Regulatory Decision Summary for Fetzima

Health Canada considers that the benefits of Fetzima outweigh the potential risks for the treatment of MDD in adults. The efficacy of levomilnacipran for the treatment of MDD was evaluated by comparing the mean treatment difference in the Montgomery Asberg Depression Rating Scale (MADRS) total score between Fetzima-treated patients and placebo-treated patients. Historically, a mean difference in the MADRS total score of at least 2 points, compared to placebo-treated patients, has been a requirement for approval together with a difference of at least 10% in the responder rate. 

The sponsor submitted four 8-week, randomized, double-blind, placebo-controlled studies [at doses of 40-120 milligrams (mg) once daily] in adult (18-78 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. Two of the studies were fixed-dose (Study LVM-MD-01 and Study LVM-MD-10) and two were flexible-dose (Study LVM-MD-02 and Study LVM-MD-03). The primary efficacy endpoint in all studies was the mean change from baseline to Week 8-endpoint on the MADRS.

In three of four pivotal studies (LVM-MD-01, -10 and -03), Fetzima demonstrated statistical superiority over placebo in the improvement of depressive symptoms. The mean treatment difference from baseline to Week 8 in MADRS total score between Fetzima-treated patients and placebo-treated patients for these studies exceeded 3 points. In addition, the responder rates in Fetzima-treated patients exceeded placebo-treated patients by 10-15%. One study (LVM-MD-02) failed to demonstrate similar results.

It is noteworthy to mention that MDD studies historically have high failure rates. The reason for this remains unclear, but baseline disease severity, dosing regimen, sample size, study location, patient population, and other factors may play a role. In this particular case, however, there is no clear explanation as to why the LVM-MD-02 study failed to demonstrate statistical superiority over placebo in the improvement of depressive symptoms. 

Consistent with MDD disease demographics, approximately two thirds (64%) of the patients were female across the pivotal studies. Given that women are twice as likely to seek treatment for MDD, a benefit to this population must be considered an integral part of the overall benefit estimation. While data from the three positive pivotal studies supports the short-term use of Fetzima at the proposed doses to treat MDD in the overall target population (moderately-severe to severe MDD), there is no clear benefit to female patients at doses greater than 40 mg/day.

The efficacy of Fetzima for the treatment of MDD beyond 8 weeks was not established, as a placebo-controlled, fixed-dose withdrawal study failed to demonstrate effectiveness of long-term maintenance treatment. The benefits of Fetzima for the treatment of mild MDD, or for patients aged 65 or older, remains unknown.

In general, no new and unexpected risks associated with the use of Fetzima were identified, compared to other SNRIs approved in Canada. The most frequently reported adverse events in clinical studies associated with the use of Fetzima included nausea, constipation, heart rate increased, hyperhidrosis, erectile dysfunction, tachycardia, vomiting, and palpitations. Females were twice as likely to experience nausea, while almost all events of dysuria and urinary hesitation occurred in male patients. There were generally no dose-related adverse reactions, except for urinary hesitation and erectile dysfunction.

Fetzima was associated with significant positive chronotropic and dromotropic effects at therapeutic doses that warrant appropriate contraindications. Healthy subjects who had serial blood pressure assessments during steady-state treatment with 120 mg levomilnacipran experienced maximal placebo-adjusted mean increases from baseline in systolic and diastolic blood pressure of 7.2 millimetres of mercury (mmHg) and 8.1 mmHg, respectively, and a change in heart pulse of 20.2 beats per minute (bpm). 

In short-term, placebo-controlled studies in patients with MDD, Fetzima was associated with mean increases of 3.0 mmHg in systolic blood pressure (SBP) and 3.2 mmHg in diastolic blood pressure (DBP), compared to a mean decrease of 0.4 mmHg SBP and no change in DBP in placebo-treated patients. Similarly, Fetzima treatment was associated with mean increases in heart rate of 7 bpm for 40 mg and 80 mg per day and 9.1 bpm for 120 mg per day, compared to a mean decrease of 0.3 bpm in placebo-treated patients.

Cardiovascular adverse events were more frequently reported for Fetzima-treated patients, including tachycardia (6%), heart rate increased (6%), palpitations (5%), blood pressure increased (3%), hypertension (3%), and hypotension (3%). These events were reported in 2% or less of patients in the placebo groups. Mean increases in blood pressure and heart rate persisted in the long-term extension study (mean heart rate of 9 bpm from baseline, mean supine SBP increases of 3.9 mmHg and supine DBP increases of 3.3 mmHg).

Fetzima has not been adequately evaluated in patients with cardiac function impairment or with an identified high risk of a serious cardiac arrhythmia, uncontrolled hypertension, or severe or unstable coronary heart disease. As these conditions may be worsened by increases in blood pressure or heart rate, cardiovascular contraindications were added to the Product Monograph at the request of Health Canada. Noting that changes in blood pressure observed in the clinical studies were independent of the dose, the cardiovascular risks associated with the use of Fetzima cannot be mitigated by dose reductions or restrictions.

Other important safety risks that have been associated with other SNRIs, including the worsening of depression and suicide risk, serotonin syndrome, abnormal bleeding, activation of mania/hypomania, discontinuation syndrome, seizures, and narrow angle glaucoma were evaluated in the clinical program for Fetzima and characterised in the Product Monograph.

Given the demographics of MDD, prescribing physicians should be aware of the absence of a clear benefit to female patients at doses greater than 40 mg/day. Patients vulnerable to changes in blood pressure and heart rate should be protected from unnecessary risk. The Fetzima Product Monograph will help prescribers manage and mitigate the risks appropriately.

For more information on Health Canadas decision, please view the Summary Basis of Decision.