Summary Basis of Decision for Viibryd

Clinical Pharmacology

Viibryd (vilazodone hydrochloride) is both a selective serotonin reuptake inhibitor and a partial agonist of the 5-hydroxytryptamine1A (5HT1A) receptors. The precise mechanism of the antidepressant effect of Viibryd is not fully understood but presumed to be related to enhancement of serotonergic activity in the central nervous system.

Vilazodone undergoes extensive metabolism in the liver that results in the formation of several metabolites. Even the most potent of the metabolites are unlikely to produce significant central nervous system effects.

Vilazodone has low potential of inhibiting and inducing cytochrome P450 (CYP) enzymes in vitro and in vivo. Vilazodone metabolism is mainly mediated by CYP3A4. An increase of approximately 50% in vilazodone maximum serum concentration (C_max) and area under the curve (AUC) was observed when co-administered with the strong CYP3A4 inhibitor, ketoconazole. Co-administration of vilazodone with the strong CYP3A4 inducer, carbamazepine, decreased the mean C_max and AUC of vilazodone by approximately 45%.

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

QT Prolongation

The effects of vilazodone on electrocardiogram (ECG) interval and hemodynamic parameters were studied in a randomized, placebo- and positive-controlled, parallel group ECG assessment study performed in 157 healthy volunteers. Volunteers who were randomized to vilazodone treatment [number of patients (n) = 66] received sequential ascending doses of 10 mg/day, 20 mg/day, 40 mg/day, 60 mg/day, and 80 mg/day over a 15 day period, with each dose being administered for three days. 

Vilazodone was associated with a dose- and concentration-related increase in heart rate at supratherapeutic doses of 60 mg/day and 80 mg/day, but not at the therapeutic 20 mg/day and 40 mg/day doses. The proportion of subjects with high heart rate values >90 bpm was larger in the vilazodone group than in the placebo group and showed dose-dependency.

Small, but statistically significant, prolongation of the QTc interval was observed at the 20 mg and 40 mg therapeutic doses, but not the 60 mg and 80 mg supratherapeutic doses. The time course (the varying activity of a medicine over time following administration) of these changes was erratic and not clearly consistent with a treatment-related effect. A concentration-effect analysis was not suggestive of QTc prolongation at therapeutic exposures. Considering the erratic time course and lack of dose-dependency, the QTc prolongation observed at the lower doses might be a reflection of imperfect control of study conditions or confounding autonomic effects.

Vilazodone was associated with a dose-dependent increase in systolic blood pressure at doses of 20 mg/day and higher in healthy volunteers.

Caution is recommended if vilazodone is administered to subjects with pre-existing hypertension. Baseline and periodic on-treatment blood pressure monitoring is recommended. Treatment-emergent hypertension may warrant discontinuation or management with anti-hypertensive therapies. Information regarding possible effects of vilazodone on heart rate and blood pressure is included in the Warnings and Precautions section of the Product Monograph.

However, no electrocardiogram or blood pressure safety signals were noted in the four Phase III studies in patients with major depressive disorder (MDD).

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

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

Clinical Efficacy

The efficacy of Viibryd (vilazodone hydrochloride) as a treatment for MDD was demonstrated in four Phase III, multicentre, randomized, double-blind, placebo-controlled studies in adult (18-70 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD.

Three of the studies were 8 weeks in duration and evaluated the efficacy of Viibryd 40 mg (Studies 1-3). The other study was 10 weeks in duration and evaluated the efficacy of Viibryd 20 mg and 40 mg (Study 4). For each study, patients were randomized to either Viibryd (20 mg or 40 mg) or placebo once daily with food. Patients were titrated over 1 week to a dose of 20 mg Viibryd daily or over 2 weeks to a dose of 40 mg Viibryd daily taken with food.

The main inclusion criteria were:

• For Studies 1 and 2 - a Hamilton Depression Scale (HAM-D)-17 score of ≥22 and a HAM-D item 1 (depressed mood) score of ≥2 at the screening and baseline visits.
• For Studies 3 and 4 - a Montgomery-Asberg Depression Rating Scale (MADRS - a validated scale for depression that is commonly used in this type of study) score of ≥26.

The primary efficacy parameter in all studies was the change in total score from baseline to week 8 (Studies 1-3) or week 10 (Study 4) in the Montgomery-Asberg Depression Rating Scale (MADRS). The secondary efficacy parameter in Studies 3 and 4 was the change from baseline in the Clinical Global Impression (CGI)-Severity score.

Additional efficacy parameters in all four studies included MADRS response rate (defined as ≥50% improvement in MADRS total score compared with baseline), change from baseline in the Hamilton Anxiety Scale (HAM-A) total score, and the Clinical Global Impressions-Improvement (CGI-I) total score. In addition, MADRS remission (defined as MADRS total score <10), HAM-D-17 total score, HAM-D-17 response (≥50% improvement in HAM-D total score compared with baseline) and remission (HAM-D17 <7), and change from baseline in HAM-D-17 total score were assessed in Studies 1 and 2. CGI-I response rates (CGI-I ≤2) were assessed in Studies 1, 3 and 4, and MADRS sustained response rate (defined as MADRS total score ≤12 for at least the last two consecutive visits during the double-blind treatment period) was assessed in Studies 3 and 4. These additional endpoints were considered exploratory and were not used to support the indication.

All of the Phase III studies had statistically and clinically significant results which indicated the efficacy of Viibryd in patients with MDD.

The data generated from the program established that results from the four pivotal studies demonstrated a consistent pattern of therapeutic response to Viibryd. Study 4 demonstrated that both the 20 mg and 40 mg doses of Viibryd were effective in the treatment of adult patients with MDD as measured by change from baseline in MADRS total score. The results of the secondary endpoint in studies 3 and 4 were consistent with the results of the primary outcome and were considered supportive.

No long term placebo-controlled, blinded studies were performed. A 52-week, uncontrolled, open-label study was conducted to assess the long-term safety of Viibryd in patients with MDD. A secondary objective of this study was to assess MADRS total score and CGI-Improvement scores over 52 weeks. The mean MADRS total score and mean CGI-Improvement scores decreased gradually during the 52-week treatment period, indicating maintenance of improvement of symptoms over time. Because this was an uncontrolled study and included no placebo or other comparator, no conclusions can be drawn about the effectiveness of Viibryd, but the results of this study are consistent with the findings in the four pivotal studies of Viibryd.

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

Clinical Safety

The safety of Viibryd was primarily established in the four pivotal studies described in the Clinical Efficacy section.

Nine hundred seventy-eight patients were exposed to a 40 mg once-daily dose of Viibryd in the combined Phase III studies. A further 288 patients were exposed to a 20 mg once-daily dose, for a total exposure of 1,266 patients equivalent to 184.1 patient-years. During the conduct of placebo-controlled Phase II studies, 903 patients (113.8 patient-years) were exposed to doses lower than 40 mg, and 227 (28.8 patient-years) were exposed to doses greater than 40 mg. Five hundred ninety-nine patients participated in an open-label, uncontrolled, 52-week study to assess the long-term safety of Viibryd.

In the four pivotal Phase III studies, Viibryd-treated patients experienced more treatment-emergent adverse events (TEAEs) than placebo-treated patients [78% versus (vs.) 64%], more serious adverse events (SAEs) (1.5% vs. 1.0%), and discontinued more often due to adverse events (AEs) (7.3% vs. 3.5%). In general, the AE profile for Viibryd-treated patients was similar to other selective serotonin reuptake inhibitors (SSRIs). The most commonly reported TEAEs (≥5% of Viibryd-treated patients at an incidence at least twice that of placebo) were diarrhea, nausea, vomiting, and insomnia. The first occurrence of these events was usually within the first week of treatment. The mean durations were 18 days for diarrhea, 15 days for nausea, 3 days for vomiting, and 28 days for insomnia.

Most of the reported TEAEs were mild or moderate. More Viibryd-treated patients reported SAEs compared to placebo (5.6% vs. 4.2%). Most of these SAEs were related to gastrointestinal disorders, nervous system disorders, and psychiatric disorders. The most over-reported TEAEs for Viibryd treatment vs. placebo treatment were diarrhea (28.1% vs. 9.5%) and nausea (23.4% vs. 6.8%). The rate of nausea was similar to that seen with other SSRIs; however the rate of diarrhea was higher than expected. Information regarding the higher frequency of diarrhea is included in the Adverse Reactions and Patient Information sections of the Product Monograph.

Treatment-emergent adverse events associated with suicide were similar between treatment groups. There was no completed suicide in the Phase III studies. There were two suicide attempts by patients treated with 40 mg vilazodone.

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