Summary Basis of Decision for Constella

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 Constella is located below.

Recent Activity for Constella

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Constella

Updated: 2025-07-10

The following table describes post-authorization activity for Constella, a product which contains the medicinal ingredient linaclotide. 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 found in Post-Authorization Activity Tables (PAATs).

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

Drug Identification Number (DIN):

  • DIN 02417162 – 145 mcg linaclotide, capsule, oral administration
  • DIN 02417170 – 290 mcg linaclotide, capsule, oral administration
  • DIN 02469510 – 72 mcg linaclotide, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 279169

2023-09-18

Issued NOC 2024-09-05

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: for the treatment of functional constipation (FC) in children and adolescents 6 to 17 years of age. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02469510) market notification

Not applicable

Date of first sale 2024-08-01

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 02417170) market notification

Not applicable

Date of first sale 2023-12-15

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 02417162) market notification

Not applicable

Date of first sale 2023-12-11

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 267569

2022-09-01

Issued NOC 2022-10-18

Submission filed to transfer ownership of the drug product from Allergan Inc. to AbbVie Corporation. An NOC was issued.

SNDS # 261787

2022-02-24

Issued NOC 2022-07-26

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

Drug product (DIN 02417162) market notification

Not applicable

Date of first sale: 2019-05-09

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 02469510) market notification

Not applicable

Date of first sale: 2019-04-04

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 (02417170) market notification

Not applicable

Date of first sale: 2019-02-26

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 218177

2018-07-12

Issued NOC 2018-08-29

Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Forest Laboratories Inc. to Allergan Inc. and to revise the design elements of the inner bottle labels. The submission was reviewed and considered acceptable. An NOC was issued.

SNDS # 198867

2016-10-05

Issued NOC

2017-11-02

Submission filed as a Level I – Supplement to request approval of a 72 µg dose of Constella (linaclotide) in patients with chronic idiopathic constipation (CIC). Based on efficacy and safety data reviewed in this submission, it can be concluded that linaclotide 72 µg is superior to placebo in the treatment of CIC with an acceptable safety profile. The manufacturing process for the new strength is similar to that used for the approved strengths with modifications made to accommodate the new strength. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 192714

2016-02-29

Issued NOC

2017-07-18

Submission filed as a Level I – Supplement to support a label change to allow patients who cannot swallow whole capsules to administer the currently approved Constella via sprinkling in water or applesauce. The benefit-risk profile of Constella (dispersed in applesauce or water) in patients in need of the new mode administration is considered favourable and not significantly different from that in patients using the oral capsules swallowed whole. This submission was considered acceptable with respect to the safety and efficacy data reviewed. The information was reviewed and considered acceptable. An NOC was issued.

Drug product (DIN 02417170) market notification

Not applicable

Date of first sale: 2014/12/17

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NC # 173813

2014/04/04

Issued No Objection Letter 2014/05/12

Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to change the Product Monograph, to add a box around the existing warning regarding the use of Constella in pediatric patients. The submission was reviewed and a No Objection Letter was issued.

Drug product (DIN 02417162) market notification

Not applicable

Date of first sale: 2014/04/29

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 161056

2012/12/14

Issued NOC 2013/12/02

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Constella

Date SBD issued: 2014-01-23

The following information relates to the New Drug Submission for Constella.

Linaclotide, 145 µg and 290 µg, capsules, oral

Drug Identification Number (DIN):

  • 02417162 - 145 µg, capsule
  • 02417170 - 290 µg, capsule

Forest Laboratories Canada Inc.

New Drug Submission Control Number: 161056

 

On December 2, 2013, Health Canada issued a Notice of Compliance to Forest Laboratories Canada Inc. for the drug product Constella.

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 Constella is favourable for the treatment of irritable bowel syndrome with constipation in adults and for the treatment of chronic idiopathic constipation in adults.

 

1 What was approved?

 

Constella, a guanylate cyclase-C agonist, was authorized for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

Constella is contraindicated for pediatric patients less than six years of age, patients who are hypersenstitive to linaclotide or to any ingredient in the formulation or component of the container and for patients with known or suspected mechanical gastrointestinal obstruction. Constella was approved for use under the conditions stated in the Constella Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Constella (145 µg and 290 µg, linaclotide) is presented as capsules. In addition to the medicinal ingredient, the capsules contain the following non-medicinal ingredients: calcium chloride dehydrate; gelatin, hypromellose; iron oxide black; iron oxide yellow; L-leucine, microcrystalline cellulose; shellac glaze; 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 Constella Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Constella approved?

 

Health Canada considers that the benefit/risk profile of Constella is favourable for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

Chronic constipation is a functional bowel disorder characterized by recurrent symptoms, including infrequent, painful defecation, hard stools requiring straining to pass, and a sense of incomplete evacuation, as well as abdominal symptoms. Chronic constipation is estimated to affect between 12% and 19% of North Americans, with a higher prevalence in women than in men and increases with age. Irritable bowel syndrome (IBS), another functional bowel disorder, is characterized by abdominal pain or abdominal discomfort associated with altered defecation, and is associated with deterioration in quality of life. Irritable bowel syndrome is a common condition, with an estimated prevalence of 10% to 15% in Western countries, with a higher prevalence in women than men. One of the subtypes of IBS is IBS-C where the altered defecation pattern is constipation. Currently, over-the-counter fibre supplements, laxatives, enemas, and suppositories are frequently recommended to treat chronic constipation and irritable bowel syndrome with constipation (IBS-C), but these are indicated only for the relief of occasional constipation. Hence, limitations of currently available treatments highlight the need for alternative, well-tolerated, and more-effective therapies that can be used long-term.

Linaclotide, the medical ingredient of Constella, is a minimally absorbed 14-amino-acid peptide that acts locally at the lumenal surface of the intestinal epithelium to stimulate guanylate cyclase subtype C (GC-C). By activating GC-C, orally administered linaclotide has been found to increase intestinal fluid secretion and intestinal transit, and to decrease visceral pain.

Efficacy of Constella in treating irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) have been demonstrated through 13 clinical studies, including 4,370 patients and 75 healthy subjects who received at least one dose of Constella. Results from these studies have shown that Constella is effective in the treatment of these conditions. When compared to placebo, Constella was statistically significantly superior to placebo on all primary and secondary endpoints.

No safety issues were identified from toxicology studies in animals except for abnormal/loose/watery faeces in monkeys. Diarrhea was identified in clinical studies as the major safety concern. A risk management plan (RMP) was submitted for diarrhea. 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 incidence and type of adverse events were comparable between placebo and Constella except for diarrhea which occurred more frequently with Constella than with placebo. During the clinical studies, there were no serious adverse events or deaths that were assessed as related to Constella. The safety of Constella has been evaluated in long-term safety studies for a period of up to 78 weeks. No new safety issues were identified during these studies which demonstrated that Constella can be used safely as a chronic treatment for CIC and IBS-C.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

In conclusion, the benefit/risk ratio of this product is considered acceptable. The 145 µg capsule of linaclotide was recommended for the treatment of CIC in adult patients and the 290 µg capsule of linaclotide was recommended for the treatment of IBS-C in adult patients.

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 Constella?

 

Submission Milestones: Constella

Submission Milestone Date
Pre-submission meeting: 2012-10-11
Submission filed: 2012-12-14
Screening  
Screening Acceptance Letter issued: 2013-02-06
Review  
Quality Evaluation complete: 2013-11-13
Clinical Evaluation complete: 2013-11-26
Biostatistics Evaluation complete: 2013-06-12
Labelling Review complete: 2013-11-26
Notice of Compliance (NOC) issued by Director General 2013-12-02

 

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 Constella?

 

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Constella is found above.

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

Irritable bowel syndrome (IBS) is a functional bowel disorder in which abdominal pain and discomfort are associated with altered defecation. The etiology and pathophysiology are poorly understood and appear to be multifactorial, resulting from a combination of visceral hypersensitivity, alteration in gastrointestinal (GI) motility, and psychosocial factors.

Chronic idiopathic constipation (CIC) is a functional GI disorder. Patients with CIC report multiple bowel and abdominal symptoms including straining, gas, hard stools, abdominal discomfort, infrequent bowel movements, bloating, a sense of incomplete evacuation, and abdominal pain.

Linaclotide, a synthetic 14-amino acid peptide, is a potent and selective guanylate cyclase-C (GC-C) agonist with visceral analgesic and secretory activities. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP results in increased intestinal fluid secretion and accelerated transit. Linaclotide has been shown to both accelerate GI transit and reduce intestinal pain.

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

Clinical Efficacy

Irritable Bowel Syndrome with Constipation

The efficacy of Constella (linaclotide) for the treatment of irritable bowel syndrome with constipation (IBS-C) was established in two double-blind, placebo-controlled, randomized, multicentre studies in adult patients (Trials 1 and 2). A total of 800 patients in Trial 1 and 804 patients in Trial 2 received treatment with Constella 290 µg or placebo once daily, and were evaluated for efficacy. In the two pivotal trials, 77% of patients were White, 19% were Black, and 12% were Hispanic.

All patients met Rome II criteria for IBS and were required, during the 2-week baseline period, to meet the following criteria:

  • a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale;
  • less than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use]; and
  • less than or equal to 5 SBMs per week.

The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take bismuth, prokinetic agents, or other drugs to treat IBS-C including laxatives (except for bisacodyl, the protocol-specified rescue medication).

The four primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment. For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint.

For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week.

Constella showed a statistically significant difference from placebo for each of the 4 primary efficacy endpoints. Constella also showed a statistically significant difference from placebo for each of the 10 secondary efficacy endpoints. Differences in Constella versus (vs.) placebo were observed within the first week of dosing and were sustained over the 26-week treatment period. Additional efficacy endpoints supported the results observed for the primary and secondary efficacy endpoints.

Overall, Constella showed statistically significant improvement in bowel habits (including SBMs, CSBMs, stool consistency, and straining) and abdominal symptoms (including abdominal pain, bloating, abdominal discomfort, and percent of abdominal pain-free days) during the 26-week treatment period in patients with IBS-C.

In conclusion, data show that Constella 290 µg administered orally once daily for a period up to 26 weeks is an effective and safe treatment of signs and symptoms of IBS-C.

Chronic Idiopathic Constipation

The efficacy of Constella for the treatment of chronic idiopathic constipation (CIC) was established in two double-blind, placebo-controlled, randomized, multicentre studies in adult patients (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 received treatment with the recommended 145 µg dose of Constella, the 290 µg dose of Constella, or placebo once daily, and were evaluated for efficacy. In the two pivotal trials, 76% of patients were White, 22% were Black, and 10% were Hispanic.

All patients met modified Rome II criteria for functional constipation. Modified Rome II criteria were less than 3 spontaneous bowel movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months:

  • Straining during greater than 25% of bowel movements;
  • Lumpy or hard stools during greater than 25% of bowel movements;
  • Sensation of incomplete evacuation during greater than 25% of bowel movements.

Patients were also required to have less than 3 complete spontaneous bowel movements (CSBMs) per week and less than or equal to 6 SBMs per week during a 2-week baseline period. Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment.

The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take bismuth, prokinetic agents, or other drugs to treat chronic constipation including laxatives (except for bisacodyl, the protocol-specified rescue medication).

The primary efficacy was assessed using overall responder analysis and the secondary endpoints were assessed using change-from-baseline analyses. The primary efficacy endpoint was the proportion (%) of patients who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period (termed a 12-week overall responder).

Constella showed a statistically significant improvement compared with placebo for the primary efficacy endpoint, 12-week CSBM overall responder, at both the 290 and 145 µg/day doses with no incremental benefit of the 290 µg dose over the 145 µg dose. The odds of a Constella patient being a 12-week CSBM overall responder were approximately 3 to 4 times those of a placebo patient.

Constella showed a statistically significant improvement compared with placebo for each of the secondary efficacy endpoints at both the 290 and 145 µg/day doses. The results were observed within the first week, often on the first day, of dosing and were sustained over the 12-week treatment period with no incremental benefit of the 290 µg dose over the 145 µg dose.

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

Clinical Safety

Irritable Bowel Syndrome with Constipation

The Safety Population in placebo-controlled trials consisted of 807 patients in the Constella group and 798 patients in the placebo group.

A total of 491 patients (60.8%) in the Constella group and 438 patients (54.9%) in the placebo group experienced at least 1 treatment-emergent adverse events (TEAEs) during the Treatment Periods. In general, there were few noteworthy differences between the Constella and placebo groups with regard to the numbers of patients who reported specific TEAEs. The most prominent exception was diarrhea, the most common TEAE observed during the trial; diarrhea was reported by 160 (19.8%) of 807 Constella patients and 24 (3.0%) of 798 placebo patients.

In terms of severity of adverse events, the Gastrointestinal Disorders System Organ Class had the highest incidence of patients with severe TEAEs, with a total of 30 patients (3.7%) in the Constella group and 14 patients (1.8%) in the placebo group experiencing severe Gastrointestinal Disorder TEAEs. Sixteen patients (2.0%) in the Constella group experienced severe diarrhea; one patient (0.1%) in the placebo group experienced severe diarrhea.

Serious adverse events (SAEs) were reported by fewer patients in the Constella group (6 patients; 0.7%) than in the placebo group (9 patients; 1.1%). There were no reported SAEs of diarrhea.

No deaths were reported amongst the randomized patients in these trials.

Chronic Idiopathic Constipation (CIC)

As with the IBS-C patient population, the safety of Constella in the CIC patient population was comparable to the safety of placebo except for diarrhea, abdominal pain and abdominal distension where the proportion of patients with diarrhea was higher in the Constella dose groups than placebo (= 1% difference). The incidence of adverse events was not dose-dependent but the severity of adverse events seemed to be dose-dependent with the 290 µg dose having the higher proportion of patients with severe treatment-emergent adverse events.

In conclusion, Constella safety (in both CIC and IBS-C) was comparable to the safety of placebo except for diarrhea which occurred more often in Constella treated patients than in placebo-treated patients. Diarrhea was included in a risk management plan (RMP) for linaclotide as an important identified risk.

No serious adverse events or deaths were assessed as being related to Constella treatment.

Long-term safety studies did not identify any new safety concerns. Diarrhea was still the most reported adverse event and the main reason for treatment discontinuation. It was also noted that a reduction in linaclotide dose from 290 µg to 145 µg seemed to enable patients, who experienced adverse events that would have led to discontinuation, to remain in the study when they might otherwise have withdrawn.

Appropriate warnings and precautions are in place in the approved Constella Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Numerous pharmacology and pharmacokinetic studies were conducted in the non-clinical assessment.

The toxicology studies revealed findings consistent with the exaggerated pharmacology that was restricted to the site of action in the intestinal tract of mice and monkeys. Linaclotide showed poor bioavailability and there was no evidence of any direct systemic effects, only those secondary to adverse effects on the intestinal tract that caused morbidity or mortality. The nonclinical program of studies was considered complete with no outstanding toxicology issues.

Based on the non-clinical data, there did not appear to be any undesirable pharmacology and/or pharmacokinetic properties that may impact human safety.

For more information, refer to the Constella 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 Constella 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 12-18 months for 145 µg capsules and the proposed shelf-life of 18-24 months for 290 µg capsules (dependant on the packaging configuration) when stored between 15oC and 25oC are considered acceptable.

The drug substance is mixed with other excipients to form a solution. The active solution is then sprayed onto microcrystalline cellulose beads, dried and sieved. The active-coated beads are then encapsulated into hard gelatin capsules and packaged.

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

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

Excipients are not of animal origin and have no potential of bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) impacts. The capsule shells are manufactured from bovine gelatin in full compliance with all applicable pharmaceutical regulatory statutes.

 

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