Summary Basis of Decision for Mar-Trientine
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Mar-Trientine is located below.
Recent Activity for Mar-Trientine
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.
The following table describes post-authorization activity for Mar-Trientine, a product which contains the medicinal ingredient trientine hydrochloride. 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.
Updated: 2023-07-07
Drug Identification Number (DIN):
DIN 02504855 - 250 mg trientine hydrochloride, capsule, oral administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02504855) market notification | Not applicable | Date of first sale: 2020-11-10 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 228708 | 2019-08-07 |
Issued NOC 2020-09-14 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Mar-Trientine
Date SBD issued: 2020-11-04
The following information relates to the New Drug Submission for Mar-Trientine.
Trientine hydrochloride
Drug Identification Number (DIN):
DIN 02504855 - 250 mg trientine hydrochloride, capsule, oral administration
Marcan Pharmaceuticals Inc.
New Drug Submission Control Number: 228708
On September 14, 2020, Health Canada issued a Notice of Compliance to Marcan Pharmaceuticals Inc. for the drug product Mar-Trientine.
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 Mar-Trientine is favourable for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
1 What was approved?
Mar-Trientine (trientine hydrochloride), a copper-chelating agent, was authorized for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of Mar-Trientine in pediatric patients younger than 5 years of age have not been established. Therefore, Health Canada has not authorized an indication for children younger than 5 years of age.
Clinical studies of trientine hydrochloride did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than patients younger than 65 years of age.
The use of Mar-Trientine is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Mar-Trientine 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.
Mar-Trientine (250 mg trientine hydrochloride) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains black ink, colloidal silicon dioxide, gelatin, iron oxide red, iron oxide yellow, sodium lauryl sulphate, stearic acid, 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 Mar-Trientine Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Mar-Trientine approved?
Health Canada considers that the benefit-harm-uncertainty profile of Mar-Trientine is favourable for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
Wilson's disease, also known as hepatolenticular degeneration, is a serious, progressive, autosomal recessive disorder that results in pathological copper accumulation, primarily in the liver and brain. If left untreated, Wilson's disease progresses to a fatal outcome.
The estimated prevalence of Wilson's disease worldwide is approximately 1 in 30,000 live births. The signs and symptoms of Wilson's disease generally first appear between 5 and 35 years of age. Clinical features at presentation vary widely. In about 40% to 50% of patients with Wilson's disease, hepatic symptoms are the initial clinical manifestation, especially if the disease manifests in the first decade of life. Hepatic symptoms may precede neurologic manifestations by as much as 10 years. Wilson's disease may also lead to ophthalmological abnormalities, including the presence of Kayser-Fleischer rings, which are found in 95% of patients who have neurologic symptoms, and more than 50% of patients without neurologic symptomatology. Prognosis for survival depends on the severity of liver and neurologic disease, and compliance with drug treatment.
The treatment of Wilson's disease includes penicillamine, a copper-chelating agent. However, approximately 30% of patients cannot tolerate penicillamine therapy due to the occurrence of serious adverse reactions, including, but not limited to, hypersensitivity reactions, hematologic abnormalities, nephritis, drug-induced lupus erythematosus, and various dermatologic manifestations.
Trientine hydrochloride, the medicinal ingredient in Mar-Trientine, is a copper-chelating agent. It aids in the elimination of copper from the body by forming a stable complex that is readily excreted by the kidneys. Trientine hydrochloride may also chelate copper in the intestinal tract, and thus inhibit copper absorption. Trientine has been authorized as a copper-chelating agent in Europe and the United States since 1985.
In accordance with the conditions and requirements set out in Health Canada's Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience), the sponsor provided evidence from the medical literature and market experience demonstrating the effectiveness of trientine hydrochloride in the treatment of Wilson's disease in patients who are intolerant to penicillamine. Results from across the studies were consistent, showing most patients responding well to trientine hydrochloride when it was used as a second-line therapy in patients who failed or were unable to tolerate penicillamine as first-line treatment. The sponsor also provided evidence that the product used in studies reported in the literature (i.e., the reference product) is representative of Mar-Trientine, by submitting the results of a comparative bioavailability study, which compared Mar-Tientine and Syprine (authorized in the United States), in healthy volunteers under fasting conditions.
Pivotal clinical data were derived from a published large retrospective cohort study, which evaluated the clinical response to chelator-based treatment of 380 patients with Wilson's disease from tertiary care centres in Central Europe and 25 additional patients from the EUROWILSON registry. In total, 467 chelator-based treatment regimens with a duration of more than six months were identified and analyzed. Of these, 326 were penicillamine treatment regimens and 141 were trientine treatment regimens. Of the 326 penicillamine treatment regimens, 294 were first-line therapies, whereas the majority of the trientine monotherapies (105 of 141) were second-line therapies. None of the patients received penicillamine and trientine simultaneously at any time.
Hepatic and neurologic outcomes were assessed at 6, 12, 24, 36, and 48 months following initiation of treatment. The outcomes were stratified by first-line and second-line treatment. Hepatic outcomes were assessed using clinical symptoms as well as liver function tests. Neurologic outcomes were assessed by the treating physician. Both hepatic and neurologic outcomes were categorized as unchanged, improved but not normal, improved to normal, deteriorated or asymptomatic.
This study demonstrated that 68.9% of patients with hepatic symptoms at baseline, who were intolerant to penicillamine as first-line therapy, had improvement in their hepatic status following trientine treatment as second-line therapy. Additionally, 51.0% of patients with neurologic disease at baseline, who were unable to tolerate penicillamine as first-line therapy, showed improvement in neurologic disease when treated with trientine as second-line therapy.
Trientine hydrochloride generally appears to be a well-tolerated agent. The most common adverse event seen soon after initiation of trientine treatment was self-limiting nausea. Occasional occurrences of skin rash and anemia have also been reported. A reduction in serum iron levels has also been observed. However, a worsening of neurologic symptoms was seen when initiating trientine in patients with pre-existing neurologic and/or psychiatric symptoms in 15.7% of patients. While this may have been due in part to the lack of efficacy in some cases, the patients who had already sustained damage to the blood-brain barrier from long-term exposure to excessive serum copper are generally thought to be especially vulnerable to worsening neurologic effects due to further transient elevation of serum copper levels following its liberation from central stores soon after initiation of copper chelation therapy. Although a paucity of information is available, such deterioration may be irreversible. Therefore, Mar-Trientine is recommended to be initiated only by physicians experienced in the management of Wilson's disease and who can individualize the benefit-risk assessment of initiating Mar-Trientine. A Serious Warnings and Precautions box has been included in the Mar-Trientine Product Monograph to highlight this potential serious adverse reaction.
A Risk Management Plan (RMP) for Mar-Trientine was submitted by Marcan Pharmaceuticals Inc. to Health Canada. Upon revisions, 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 Mar-Trientine 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 Mar-Trientine was accepted.
Overall, the benefit-harm-uncertainty profile of Mar-Trientine is considered favourable for use by qualified physicians for the treatment of Wilson's disease in patients who are intolerant to penicillamine. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Mar-Trientine 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 Mar-Trientine?
The New Drug Submission for Mar-Trientine was filed as a submission that substantially relies on literature and market experience, in accordance with the conditions and requirements set out in Health Canada's Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). Although a submission relying on third-party data may differ in the source of information used to support safety and effectiveness, it has to meet the same standards for approval as a conventional submission (that contains complete study reports of clinical safety and efficacy), i.e., to provide substantial evidence of safety and efficacy, as stipulated in the Food and Drug Regulations.
Submission Milestones: Mar-Trientine
| Submission Milestone | Date |
|---|---|
| Submission filed | 2019-08-07 |
| Screening | |
| Screening Deficiency Notice issued | 2019-09-23 |
| Response filed | 2019-10-30 |
| Screening Acceptance Letter issued | 2019-11-21 |
| Review | |
| Biopharmaceutics Evaluation complete | 2020-08-04 |
| Review of Risk Management Plan complete | 2020-08-11 |
| Quality Evaluation complete | 2020-09-03 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment | 2020-09-04 |
| Clinical/Medical Evaluation complete | 2020-09-14 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2020-09-14 |
The Canadian regulatory decision on the review of Mar-Trientine was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the European Medicines Agency (EMA) 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.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
No formal pharmacological studies have been conducted for trientine hydrochloride, the medicinal ingredient in Mar-Trientine.
Trientine hydrochloride is a copper-chelating agent that aids in the elimination of copper from the body by forming a stable complex that is readily excreted by the kidneys. Additionally, trientine hydrochloride may chelate copper in the intestinal tract, and thus inhibit copper absorption.
Based on published data, urinary copper excretion increases significantly in the first six hours following administration of trientine in healthy volunteers and patients with Wilson's disease. As urinary zinc levels and, to a lesser extent, iron levels increase in parallel with urinary trientine excretion, it is likely that absorbed trientine can also combine with zinc and iron to promote their urinary excretion.
Based on the limited submitted studies, the pharmacokinetics of trientine was found to be similar between patients with Wilson's disease and healthy volunteers, and between adult and adolescent patients with Wilson's disease. No pharmacodynamic and pharmacokinetic data are available for children under 12 years of age. A comparison of the pharmacokinetic parameters of trientine evaluated in patients with Wilson's disease and healthy volunteers suggests similarity in both the absolute values and variability. In a non-fasted state, the maximum plasma concentration of trientine is reduced, suggesting a food effect on the absorption of trientine.
While placental transfer for trientine has not been investigated, its low molecular weight suggests that fetal exposure could be expected. An evaluation of the small number of pregnancies in women with Wilson's disease suggests that trientine is reasonably safe for the fetus, particularly in comparison to taking a treatment break for the duration of the pregnancy. Claims of a teratogenic effect of copper chelation due to induction of copper deficiency have not been supported by data from human pregnancies. However, a retrospective study demonstrated an unexpectedly high number of spontaneous abortions in women with Wilson's disease using trientine during pregnancy. The study was not designed to assess causation.
There is insufficient information available to determine if trientine is excreted in human milk or if maternal milk concentrations of copper and zinc are adequate for infant development.
For further details, please refer to the Mar-Trientine Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
In accordance with the conditions and requirements set out in Health Canada's Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience), evidence of the clinical efficacy of Mar-Trientine in the treatment of Wilson's disease was obtained primarily from published references and market experience. The sponsor provided pivotal clinical data from a published large retrospective analysis, which evaluated the clinical response to chelator-based treatment of 380 patients with Wilson's disease from tertiary care centres in Central Europe and 25 additional patients from the EUROWILSON registry.
Of these 405 patients, 207 patients (51.1%) presented with hepatic symptoms only, 92 patients (22.7%) presented with neurologic symptoms only, 52 patients (12.8%) presented with hepatic and neurologic symptoms, and 54 patients (13.3%) were asymptomatic. Twenty-one patients (5.2%) presented with fulminant Wilson's disease with hepatic failure.
In line with current treatment guidelines for Wilson's disease, patients generally received initial treatment with chelation therapy, if symptomatic. Changes in treatments were common in the study dataset. In total, 467 chelator-based treatment regimens with a duration of more than six months were identified and analyzed. Of these, 326 were penicillamine treatment regimens and 141 were trientine treatment regimens. Of the 326 penicillamine treatment regimens, 294 were first-line therapies, whereas the majority of the trientine monotherapies (105 of 141) were second-line therapies. None of the patients received penicillamine and trientine simultaneously at any time.
From patient records, hepatic and neurologic outcomes were assessed at 6, 12, 24, 36, and 48 months following initiation of treatment. The outcomes were stratified by first-line and second-line treatment. Hepatic outcomes were assessed using clinical symptoms as well as liver function tests. Neurologic outcomes were assessed by the treating physician. Both hepatic and neurologic outcomes were categorized as unchanged, improved but not normal, improved to normal, deteriorated or asymptomatic.
In patients presenting with hepatic symptoms, comparable rates of improvement in hepatic status were observed between first-line penicillamine treatment (90.7%) and first-line trientine treatment (92.6%). When these chelator-based therapies were given as second-line therapy, rates of improvement were generally lower, but still comparable between treatments (75.0% for penicillamine and 68.9% for trientine). For patients with hepatic symptoms, the observed proportion of patients who maintained stable hepatic disease was comparable for penicillamine and trientine treatments in both the first-line and second-line settings. Comparable and low rates of deterioration in hepatic status were observed in patients with hepatic symptoms who received first-line treatment with penicillamine and trientine. A non-significant trend toward increased rates of hepatic deterioration was seen when trientine was used as second-line treatment, compared to second-line penicillamine treatment, although the vast majority (91.1%) of patients who received trientine as second-line treatment were observed to have no such deterioration. No worsening in hepatic status was observed for any patient who received either of the chelation monotherapy treatment regimens and who initially presented without hepatic symptoms.
With respect to neurologic outcomes in patients with Wilson's disease who had symptomatic neurologic disease at baseline, no statistically significant differences were found in the rates of improvement in neurologic status with first-line penicillamine treatment (67.5%) compared to first-line trientine treatment (55.0%), or with second-line penicillamine treatment (23.1%) versus second-line trientine treatment (51.0%). Stable neurologic disease was observed in 27.2% of first-line penicillamine treatments compared to 25.0% of first-line trientine treatments, while stable neurologic disease was reported in 69.2% of second-line penicillamine treatment regimens compared to 33.3% of second-line trientine treatments. A significantly higher rate of neurologic worsening was observed for symptomatic patients who received first-line treatment with trientine (20.0%) compared to first-line treatment with penicillamine (5.3%) (p = 0.04). The rate of neurologic worsening was not significantly different in patients treated with second-line trientine (15.7%) compared to second-line penicillamine (7.3%).
Overall, these efficacy analyses demonstrate the utility of trientine in the treatment of patients with Wilson's disease as second-line therapy in patients intolerant to penicillamine. Improvement in the hepatic status was found in 68.9% of patients presenting hepatic symptoms at baseline, while 51.0% of patients with pre-existing neurologic disease showed improvement in neurologic disease, when treated with trientine as second-line therapy.
A number of other smaller observational studies were also presented and reviewed. Results were generally consistent across studies, supporting the efficacy of trientine in the treatment of Wilson's disease when used as second-line therapy in patients who were intolerant to penicillamine.
Indication
The New Drug Submission for Mar-Trientine was filed by the sponsor with the following indication:
- Mar-Trientine (trientine hydrochloride) is indicated for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
To ensure safe and effective use of the product, Health Canada revised the proposed indication to include a caveat statement related to the initiation of treatment with Mar-Trientine. Accordingly, Health Canada approved the following indication:
- Mar-Trientine (trientine hydrochloride) is indicated for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
Mar-Trientine should only be initiated by physicians experienced in the management of Wilson's disease.
For more information, refer to the Mar-Trientine Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The sponsor provided pivotal clinical data from a published large retrospective analysis (described in Clinical Efficacy), which evaluated the clinical response to chelator-based treatment of 405 patients with Wilson's disease. Over a median follow-up period of 13.3 years, the proportion of discontinued treatment regimens for any reason was 43.6% for penicillamine treatment regimens and 25.5% for trientine treatment regimens.
Trientine hydrochloride generally appears to be a well-tolerated agent. The most common adverse event seen soon after initiation of trientine treatment was self-limiting nausea. Occasional occurrences of skin rash and anemia have also been reported. A reduction in serum iron levels has also been observed. A worsening of neurologic symptoms when initiating trientine in patients with pre-existing neurologic and/or psychiatric symptoms was seen in 15.7% of patients. Although this may have been due in part to the lack of efficacy in some cases, the patients who had already sustained damage to the blood-brain barrier from long-term exposure to excessive serum copper appeared to be especially vulnerable to worsening neurologic effects of the transient elevation of serum copper levels, when copper was liberated from central stores following initiation of copper chelation therapy. While a paucity of information is available, such deterioration may be irreversible. Therefore, Mar-Trientine is recommended to be initiated only by physicians experienced in the management of Wilson's disease and who can individualize the benefit-risk assessment of initiating Mar-Trientine. A Serious Warnings and Precautions box has been added to the Mar-Trientine Product Monograph to highlight this potential serious adverse reaction.
For more information, refer to the Mar-Trientine Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical data provided for Mar-Trientine (trientine hydrochloride) rely on literature sources. Overall, trientine is considered to have moderate acute toxicity after oral administration.
Orally administered trientine is absorbed by the plasma membrane of intestinal epithelial cells. The uptake characteristics of trientine investigated using brush-border membrane vesicles isolated from the small intestine of rats are similar to those of spermine and spermidine. These physiological polyamines may inhibit trientine uptake and their presence in the gastrointestinal tract is likely to contribute to variability in the trientine bioavailability.
Trientine is rapidly metabolized into two main acetylated metabolites, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT). The metabolite MAT contributes to the overall cupriuretic effect of trientine, but the extent of its contribution remains unknown. Trientine and its metabolites are distributed throughout most rat tissues, particularly the liver and kidneys. The plasma elimination half-life of trientine ranges from 0.5 to 2 hours. Trientine is mainly excreted in the urine in the form of its acetylated metabolites.
The main toxicological findings were consistent across different species. These encompassed reduced body weight gain, altered urinary electrolytes, low plasma copper concentrations, liver findings, and histopathological changes in the lungs, including persistent irreversible inflammation or a toxic effect on bronchoalveolar epithelial cells. In dogs, reversible underactivity, tremors, abnormal gait, limited use of limb, and prone posture were observed following administration of high levels of trientine (up to 200 mg/kg/day).
Trientine exhibited genotoxicity in several in vitro assays. However, no mutagenic activity was observed in relevant in vivo tests. Thus, the genotoxicity profile of trientine is considered to be of low concern. Carcinogenicity studies have not been conducted with trientine.
Trientine demonstrated reproductive toxicity, which was likely due to the induced copper deficiency.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Mar-Trientine Product Monograph. In view of the intended use of Mar-Trientine, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Mar-Trientine 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 Mar-Trientine 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 24 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 (ICH) limits and/or qualified from toxicological studies.
The 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 origin are used in the formulation of Mar-Trientine. The only excipient of animal origin is the gelatin component of the capsule shell. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| MAR-TRIENTINE | 02504855 | MARCAN PHARMACEUTICALS INC | TRIENTINE HYDROCHLORIDE 250 MG |