Summary Basis of Decision for Waymade-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 Waymade-Trientine is located below.
Recent Activity for Waymade-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 Waymade-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: 2023-07-12
Drug Identification Number (DIN):
DIN 02515067 – 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 02515067) market notification | Not applicable | Date of first sale: 2021-07-05 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 237287 | 2020-03-20 | Issued NOC 2021-04-20 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Waymade-Trientine
Date SBD issued: 2021-08-25
The following information relates to the New Drug Submission for Waymade-Trientine.
Trientine hydrochloride
Drug Identification Number (DIN):
- DIN 02515067 ‑ 250 mg trientine hydrochloride, capsule, oral administration
Waymade PLC
New Drug Submission Control Number: 237287
On April 20, 2021, Health Canada issued a Notice of Compliance to Waymade PLC for the drug product Waymade-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 Waymade‑Trientine is favourable for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
Waymade-Trientine should only be initiated by physicians experienced in the management of Wilson’s disease.
1 What was approved?
Waymade‑Trientine, a copper‑chelating agent, was authorized for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
Waymade‑Trientine should only be initiated by physicians experienced in the management of Wilson’s disease.
Health Canada has not authorized an indication for children younger than 5 years of age, as data are lacking to establish the safety and effectiveness of trientine hydrochloride in this subpopulation.
Clinical studies of trientine hydrochloride did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than patients younger than 65 years of age.
Waymade-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.
Waymade-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.
Waymade-Trientine (250 mg trientine hydrochloride) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains black ink, gelatin, purified water, stearic acid, sunset yellow FCF, 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 Waymade-Trientine Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Waymade-Trientine approved?
Health Canada considers that the benefit‑harm‑uncertainty profile of Waymade‑Trientine is favourable for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
Waymade‑Trientine should only be initiated by physicians experienced in the management of Wilson’s disease.
Wilson’s disease is a rare inherited disorder characterized by the accumulation of copper in the body, particularly in the liver, brain, and eyes. The first signs and symptoms of Wilson’s disease generally appear between 5 and 35 years of age, most often during the teenage years. Wilson’s disease typically presents with some combination of liver disease and neurologic and/or psychiatric issues. Initial symptoms are often non‑specific, which can delay the diagnosis.
Clinical features at presentation vary widely. Hepatic symptoms are often present during the initial clinical manifestation of the disease, particularly if this occurs within the first decade of life. This is seen in an estimated 40‑50% of patients with Wilson’s disease. In some cases, hepatic symptoms have preceded neurologic symptoms by as much as 10 years. Generally, patients with neurologic symptoms have some degree of liver disease at presentation. Wilson’s disease may also lead to ophthalmological abnormalities, including the presence of Kayser‑Fleischer rings. These are present in 95% of patients with neurologic symptoms, and in more than 50% of patients without neurologic symptoms.
The general prevalence of Wilson’s disease is estimated at 1 in 30,000 live births worldwide. As most patients are compound heterozygotes for known mutations, the genetic prevalence is higher, at approximately 1 in 7,000 live births. It has been estimated that approximately one out of 90 persons carries an abnormal copy of the ATP7B gene, which codes for a copper‑transporting P‑type ATPase enzyme.
Penicillamine, a chelating agent, is generally recommended as first‑line therapy for the treatment of Wilson’s disease. 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.
If left untreated, Wilson’s disease will typically progress to a fatal outcome. The prognosis for patients who adhere to treatment has generally been positive, even in some patients with advanced hepatic disease. However, patients who cannot tolerate penicillamine or who do not have an adequate response to it need alternative drug treatments to improve prognosis and quality of life.
Trientine hydrochloride, the medicinal ingredient in Waymade‑Trientine, is a chelating compound used for the removal of excess copper from the body, and has previously been authorized in Canada and in other jurisdictions for the treatment of Wilson’s disease. The New Drug Submission (NDS) for Waymade‑Trientine was a Submission Relying on Third‑Party Data (SRTD). Instead of original clinical data, the sponsor submitted evidence from medical literature to support the efficacy of trientine hydrochloride for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
A retrospective analysis conducted by Weiss and coauthors (2013) was identified as pivotal by the sponsor. This study evaluated the clinical response to treatment in 405 patients with Wilson’s disease, including 380 patients who were treated according to the standard of care by specialist physicians, and 25 patients registered in the EUROWILSON patient registry who received trientine monotherapy. The diagnosis of Wilson’s disease was confirmed in all patients using the Leipzig score and a mutational analysis. The data analyzed in this study were collected for a mean period of 13.3 years after the initiation of treatment for Wilson’s disease.
In line with the current treatment guidelines at the time of the study, patients who were symptomatic were initially treated with chelation therapy (either penicillamine or trientine). The data included in the analysis were based on stable drug treatment periods of at least six consecutive months. Efficacy was analysed separately for initial and subsequent treatment regimens for both penicillamine and trientine. Hepatic and neurologic outcomes were evaluated retrospectively from patient records at 6, 12, 24, 36, and 48 months following initiation of each treatment regimen. Outcome measures were stratified by first‑line and second‑line treatment use. None of the patients included in the study dataset received penicillamine and trientine concurrently at any given time.
In patients with symptomatic hepatic disease at the initiation of treatment, comparable rates of improvement in hepatic status were observed between patients receiving penicillamine or trientine as a first‑line treatment (90.7% and 92.6%, respectively), and between patients receiving penicillamine or trientine as a second‑line treatment (75.0% and 68.9%, respectively). The observed incidence of patients who maintained stable hepatic disease over the treatment period was also comparable in both the first‑line and second‑line settings between penicillamine and trientine. Deterioration in hepatic status was uncommon in patients who received penicillamine or trientine as a first‑line treatment, and its incidence was similar in both groups. In the second‑line setting, a non‑significant increase was observed in the incidence of hepatic deterioration following treatment with trientine, compared to treatment with penicillamine. However, no signs of deterioration were observed in 91.1% of patients who received trientine as a second‑line treatment. No worsening in hepatic status was observed in any patient who received either treatment regimen and who initially presented without hepatic symptoms.
In patients with symptomatic neurologic disease at the initiation of treatment, no statistically significant differences were found in the rates of improvement of neurologic status between pencillamine and trientine treatment in either the first‑line setting (67.5% and 55.0%) or second‑line setting (23.1% and 51.0%). Stable neurologic disease was observed in 27.2% of patients treated with penicillamine and 25.0% of patients treated with trientine as a first‑line therapy, and in 69.2% of patients treated with penicillamine and 33.3% of patients treated with trientine as a second‑line therapy. In the first‑line setting, a higher rate of neurologic worsening was observed in symptomatic patients who received trientine than in those who received penicillamine (20.0% and 5.3%, respectively). This difference was found to be statistically significant (p = 0.04). However, 80.0% of neurologically symptomatic patients who received trientine as a first‑line treatment did not have neurologic worsening, and showed improved or stable neurologic disease. Neurologic worsening was not significantly different between patients treated with trientine or penicillamine as a second‑line therapy (15.7% and 7.3%, respectively).
Collectively, the results of the efficacy analyses demonstrate the utility of trientine as a treatment for patients with Wilson’s disease, as a second‑line therapy for patients intolerant to penicillamine. In patients with symptomatic hepatic disease, hepatic improvement was observed in 69% of individuals given trientine as second‑line therapy (due to inadequate response or intolerance to penicillamine). In patients with symptomatic neurologic disease, an improvement in neurologic symptoms was observed in 51% of individuals given trientine as a second‑line therapy.
The clinical safety data reviewed indicate that trientine is generally a well‑tolerated agent. During a follow‑up period with a median of over 13 years, 43.6% of patients treated with penicillamine and 25.5% of patients treated with trientine discontinued treatment for any reason.
In the pivotal study dataset, 28.8% of patients treated with pencillamine and 7.1% of patients treated with trientine discontinued treatment due to adverse events, and this difference was statistically significant (p = 0.04). Self‑limiting nausea was the most common adverse event observed soon after initiation of treatment with trientine. Skin rash and anemia were also reported. Iron deficiency has also been observed with trientine administration, which is attributed to its chelating properties and may be managed through oral iron supplementation.
A Serious Warnings and Precautions box was added to the Product Monograph to highlight the risk of worsening neurologic or neurocognitive functioning, which can be irreversible. This may occur in patients with pre‑existing neurologic and/or neuropsychiatric impairment due to Wilson’s disease, and who are treated with Waymade‑Trientine, or other chelating agents. Accordingly, it is recommended that treatment with Waymade‑Trientine should only be initiated by physicians experienced in the management of Wilson’s disease.
A Risk Management Plan (RMP) for Waymade‑Trientine was submitted by Waymade PLC 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 Waymade‑Trientine Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look‑alike sound‑alike attributes, was conducted and the proposed name Waymade‑Trientine was accepted.
Waymade‑Trientine 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 Waymade‑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 Waymade-Trientine?
The New Drug Submission for Waymade‑Trientine was filed as a Submission Relying on Third‑Party Data (SRTD), according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience).
Trientine hydrochloride, the medicinal ingredient in Waymade‑Trientine, has previously received market authorization for the treatment of Wilson’s disease in several jurisdictions. In Canada, Mar‑Trientine (trientine hydrochloride) was authorized in September 2020 for the treatment of patients with Wilson’s disease who are intolerant to penicillamine. In the United States, trientine hydrochloride is marketed under the brand name Syprine, and a number of generic products (including Navinta) are also available which have an identical formulation to Waymade‑Trientine. In Europe, trientine dihydrochloride (known in North America as trientine hydrochloride) received market authorization under the name Cufence in 2019 for the treatment of Wilson’s disease in patients who are intolerant to D‑penicillamine. Another drug product, Cuprior (trientine tetrahydrochloride), has been marketed in Europe since 2017 with the same indication. In Australia, a formulation of trientine, identical to that of Waymade‑Trientine, was authorized in January 2021 for use in patients with Wilson’s disease who are intolerant to penicillamine.
Submission Milestones: Waymade-Trientine
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2019-10-02 |
| Submission filed | 2020-03-20 |
| Screening | |
| Screening Deficiency Notice issued | 2020-04-24 |
| Response filed | 2020-05-12 |
| Screening Acceptance Letter issued | 2020-06-23 |
| Review | |
| Review of Risk Management Plan complete | 2021-03-04 |
| Non-Clinical Evaluation complete | 2021-03-26 |
| Quality Evaluation complete | 2021-04-12 |
| Labelling Review complete | 2021-04-14 |
| Clinical/Medical Evaluation complete | 2021-04-16 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-04-20 |
The Canadian regulatory decision on the review of Waymade‑Trientine was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drugs Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- 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
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. Trientine hydrochloride may also chelate copper in the intestinal tract and thus, inhibit copper absorption.
Renal clearance studies were conducted with both penicillamine and trientine in patients with confirmed Wilson’s disease. Patients had received penicillamine for at least one year or had not previously received treatment with any chelating agent. The rate of urinary copper excretion increased significantly in the first six hours after the administration of trientine, depleting excess deposits of copper in the liver. A gradual increase in the rate was observed, which peaked at 18 months after the start of therapy, and approached the normal range after one or two years. The effects of trientine on renal clearance may be due to its antagonistic action on intestinal copper absorption as well as its chelating activity. Although the observed effect of trientine was smaller than that of penicillamine on a molar basis, trientine hydrochloride was determined to be effective as a cupriuretic agent in patients with Wilson’s disease. The difference in cupriuretic effect is attributed to a difference in the selectivity of the two chelating agents for different copper pools within the body.
The pharmacokinetics of trientine is similar between healthy volunteers and patients with Wilson’s disease. It is also similar between adult and adolescent patients with Wilson’s disease, although limited data are available in adolescents. There are no pharmacokinetic or pharmacodynamic data in children under 12 years of age.
Following oral administration, the absorption of trientine hydrochloride is low and variable in patients with Wilson’s disease. The time at which the maximum plasma concentration is observed (tmax) occurs 0.5 to 4 hours after dosing, and shows a biexponential decline in serum concentrations. Food further inhibits absorption, as the maximum plasma concentration (Cmax) of trientine was reduced in the non‑fasted state. Instructions are therefore included in the Waymade‑Trientine Product Monograph regarding the timing of doses in relation to food intake.
Data from healthy volunteers indicate that the central and peripheral volumes of trientine are large; however, no data pertaining to organ‑specific tissue distribution are currently available. In non‑clinical studies, wide distribution was observed in rat tissues, particularly in the liver and kidney.
Trientine undergoes acetylation to produce two major metabolites. One of these metabolites, N(1)‑acetyltriethylene tetramine (MAT), may participate in the overall activity of trientine, but the extent of its effects on copper concentrations is unknown. Trientine and its metabolites are rapidly excreted in urine, with trace amounts still detectable after 24 hours. Unabsorbed trientine is eliminated through fecal excretion.
For further details, please refer to the Waymade‑Trientine Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The New Drug Submission (NDS) for Waymade‑Trientine was a Submission Relying on Third-Party Data (SRTD). Instead of original clinical data, the sponsor submitted evidence from medical literature to support the efficacy of trientine hydrochloride (the medicinal ingredient in Waymade‑Trientine) for the treatment of patients with Wilson's disease who are intolerant to penicillamine. One study, conducted by Weiss and coauthors (2013) was considered pivotal by Health Canada. A number of observational studies were submitted as supportive evidence.
The study by Weiss was a retrospective analysis which evaluated the clinical response to treatment in patients with Wilson’s disease. In total, 405 patients were evaluated, including 380 patients who were treated according to the standard of care by specialist physicians. The remaining 25 patients were registered in the EUROWILSON patient registry, all of whom received trientine monotherapy as treatment for Wilson’s disease. The diagnosis of Wilson’s disease was confirmed in all patients using the Leipzig score and a mutational analysis.
In line with the current treatment guidelines at the time of the study, patients who were symptomatic were initially treated with chelation therapy. The choice of initial chelating agent for each patient (penicillamine or trientine) was left to the discretion of the attending physician. None of the patients included in the study dataset received penicillamine and trientine concurrently at any given time. Efficacy was determined for both first‑line and second‑line study treatments for the last available follow‑up evaluation, within a 6‑month to 48‑month follow‑up period. Additionally, efficacy was analyzed separately for initial and subsequent treatment regimens for both penicillamine and trientine. The data included in the analysis were collected for a mean period of 13.3 years after the initiation of treatment for Wilson’s disease and based on stable drug treatment periods of at least six consecutive months.
Hepatic and neurologic outcomes were evaluated retrospectively from patient records at 6, 12, 24, 36, and 48 months following initiation of each treatment regimen. Outcome measures were stratified by first‑line and second‑line treatment use. Hepatic outcome measures were determined based on clinical symptoms and liver function tests. The presence and/or progress of neurologic disease was determined based on physician assessment. Baseline patient characteristics were generally well balanced across treatment groups.
Out of 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 both hepatic and neurologic symptoms, and 54 patients (13.3%) were asymptomatic. At the time of diagnosis, 21 patients (5.2%) presented with hepatic failure with a fulminant disease course. Approximately 30% of patients had established cirrhosis at study entry.
In patients with symptomatic hepatic disease at the initiation of treatment, comparable rates of improvement in hepatic status were observed between patients receiving penicillamine or trientine as a first‑line treatment (90.7% and 92.6%, respectively), and between patients receiving penicillamine or trientine as a second‑line treatment (75.0% and 68.9%, respectively). The observed incidence of patients who maintained stable hepatic disease over the treatment period was also comparable in both the first‑line and second‑line settings between penicillamine and trientine. Deterioration in hepatic status was uncommon and occurred with a similar incidence in patients who received penicillamine or trientine as a first‑line treatment. In the second‑line setting, a non‑significant increase was observed in the incidence of hepatic deterioration following treatment with trientine, compared to treatment with penicillamine. However, no signs of deterioration were observed in 91.1% of patients who received trientine as a second‑line treatment. No worsening in hepatic status was observed in any patient who received either treatment regimen and who initially presented without hepatic symptoms.
In patients with symptomatic neurologic disease at the initiation of treatment, no statistically significant differences were found in the rates of improvement of neurologic status between pencillamine and trientine treatment in either the first‑line setting (67.5% and 55.0%) or second‑line setting (23.1% and 51.0%). Stable neurologic disease was observed in 27.2% of patients treated with penicillamine and 25.0% of patients treated with trientine as a first‑line therapy, and in 69.2% of patients treated with penicillamine and 33.3% of patients treated with trientine as a second‑line therapy. In the first‑line setting, a higher rate of neurologic worsening was observed in symptomatic patients who received trientine than in those who received penicillamine (20.0% and 5.3%, respectively). This difference was found to be statistically significant (p = 0.04). However, 80.0% of neurologically symptomatic patients who received trientine as a first‑line treatment did not have neurologic worsening, and showed improved or stable neurologic disease. Neurologic worsening was not significantly different between patients treated with trientine or penicillamine as a second‑line therapy (15.7% and 7.3%, respectively).
Collectively, the results of the efficacy analyses demonstrate the utility of trientine as a treatment for patients with Wilson’s disease as second‑line therapy for patients intolerant to penicillamine. In patients with symptomatic hepatic disease, hepatic improvement was observed in 69% of individuals given trientine as second-line therapy (due to intolerance to or inadequate response to penicillamine). In patients with symptomatic neurologic disease, an improvement in neurologic symptoms was observed in 51% of individuals given trientine as a second‑line therapy.
Indication
Health Canada approved the following indication:
- Waymade‑Trientine (trientine hydrochloride) is indicated for the treatment of patients with Wilson's disease who are intolerant to penicillamine.
- Waymade‑Trientine should only be initiated by physicians experienced in the management of Wilson's disease.
For more information, refer to the Waymade‑Trientine Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety data reviewed indicate that trientine is generally a well‑tolerated agent. During a follow‑up period with a median of over 13 years, 43.6% of patients treated with penicillamine and 25.5% of patients treated with trientine discontinued treatment for any reason.
In the pivotal study dataset, 28.8% of patients treated with pencillamine and 7.1% of patients treated with trientine discontinued treatment due to adverse events, and this difference was statistically significant (p = 0.04). Self‑limiting nausea was the most common adverse event observed soon after initiation of treatment with trientine. Skin rash and anemia were also reported. Iron deficiency has also been observed with trientine administration, which is attributed to its chelating properties and may be managed through oral iron supplementation.
A number of smaller observational studies were also reviewed as part of this submission. Results were generally consistent across studies, supporting the safety and efficacy of trientine in the treatment of Wilson’s disease when used as second‑line therapy.
A Serious Warnings and Precautions box was added to the Product Monograph to highlight the risk of worsening neurologic or neurocognitive functioning, which can be irreversible. This may occur in patients with pre‑existing neurologic and/or neuropsychiatric impairment due to Wilson’s disease, and who are treated with Waymade‑Trientine or other chelating agents. Accordingly, it is recommended that treatment with Waymade‑Trientine should only be initiated by physicians experienced in the management of Wilson’s disease.
For more information, refer to the Waymade‑Trientine Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Non‑clinical toxicology studies with trientine were conducted in mice, rats, and dogs. The main toxicological findings were consistent across different species. These include 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, neurologic signs were observed following administration of high levels of trientine, the nature of which were unclear.
In mice, inflammation of the lungs was observed following administration of trientine in drinking water, including alveolar histiocytic infiltration, liver periportal fatty infiltration, and hematopoietic cell proliferation in the spleen. Male mice had reduced body and kidney weights, as well as reduced renal cytoplasmic vacuolization. The no‑observed-adverse‑effect level (NOAEL) was considered to be 92 mg/kg/day in males and 99 mg/kg/day in females.
Oral doses of trientine up to 600 mg/kg/day were administered to rats for 26 weeks. Dose‑dependent increases were observed in the incidence and severity of focal chronic interstitial pneumonitis with fibrosis of the alveolar walls, which is indicative of persistent inflammation or a toxic effect on alveolar cells. The accumulation of trientine in bronchial epithelial cells and alveolar pneumocytes is believed to have a cytotoxic effect which leads to chronic interstitial pneumonitis. The NOAEL was considered to be 50 mg/kg/day for females, and no NOAEL was established for males.
Repeat‑dose toxicity studies were conducted in which dogs were administered oral doses of trientine up to 200 mg/kg/day. Underactivity, tremors, abnormal gait, limited use of limbs, and prone posture were all observed and were found to be reversible. The NOAEL was established at 50 mg/kg/day.
A reproductive toxicity study was conducted in which pregnant dams and fetuses were exposed to doses of 3,000, 6,000, and 12,000 ppm trientine in drinking water. Stronger adverse effects were observed in fetuses than in maternal animals. At doses higher than 3,000 ppm (calculated as approximately 500 mg/kg/day in pregnant mice), low dose‑dependent copper concentrations were observed in fetal tissues and morphological abnormalities were observed in the brain. At doses of 6,000 or 12,000 ppm, fetal resorption increased and fetal viability was reduced in a dose‑dependent manner. Serum copper concentrations were lower in dams that experienced total resorption at these doses. The observed effects may be partially due to induced copper deficiency.
Trientine was found to be genotoxic in several in vitro assays, but no mutagenic activity was observed in in vivo assays. The genotoxicity profile of trientine is therefore considered to be of low concern. No carcinogenicity studies have been conducted with trientine.
The results of the non‑clinical studies as well as the potential risks to humans have been included in the Waymade‑Trientine Product Monograph. Considering the intended use of Waymade‑Trientine, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Waymade‑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 Waymade‑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 2 ºC to 8 ºC.
Proposed limits of drug‑related impurities are considered adequately qualified (i.e., within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
All non‑medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| WAYMADE-TRIENTINE | 02515067 | WAYMADE PLC | TRIENTINE HYDROCHLORIDE 250 MG |