CLINICAL STUDY RESULTS

Fixed-dose studies
MADRS

Asnis et al—Fixed-dose study

Significant improvement in depressive symptoms across 3 dosage strengths

In the Asnis et al fixed-dose study, significant reductions in depressive symptoms vs placebo were achieved in MDD patients with a mean baseline MADRS total score of 361,2,13

Primary Efficacy Endpoint:
MADRS Mean Total Score Reduction From Baseline at Week 81,2
MADRS

The primary efficacy endpoint was the change in MADRS total score from baseline to week 8 in the modified intent-to-treat (mITT) population.1,2

The LS mean difference (95% confidence interval [CI]) from placebo in change from baseline in MADRS total score was -3.2 (-5.9, -0.5) at 40 mg/day, -4.0 (-6.7, -1.3) at 80 mg/day, and -4.9 (-7.6, -2.1) at 120 mg/day.1,2

Mean baseline MADRS total score values: 36.0 (40 mg), 36.1 (80 mg), 36.0 (120 mg), 35.6 (placebo).1

Randomized, double-blind, placebo-controlled, multicenter, 8-week study to determine the efficacy, safety, and tolerability of FETZIMA in adults aged 18 to 65 years who were diagnosed with MDD. Mixed-effects model repeated-measure (MMRM) analyses shown. FETZIMA treatment was initiated once daily at 20 mg on day 1, followed by 40 mg on day 3; 80 mg/day and 120 mg/day target doses were reached on day 5 and day 8, respectively. Patients continued on target doses until the end of week 8. FETZIMA was administered with or without food.1,2
*Least squares.

Bakish et al—Additional fixed-dose study1,3


  • Both doses (40 mg and 80 mg/day) achieved significant improvement in depressive symptoms vs placebo1,3
    • MADRS mean total score change from baseline at week 8: -14.6 at 40 mg/day (n=185; P<0.01); -14.4 at 80 mg/day (n=187; P<0.01); -11.3 for placebo (n=185)1,3

The primary efficacy endpoint was the change in MADRS total score from baseline to week 8 in the mITT population.1,3

The LS mean difference (95% CI) from placebo in change from baseline in MADRS total score was -3.3 (-5.5, -1.1) at 40 mg/day and -3.1 (-5.3, -1.0) at 80 mg/day.1,3

Mean baseline MADRS total score values: 30.8 (40 mg), 31.2 (80 mg), 31.0 (placebo).1

Randomized, double-blind, placebo-controlled, multicenter, 8-week study to determine the efficacy, safety, and tolerability of FETZIMA in adults aged 18 to 75 years who were diagnosed with MDD. Patients were randomized to receive FETZIMA (n=372) or placebo (n=185). MMRM analyses shown. FETZIMA treatment was initiated once daily at 20 mg on day 1, followed by 40 mg on day 3; 80 mg/day target dose was reached on day 6. Patients continued on target doses until the end of week 8. FETZIMA was administered with or without food.1,3

SDS

Asnis et al—Fixed-dose study

Significant improvement in functional impairment

Secondary Efficacy Endpoint:
SDS Mean Total Score Reduction From Baseline at Week 82
chart
  • The difference was not statistically significant vs placebo at 40 mg/day and was statistically significant vs placebo at 80 mg and 120 mg/day2

The secondary efficacy endpoint was the change in SDS total score from baseline to week 8 in the mITT population.1,2

The LS mean difference (95% CI) from placebo in change from baseline in SDS total score was -1.4 (-3.4, 0.6) at 40 mg/day, -2.5 (-4.5, -0.5) at 80 mg/day, and -2.6 (-4.6, -0.5) at 120 mg/day.2,13

Mean baseline SDS total score values: 21.1 (40 mg), 21.4 (80 mg), 21.3 (120 mg), 21.5 (placebo).2

NS=Not significant.

Randomized, double-blind, placebo-controlled, multicenter, 8-week study to determine the efficacy, safety, and tolerability of FETZIMA in adults aged 18 to 65 years who were diagnosed with MDD. Mixed-effects model repeated-measure (MMRM) analyses shown. FETZIMA treatment was initiated once daily at 20 mg on day 1, followed by 40 mg on day 3; 80 mg/day and 120 mg/day target doses were reached on day 5 and day 8, respectively. Patients continued on target doses until the end of week 8. FETZIMA was administered with or without food.1,2

Bakish et al—Additional fixed-dose study1,3


  • Both doses (40 mg and 80 mg/day) achieved significant improvement in functional impairment vs placebo1,3
    • SDS mean total score change from baseline at week 8: -7.3 at 40 mg/day (P<0.05); -8.2 at 80 mg/day (P<0.01); -5.4 for placebo3

The secondary efficacy endpoint was the change in SDS total score from baseline to week 8 in the mITT population.1,3

The LS mean difference (95% CI) from placebo in change from baseline in SDS total score was -1.8 (-3.6, 0.0) at 40 mg/day and -2.7 (-4.5, -0.9) at 80 mg/day.1,3

Mean baseline SDS total score values: 16.7 (40 mg), 17.6 (80 mg), 16.4 (placebo).3

Randomized, double-blind, placebo-controlled, multicenter, 8-week study to determine the efficacy, safety, and tolerability of FETZIMA in adults aged 18 to 75 years who were diagnosed with MDD. Patients were randomized to receive FETZIMA (n=372) or placebo (n=185). MMRM analyses shown. FETZIMA treatment was initiated once daily at 20 mg on day 1, followed by 40 mg on day 3; 80 mg/day target dose was reached on day 6. Patients continued on target doses until the end of week 8. FETZIMA was administered with or without food.1,3

MADRS by Study Visit

Asnis et al—Fixed-dose study

Significant improvement in depressive symptoms across the therapeutic range

Significant reductions in depressive symptoms vs placebo were achieved at week 8 in MDD patients with a mean baseline MADRS total score of 361,2,13

MADRS Mean Total Score by Study Visit2
chart
Treatment Week
Mean baseline MADRS total score values: 36.0 (40 mg), 36.1 (80 mg), 36.0 (120 mg), 35.6 (placebo)1

  • Whether the statistically significant differences observed at time points earlier than 8 weeks represent clinically relevant treatment effects is unknown

The primary efficacy endpoint was the change in MADRS total score from baseline to week 8 in the mITT population. MMRM analysis shown.1,2

The LS mean difference (95% CI) from placebo in change from baseline in MADRS total score was -3.2 (-5.9, -0.5) at 40 mg/day, -4.0 (-6.7, -1.3) at 80 mg/day, and -4.9 (-7.6, -2.1) at 120 mg/day.1,2

Reproduced with permission ©2013; Physicians Postgraduate Press, Inc.

Flexible-dose study
MADRS

Sambunaris et al—Flexible-dose study

Significant improvement in depressive systems across the therapeutic range

Significant reductions in depressive symptoms vs placebo were achieved in MDD patients with a mean baseline MADRS total score of 351,4,13

Primary Efficacy Endpoint:
MADRS Mean Total Score Reduction From Baseline at Week 81,4
chart chart

The primary efficacy endpoint was the change in MADRS total score from baseline to week 8 in the mITT population.1,4

The LS mean difference (95% CI) from placebo in change from baseline in MADRS total score was -3.1 (-5.3, -0.9).1,4

Mean baseline MADRS total score values: 35.0 for FETZIMA and 35.2 for placebo.1

Randomized, double-blind, placebo-controlled, multicenter, 8-week study to determine the efficacy, safety, and tolerability of FETZIMA in adults aged 18 to 80 years who were diagnosed with MDD. MMRM analyses shown. FETZIMA treatment was initiated once daily at 20 mg on day 1, followed by 40 mg on day 3. Dose increase to 80 mg/day permitted at end of week 1 or 2; increase from 40 mg to 80 mg/day or 80 mg to 120 mg/day permitted at end of week 4 based on patient response and tolerability. Patients continued on target doses until the end of week 8. FETZIMA was administered with or without food.1,4

SDS

Sambunaris et al—Flexible-dose study

Significant improvement in functional impairment

Significant improvement in functional impairment vs placebo was achieved in MDD patients with a mean baseline SDS total score of 204,13

Secondary Efficacy Endpoint:
SDS Mean Total Score Reduction From Baseline at Week 84
chart

The secondary efficacy endpoint was the change in SDS total score from baseline to week 8 in the mITT population.1,4

The LS mean difference (95% CI) from placebo in change from baseline in SDS total score was -2.6 (-4.2, -1.1).4

Mean baseline SDS total score values: 20.1 for FETZIMA and 19.7 for placebo.4

Randomized, double-blind, placebo-controlled, multicenter, 8-week study to determine the efficacy, safety, and tolerability of FETZIMA in adults aged 18 to 80 years who were diagnosed with MDD. MMRM analyses shown. FETZIMA treatment was initiated once daily at 20 mg on day 1, followed by 40 mg on day 3. Dose increase to 80 mg/day permitted at end of week 1 or 2; increase from 40 mg to 80 mg/day or 80 mg to 120 mg/day permitted at end of week 4 based on patient response and tolerability. Patients continued on target doses until the end of week 8. FETZIMA was administered with or without food.1,4

MADRS by Study Visit

Sambunaris et al—Flexible-dose study

Significant improvement in depressive symptoms across the therapeutic range

Significant reductions in depressive symptoms vs placebo were achieved at week 8 in MDD patients with a mean baseline MADRS total score of 351,4,13

MADRS Mean Total Score by Study Visit4
chart
Treatment Week
Mean baseline MADRS total score values: 35.0 for FETZIMA and 35.2 for placebo1

  • Whether the statistically significant differences observed at time points earlier than 8 weeks represent clinically relevant treatment effects is unknown

The primary efficacy endpoint was the change in MADRS total score from baseline to week 8 in the mITT population. MMRM analysis shown.1,4

The LS mean difference (95% CI) from placebo in change from baseline in MADRS total score was -3.1 (-5.3, -0.9).1,4

Reproduced with permission.

To learn about FETZIMA safety information, visit Adverse Event Profile

FETZIMA INDICATION AND USAGE

  • FETZIMA (levomilnacipran) extended-release capsules is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of Major Depressive Disorder (MDD) in adults.
  • FETZIMA is not approved for the management of fibromyalgia, and its efficacy and safety have not been established for that use.

IMPORTANT SAFETY INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.
FETZIMA is not approved for use in pediatric patients.

Contraindications

  • FETZIMA is contraindicated in patients with a hypersensitivity to levomilnacipran, milnacipran HCl, or to any excipient in the formulation.
  • The use of MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA is contraindicated due to an increased risk of serotonin syndrome. The use of FETZIMA within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
    Starting FETZIMA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated due to an increased risk of serotonin syndrome.
Warnings and Precautions
  • All patients being treated with antidepressants should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment and when increasing or decreasing the dose. Consider changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, or suicidality that are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants should be alerted about the need to monitor patients daily. Prescriptions for FETZIMA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
  • Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Symptoms of serotonin syndrome may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms. If symptoms of serotonin syndrome occur, discontinue FETZIMA immediately and initiate supportive treatment. If concomitant use of FETZIMA with other serotonergic drugs is clinically warranted, patients should be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
  • SNRIs, including FETZIMA, have been associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Pre-existing hypertension should be controlled before initiating treatment with FETZIMA. Use with caution in patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. Concomitant use of FETZIMA with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. For patients who experience a sustained increase in blood pressure, discontinuation or other appropriate medical intervention should be considered.
  • SNRIs, including FETZIMA, have been associated with an increase in heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with FETZIMA. For patients who experience a sustained increase in heart rate, discontinuation or other appropriate medical intervention should be considered.
  • SSRIs and SNRIs, including FETZIMA, may increase the risk of bleeding events, some serious. Concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants may add to this risk.
  • Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. The pupillary dilation that occurs following use of many antidepressant drugs including FETZIMA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
  • FETZIMA can affect urethral resistance. In clinical studies, urinary hesitation occurred in 4%, 5% and 6% of FETZIMA-treated patients receiving doses of 40, 80, and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised when using FETZIMA in patients prone to obstructive urinary disorders.
  • Symptoms of mania/hypomania were reported in 0.2% of FETZIMA-treated patients and 0.2% of placebo-treated patients in clinical studies. As with all antidepressants, FETZIMA should be used cautiously in patients with a history or family history of bipolar disorder, mania or hypomania. Prior to initiating treatment with FETZIMA, patients should be adequately screened to determine if they are at risk for bipolar disorder. FETZIMA is not approved for use in treating bipolar depression.
  • FETZIMA should be prescribed with caution in patients with a seizure disorder.
  • Discontinuation symptoms, some serious, have been reported with discontinuation of serotonergic antidepressants such as FETZIMA. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients when discontinuing FETZIMA. If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate.
  • Advise patients that if they are treated with diuretics or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking FETZIMA. Although no cases of hyponatremia resulting from FETZIMA treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. FETZIMA should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Adverse Reactions

The most commonly observed adverse reactions in MDD patients treated with FETZIMA in placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were: nausea (17% vs 6%), constipation (9% vs 3%), hyperhidrosis (9% vs 2%), heart rate increased (6% vs 1%), erectile dysfunction (6% vs 1%), tachycardia (6% vs 2%), vomiting (5% vs 1%), and palpitations (5% vs 1%).

Please also see the full Prescribing Information.


IMPORTANT SAFETY INFORMATION
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