the time interval.

The primary efficacy analysis showed that in both studies, the rates of composite responders were statistically significantly larger (p<0.001, pooled analysis) with Viberzi as compared to placebo, with a difference of 10.3%, in the 12-week interval and 11.5% in the 26-week interval. The magnitude of treatment benefit is considered to be modest to moderate given the non-serious nature of condition and the symptomatic nature of the treatment. The primary analysis was supported by various sensitivity analyses and to some extent by the secondary endpoints analyses. The sponsor reported no large significant discrepancy in treatment benefit according to various factors, with the possible exception of a relatively large benefit of Viberzi 75 mg BID (larger than that of the 100 mg BID) in patients 65 years and older, so that the need for the 100 mg dose was not clear in elderly patients. This finding and the higher rates of adverse events in this subpopulation prompted a request to the sponsor to change the dosing recommendation from 100 mg BID to 75 mg BID in elderly patients.

The analysis of the individual components of the primary endpoint showed that the rates of responders for the "stool consistency" component were significantly larger with Viberzi as compared to placebo (difference in rates of approximately 13%). However, the rates of responders using the "abdominal pain" component were not larger with Viberzi with a difference in rates of 4.3% to 4.5%. Post-hoc analyses using a more stringent pain criterion (≥40% improvement threshold in pain) showed a more favourable difference in rates between placebo and Viberzi of approximately 7%; however, even at this threshold, such a difference and related benefit is of relatively small clinical significance (Number Needed to Treat (NNT) = 14). Since Viberzi was considered to be somewhat efficacious on pain (given the composite responder effect, and the sensitivity analysis using the different pain improvement threshold), the original indication filed with the drug submission was amended by adding a qualifying statement to reflect the possibly lesser efficacy on pain.

The New Drug Submission for Viberzi was filed with the following indication:

  • Viberzi (eluxadoline) is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

Health Canada authorized the following indication:

  • Viberzi (eluxadoline) is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.
  • In the clinical trials, Viberzi improved abnormal stool consistency more prominently than abdominal pain.

For more information, refer to the Viberzi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The pivotal safety data for Viberzi (eluxadoline) was derived from two pivotal Phase III studies, Study 1 and Study 2 described in the Clinical Efficacy section, and a Phase II study. All three studies were randomized, parallel-group, placebo-controlled clinical studies in adult patients with IBS-D.

Exposure population in the studies included 1,032 patients exposed to Viberzi 100 mg BID (505 for 6 months, and 243 for 1 year), and 807 patients exposed to Viberzi 75 mg BID (496 for 6 months, and 245 for 1 year).

Approximately 56% of the patients treated with Viberzi 100 mg, 60% of those with Viberzi 75 mg, and 55% of those with placebo reported one or more adverse events. The most common adverse reactions were more frequently reported with Viberzi as compared to placebo, e.g., constipation (8.1% vs. 2.5%), nausea (7.1% vs. 5.0%), vomiting (4.2% vs. 1.2%) and abdominal pain (6.6% vs. 3.9%). In the Phase III studies, the proportion of patients treated with Viberzi 100 mg who reported mild, moderate, and severe adverse events were 24%, 25% and 10%, respectively.

Severe adverse events of increased levels of AST and/or ALT, and 2 cases of pancreatitis were reported only in Study 1 with Viberzi 100 mg (none with placebo). There were also 2 cases of acute pancreatitis in Study 2 with Viberzi (one with 75 mg, and one with 100 mg).

Overall 8.3% of the patients treated with Viberzi 75 mg, 7.8% of the patients treated with Viberzi 100 mg, and 4.3% of patients treated with placebo discontinued treatment prematurely due to an adverse reaction. In the Viberzi treatment groups, the most common reasons for discontinuation due to adverse reactions were constipation (1% for 75 mg and 2% for 100 mg) and abdominal pain (1% for both 75 mg and 100 mg). In comparison, less than 1% of patients in the placebo group withdrew due to constipation or abdominal pain.

Serious adverse events were reported more frequently with Viberzi 100 mg (4.0%), and Viberzi 75 mg (4.2%), as compared to placebo (2.6%). There were no serious adverse events of constipation; however, serious adverse reactions of pancreatitis and sphincter of Oddi spasm were reported. Sphincter of Oddi spasm occurred in 0.2% (2/807) of patients that received 75 mg and 0.8% (8/1032) of patients that received 100 mg Viberzi vs. 0% in patients that received placebo. Cases of sphincter of Oddi spasm occurred within the first month of treatment. All events resolved upon discontinuation of Viberzi. Five additional cases of pancreatitis, possibly not associated with sphincter of Oddi spasm, were reported in 2 (0.2%) patients that received Viberzi 75 mg and 3 (0.3%) patients that received Viberzi 100 mg vs. 0% in patients that received placebo. Among the five cases of pancreatitis, 1 case was in a patient with excessive alcohol intake, 1 case in a patient with biliary sludge, and 1 case in a patient who discontinued Viberzi 2 weeks prior to onset of symptoms. All pancreatic events were resolved/improved upon discontinuation of Viberzi (4/5 within 1 week).

An analysis of adverse events by Prior Cholecystectomy Status showed clearly that patients with no gallbladder were at a higher risk of adverse drug reactions including serious adverse drug reactions of pancreatitis, or increased levels of hepatic enzymes, and serious abdominal pain. For example, pancreatitis and increased levels of hepatic enzymes or hepatitis associated with sphincter of Oddi spasm were reported in 8 patients treated with Viberzi 100 mg; all of which were patients without a gallbladder (e.g., prior cholecystectomy). No cases were reported with placebo. The difference between placebo and Viberzi 100 mg in proportions of patients with GI adverse events was also larger in patients without a gallbladder (12.2%) as compared to those with a gallbladder (6.9%), for a differential of approximately +5.3%. Given the moderate treatment benefit of Viberzi 100 mg BID (difference vs. placebo in rates of composite responders of 10%), a contraindication was added for patients without gallbladder. This is in line with the findings of a Phase II study where a total of 4 serious adverse events of pancreatitis occurred with eluxadoline only. This prompted the sponsor to implement an amendment to exclude patients with pancreatitis-related conditions from enrolment. Subsequently, no other pancreatitis events were noted.

Abuse potential and dependence were assessed in two human abuse potential studies, which showed that as compared to placebo, eluxadoline oral and intranasal doses of 300 mg and 1,000 mg produced small but significant increases on both positive subjective measures (e.g., Drug Liking and High) and negative subjective measures (e.g., Drug Disliking and Dysphoria). In both studies, euphoria was reported to be 3- to 5-fold higher than placebo in non-dependent, recreational opioid users treated with single oral doses of eluxadoline 100 mg to 1,000 mg; and was higher than placebo (0%) with intranasal doses of eluxadoline 100 mg (21.9%) and 200 mg (18.8%). Therefore, eluxadoline can produce psychological dependence. In rats, a single intravenous dose of eluxadoline hydrochloride salt (5 mg/kg) caused respiratory depression. In a drug discrimination study in monkeys, intravenous administration of eluxadoline hydrochloride salt (10 mg/kg) substituted for morphine discriminative stimuli. In another study, monkeys self-administered eluxadoline hydrochloride salt (3.2 mg/kg) to a degree that was less than that of heroin but greater than that of saline. Finally, Viberzi tablets can be easily crushed, therefore, the potential for intravenous abuse of eluxadoline from crushed tablets in humans cannot be ruled out. In the 52-week pivotal Phase III clinical study, no evidence of significant physical dependence or withdrawal from Viberzi was detected.

The post-marketing data from13 months of use in the United States suggested that, based on the sponsor's estimated patients exposure of approximately 71,000 patients, the cumulated rates of sphincter of Oddi spasm and pancreatitis (0.28%) was not significantly larger than those reported in the clinical studies. Furthermore, the breakdown of the number of cases of pancreatitis or sphincter of Oddi spasm per gallbladder status shows that the majority (estimated to approximately 70% to 85%) occurred in patients with no gallbladder. It is noteworthy that in the United States there is no contraindication for patients without gallbladder.

Overall, Viberzi demonstrated a benefit in improving stool consistency and to a lesser extent abdominal pain. This drug has a relatively acceptable safety profile with pancreatitis identified as a risk, mainly present in patients without gallbladder (mitigated by a corresponding contraindication). There is no other prescription drug approved in Canada for this indication. Therefore, Viberzi has a favourable benefit-harm-uncertainty profile for the specified indication.

Appropriate warnings and precautions are in place in the approved Viberzi Product Monograph to address the safety concerns identified at the time of the review.

For more information, refer to the Viberzi Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical development program for Viberzi consisted mainly of studies in various animal species to examine the pharmacology and pharmacokinetics of Viberzi, as well as to evaluate the toxicity potential of the product and its tolerance. Based on the results of these studies, Viberzi was considered to have an overall acceptable safety profile for its subsequent use in clinical studies. The results of the non-clinical studies, as well as the potential risks to humans, have been included in the Viberzi Product Monograph. In view of the intended use of Viberzi, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Viberzi Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Viberzi has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development were considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months at 15-30oC is acceptable for Viberzi tablets packaged in the proposed bottles and blisters.

Proposed limits of drug-related impurities are considered adequately qualified; i.e., within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

None of the excipients in eluxadoline tablets are of human or animal origin.