Summary Basis of Decision for Trintellix

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 Trintellix is located below.

Recent Activity for Trintellix

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 decision was negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Trintellix

Updated: 2025-08-05

The following table describes post-authorization activity for Trintellix, a product which contains the medicinal ingredient vortioxetine (as vortioxetine hydrobromide). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

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

Drug Identification Number (DIN):
  • DIN 02432919 - 5 mg vortioxetine, tablet, oral administration
  • DIN 02432927 - 10 mg vortioxetine, tablet, oral administration
  • DIN 02432935 - 15 mg vortioxetine, tablet, oral administration
  • DIN 02432943 - 20 mg vortioxetine, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 274021 2023-04-03 Issued NOC 2024-05-27 Submission filed as a Level I – Supplement to update the PM with new safety and efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box, Indications and Clinical Use, Warnings and Precautions, Adverse Reactions, Dosage and Administration, and Overdosage sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 271177 2023-01-06 Issued NOC 2023-06-16 Submission filed as a Level I – Supplement to add a QR code to the outer carton labels. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 248464 2021-01-18 Issued NOC
2021-08-05		 Submission filed as a Level II – Supplement (Safety) to update the Product Monograph (PM) with new safety information and to update the PM to the new template. The submission was reviewed and considered acceptable. As a result of the SNDS, additions were made to the Warnings and Precautions, Adverse Reactions, and Drug Interactions sections, and Part III: Patient Medication Information of the PM. An NOC was issued.
SNDS # 237793 2020-03-31 Issued NOC
2021-03-11		 Submission filed as a Level I – Supplement to update the Product Monograph (PM) with safety information regarding pediatric use, and hepatic impairment. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections and Part III: Patient Medication Information of the PM. An NOC was issued.
SNDS # 243819 2020-09-18 Issued NOC
2021-02-12		 Submission filed as a Level II – Supplement (Safety) to update the Product Monograph (PM) to reflect revisions in the company core data sheet. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Drug Interactions sections and Part III: Patient Medication Information of the PM. An NOC was issued.
Summary Safety Review Not applicable Posted 2021-01-06 Summary Safety Review posted for Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-norepinephrine Reuptake Inhibitors (SNRIs) (Assessing the potential risk of sexual dysfunction despite treatment discontinuation).
NC # 223451 2019-01-04 Issued NOL
2019-04-15		 Submission filed as a Level II (90 day) Notifiable Change to update the Product Monograph (PM) with new safety information. As a result of the NC, additions were made to the Adverse Reactions section and Part III: Consumer Information of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 219178 2018-08-14 Issued NOL
2018-12-19		 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions, Drug Interactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 212548 2018-01-03 Issued NOC
2018-12-07		 Submission filed as a Level I – Supplement to update the Product Monograph (PM) with preliminary pediatric clinical trial data. The submission was reviewed and considered acceptable. As a result of the SNDS, additions were made to the Warnings and Precautions, Adverse Reactions sections and Part III: Consumer Information of the PM. An NOC was issued.
SNDS # 192358 2016-02-16 Cancellation Letter Received
2017-04-18		 Submission filed as a Level I - Supplement to add results of a clinical trial to the PM. A NON was issued 2017-01-30. The sponsor cancelled the submission.
NC # 183464 2015-04-01 Issued No Objection Letter 2015-07-16 Submission filed as a Level II (120 day) Notifiable Change (Safety Change) to revise the existing text and layout of the inner blister labels for clarity. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DINs 02432919, 02432927, 02432943) market notification Not applicable Date of first sale 2014-10-28 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 159019 2012-09-28 Issued NOC
2014-10-22		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Trintellix

Date SBD issued: 2014-12-11

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

Vortioxetine (as vortioxetine hydrobromide), 5 mg, 10 mg, 15 mg, and 20 mg, tablets, oral

Drug Identification Number (DIN):

  • 02432919 - 5 mg tablet
  • 02432927 - 10 mg tablet
  • 02432935 - 15 mg tablet
  • 02432943 - 20 mg tablet

Lundbeck Canada Inc.

New Drug Submission Control Number: 159019

 

On October 22, 2014, Health Canada issued a Notice of Compliance to Lundbeck Canada Inc. for the drug product, Trintellix.

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 Trintellix is favourable for the treatment of major depressive disorder (MDD) in adults.

1 What was approved?

 

Trintellix, an antidepressant drug, was authorized for the treatment of major depressive disorder (MDD) in adults.

The efficacy of Trintellix (vortioxetine, as vortioxetine hydrobromide) in providing symptomatic relief of MDD was demonstrated in double-blind, placebo-controlled clinical studies of up to 8-weeks duration. The efficacy in maintaining an antidepressant response for up to 24 weeks was demonstrated in a double-blind, placebo-controlled study in patients with MDD who initially responded to 12-weeks of acute, open-label treatment with Trintellix.

Physicians who elect to use Trintellix for extended periods should periodically re-evaluate the usefulness of the drug for individual patients.

The starting and recommended dose of Trintellix is 10 mg vortioxetine once daily for adults less than 65 years of age. Depending on individual patient response, the dose may be increased to a maximum of 20 mg vortioxetine once daily, as tolerated. A dose decrease to a minimum of 5 mg vortioxetine once daily may be considered for patients who do not tolerate higher doses. The lowest effective dose of 5 mg/day should always be used as the starting dose in elderly patients (≥65 years of age).

The efficacy and safety of Trintellix have not been evaluated in patients below18 years of age. Trintellix is not indicated for use in patients below the age of 18.

Trintellix is contraindicated for patients with a known hypersensitivity to vortioxetine or any of the excipients of the drug product, as well as for patients concomitantly using monoamine oxidase inhibitors (MAOIs). At least 14 days should be allowed after discontinuing treatment with a MAOI before starting treatment with Trintellix. Due to the long half-life of Trintellix, at least 21 days should elapse after discontinuing Trintellix treatment, before starting a MAOI.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes. Trintellix was approved for use under the conditions stated in the Trintellix Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Trintellix (5 mg, 10 mg, 15 mg, and 20 mg vortioxetine, as vortioxetine hydrobromide) is presented as a tablet. In addition to the medicinal ingredient, the tablet also contains hydroxypropylcellulose, hypromellose, iron oxide red and/or iron oxide yellow, macrogol 400, magnesium stearate, mannitol, microcrystalline cellulose, sodium starch glycolate (type A), and titanium dioxide (E 171).

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

 

2 Why was Trintellix approved?

 

Health Canada considers that the benefit/risk profile of Trintellix is acceptable for the treatment of major depressive disorder (MDD) in adults.

Depression is a major cause of illness and disability throughout the world. Major depressive disorder is characterized by one or more major depressive episodes (MDE). A MDE is characterized by at least 2 weeks of depressed mood or loss of interest or pleasure in nearly all activities, accompanied by at least four additional symptoms of depression. Abnormalities in serotonergic function are considered to have a major role in depression and several other mental illnesses. Pharmacological agents that enhance serotonin levels and serotonergic activity in the brain are therefore predicted to be effective antidepressant therapies. There are several antidepressant therapies approved in Canada for the indication of the treatment of MDD. These products belong to various drug classes, such as: tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs), and serotonin and norepinephrine re-uptake inhibitors (SNRIs). Most of these approved therapies are thought to exert their therapeutic effects in depression by increasing levels of serotonin (and norepinephrine for SNRIs and tricyclic antidepressants) in the brain mainly through inhibition of the serotonin transporter 5-HTT and/or the norepinephrine transporter. The antidepressant effect of vortioxetine is thought to be related to modulation of serotonergic neurotransmission in the central nervous system through mechanisms that include inhibition of reuptake of serotonin (5-HT) at the 5-HT transporter (5-HTT) to enhance serotonin levels in the brain and activity at several human 5-HT receptors.

The assessment of the efficacy of Trintellix for the acute treatment of MDD was based on 11 pivotal, short-term (6- or 8-week), randomized, double-blind, placebo-controlled Phase III studies in patients diagnosed with MDD. More than 3,000 patients were treated with Trintellix in the short-term MDD studies. In all studies, the primary efficacy endpoint was the mean change from baseline to Week 6/8 in the Montgomery Asberg Depression Rating Scale (MADRS) or the 24-item Hamilton Depression Rating Scale (HAM-D24) total score. For the doses of 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day, the efficacy of Trintellix for the acute treatment of MDD was demonstrated in at least one of the clinical studies as measured by improvement in the primary efficacy endpoint. The efficacy of Trintellix (5 mg/day or 10 mg/day) for maintaining an antidepressant response for up to 24 weeks was demonstrated in a double-blind placebo-controlled study in patients with MDD who had achieved remission during 12 weeks of open-label treatment with Trintellix (5 mg/day or 10 mg/day). It is not known whether patients who may only achieve remission during acute treatment with higher doses of Trintellix [for example (e.g.), 15 or 20 mg/day] would continue to require these higher doses during long-term treatment to maintain the antidepressant effect. The safety of long-term treatment with the higher doses was evaluated in two 52-week, open-label studies.

The most common adverse events (AEs) reported with Trintellix in the clinical studies were gastrointestinal AEs such as nausea, vomiting and constipation, with the majority of nausea AEs being transient and the highest incidence occurring during the first week of treatment. Nausea was also the most common AE leading to discontinuation of treatment in the short-term clinical studies. The overall AE profile of Trintellix was consistent with the pharmacology characterised for this drug. Also, the overall safety profile of Trintellix is expected to be similar to that of other approved antidepressants that affect serotonin levels and neurotransmission. Therefore, class safety issues that are identified in the labels for other antidepressants are also described in the Trintellix Product Monograph [e.g., suicidality, discontinuation symptoms, bone fracture risks, abnormal bleeding events, serotonin syndrome/neuroleptic malignant syndrome, activation of mania/hypomania, hyponatremia, potential effects on newborns exposed to antidepressants during the third trimester, sexual dysfunction, concomitant use with monoamine oxidase inhibitors (MAOIs) and other serotonergic drugs].

A Risk Management Plan (RMP) for Trintellix was submitted by Lundbeck Canada 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.

Overall, the pivotal studies indicated that the benefits of Trintellix therapy outweigh the risks for the intended patient population and in the conditions of use defined in the Trintellix Product Monograph. Appropriate contraindications, warnings and precautions are in place in the Trintellix 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 Trintellix?

 

A New Drug Submission (NDS) for Trintellix was filed with Health Canada on September 28, 2012. Due to issues identified in the review of the clinical studies, a benefit/risk profile of Trintellix could not be assessed. A Notice of Deficiency (NOD) was issued for Trintellix on August 13, 2013. The sponsor submitted a response to the NOD and all of the concerns that led to the NOD were satisfactorily addressed. A Notice of Compliance was issued on October 22, 2014. For more information, see the Clinical Efficacy section.

 

Submission Milestones: Trintellix

Submission Milestone Date
Pre-submission meeting: 2012-05-09
Submission filed: 2012-09-28
Screening 1  
Screening Acceptance Letter issued: 2012-11-16
Review 1  
Biopharmaceutics Evaluation complete: 2013-05-13
Quality Evaluation complete: 2013-07-25
Clinical Evaluation complete: 2013-08-12
Notice of Deficiency (NOD) issued by Director General (safety and efficacy issues): 2013-08-13
Response filed: 2013-11-08
Screening 2  
Screening Acceptance Letter issued: 2013-12-27
Review 2  
Quality Evaluation complete: 2014-09-19
Clinical Evaluation complete: 2014-10-22
Labelling Review complete: 2014-10-19
Notice of Compliance issued by Director General: 2014-10-22

 

The Canadian regulatory decision on the non-clinical and clinical review of Trintellix was based on a critical assessment of the Canadian data package. The Day 120 List of Questions from the European Medicines Agency (EMA) was consulted. Foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA), the United States Food and Drug Administration (FDA), as well as from the Therapeutic Goods Administration (TGA) in Australia were used as an added reference.

Based on a Look Alike Sound Alike (LASA) report submitted by the sponsor on August 29, 2014, the initial brand name proposed was rejected. Following a second product name assessment for the back-up name provided by the sponsor on September 25, 2014, the trade name Trintellix was found to be acceptable (September 29, 2014).

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 Trintellix?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Trintellix 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 antidepressant effect of Trintellix (active ingredient vortioxetine) is thought to be related to modulation of serotonergic neurotransmission in the central nervous system through mechanisms that include inhibition of reuptake of serotonin (5-HT) at the 5-HT transporter (5-HTT) and activity at several human 5-HT receptors, including 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, and 5-HT3, 5-HT1D and 5-HT7 receptor antagonism. The precise contribution of the individual targets to the net effect of vortioxetine and the exact mechanism of action are not fully understood.

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

The cytochrome 450 (CYP) enzyme CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major pharmacologically inactive metabolite. Co-administration of 10 mg/day vortioxetine with a strong CYP2D6 inhibitor was shown to increase Trintellix exposure by approximately 2-fold. Therefore it is recommended that the dose of vortioxetine be reduced by half when co-administering with strong CYP2D6 inhibitors. A dose adjustment may also be considered, depending on individual patient response, when a broad spectrum CYP inducer is used concomitantly with Trintellix.

Due to the extensive hepatic metabolism of vortioxetine, caution is advised when treating patients with mild or moderate hepatic impairment. As there are no data evaluating the effects of severe hepatic impairment on the pharmacokinetics of vortioxetine, Trintellix is not recommended for patients with severe hepatic impairment.

Renal impairment (mild, moderate or severe) was estimated to increase the exposure to vortioxetine by up to 30% in one Phase I study. No dose adjustment is necessary based on renal function, but caution is recommended in the treatment of these patients

The results of two comparative bioavailability studies provided bridging of the Trintellix commercial tablet formulation to the earlier clinical trial formulations. The effect of food on the bioavailability was also studied, and the results support the dosing recommendation that Trintellix may be taken with or without food.

The clinical pharmacological data support the use of Trintellix for the specified indication. For further details, please refer to the Trintellix Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Trintellix 5 mg, 10 mg, 15 mg, and 20 mg once daily in the treatment of major depressive disorder (MDD) was evaluated in a total of eleven short-term, randomized, double-blind, placebo-controlled studies; ten studies in adults, and one study specifically in elderly patients. All studies included male and female inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. The studies in adults included patients 18 to 75 years old (mean age range 43 to 47 years) with baseline total scores on the Montgomery Asberg Depression Rating Scale (MADRS) ≥26 in seven studies, ≥30 in two studies and ≥22 in one study. The study of elderly patients included patients who were 65 years of age or older (range 64 to 88 years), with at least one previous major depressive episode before 60 years of age, a baseline MADRS total score ≥26 and no comorbid cognitive impairment (Mini Mental State Examination score <24). Approximately two-thirds of the patients included in all short-term studies were female.

All short-term studies were of similar design. More than 3,000 patients were treated with Trintellix in the short-term MDD studies. Patients received fixed doses of Trintellix 5 mg, 10 mg, 15 mg or 20 mg once daily or placebo for 6 or 8 weeks (two 6-week studies, nine 8-week studies). In six of the studies, including the study in elderly patients, some patients received an approved antidepressant as an active reference comparator. Five of the studies in adults were conducted in countries outside the United States (non-United States) and five were conducted only in the United States. The study in elderly patients included patients from non-United States countries and from the United States. The primary efficacy endpoint was the mean change from baseline to Week 6/Week 8 in the MADRS total score (seven studies) or the 24-item Hamilton Rating Scale for Depression (HAM-D24) (four studies).

For the doses of 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day, the efficacy of Trintellix for the acute treatment of MDD was demonstrated in at least one of the clinical studies (including the study in elderly patients), as measured by improvement in the primary efficacy endpoint (mean change from baseline to Week 6/8 in MADRS or HAM-D24 total score). In view of the observed differences in treatment effects between studies conducted outside the United States and in the United States, the results are summarized in the following tables by non-United States and United States studies.

Change from Baseline to Week 6/8 in MADRS or HAM-D24 Total Score
Study number [Primary Measure] Treatment group Number of patients Mean baseline score (SD) LS Mean change from baseline (SE) LS Mean difference from placebo (95% CI)

a Study duration 6 weeks

b Study duration 8 weeks

c Positive only for the 20 mg dose

* p<0.05 statistically significant

Note: Table only includes doses of 5-20 mg
Study 1a
[MADRS]
Non-United States
Positive		 Trintellix 5 mg
Trintellix 10 mg
Placebo		 108
100
105		 34.1 (2.6)
34.0 (2.8)
33.9 (2.7)		 -20.4 (1.0)
-20.2 (1.0)
-14.5 (1.0)		 -5.9 (-8.6, -3.2)*
-5.7 (-8.5, -2.9)*
Study 2b
[MADRS]
Non-United States
Failed		 Trintellix 5 mg
Trintellix 10 mg
Placebo		 155
151
145		 32.7 (4.8)
31.8 (3.9)
31.7 (4.3)		 -16.5 (0.8)
-16.3 (0.8)
-14.8 (0.8)		 -1.7 (-3.9, 0.5)NS
-1.5 (-3.7, 0.7)NS
Study 3b
[HAM-D24]
Non-United States
Positive		 Trintellix 5 mg
Trintellix 10 mg
Placebo		 139
139
139		 32.2 (5.0)
33.1 (4.8)
32.7 (4.4)		 -15.4 (0.7)
-16.2 (0.8)
-11.3 (0.7)		 -4.12 (-6.2, -2.1)*
-4.9 (-7.0, -2.9)*
Study 4b
[MADRS]
Non-United States
Positive		 Trintellix 15 mg
Trintellix 20 mg
Placebo		 149
151
158		 31.8 (3.4)
31.2 (3.4)
31.5 (3.6)		 -17.2 (0.8)
-18.8 (0.8)
-11.7 (0.8)		 -5.5 (-7.7, -3.4)*
-7.1 (-9.2, -5.0)*
Study 5b
[MADRS]
Non-United States
Negative		 Trintellix 5 mg
Trintellix 10 mg
Trintellix 20 mg
Placebo		 142
147
149
152		 31.6 (3.7)
31.8 (4.0)
31.7 (3.7)
31.6 (3.6)		 -14.6 (0.8)
-15.7 (0.8)
-15.8 (0.8)
-13.9 (0.8)		 -0.6 (-3.3, 2.0)NS
-1.7 (-4.3, 0.9)NS
-1.8 (-4.4, 0.8)NS
Study 6a
[HAM-D24]
United States
Negative		 Trintellix 5 mg
Placebo		 292
286		 32.7 (5.4)
32.1 (5.5)		 -14.6 (0.7)
-13.9 (0.7)		 -0.74 (-2.5, 1.0)NS
Study 7b
[HAM-D24]
United States
Negative		 Trintellix 5 mg
Placebo		 153
149		 29.8 (5.6)
29.5 (6.1)		 -11.1 (0.7)
-10.5 (0.8)		 -0.6 (-2.6, 1.5)NS
Study 8bc
[MADRS]
United States		 Trintellix 15 mg
Trintellix 20 mg
Placebo		 145
147
153		 31.9 (4.1)
32.0 (4.4)
31.6 (4.2)		 -14.3 (0.9)
-15.6 (0.9)
-12.8 (0.8)		 -1.5 (-3.9, 0.9)NS
-2.8 (-5.1, -0.4)*
Study 9bc
[MADRS]
United States		 Trintellix 10 mg
Trintellix 20 mg
Placebo		 154
148
155		 32.3 (4.5)
32.5 (4.3)
32.0 (4.0)		 -13.0 (0.8)
-14.4 (0.9)
-10.8 (0.8)		 -2.2 (-4.5, 0.1)NS
-3.6 (-5.9, -1.4)*
Study 10b
[MADRS]
United States
Negative		 Trintellix 10 mg
Trintellix 15 mg
Placebo		 143
142
149		 34.1 (4.1)
33.7 (4.5)
33.4 (4.5)		 -13.7 (1.1)
-13.4 (1.1)
-12.9 (1.0)		 -0.79 (-3.7, 2.1)NS
-0.5 (-3.4, 2.5)NS
Study 11b
(elderly)
[HAM-D24]
Non-United States and United States
Positive		 Trintellix 5 mg
Placebo		 155
145		 29.2 (5.0)
29.4 (5.1)		 -13.7 (0.7)
-10.3 (0.8)		 -3.3 (-5.3, -1.3)*

Overall, the efficacy of Trintellix was demonstrated in the non-United States studies with doses of 5 mg, 10 mg (2 studies each), 15 mg and 20 mg (1 study each), and the efficacy was demonstrated in 2 United States studies with 20 mg Trintellix. In elderly patients, efficacy was demonstrated with the 5 mg dose, the only dose evaluated in this study, and the results of this study were driven by the larger subgroup of patients from outside the United States. The factors contributing to the geographic variability in the observed treatment effects in the short-term MDD studies remain uncertain. Therefore, the differences in the treatment effects in the non-United States and United States studies have been noted in the Trintellix Product Monograph so that prescribers are aware of the differences.

The efficacy of Trintellix (5 mg/day or 10 mg/day) for maintaining an antidepressant response for up to 24 weeks was demonstrated in a non-United States study in which patients with MDD who had achieved remission for the last 2 weeks of an initial 12-week open-label treatment period with Trintellix (5 mg/day or 10 mg/day) were randomized to placebo or Trintellix (5 mg/day or 10 mg/day) and observed for relapse during a double-blind period of at least 24 weeks. Trintellix was superior to placebo on the primary efficacy measure, the time to relapse of MDD within the first 24 weeks of the double-blind period, with the risk of relapse being two times higher in the placebo group than in the Trintellix group. This study only evaluated the efficacy of the 5 mg and 10 mg doses in a non-United States study population and the majority of patients (70%) were treated with 10 mg Trintellix from the end of the open-label period throughout the double-blind period. Therefore, it is not known whether the patients who may only achieve remission during acute treatment with higher doses of Trintellix (e.g., 15 or 20 mg/day) would continue to require these higher doses during long-term treatment to maintain the antidepressant effect. As a post-marketing commitment, the United States Food and Drug Administration (FDA) has requested an additional long-term maintenance study evaluating a broader dose range, including higher doses, in United States patients.

The sponsor was issued a Notice of Deficiency (NOD) for this New Drug Submission (NDS) on August 13, 2013. The NOD requested the results from a negative pivotal Phase III study in patients with MDD that were not included in the NDS. The Response to NOD addressed this major concern by providing the report for this negative study, as well as three additional Phase III studies that were completed between the time of the initial filing of the NDS and the filing of the Response to NOD. The responses to the major concern and all other concerns raised in the NOD were addressed in the Response to NOD and review of the NDS resumed. Based on the available data, the benefit/risk profile of Trintellix for adult patients with MDD was considered acceptable, and a Notice of Compliance was issued.

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

Clinical Safety

The clinical safety of Trintellix (active ingredient vortioxetine) was based on data collected from MDD clinical studies which included more than 6,700 adult patients, of whom 3,460 were treated with Trintellix (5 to 20 mg/day) in short-term placebo-controlled studies of up to 8 weeks in duration. An additional 200 patients were treated with Trintellix in a long-term placebo-controlled study of up to 24 to 64 weeks. At the time the NDS was submitted, 1,299 patients had completed 52-week open-label extension studies with Trintellix flexible daily doses in the 2.5-20 mg range. Most of the patients included in the MDD studies were less than 65 years of age. In a study conducted specifically in patients 65 years of age or older, 155 patients were treated with Trintellix 5 mg/day. Less than 100 elderly patients included in the short-term studies in adults were treated with Trintellix at doses above 5 mg/day.

In the short-term clinical studies, the most common adverse events (≥5% of patients and at least twice the rate of placebo) reported with Trintellix were gastrointestinal (GI) adverse events (AEs), including nausea, vomiting and constipation. The majority of nausea AEs were transient and the highest incidence occurred during the first week of treatment. However, nausea was the most common AE leading to discontinuation of Trintellix treatment.

Other common (incidence ≥1% and higher than rate of placebo) GI AEs in the pooled short-term trials included: diarrhea, dry mouth, dyspepsia, flatulence and abdominal discomfort. Also, non-GI common events were dizziness, somnolence/sedation, fatigue, nasopharyngitis, insomnia, abnormal dreams, hyperhidrosis, pruritus generalised, arthralgia and decreased appetite.

The AE profile of Trintellix in the long-term placebo controlled study was consistent with that observed in the short-term studies.

Abrupt discontinuation of Trintellix was associated with an increased frequency of discontinuation-related AEs, compared to placebo, when spontaneously reported or actively collected with the Discontinuation Emergent Signs and Symptoms checklist (DESS). The most common symptoms associated with discontinuation were headache, increased dreaming/nightmares, mood swings, muscle tension/stiffness, sudden outbursts of anger, dizziness/vertigo and nose running. Therefore, despite the relatively long half-life (mean 66 hours) of vortioxetine, a gradual reduction in dose rather than abrupt discontinuation is recommended.

Trintellix was assessed for effects on electrocardiogram (ECG) parameters in a dedicated QT/QTc study at a therapeutic dose of 10 mg once a day (QD) and a supratherapeutic dose of 40 mg QD for 14 days in healthy subjects. The maximum mean difference from placebo in the QT interval corrected by Framingham formula (QTcFm) was 4.0 ms [90% confidence interval (CI) 1.3, 6.7] at 4 hours for the therapeutic 10 mg QD dose, and 4.6 ms (90% CI 2.2, 7.1) at 4 hours for the 40 mg QD dose. The changes in QTcFm did not reach the threshold of regulatory concern (upper bound of the 90% CI of 10 ms), and there was no plasma-concentration-QTc relationship observed. No noteworthy effects on the PR interval or QRS duration were observed in this study.

In the dedicated QT/QTc study, treatment with Trintellix 10 or 40 mg/day for 14 days was associated with a modest mean decrease in heart rate of about -5 beats per minute on Day 14, and maximum mean increases in systolic blood pressure of 2.8 mmHg for 10 mg QD and 4.8 mmHg for 40 mg QD on Day 14.

Trintellix was not associated with an increased incidence of individual potentially clinically significant changes in vital signs (blood pressure, pulse, body weight) or electrocardiogram (ECG) parameters in the short-term, placebo-controlled studies in MDD patients.

The Arizona Sexual Experience Scale (ASEX) was used to evaluate sexual dysfunction during treatment with Trintellix in 7 short-term studies in MDD and one short-term study in Generalised Anxiety Disorder. In the pooled analysis, Trintellix was associated with a higher incidence of treatment-emergent sexual dysfunction as per the ASEX compared to placebo. In men, the incidences of sexual dysfunction ranged from 16% to 29% with Trintellix 5-20 mg compared to 14% with placebo. In women, the incidences ranged from 22% to 34% with Trintellix 5-20 mg compared to 20% with placebo.

Based on its pharmacology, the overall safety profile of Trintellix is expected to be similar to that of other approved antidepressants that exert their therapeutic effects by enhancing serotonin levels and neurotransmission. Therefore, class safety issues that have been identified for other antidepressants are also described in the Trintellix Product Monograph [e.g., suicidality, discontinuation symptoms, bone fracture risks, abnormal bleeding events, serotonin syndrome/neuroleptic malignant syndrome, seizures, psychomotor impairment, mydriasis, activation of mania/hypomania, abuse/misuse potential, hyponatremia, potential effects on newborns exposed to antidepressants during the third trimester, sexual dysfunction, concomitant use with monoamine oxidase inhibitors (MAOIs) and other serotonergic drugs].

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

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical program, that is (i.e.) the primary and secondary pharmacodynamics, safety pharmacology, pharmacokinetics, and toxicology, was considered complete and adequate. There are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Trintellix Product Monograph.

For more information, refer to the Trintellix 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 Trintellix 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 is considered acceptable.

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

The drug product is an immediate-release tablet consisting of commonly used excipients in amounts consistent with their intended functions. The product is film-coated for aesthetics. The excipients used in the drug product formulation are not of animal or human origin.

The formulations of the 10 mg, 15 mg and 20 mg commercial product are identical to the formulations used in the pivotal clinical studies. The 15 mg and 20 mg strengths are proportional to each other. The 5 mg strength is proportionally formulated to the 10 mg clinical formulation. The drug product is not a dose proportional series. Comparative dissolution profiles between the 5 mg commercial formulation and the 10 mg clinical/commercial formulation in multiple media demonstrate no significant difference in drug release rate and support acceptance of the 5 mg tablet.

 

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