Summary Basis of Decision for Trulance

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 Trulance is located below.

Recent Activity for Trulance

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.

The following table describes post-authorization activity for Trulance, a product which contains the medicinal ingredient plecanatide. 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.

 

Updated: 2024-06-18

Drug Identification Number (DIN):

DIN 02493012 – 3 mg plecanatide, tablet, oral administration

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

Drug product (DIN 02493012) market notification

Not applicable

Date of first sale: 2022-01-12

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

SNDS # 252946

2021-05-19

Cancellation Letter Received 2021-07-02

Submission filed as a Level I – Supplement for a change in the specification for the drug substance tests and acceptance criteria. The change was not in scope of an SNDS but was considered to be a Level III change. The sponsor cancelled the submission administratively.

NDS # 249257

2021-02-05

Issued NOC 2021-03-22

Submission filed to transfer ownership of the drug product from Cipher Pharmaceuticals Inc. to Bausch Health, Canada Inc. An NOC was issued.

NDS # 215288

2018-09-20

Issued NOC 2019-10-10

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Trulance

Date SBD issued: 2020-01-27

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

Plecanatide

Drug Identification Number (DIN):

  • DIN 02493012 - 3 mg tablet, oral administration

Cipher Pharmaceuticals Inc.

New Drug Submission Control Number: 215288

 

On October 10, 2019, Health Canada issued a Notice of Compliance to Cipher Pharmaceuticals Inc. for the drug product Trulance.

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 Trulance is favourable for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

 

1 What was approved?

 

Trulance, a guanylate cyclase-C agonist, was authorized for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

The safety and efficacy of Trulance in pediatric patients between the ages of 6 and 18 years have not been established. Trulance is contraindicated in pediatric patients less than 6 years of age.

Of the 1,456 patients in placebo-controlled clinical studies of Trulance, 114 (7.8%) were 65 years of age and over. The clinical studies did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from patients 18 years to less than 65 years of age.

Trulance is contraindicated for

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
  • Patients less than 6 years of age due to the risk of serious dehydration.
  • Patients with known or suspected mechanical gastrointestinal obstruction.

Trulance 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.

Trulance (3 mg plecanatide) is presented as a tablet. In addition to the medicinal ingredient, plecanatide, the tablet contains magnesium stearate and microcrystalline cellulose.

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

 

2 Why was Trulance approved?

 

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

Irritable bowel syndrome (IBS) is characterized by recurrent episodes of abdominal pain and discomfort with associated alterations in bowel habits. The altered bowel habits may include diarrhea (IBS-D), constipation (IBS-C), or a mixed pattern (IBS-M) of diarrhea and constipation. Abdominal discomfort or pain is a symptom required for the diagnosis of IBS, and the predominant abnormal bowel pattern serves as the basis for subtyping the condition as diarrhea predominant, constipation predominant, or mixed IBS.

For IBS-C, treatment options include linaclotide, osmotic laxatives, and-cognitive behavioral therapy and hypnotherapy to improve symptoms.

The active ingredient of Trulance, plecanatide, is a structural analog of human uroguanylin, and similarly to uroguanylin, is a potent and selective guanylate cyclase-C agonist with visceral analgesic and secretory activities.

Trulance has been shown to be efficacious in adult patients with IBS-C. The market authorization was based on two pivotal Phase III, randomized, multicentre, double-blind, placebo-controlled studies, Study SP304203-04 and Study SP304203-05. Adult patients aged 18 to 85 years (inclusive) with IBS-C, as defined by Rome III criteria, were included in the study population.

The primary efficacy endpoint in both pivotal studies was the percentage of overall responders defined as patients who were abdominal pain intensity weekly responders and complete spontaneous bowel movement (CSBM) weekly responders in the same week for at least 6 out of the first 12 weeks of treatment.

  • An abdominal pain intensity weekly responder was defined as a patient who experienced a decrease in the weekly average IBS-related daily abdominal pain severity score of at least 30% compared with baseline weekly average.
  • A CSBM responder was defined as a patient who experienced an increase of at least one CSBM per week from baseline.

In Study SP304203-04, the overall responder rate was significantly better in both the Trulance 3 mg treatment arm and the Trulance 6 mg treatment arm (30.2% and 29.5%, respectively) compared with placebo (17.8%). The effect was apparent as early as Week 1. Most of the key secondary efficacy endpoints supported the primary efficacy endpoint.

The percentage of abdominal pain responders for at least 6 out of the first 12 weeks of treatment was statistically significantly higher in both of the Trulance treatment arms compared with placebo (41.3%, 44.7% and 31.6% for Trulance 3 mg, Trulance 6 mg, and for placebo, respectively). The number and percentage of stool frequency responders for at least 6 out of the first 12 weeks of treatment were also statistically significantly higher in both Trulance treatment arms compared with placebo (48.1%, 45%, and 35.0% for Trulance 3 mg, Trulance 6 mg, and placebo, respectively). The treatment difference between Trulance 3 mg and placebo was higher for the stool frequency component than for the abdominal pain component.

In Study SP304203-05, the overall responder rate was significantly higher in both Trulance treatment groups compared with placebo (21.5%, 24.0% and 14.2% for Trulance 3 mg, Trulance 6 mg, and for placebo, respectively). The response was evident as early as Week 1. Most of the key secondary efficacy endpoints supported the primary efficacy endpoint.

The percentages of abdominal pain responders for at least 6 out of the first 12 weeks of treatment were statistically significantly higher in both of the Trulance treatment arms compared with placebo (32.6%, 34.0% and 23.2% for Trulance 3 mg, Trulance 6 mg, and placebo, respectively). The percentages of stool frequency responders for at least 6 out of the first 12 weeks of treatment were also higher in both Trulance treatment arms compared with placebo (34.2%, 39.1%, and 28.0% for Trulance 3 mg, Trulance 6 mg; and placebo, respectively). The treatment difference between Trulance 3 mg and placebo was higher for the abdominal pain component than that for the stool frequency component.

Overall, the efficacy data in both pivotal studies were supportive of the proposed indication for Trulance 3 mg. The Trulance 6 mg dosage did not demonstrate additional treatment benefit over the 3 mg dose; therefore, the dosage of Trulance 6 mg once daily is not recommended in IBS-C. Clinical studies of Trulance did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from patients 18 years to less than 65 years of age.

In the pooled data from both pivotal studies, the most frequently reported adverse event (AE) in patients treated with Trulance (3 mg and 6 mg) was diarrhea (4.1%). Other AEs reported in at least 1% of either active treatment group included headache, nausea, influenza, nasopharyngitis, urinary tract infection, upper respiratory tract infection and dizziness. Of these AEs, diarrhea occurred more frequently in patients treated with Trulance compared with placebo (4.1% versus [vs.] 1.0%). The most frequently reported study-drug-related AEs in patients treated with Trulance were diarrhea and nausea. The incidence of these events was higher in patients treated with Trulance than placebo (diarrhea 3.7% vs. 0.5%; nausea 1.0% vs. 0.5%, respectively), but was similar between the 3 mg and 6 mg Trulance arms (diarrhea 3.9% and 3.6%, respectively; nausea 1.1% and 0.8%, respectively). The incidence of severe diarrhea was higher in the combined Trulance arms than in the placebo arm (0.7% vs. 0.1%), and was also higher in the 3 mg Trulance arm than in the 6 mg Trulance arm (1.0% vs. 0.4%). The risk of severe diarrhea is mitigated through labelling.

When Trulance was taken with food, there was a greater incidence of mild, moderate and severe cramping compared to the fasted state. Patients experiencing gastrointestinal adverse events should be advised to avoid high-fat, high-calorie meals near the time of dosing.

Studies in juvenile mice suggested that very young mice exhibited increased sensitivity to the medicinal ingredient of Trulance, plecanatide, compared with young adult or slightly older juvenile animals. Mortality in juvenile mice was addressed in the relevant sections of the Trulance Product Monograph. Trulance is contraindicated in patients less than 6 years of age due to the risk of serious dehydration based on the data from the juvenile toxicity studies in mice.

The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Trulance:

  • Trulance is contraindicated in patients less than 6 years of age.
  • Avoid use of Trulance in patients between 6 years and 18 years of age.

A Risk Management Plan (RMP) for Trulance was submitted by Cipher Pharmaceuticals 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 Trulance 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 Trulance was accepted.

Overall, the benefit-risk is favourable for Trulance (3 mg dose) for the treatment of IBS-C in adults. Appropriate warnings and precautions are in place in the Trulance 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 Trulance?

 

Submission Milestones: Trulance

Submission Milestone Date
Submission filed: 2018-09-20
Screening  
Screening Deficiency Notice issued: 2018-11-08
Response filed: 2018-11-21
Screening Acceptance Letter issued: 2018-12-14
Review  
Review of Risk Management Plan complete: 2019-07-11
Quality Evaluation complete: 2019-10-03
Clinical/Medical Evaluation complete: 2019-10-07
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2019-10-07
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate: 2019-10-10

 

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

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 Trulance?

 

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's life cycle.

The PAAT for Trulance 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

The medicinal ingredient of Trulance, plecanatide, is a potent and selective guanylate cyclase-C (GC-C) agonist with visceral analgesic and secretory activities. Plecanatide binds to GC-C receptors in a pH-dependent manner and is more active at slightly acidic pH levels. Both plecanatide 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 of intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies.

Plecanatide is minimally absorbed with negligible systemic availability following oral administration. Concentrations of plecanatide and its active metabolite in plasma are below the limit of quantitation after an oral 3 mg dose of Trulance. Plecanatide is expected to be minimally distributed in tissues.

The clinical pharmacological data support the use of Trulance for the specified indication.

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

Clinical Efficacy

The efficacy of Trulance (plecanatide) 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: Study SP304203-04 and SP304203-05. In the Intention-to-Treat (ITT) population, a total of 699 patients (Study SP304203-04) and 754 patients (Study SP304203-05) received treatment with Trulance (3 mg or 6 mg) once daily and were evaluated for efficacy. In clinical studies, study medication was administered without regard to food intake. Demographics for these studies included an overall mean age of 44 years (range 18 to 83 years), 74% female, 73% white, and 22% black.

All patients met the Rome III criteria for IBS for the last 3 months prior to the screening visit, with symptom onset for at least 6 months prior to diagnosis. Diagnosis required recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with two or more of the following:

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

The efficacy of Trulance was assessed using an overall responder analysis based on abdominal pain intensity and a stool frequency responder (Complete Spontaneous Bowel Movement [CSBM) endpoint).

Patients also met the IBS-C differentiation criteria for constipation, characterized by a stool pattern in which ≥25% of defecations were hard or lumpy stools (Bristol Stool Form Scale [BSFS] score of 1 or 2) and ≤25% of reported spontaneous bowel movements (occurring without the use of laxatives) were loose or watery stools of a BSFS score of 6 or 7.

The primary efficacy endpoint in both pivotal studies was the percentage of overall responders defined as patients who were abdominal pain intensity weekly responders and CSBM weekly responders in the same week for at least 6 out of the first 12 weeks of treatment.

  • An abdominal pain intensity weekly responder was defined as a patient who experienced a decrease in the weekly average IBS-related daily abdominal pain severity score of at least 30% compared with baseline weekly average.
  • A CSBM responder was defined as a patient who experienced an increase of at least one CSBM per week from baseline.

In Study SP304203-04, the overall responder rate was significantly better in both the Trulance 3 mg treatment arm and the Trulance 6 mg treatment arm (30.2% and 29.5%, respectively) compared with placebo (17.8%). The effect was apparent as early as Week 1, and reached its maximum by Week 5 with no significant change thereafter. After discontinuation the reverse to baseline values was complete by Week 14.

The percentage of abdominal pain responders for at least 6 out of the first 12 weeks of treatment was statistically significantly higher in both of the Trulance treatment arms compared with placebo (41.3%, 44.7% and 31.6% for Trulance 3 mg, Trulance 6 mg, and for placebo, respectively). The percentages of stool frequency responders for at least 6 out of the first 12 weeks of treatment were also statistically significantly higher in both Trulance treatment arms compared with placebo (48.1%, 45%, and 35.0% for Trulance 3 mg, Trulance 6 mg; and placebo, respectively). The treatment difference between Trulance 3 mg and placebo was higher for the stool frequency component than that for the abdominal pain component.

In Study SP304203-05, the overall responder rate was significantly higher in both Trulance treatment groups compared with placebo (21.5%, 24.0% and 14.2% for Trulance 3 mg, Trulance 6 mg, and for placebo, respectively). The response was evident as early as Week 1, and steadily increasing thereafter up to Week 12.

The percentages of abdominal pain responders for at least 6 out of the first 12 weeks of treatment were statistically significantly higher in both of the Trulance treatment arms compared with placebo (32.6%, 34.0% and 23.2% for Trulance 3 mg, Trulance 6 mg, and placebo, respectively). The percentages of stool frequency responders for at least 6 out of the first 12 weeks of treatment were also higher in both Trulance treatment arms compared with placebo (34.2%, 39.1%, and 28.0% for Trulance 3 mg, Trulance 6 mg; and placebo, respectively). The treatment difference between Trulance 3 mg and placebo was higher for the abdominal pain component than that for the stool frequency component.

Three key secondary efficacy endpoints were assessed: sustained efficacy responder, change from baseline in stool consistency, and change from baseline in severity of straining with bowel movements. Sustained efficacy responders were patients who were weekly responders, i.e., met the criteria for abdominal pain intensity and CSBM responder in the same week for at least 6 of the 12 treatment weeks and at least 2 of the 4 treatment weeks in Month 3 of treatment.

In both studies, patients treated with Trulance resulted in a significantly greater percentage of sustained efficacy responders. Trulance demonstrated significant improvements in stool consistency and straining scores compared with placebo in both studies. For each study, significant differences from placebo in mean change from baseline began at Week 1 and continued throughout the treatment period.

Overall, the efficacy data in both pivotal studies were supportive for the use of Trulance 3 mg for the proposed indication. The Trulance 6 mg dosage did not demonstrate additional treatment benefit over the 3 mg dose; therefore, the dosage of Trulance 6 mg once daily is not recommended in IBS-C. Clinical studies of TRULANCE did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from patients 18 years to less than 65 years of age.

Indication

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

  • Trulance (plecanatide) is indicated for treatment of irritable bowel syndrome with constipation (IBS-C) in adults

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

Clinical Safety

The clinical safety of Trulance in patients with irritable bowel syndrome with constipation (IBS-C) was evaluated in two pivotal Phase III, placebo-controlled studies (Studies SP304203-04 and SP304203-05, see Clinical Efficacy) involving a total of 1,879 patients (1,255 patients treated with Trulance and 624 treated with placebo). A total of 17 patients (0.8%) experienced 20 serious adverse events (SAEs), with the incidence being similar in patients treated with placebo (0.8%), 3 mg Trulance (0.8%) and 6 mg Trulance (0.7%). Increased levels of transaminases were reported in 2 patients (0.1% for patients treated with Trulance, 0% for placebo). All other SAEs were reported as <0.1% in the combined Trulance group. None of SAEs in the placebo-controlled studies were considered related to the study drug.

In the pooled data from the pivotal studies, the most frequently reported adverse event (AE) in patients treated with Trulance was diarrhea (4.1%). Other AEs reported in at least 1% of either active treatment group included headache, nausea, influenza, nasopharyngitis, urinary tract infection, upper respiratory tract infection and dizziness. Of these events, diarrhea occurred more frequently in the patients treated with Trulance than those treated with placebo (4.1% vs. 1.0%).

The most frequently reported study drug-related AEs in the combined Trulance group were diarrhea and nausea. The incidence of these events was higher in the combined Trulance group than in the placebo group (3.7% versus 0.5% for diarrhea; 1.0% versus 0.5% for nausea), but was similar between the 3 mg and 6 mg Trulance groups (3.9% and 3.6%, respectively, for diarrhea; 1.1% and 0.8%, respectively, for nausea).

Risk of severe dehydration in pediatric patients less than 6 years of age was identified in juvenile animal studies. Trulance is contraindicated in patients less than 6 years of age. Lack of clinical safety and efficacy data exist for patients between 6 and 18 years of age.

The following warnings have been included in a Serious Warnings and Precautions box in the Trulance Product Monograph:

  • Trulance is contraindicated in patients less than 6 years of age.
  • Avoid use of Trulance in patients between 6 years and 18 years of age.

Drug exposure to breast-fed infants might lead to potential serious complications. The risk is mitigated through labelling.

Risk of serious diarrhea is another safety concern as diarrhea was reported as the most frequent AE in the Phase III clinical studies. The risk is mitigated through proper labelling.

Risk of lower gastrointestinal hemorrhage was identified in post-marketing studies with Trulance. This risk is mitigated through labelling.

Overall, the safety profile of Trulance is considered favourable for the treatment of IBS-C in adults. Appropriate warnings and precautions are in place in the approved Trulance Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical studies were conducted with plecanatide, the medicinal ingredient of Trulance. The pivotal toxicology studies included chronic toxicity studies in mice and monkeys, carcinogenicity studies in mice and rats, and reproductive and developmental toxicity studies in mice and rabbits. The test results provided substantial margins of safety compared with the recommended dose in humans of 3 mg/day for the commercial drug product. Animals in these studies exhibited ample systemic exposure to plecanatide, in contrast with studies in patients in which plasma levels were below the lower limit of quantitation of the bioanalytical assay (hence safety margins were determined based on dose rather than exposure). In addition, plecanatide exhibited no potential for genetic toxicity in a standard battery of tests and was not carcinogenic in long-term rat and mouse carcinogenicity studies.

Studies in juvenile mice suggest that very young mice exhibit increased sensitivity to plecanatide compared with young adult or slightly older juvenile animals. Mortality in juvenile mice was addressed in the relevant sections of the Trulance Product Monograph. Trulance is also contraindicated in patients less than 6 years of age due to the risk of serious dehydration based on the data from the juvenile toxicity studies in mice.

Overall, the toxicology data support the use of Trulance for the proposed indication.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Trulance Product Monograph. In view of the intended use of Trulance, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Trulance 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 Trulance 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 36 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 (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

No excipients of human or animal origin are used in the Trulance tablets. The magnesium stearate has been certified by the supplier to be of vegetable origin.

 

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