Summary Basis of Decision for Fetzima

 

Clinical Pharmacology

Fetzima is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). The exact mechanism of the antidepressant effect of levomilnacipran (the medicinal ingredient in Fetzima) is unknown but is thought to be related to the potentiation of both serotonin and norepinephrine through the inhibition of their re-uptake in the central nervous system.

The clinical pharmacology data submitted by the sponsor included reports on the human pharmacodynamic and pharmacokinetic studies. Key findings from these studies are as follows:

• The cytochrome P450 (CYP) 3A4 is a major enzyme catalyzing the metabolism of levomilnacipran to its major pharmacologically inactive metabolite. Concomitant use of Fetzima and ketoconazole (potent inhibitor of CYP3A4) can increase levomilnacipran plasma concentration (Cmax) by 39% and the extent of exposure (AUC) by 57%. Therefore, concomitant use of Fetzima with potent inhibitors of CYP3A4 may result in higher concentrations of Fetzima. In contrast, concomitant use of Fetzima with carbamazepine (inducer of CYP3A4) can reduce levomilnacipran plasma exposure (Cmax by 26% and AUC by 29%). However, no dosing adjustment is recommended when Fetzima is co-administered with inducers of CYP3A4.
• Substrates of CYP3A4 and inhibitors of other CYP enzymes are not expected to significantly affect levomilnacipran plasma exposure. Therefore, no dosing adjustment is recommended with use of these substrates.
• Renal excretion plays a predominant role in the elimination of levomilnacipran. In mild (creatinine clearance of 50 - 79 mL/min), moderate (creatinine clearance of 30 - 49 mL/min), or severe (creatinine clearance <30 mL/min) renal impairment, AUC increased by 23%, 93%, or 180%, respectively, the apparent clearance of levomilnacipran decreased by 19%, 49%, or 64%, respectively and the terminal elimination half-life increased by 28%, 43%, or 105%, respectively, relative to healthy subjects with normal renal function.  Dosing adjustment is therefore necessary for patients with moderate or severe renal impairment.

Serious drug interactions with the co-administration of monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitor (SSRI) or selective serotonin and norepinephrine reuptake inhibitor (SNRI) treatment or with other serotonergic drugs can lead to serious, sometimes fatal, drug interactions. Fetzima is therefore contraindicated with the co-administration of MAOIs, including linezolid (an antibiotic) and methylene blue (a dye used in certain surgeries), or within 14 days of terminating treatment with MAOIs.

Two comparative bioavailability studies that compared the Fetzima commercial capsule formulation to earlier clinical study formulation were also provided. The results of these studies successfully bridged the commercial capsule formulation to the clinical study formulation.

The effect of food on the bioavailability of levomilnacipran (the medicinal ingredient in Fetzima) was also assessed, and the results support the dosing recommendation that Fetzima may be taken with or without food.

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

Clinical Efficacy

The market authorization of Fetzima was based primarily on three pivotal Phase III studies (LVM-MD-01, LVM-MD-10, and LVM-MD-03) of which study results demonstrated efficacy for use of Fetzima for short-term symptomatic relief of MDD. Of these, two were fixed-dose (Study LVM-MD-01 and Study LVM-MD-10) and one was a flexible-dose (Study LVM-MD-03). In addition, a pivotal 8-week flexible-dose study (LVM-MD-02) was included as part of the pivotal studies submitted, but failed to demonstrate superiority over placebo. The reason for the failed results obtained within this study remains unknown. Nonetheless, data collected from this study did factor as part of the decision when evaluating Fetzima's overall safety profile.

The three pivotal studies which demonstrated efficacy were of similar design and duration (8 weeks) and explored treatments with Fetzima 40 to 120 mg/day in adult patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. A total of 1,130 patients were exposed to Fetzima 40, 80, or 120 mg/day in these studies.

The study design for all three studies included a 1-week single-blind placebo lead-in period, followed by an 8-week, double-blind treatment period. The starting dose in each study was 20 mg/day, followed by an upward titration to target doses of 40, 80, or 120 mg/day depending on the study.

For all three pivotal studies, the primary efficacy endpoint was the change from baseline to Week 8 endpoint on the Montgomery Asberg Depression Rating Scale (MADRS) total score. The MADRS is a ten-item diagnostic questionnaire used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. Historically, a mean treatment difference of at least two points from placebo has been a requirement for approval, together with a difference of at least 10% in the MADRS responder rate.

The secondary endpoint within all three pivotal studies was the change from baseline to Week 8-endpoint on the Sheehan Disability Scale (SDS) total score. The SDS is a validated scale which measures the extent emotional symptoms disrupt patients functioning in three life domains, that of work/school, social life, and family life.

Additional efficacy assessments, which varied within each pivotal study, were conducted to further support the primary and secondary efficacy endpoints. These additional efficacy assessments included:

• 17-item, Hamilton Rating Scale for Depression (HAMD-17);
• Clinical Global Impressions-Improvement (CGI-I);
• Clinical Global Impressions-Severity (CGI-S);
• Motivation and Energy Inventory-Short Form;
• MADRS response and remission rates.

Efficacy results obtained from all three studies (LVM-MD-01, LVM-MD-10 and LVM-MD-03) demonstrated that the primary efficacy endpoint was met with Fetzima showing a statistical superiority over placebo in the improvement of depressive symptoms. In each of the three studies, the mean treatment difference between all Fetzima treatment groups and their respective placebo groups exceeded three points on the MADRS total score.

The additional pivotal flexible-dose study (LVM-MD-02) which failed to demonstrate superiority over placebo was similar in design to study LVM-MD-03. However, after 8 weeks of double-blind treatment, the Fetzima treatment group (40-120 mg per day) did not show a significant improvement (decrease) in mean change from baseline on MADRS total score when compared with the placebo group (see table 1 below)

Table 1: Summary of the Least Square Mean Difference from Placebo in Change from Baseline for MADRS Score in Placebo-Controlled Studies (Intent-to-Treat Population)

Study	FETZIMA
	40 mg	80 mg	120 mg	40-120 mg
LVM-MD-01 (fixed-dose) LSMD 95% CI p-value	-3.23 (-5.92, -0.54) 0.0186	-3.99 (-6.69, -1.29) 0.0038	-4.86 (-7.59, -2.12) 0.0005	NA
LVM-MD-10 (fixed-dose) LSMD 95% CI p-value	-3.30 (-5.46, -1.15) 0.0027	-3.14 (-5.29, -0.99) 0.0043	NA	NA
LVM-MD-03 (flexible-dose) LSMD 95% CI p-value	NA	NA	NA	-3.10 (-5.26, -0.94) 0.0051
LVM-MD-02 (flexible-dose) LSMD 95% CI p-value	NA	NA	NA	-1.49 (-4.02, 1.05) 0.2492
LSMD = Least Squares Mean Difference; CI = Confidence Interval; NA = Not applicable

In each of the pivotal trials which showed efficacy based on the primary endpoint, MADRS responder rates in the Fetzima groups exceeded the placebo by 10 15%, with the exception of the 40 mg/day and 80 mg/day treatment groups in the LVM MD 01 study (see table 2 below).

Table 2: Summary of MADRS Response Rate at Week 8 (Intent-to-Treat Population)

STUDY	PLACEBO	FETZIMA
		40 mg	80 mg	120 mg	40-120 mg
LVM-MD-01 (fixed-dose) Responder, n/N (%) Odds Ratio p-value	51/175 (29.1);	64/176 (36.4) 1.442 0.1129	66/177 (37.3) 1.508 0.0742	73/176 (41.5) 1.793 0.0107	NA
LVM-MD-10 (fixed-dose) Responder, n/N (%) Odds Ratio p-value	62/185 (33.5)	90/185 (48.6) 1.871 0.0035	87/187 (46.5) 1.744 0.0095	NA	NA
LVM-MD-03 (flexible-dose) Responder, n/N1 (%) Odds Ratio p-value	63/214 (29.4)	NA	NA	NA	90/215 (41.9) 1.715 0.0083

As for the SDS secondary endpoint, all three pivotal studies which showed efficacy in the MADRS total score were also accompanied by a decrease in depression-related functional disability demonstrated by a statistically significant superiority compared to placebo on the SDS total score.

Statistically significant improvements were also seen in the HAMD-17, CGI-I, and CGI-S scores contributing to further support the efficacy results seen with the primary and secondary endpoints.

When conducting a subgroup analysis by gender, the results obtained were inconsistent across the three pivotal studies; however, these clinical studies were not designed with adequate power to detect a gender difference. Both fixed-dose clinical studies showed better response to treatment in male patients. Female patients in these studies either had a reduced treatment response at doses above 40 mg/day compared to males (Study LVM-MD-01) or failed to demonstrate clinically significant improvements in study outcomes over placebo (Study LVM-MD-10). Knowing the demographics of MDD comprises largely of females, prescribing physicians should be mindful of the absence of a clear benefit to female patients at doses greater than 40 mg/day.

A dose-response relationship was also not consistent across the three pivotal studies.  Only study LVM-MD-01 showed a trend of increasing treatment difference with increasing daily dose, but increased efficacy at higher doses appeared to be driven entirely by male patients. Only one of the two fixed-dose studies compared all three approved daily doses of levomilnacipran.

Supportive Study

The supportive Phase II study (F02695-LP-2-02) had a similar study design to that of the pivotal Phase III studies along with the same primary and secondary efficacy endpoints (MADRS and SDS), however the study duration was slightly longer (10 weeks). The efficacy results obtained from this study support those previously noted in three pivotal studies but was considered to be a supportive study since the doses used (75 and 100 mg/day) did not correspond to those used in the pivotal studies (40, 80, and 120 mg/day).

Long-Term Maintenance of Effect

A placebo-controlled, fixed-dose withdrawal study (LVM-MD-05) which evaluated the long-term use of Fetzima failed to demonstrate a long-term effect. The primary efficacy parameter for this study was the time to relapse during a double-blind treatment period, defined as the number of days from the randomization date to the relapse date (first occurrence). Results from this study demonstrated that the treatment difference was not statistically significant. A lower than expected overall relapse rate in the placebo group (20.5% actual compared to 38% expected) likely contributed to the failure of this study. Other factors included a higher than expected number of discontinuations in the open-label period leading to reduced number of subjects randomized to the double-blind phase. The discontinuation rate in the double-blind period was also higher than expected in the treatment group, particularly among male patients (33% compared to 17% among female patients). Among prematurely discontinued males treated with levomilnacipran, 'lost to follow-up' was the most frequent explanation (14.1%). Conversely, only 4 of 138 (2.9%) levomilnacipran-treated females in the double-blind period were lost to follow-up. The reason for this discrepancy among male and female discontinuations is not clear.

Overall Efficacy

The short-term efficacy of Fetzima 40 mg to 120 mg administered once daily was established in four studies: three pivotal studies (LVM-MD-01, LVM-MD-10, and LVM-MD-03) and one supportive study (F02695-LP-2-02). In each of these four studies, statistically significant improvement was seen for the Fetzima treatment groups relative to the placebo groups for the primary endpoint (change from baseline to endpoint in the MADRS total score) and secondary endpoint (change from baseline to endpoint in the SDS total score). In addition, statistically significant and clinical relevant improvements were also seen in HAMD-17, CGI-S scores and MADRS responder and remitter rates further contributing to the efficacy results of Fetzima compared to placebo.

Across the pivotal studies, consistent with MDD disease demographics, approximately two thirds (64%) of the patients were female. Knowing women are twice as likely to seek treatment for MDD; a benefit to this population was considered as an integral part of the overall benefit estimation. While data from the three pivotal Phase III studies, in addition to that of a supportive Phase II study, support the short-term use of Fetzima for symptomatic relief of moderately-severe to severe MDD, it is important to note that there is no clear benefit for female patients at doses greater than 40 mg/day.

In addition, the efficacy of Fetzima for the treatment of MDD beyond 8 weeks was not established, as a placebo-controlled dose withdrawal study failed to demonstrate effectiveness of long-term maintenance treatment. 

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

Clinical Safety

The safety of Fetzima was evaluated in 2,673 patients (18 to 78 years of age) who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD and participated in clinical studies. Among the 2,673 Fetzima-treated patients, 1,583 were exposed to Fetzima in short-term, placebo-controlled studies (see Clinical Efficacy).
A total of 737 patients were exposed to Fetzima for at least 6 months and 367 were exposed for one year. In these studies Fetzima was given at doses ranging from 40 to 120 mg once daily.

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 Fetzima-treated MDD patients in placebo-controlled studies with an incidence of ≥5% and at least twice the rate of placebo, included nausea, increased heart rate, erectile dysfunction, hyperhidrosis, constipation, tachycardia, vomiting, and palpitations. Female patients were twice as likely to experience nausea, while adverse events of dysuria and urinary hesitation occurred mainly in male patients. There were generally no dose-related adverse reactions with the exception of erectile dysfunction and urinary hesitation.

In short-term placebo-controlled studies conducted in MDD patients, 9% of the 1,583 patients who received Fetzima (40 to 120 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,040 placebo-treated patients. The most common adverse event leading to discontinuation Fetzima-treated patients was nausea (1.5%).

Fetzima was associated with significant positive chronotropic and dromotropic effects at therapeutic doses, which warranted suitable labelling within the Fetzima Product Monograph. In short-term placebo-controlled studies in patients with MDD, Fetzima (40 mg to 120 mg) was associated with mean increases of 3.0 mmHg in systolic blood pressure (SBP) and 3.2 mmHg in diastolic blood pressure (DBP) after 8 to 10 weeks of treatment, compared to a mean decrease of 0.4 mmHg SBP and no change in DBP in placebo-treated patients. Approximately 10% of Fetzima-treated patients experienced a categorical shift in blood pressure from normotensive/prehypertension to Stage I/Stage II hypertension, compared to 7% of placebo-treated patients.

Fetzima treatment was also associated with mean increases in heart rate of 7.2 bpm for 40 mg and 80 mg/day and 9.1 bpm for 120 mg/day, compared to a mean decrease of 0.3 bpm in placebo-treated patients. While these changes are significant, they do not represent the maximal increases that can be observed with levomilnacipran (the timing of the measurements in relation to dosing was not specified). In healthy volunteers who had serial blood pressure assessments during steady-state treatment with 120 mg Fetzima the mean difference from placebo in systolic blood pressure ranged from 3.8 to 7.2 mmHg and the mean difference from placebo in diastolic blood pressure ranged from 6.1 to 8.1 mmHg. Similarly, Fetzima 120 mg/day was associated with a maximum placebo-adjusted increase from baseline in heart rate of 20.2 bpm in healthy subjects with serial electrocardiogram (ECG) data collection.

Cardiovascular adverse events were more frequently reported in Fetzima-treated patients compared to placebo-treated patients which included 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. Correspondingly, knowing the demographics of MDD comprises largely of females, prescribing physicians should be aware of the absence of a clear benefit to female patients at doses greater than 40 mg/day to avoid exposing them to unnecessary health risks.

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

Other important safety risks which have been associated with use of SNRIs (like that of Fetzima) include behavioural and emotional changes, including self-harm. Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo. However, the small denominators in the clinical trials database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Further important safety risks associated with use of SNRIs include serotonin syndrome, abnormal bleeding, activation of mania/hypomania, discontinuation syndrome, seizures, and narrow angle glaucoma. Accordingly, a number of class warnings were included in the Fetzima Product Monograph to highlight these potential safety issues

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