Summary Basis of Decision for Ibsrela

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 Ibsrela is located below.

Recent Activity for Ibsrela

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.

Summary Basis of Decision (SBD) for Ibsrela

Date SBD issued: 2020-08-24

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

Tenapanor (supplied as tenapanor hydrochloride)

Drug Identification Number (DIN):

  • DIN 02498049 - 50 mg tablet, oral administration

Knight Therapeutics Inc.

New Drug Submission Control Number: 224850

On April 15, 2020, Health Canada issued a Notice of Compliance to Knight Therapeutics Inc. for the drug product, Ibsrela.

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-harm-uncertainty profile of Ibsrela is favourable for the treatment of irritable bowel syndrome with constipation in adults.

1 What was approved?

Ibsrela, a sodium/hydrogen exchanger 3 inhibitor, was authorized for the treatment of irritable bowel syndrome with constipation in adults.

Ibsrela is contraindicated in:

  • pediatric patients under 6 years of age due to the risk of serious dehydration;
  • patients with known or suspected mechanical gastrointestinal obstruction;
  • patients who are hypersensitive to tenapanor (medicinal ingredient in Ibsrela) or to any ingredient in the formulation or component of the container.

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

Ibsrela (50 mg tenapanor, supplied as tenapanor hydrochloride) is presented as a tablet. In addition to the medicinal ingredient tenapanor, the tablet also contains colloidal silicon dioxide, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, propyl gallate, stearic acid, tartaric acid, and titanium dioxide and triacetin.

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 Ibsrela Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Ibsrela approved?

Health Canada considers that the benefit-harm-uncertainty profile of Ibsrela is favourable for the treatment of irritable bowel syndrome with constipation (IBS‑C) in adults.

Irritable Bowel Syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract characterized by recurrent abdominal pain with alteration in bowel habits including diarrhea, constipation or alternation between both. While IBS is not considered a life-threatening disease, it compromises the patient's quality of life. It is the most common disorder seen by gastroenterologists and affects approximately 10% of the general population. The prevalence of IBS in women is higher than in men with an odds ratio of 1.67. Women are also more likely to have constipation-predominant IBS as compared with men.

There are no pathognomonic diagnostic parameters for IBS, therefore, its diagnosis is reached by exclusion of other diseases. Diagnostic criteria have been developed to help with the diagnosis of IBS. The most current criteria are the Rome IV criteria, which are an update of the Rome III criteria.

According to the Rome IV criteria, IBS is defined as recurrent abdominal pain at least one day per week in the last three months associated with two or more of the following features:

  • related to defecation;
  • associated with a change in stool frequency;
  • associated with a change in stool form.

According to the Rome III criteria, IBS is defined as recurrent abdominal pain or discomfort at least three days per month in the last three months, with onset at least six months previously, associated with two or more of the following features:

  • improvement with defecation;
  • onset associated with a change in frequency of stool;
  • onset associated with a change in form (appearance) of stool.

The pathophysiology of IBS is not well understood. Treatment is often multifactorial and varies based on the subtype of IBS. Some of the available treatments for IBS‑C include: diet modifications/avoiding triggers; supplements to modify stool consistency (e.g., psyllium, peppermint oil, and probiotics); psychological therapies (e.g., cognitive behavioural therapy and/or hypnotherapy); pharmacological therapies (e.g., antispasmodics, certain antidepressants, guanylate cyclase-C agonists (linaclotide, plecanatide). Plecanatide, a second guanylate cyclase-C agonist, was also recently approved in Canada as a treatment option.

Tenapanor, the medicinal ingredient in Ibsrela, is a small molecule sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) inhibitor that is minimally absorbed by design. The Na+/H+ antiporter NHE3 plays a central role in the sodium re-uptake process in the gastrointestinal tract and is a major contributor in maintaining intestinal water and sodium homeostasis. In constipation-related disorders such as IBS-C, Ibsrela inhibits NHE3 and reduces absorption of sodium from the small intestine and colon, thereby leading to an increase in water secretion into the intestinal lumen. This accelerates intestinal transit time and results in a softer stool consistency. In contrast, other drug therapies indicated for the treatment of IBS-C in Canada (linaclotide and plecanatide) act to soften stools through secretion of chloride in the gastrointestinal tract.

Ibsrela has been shown to be efficacious for the management of IBS‑C. The market authorization of Ibsrela was based on efficacy and safety data derived from two pivotal Phase III, multicentre, randomized, double-blind, placebo-controlled, clinical trials (TEN‑01‑301 and TEN‑01‑302). In total, 606 adult patients in TEN‑01‑301 and 593 adult patients in TEN‑01‑302, diagnosed with IBS‑C based on the Rome III criteria, were randomized 1:1 to receive either Ibsrela 50 mg or placebo twice daily.

In both pivotal studies, the primary endpoint was the proportion of responders, where a responder was defined as a patient achieving both the stool frequency and abdominal pain responder criteria in the same week for at least 6 of the first 12 weeks of treatment (i.e., 6/12 overall combined responder). The stool frequency (complete spontaneous bowel movement [CSBM]) and abdominal pain responder criteria assessed each week were defined as:

  • CSBM responder, a patient who experienced an increase of at least one CSBM in weekly average from baseline.
  • Abdominal pain responder, a patient who experienced at least a 30% reduction in the weekly average of abdominal pain score compared with baseline.

Both pivotal studies met the primary endpoint, demonstrating a modest, but clinically significant treatment benefit for Ibsrela. In the TEN‑01‑301 study, 27% of patients in the Ibsrela group were overall combined responders compared to 19% in the placebo group. The difference (95% confidence interval [CI]) in response rates of 8% (2%, 15%) was statistically significant (p = 0.02). In the TEN‑01‑302 study, 37% of patients in the Ibsrela group were overall combined responders compared to 24% in the placebo group and the difference in response rates of 13% (6%, 20%) was statistically significant (p<0.001).

In the safety analysis, the most commonly reported adverse event was diarrhea. In both studies, severe diarrhea was reported in 2.5% of Ibsrela-treated patients. In addition, diarrhea was reported at a higher frequency in patients with mild to moderate renal impairment than in patients with normal renal function. In study D5610C00001 in which patients with chronic kidney disease (estimated glomerular filtration rate [eGFR] 25‑70 mL/min/1.73m2) with Type 2 diabetes mellitus were treated with Ibsrela for an unrelated indication, three drug‑related adverse events (2 Ibsrela‑treated patients and 1 placebo-treated patient) of hyperkalemia requiring hospitalization and medical treatment were reported. However, no signal of hyperkalemia was found in the IBS-C pivotal studies in patients with mild to moderate renal impairment.

Safety and efficacy of Ibsrela have not been established in patients with hepatic impairment or severe renal impairment, end stage renal disease, or in patients under 18 years of age. Patients with serum creatinine above 176 µmol/L, which includes all patients with severe renal impairment, and patients with hepatic impairment were excluded from both pivotal studies. A pharmacokinetic study conducted in patients with hepatic impairment was not available to Health Canada in the New Drug Submission for Ibsrela.

Ibsrela is contraindicated in patients younger than 6 years of age due to a serious risk of dehydration. In young juvenile rats (less than 1 week old; approximate human age equivalent of less than 2 years of age), oral administration of Ibsrela resulted in decreased body weight and mortality due to dehydration. Although there are no data available in older juvenile rats, given the deaths in younger rats and the lack of clinical safety and efficacy data in pediatric patients, the use of Ibsrela in patients 6 years to less than 18 years of age is not recommended. A Serious Warnings and Precautions box describing this serious warning has been included in the Ibsrela Product Monograph.

A Risk Management Plan (RMP) for Ibsrela was submitted by Knight Therapeutics Inc. 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Ibsrela Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Ibsrela was accepted.

Overall, the therapeutic benefits of Ibsrela seen in the TEN‑01‑301 and TEN‑01‑302 pivotal studies are positive. Ibsrela 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 Ibsrela 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 Ibsrela?

Submission Milestones: Ibsrela

Submission MilestoneDate
Pre-submission meeting:2018-11-15
Submission filed:2019-02-26
Screening
Screening Deficiency Notice issued:2019-04-17
Response filed:2019-05-09
Screening Acceptance Letter issued:2019-06-20
Review
Review of Risk Management Plan complete:2020-03-09
Quality Evaluation complete:2020-04-02
Clinical/Medical Evaluation complete:2020-04-07
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2020-04-14
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2020-04-15

The Canadian regulatory decision on the quality, non-clinical, and clinical review of Ibsrela was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.

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

5 What post-authorization activity has taken place for Ibsrela?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (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. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Ibsrela. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

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 Ibsrela is tenapanor. Tenapanor is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the small intestine and colon, and is primarily responsible for the absorption of dietary sodium. When taken orally, tenapanor acts locally by reducing the dietary uptake of sodium resulting in an increased water secretion into the intestinal lumen, which accelerates intestinal transit time and results in a softer stool consistency.

Given that tenapanor is minimally absorbed systemically, many studies were based on its pharmacodynamic effects. As an example, the food effect study compared the effects of the drug when taken at different times in comparison to (salt-limited) food. The results of the study indicated that the optimal timing for Ibsrela is approximately 5 to 10 minutes prior to consuming a meal (i.e., twice daily ‑ one 50 mg tablet with breakfast, and one 50 mg tablet with dinner). This resulted in the greatest elimination of stool sodium.

The plasma concentrations of tenapanor were below the limit of quantitation (0.5 ng/mL) in the majority of samples from healthy subjects and patients. In healthy volunteers, following a single and repeated oral administration, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t1/2) could not be determined.

Tenapanor forms a primary metabolite, M1, which has been found to have no pharmacological effect, but was detected in the plasma. Consequently, drug-drug interaction studies were conducted based on changes in the pharmacokinetic properties of tenapanor and the metabolite M1, thereby making the metabolite M1 a surrogate for the drug-drug interaction studies. There was no significant inhibition or induction of the cytochrome P450 3A4 (CYP3A4) enzyme using midazolam as a substrate when Ibsrela was administered twice daily for 13 days in healthy subjects. Additionally, a single 50 mg dose of Ibsrela, along with repeated doses of itraconazole 200 mg (a potent CYP3A4/5 inhibitor) resulted in a decrease of the mean AUC and Cmax of M1 by 50% in healthy subjects. Lastly, no significant effect on peptide transporter 1 (PepT1) activity using cefadroxil as a substrate was seen when Ibsrela 50 mg was given twice daily for 12 days in healthy subjects.

A pharmacokinetic study using Ibsrela conducted in patients with hepatic impairment was not available to Health Canada in the New Drug Submission. These patients were specifically excluded in the pivotal studies TEN-01-301 and TEN‑01‑302. Similarly, no formal renal impairment study was included, and patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m2) were also excluded from both pivotal studies. Additionally, no formal thorough QT prolongation study was conducted, although there was a Phase I study in which healthy subjects received a dose level of tenapanor that produced 3 times the mean Cmax of M1 at the recommended dosage, and there was no impact on the QT interval.

Overall, there were very few safety concerns raised in the studies provided, and those noted were primarily gastrointestinal in nature, as one would anticipate based on the effects of the drug.

Clinical Efficacy

The efficacy of Ibsrela for the treatment of irritable bowel syndrome with constipation (IBS‑C) was based primarily on two pivotal Phase III, multicentre, randomized, double‑blind, placebo‑controlled, clinical studies (TEN‑01‑301 and TEN-01‑302).

Prior to enrolling in either study, all patients had to meet the Rome III criteria for IBS-C. Patients were further required to meet the following clinical criteria during a 2-week screening period:

  • a mean abdominal pain score of at least 3 on an 11-point numerical rating scale, where a score of 0 indicates no pain and 10 indicates very severe pain;
  • fewer than 3 complete spontaneous bowel movements (CSBMs) per week, where a CSBM is defined as a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation (an SBM is a bowel movement occurring in the absence of laxative use), and
  • fewer than or equal to 5 SBMs per week.

The design of the two pivotal trials were identical through the first 12 weeks of treatment, and thereafter differed as follows: TEN-01-301 included a 4-week randomized withdrawal (RW) period, and TEN-01-302 continued for 14 additional weeks with double-blind treatment (overall 26 weeks) to evaluate long-term efficacy.

In these studies, 606 adult patients in TEN-01-301 and 593 adult patients in TEN-01-302 received treatment with either Ibsrela 50 mg or placebo twice daily and were evaluated for efficacy and safety.

In both pivotal studies, the primary endpoint was the proportion of combined responders, where a combined responder was defined as a patient who met both the abdominal pain intensity and stool frequency responder criteria in the same week for at least 6 of the first 12 weeks of treatment (i.e., 6/12 week overall combined responder). The abdominal pain and stool frequency responder criteria assessed each week were defined as:

  • abdominal pain responder, a patient who experienced a decrease of at least 30% in abdominal pain score when compared to the baseline score.
  • stool frequency responder, a patient who experienced an increase of at least one CSBM from baseline.

The responder rates for the components of this composite endpoint (CSBMs and abdominal pain) were pre-specified key secondary endpoints. Durability of efficacy response was evaluated in both studies based on a patient being a weekly responder for at least 9 out of the 12 weeks of treatment. In addition, the durability of efficacy was assessed for a longer period in TEN-01-302 based on a patient being a weekly responder for at least 13 out of the 26 weeks of treatment.

Both pivotal studies met their primary endpoint (i.e., the 6/12 week overall combined responder) where the responder rate is shown to be statistically significantly higher in the Ibsrela-treated patients that in the placebo-treated patients. Therefore, the efficacy of Ibsrela in the treatment of adults with IBS-C has been demonstrated in two adequate and well‑controlled studies.

TEN-01-301

In TEN-01-301, 27.0% (83/307) of patients in the Ibsrela group and 18.7% (56/299) in the placebo group were 6/12 week overall combined responders. The risk difference (95% confidence interval [CI]) in 6/12 week overall combined responder rates for Ibsrela versus placebo was 8.3% (1.7%, 15.0%), which was statistically significant (p = 0.02).

The results for the key secondary endpoint of 6/12 week overall CSBM responder rate were not statistically significant. One hundred and four patients (33.9%) in the Ibsrela group and 88 patients (29.4%) in the placebo group were 6/12 week overall CSBM responders. The risk difference (95% CI) in the 6/12 week overall CSBM responder rates for Ibsrela versus placebo was 4.4% (-3.0%, 11.8%), p = 0.27. Since the between-group difference was not statistically significant, all other key secondary analyses were exploratory based on the pre-specified sequential testing procedure. However, in post hoc testing, treatment differences for the key secondary efficacy endpoints of 6/12 week overall abdominal pain, and 9/12 week overall combined, CSBM, and abdominal pain responder rates were all nominally statistically significant in favour of Ibsrela over placebo. Improvements in CSBM frequency and abdominal pain were observed with Ibsrela as early as one week after starting treatment.

In the randomized withdrawal phase, Ibsrela-treated patients re-randomized to placebo demonstrated a worsening on average of CSBM frequency and abdominal pain severity over the 4-week period, but the improvement remained as compared to baseline. Patients who continued on Ibsrela maintained their response to therapy on average over the additional 4 weeks. Patients on placebo who were re-randomized to Ibsrela had an average increase in CSBM frequency and a decrease in abdominal pain.

TEN-01-302

In TEN 302, 107 patients (36.5%) in the Ibsrela group and 71 patients (23.7%) in the placebo group were 6/12 week overall combined responders. The risk difference (95% CI) in 6/12 week overall responder rates for Ibsrela versus placebo was 12.9% (5.5%, 20.2%), which was statistically significant (p<0.001).

The between-group differences of Ibsrela and placebo were statistically significant for all key secondary endpoints, including responder rates for the following: 6/12 week overall CSBM, 6/12 week overall abdominal pain, 9/12 week overall combined, 9/12 week overall CSBM, 9/12 week overall abdominal pain, 13/26 week overall combined, 13/26 week overall CSBM, and 13/26 week overall abdominal pain. Improvements in CSBM frequency and abdominal pain were observed with Ibsrela as early as one week after starting treatment.

Sustained efficacy over the 26-week treatment period demonstrated durability of effect.

Indication

The New Drug Submission for Ibsrela was filed by the sponsor with the following indication, which Health Canada subsequently approved:

  • Ibsrela (tenapanor) is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

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

Clinical Safety

The safety of Ibsrela for the treatment of irritable bowel syndrome with constipation (IBS-C) was based primarily on two pivotal Phase III studies (TEN‑01‑301 and TEN‑01‑302) previously described in the Clinical Efficacy section. Additional data from Phase II studies was also included as part of the safety evaluation.

The incidence of patients reporting a treatment-emergent adverse event (TEAE) was 44% in the Ibsrela 100 mg dose group and 33% in the placebo group. A TEAE was considered drug‑related in 20% of the Ibsrela 100 mg dose group and 8.3% in the placebo group. A TEAE was considered severe in 2.2% and 0.3% of patients in the Ibsrela 100 mg group and placebo group, respectively. There were 1.2% and 1.1% patients with serious adverse events in the Ibsrela 100 mg group and placebo group, respectively.

Diarrhea was the most common TEAE (14.8% the Ibsrela 100 mg group and 2.3% in the placebo group), often occurring during the first week of treatment. Serious TEAEs of hyperkalemia have also been reported in study D5610C00001 in patients with chronic kidney disease (defined by estimated glomerular filtration rate [eGFR] from 25 to 70 mL/min/1.73m2) and type 2 diabetes mellitus treated with Ibsrela for an unapproved, unrelated indication. Three serious adverse reactions of hyperkalemia resulting in hospitalization were reported, 2 Ibsrela‑treated patients and 1 placebo‑treated patient. Overall, there were 7 (9%) Ibsrela-treated patients who experienced hyperkalemia or increase in blood potassium relative to 1 (1%) placebo‑treated patient.

There were 77 (7.2%) and 9 (1.2%) patients who discontinued treatment due to adverse events in the Ibsrela 100 mg group and the placebo group, respectively. Diarrhea was the most commonly observed adverse event leading to study discontinuation (5.9%) in the Ibsrela 100 mg group compared to the placebo group (0.5%). Most often, the diarrhea was mild to moderate in severity. Nonetheless, severe diarrhea leading to study discontinuation was experienced in 1.7% (18/1,073) of patients receiving daily Ibsrela 100 mg compared to 0.14% (1/738) of patients receiving placebo.

In the combined pivotal studies, there were 368 patients (31%) with baseline renal impairment (defined as estimated glomerular filtration rate lower than 90 mL/min/1.73m2). In patients with renal impairment, diarrhea, including severe diarrhea, was reported in 20% (39/194) of Ibsrela-treated patients and 0.6% (1/174) of placebo-treated patients. In patients with normal renal function at baseline, diarrhea, including severe diarrhea, was reported in 13% (53/407) of Ibsrela-treated patients and 3.5% (15/426) of placebo-treated patients. No other differences in the safety profile were reported in the renal impaired subgroup. The incidence of diarrhea and severe diarrhea in Ibsrela-treated patients did not correspond to the severity of renal impairment.

Ibsrela is contraindicated in children up to 6 years of age and is not recommended in children between 6 and 18 years of age due to the risk of serious dehydration. A Serious Warnings and Precautions box describing this serious warning has been included in the Ibsrela Product Monograph. Ibsrela is also contraindicated in patients with known or suspected mechanical gastrointestinal obstruction and patients who are hypersensitive to tenapanor or to any ingredient in the formulation or component of the container.

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

7.2 Non-Clinical Basis for Decision

Tenapanor (the medicinal ingredient in Ibsrela) is a sodium-proton-exchanger subtype 3 (NHE3) inhibitor that is minimally absorbed following oral administration. Tenapanor reduces sodium uptake from the gut and increases the fluid (water) volume in the lumen, which accelerates intestinal transit time and results in a softer stool consistency both in animals and in humans. Ibsrela has also been shown to reduce abdominal pain by decreasing visceral hypersensitivity and by decreasing intestinal permeability in animal models. In rat model of colonic hypersensitivity, tenapanor reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability.

The non‑pharmacology studies indicate that tenapanor is effective and safe to use in an irritable bowel syndrome animal model and support future human studies.

However, the dosage varied in different animal models and dosage findings may not be directly extrapolated from animal studies to clinical studies. As tenapanor inhibits sodium absorption, long-term use may cause hyponatremia and the sodium levels in blood should be monitored in clinical studies. It is unclear from animal pharmacology studies whether the long‑term use of tenapanor may cause other electrolyte imbalances, such as hypokalemia or hypomagnesemia.

Toxicology

Overall, the toxicology data do not raise any safety issues that would preclude the approval of Ibsrela for the proposed indication. Any potential safety concerns noted in the non-clinical toxicology studies were addressed in the Ibsrela Product Monograph.

The general toxicology studies, conducted with tenapanor in rats, mice, and dogs, indicated that tenapanor has reasonable margins of safety relative to the human recommended dose. Rats were the most sensitive species with No Observed Adverse Effects Levels (NOAELs) of 3 and 10 mg/kg/day in a 6 month study in males and females, respectively, which provided safety margins of 0.29 times and 0.97 times the equivalent human recommended dose based on body surface area. The NOAELs in mice and dogs were 50 mg/kg/day (1 month study), and 1,000 mg/kg/day (9 month study), respectively, which provided safety margins of 2.4 times and >100 times the equivalent human recommended dose based on body surface area. Notable findings at or below the NOAEL in all three species were soft feces, decreased defecation and reversible diarrhea, which were expected pharmacological effects of tenapanor in the gastrointestinal tract. At higher dose levels in rodents, severe diarrhea was noted, which resulted in dehydration, weight loss, hemoconcentration, and death. Consistent with the non-clinical data, diarrhea was also the most common adverse reaction in tenapanor-treated patients in pivotal clinical studies, with severe diarrhea leading to study discontinuation in 1.7% of patients. The risk of severe diarrhea and resulting dehydration has been adequately addressed through labelling in the Warnings and Precautions section of the Ibsrela Product Monograph.

Tenapanor exhibited no potential for genotoxicity in a standard battery of tests and was not carcinogenic in long-term rat and mouse carcinogenicity studies. Tenapanor did not affect male or female fertility, or embryo-fetal development in reproduction and development studies in rats, mice, or rabbits.

When administered to young juvenile rats (<1 week old; approximately equivalent to human pediatric patients <2 years of age) starting on postnatal day (PND) 5 at doses ranging from 0.03 to 10 mg/kg/day via oral gavage, tenapanor was not well tolerated and resulted in reduced body weight and premature mortality (likely due to dehydration). These effects were observed as early as PND8 and at doses as low as 0.3 mg/kg/day, substantially lower than the human recommended dose for adults. These findings indicate that young children (<2 years of age) may be susceptible to tenapanor-related toxicity. However, there are uncertainties regarding safety of Ibsrela in pediatric patients >2 years of age as there are no studies in older juvenile rats (dosing initiated at PND21) that directly address human age equivalence of >2 years to <18 years. Mortality in juvenile rats was adequately addressed in the relevant sections of the Ibsrela Product Monograph.

For more information, refer to the Ibsrela 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 Ibsrela 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 are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 18 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).

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

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

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

None of the excipients used in the formulation of Ibsrela is of human or animal origin.

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