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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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
FETZIMA is not approved for use in pediatric patients [see Use In Specific Populations].
The active ingredient of FETZIMA is levomilnacipran, which is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). The chemical name of levomilnacipran is (1S,2R)-2( aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride; its empirical formula is C15H23ClN2O and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial US approval: 2013) is the 1S,2R-enantiomer of milnacipran. The chemical structure is:
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FETZIMA capsules are intended for oral administration only. Each FETZIMA capsule contains extended-release beads with 23.0, 45.9, 91.8, or 137.8 mg of levomilnacipran hydrochloride equivalent to 20, 40, 80, or 120 mg of levomilnacipran, respectively. Inactive ingredients include sugar spheres, ethylcellulose, talc, povidone, triethyl citrate, hypromellose, and titanium dioxide. Inactive ingredients also include shellac glaze, black iron oxide, yellow iron oxide (20 mg and 40 mg capsules only), and red iron oxide (80 mg and 120 mg capsules only).
FETZIMA® is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies].
FETZIMA is not approved for the management of fibromyalgia. The efficacyand safety of FETZIMA for the management of fibromyalgia have not been established.
The recommended dosage range for FETZIMA is 40 mg to 120 mg once daily, with or withoutfood. FETZIMA should be initiated at 20 mg once daily for 2 days and then increased to 40 mgonce daily. Based on clinical response and tolerability, FETZIMA may be increased inincrements of 40 mg at intervals of 2 or more days. The maximum recommended dosage is 120mg once daily.
Take FETZIMA at approximately the same time each day. Swallow FETZIMA whole; do notopen, chew, or crush the capsule.
Prior to initiating treatment with FETZIMA or another antidepressant, screen patients for apersonal or family history of bipolar disorder, mania, or hypomania [see WARNINGS ANDPRECAUTIONS].
Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such asFETZIMA. Gradual dose reduction is recommended, instead of abrupt discontinuation,whenever possible. Monitor patients for these symptoms when discontinuing FETZIMA. Ifintolerable 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[seeWARNINGS ANDPRECAUTIONS].
At least 14 days must elapse between discontinuation of an MAOI intended to treat psychiatricdisorders and initiation of therapy with FETZIMA. Conversely, at least 7 days should be allowedafter stopping FETZIMA before starting an MAOI antidepressant [see CONTRAINDICATIONS].
The maximum recommended dosage of FETZIMA should not exceed 80 mg once daily whenused with strong CYP3A4 inhibitors [see DRUG INTERACTIONS]
FETZIMA (levomilnacipran) is available as 20 mg, 40 mg, 80 mg, and 120 mg extended-releasecapsules.
| Capsule Strength | Capsule Color/Shape | Capsule Markings |
| 20 mg | yellow cap white body | black “FL” on cap black “20” on body |
| 40 mg | yellow cap yellow body | black “FL” on cap black “40” on body |
| 80 mg | pink cap white body | black “FL” on cap black “80” on body |
| 120 mg | pink cap pink body | black “FL” on cap black “120” on body |
FETZIMA extended-release capsules are supplied in the following configurations:
| Capsule Strength | Capsule Color/Shape | Capsule Markings | Package Configuration | NDC Code |
| 20 mg | yellow cap white body | black “FL” on cap black “20” on body | Bottle / 30 count | 0456-2220-30 |
| Hospital Unit Dose (Blister) / 10 x 10 | 0456-2220-63 | |||
| 40 mg | yellow cap yellow body | black “FL” on cap black “40” on body | Bottle / 30 count | 0456-2240-30 |
| Bottle / 90 count | 0456-2240-90 | |||
| Hospital Unit Dose (Blister) / 10 x 10 | 0456-2240-63 | |||
| 80 mg | pink cap white body | black “FL” on cap black “80” on body | Bottle / 30 count | 0456-2280-30 |
| Bottle / 90 count | 0456-2280-90 | |||
| Hospital Unit Dose (Blister) /10 x 10 | 0456-2280-63 | |||
| 120 mg | pink cap pink body | black “FL” on cap black “120” on body | Bottle / 30 count | 0456-2212-30 |
| Bottle / 90 count | 0456-2212-90 | |||
| Hospital Unit Dose (Blister) / 10 x 10 | 0456-2212-63 |
FETZIMA Titration Pack is supplied in the following configuration:
| Capsule Strength | Capsule Color/Shape | Capsule Markings | Package Configuration | NDC Code |
| 20 mg | yellow cap white body | black “FL” on cap black “20” on body | Titration Pack (Blister) containing two 20 mg capsules and twenty-six 40 mg capsules | 0456-2202-28 |
| 40 mg | yellow cap yellow body | black “FL” on cap black “40” on body |
All package configurations: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature].
Distributed by:AbbVie, Inc., 1 N Waukegan Rd., North Chicago, IL 60064. Revised: Apr 2024
The following adverse reactions are discussed in greater detail in other sections of the label.
Because clinical trials are conducted under widely varying conditions, adverse reaction ratesobserved in the clinical trials of a drug cannot be directly compared to rates in the clinical studiesof another drug and may not reflect the rates observed in clinical practice.
The safety of FETZIMA was evaluated in 3,317 patients (18 to 78 years of age) diagnosed withMDD who participated in clinical studies, representing 1,186 patient-years of exposure. Amongthe 3,317 FETZIMA-treated patients, 1,583 were exposed to FETZIMA in short-term, placebocontrolledstudies. There were 825 patients who continued from short-term studies into aoneyear,open-label extension study.
Of the 3,317 patients exposed to at least one dose of FETZIMA, 895 patients were exposed toFETZIMA for at least 6 months and 367 were exposed for one year. In these studies, FETZIMAwas given at doses ranging from 40 mg to 120 mg once daily and was given without regard tofood.
In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patientswho received FETZIMA (40 mg to 120 mg) discontinued treatment due to an adverse reaction,compared with 3% of the 1,040 placebo-treated patients in those studies. The most commonadverse reaction leading to discontinuation in at least 1% of the FETZIMA-treated patients in theshort-term placebo-controlled studies was nausea (1.5%).
The most commonly observed adverse reactions in FETZIMA-treated MDD patients in placebocontrolledstudies (incidence ≥ 5% and at least twice the rate of placebo) were: nausea,constipation, hyperhidrosis, heart rate increased, erectile dysfunction, ejaculation disorder,tachycardia, vomiting, and palpitations.
Table 3 shows the incidence of adverse reactions that occurred in ≥ 2% of FETZIMA-treatedMDD patients and at least twice the rate of placebo in the placebo-controlled studies.
Table 3 :Adverse Reactions Occurring in ≥ 2% of FETZIMA-treatedPatients and at Least Twice the rate of Placebo-treated Patientsin Pooled MDD Studies
| System Organ Class Preferred Term |
Placebo (N =1040) % |
FETZIMA 40 mg to 120 mg per day (N = 1583) % |
| Gastrointestinal disorders | ||
| Nausea | 6 | 17 |
| Constipation | 3 | 9 |
| Vomiting | 1 | 5 |
| Cardiac disorders | ||
| Tachycardiaa | 2 | 6 |
| Palpitations | 1 | 5 |
| Reproductive system and breast disordersb | ||
| Erectile dysfunctionc | 1 | 6 |
| Testicular paind | <1 | 4 |
| Ejaculation disordere | <1 | 5 |
| Investigations | ||
| Heart rate increasedf | 1 | 6 |
| Blood pressure increasedg | 1 | 3 |
| Renal and urinary disorders | ||
| Urinary hesitation | 0 | 4 |
| Skin and subcutaneous tissue disorders | ||
| Hyperhidrosis | 2 | 9 |
| Rashh | 0 | 2 |
| Vascular disorders | ||
| Hot flush | 1 | 3 |
| Hypotensioni | 1 | 3 |
| Hypertensionj | 1 | 3 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 1 | 3 |
| a Tachycardia also includes: sinus tachycardia and postural orthostatic tachycardia syndrome b Percentage is relative to the number of patients in the associated demographic sex category.Fewer than 2% of FETZIMA-treated MDD female patients in placebo-controlled clinicalstudies reported adverse events related to sexual function. c Erectile dysfunction includes: erectile dysfunction, organic erectile dysfunction, andpsychogenic erectile dysfunction d Testicular pain includes: testicular pain, epididymitis, and seminal vesiculitis e Ejaculation disorder includes: ejaculation disorder, ejaculation delayed, ejaculation failure,and premature ejaculation f Heart rate increased also includes: orthostatic heart rate response increased g Blood pressure increased also includes: blood pressure systolic increased, blood pressurediastolic increased, and blood pressure orthostatic increased h Rash also includes: rash generalized, rash maculo-papular, rash erythematous, and rashmacular i Hypotension also includes: orthostatic hypotension and dizziness postural j Hypertension also includes: labile hypertension N = number of patients in the Safety Population |
||
In pooled data from the short-term placebo-controlled fixed-dose studies, there were no doserelatedadverse reactions (greater than 2% overall incidence) in patients treated with FETZIMAacross the dose range 40 mg to 120 mg once daily, with the exception of erectile dysfunction andurinary hesitation (see Table 4).
Table 4 :Dose-Related Adverse Reactions
| System Organ Class Preferred Term | Placebo (N = 362) % |
FETZIMA | ||
| 40 mg per day (N = 366) % |
80 mg per day (N = 367) % |
120 mg per day (N = 180) % |
||
| Urinary hesitation | 0 | 4 | 5 | 6 |
| Erectile dysfunctiona | 2 | 6 | 8 | 10 |
| a Percentage is relative to the number of male patients. N = number of patients in the Safety Population |
||||
Other infrequent adverse reactions, not described elsewhere in the label, occurring at anincidence of < 2% in MDD patients treated with FETZIMA were:
Cardiac disorders: Angina pectoris; Supraventricular and Ventricular extrasystoles
Eye disorders: Dry eye; Vision blurred; Conjunctival hemorrhage
General disorders: Chest pain; Thirst
Gastrointestinal disorders: Abdominal pain; Flatulence
Investigations disorders: Blood cholesterol increased; Liver function test abnormal
Nervous System disorders: Migraine; Paraesthesia; Syncope; Extrapyramidal disorder
Psychiatric disorders: Agitation; Anger; Bruxism; Panic attack; Tension; Aggression
Renal and Urinary disorder: Pollakiuria; Hematuria; Proteinuria
Respiratory, thoracic and mediastinal disorders: Yawning
Skin and subcutaneous tissue disorders: Dry skin; Pruritus; Urticaria
The following adverse reaction has been identified during post-approval use of FETZIMA orother selective serotonin and norepinephrine reuptake inhibitors. Because these reactions arereported voluntarily from a population of uncertain size, it is not always possible to reliablyestimate their frequency or establish a causal relationship to drug exposure.
Cardiac disorders:Takotsubo cardiomyopathy
Respiratory, thoracic and mediastinal disorders: Anosmia, Hyposmia
Table 5 includes clinically important drug interactions with FETZIMA.
Table 5: Clinically Important Drug Interactions with FETZIMA
Monoamine Oxidase Inhibitors (MAOIs)| Clinical Impact: | Concomitant use of SSRIs and SNRIs including FETZIMA with MAOIs increases the risk of serotonin syndrome. |
| Intervention: | Concomitant use of FETZIMA is contraindicated:
|
| Examples: | selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
| Other Serotonergic Drugs | |
| Clinical Impact: | Concomitant use of FETZIMA with other serotonergic drugs increases the risk of serotonin syndrome. |
| Intervention: | Monitor for symptoms of serotonin syndrome when FETZIMA is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, immediately discontinue FETZIMA and/or concomitant serotonergic drugs [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]. |
| Examples: | other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort |
| Drugs that Interfere with Hemostasis | |
| Clinical Impact: | Concomitant use of FETZIMA with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of FETZIMA on the release of serotonin by platelets. |
| Intervention: | Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when FETZIMA is initiated or discontinued [see WARNINGS AND PRECAUTIONS]. |
| Examples: | NSAIDs, aspirin, and warfarin |
| Strong CYP3A Inhibitors | |
| Clinical Impact: | Concomitant use of FETZIMA with strong CYP3A4 inhibitors increases levomilnacipran exposure [see Pharmacokinetics]. |
| Intervention: | The dose of FETZIMA should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors [see DOSAGE AND ADMINISTRATION.] |
| Examples: | Ketoconazole, itraconazole, clarithromycin |
| Alcohol | |
| Clinical Impact: | Concomitant use of FETZIMA and alcohol may result in accelerated release of levomilnacipran. |
| Intervention: | Avoid concomitant use of FETZIMA and alcohol [see CLINICAL PHARMACOLOGY]. |
FETZIMA is not a controlled substance.
FETZIMA has not been systematically studied in animals or humans for its potential for abuse.There was no evidence suggestive of drug-seeking behavior in the clinical studies. It is notpossible to predict on the basis of clinical experience the extent to which a CNS active drug willbe misused, diverted, and/or abused once marketed. Consequently, physicians should carefullyevaluate patients for a history of drug abuse and follow such patients closely, observing them forsigns of misuse or abuse of FETZIMA (e.g., development of tolerance or drug-seeking behavior).
FETZIMA has not been systematically studied in animals or humans for its potential for dependence.
Included as part of the PRECAUTIONS section.
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients aged 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.
Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients
| Age Range | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated |
| Increases Compared to Placebo | |
| <18 years old | 14 additional patients |
| 18-24 years old | 5 additional patients |
| Decreases Compared to Placebo | |
| 25-64 years old | 1 fewer patient |
| ≥65 years old | 6 fewer patients |
| *Fetzima is not approved for use in pediatric patients. | |
It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.
Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing FETZIMA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Serotonin-norepinephrine reuptake inhibitors (SNRIs), including FETZIMA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see CONTRAINDICATIONS, DRUG INTERACTIONS]. Serotonin syndrome can also occur when these drugs are used alone.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of FETZIMA with MAOIs is contraindicated. In addition, do not initiate FETZIMA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking FETZIMA, discontinue FETZIMA before initiating treatment with the MAOI [see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS, DRUG INTERACTIONS].
Monitor all patients taking FETZIMA for the emergence of serotonin syndrome. Discontinue treatment with FETZIMA and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. If concomitant use of FETZIMA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
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. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. For patients who experience a sustained increase in blood pressure while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered.
Table 2 shows the mean changes in blood pressure, sustained hypertension, and upward shifts in hypertensive status that were observed in FETZIMA-treated adult patients in the short-term placebo-controlled studies.
Table 2 : Blood Pressure Mean Changes, Sustained Hypertension, and Upward Shifts in Hypertensive Status with FETZIMA (in Adults)
| Placebo | FETZIMA 40 to 120 mg/day | |
| Mean change from baseline to end of treatment, mm Hg | ||
| Systolic blood pressure (SBP) | -0.4 | 3.0 |
| Diastolic blood pressure (DBP) | -0.0 | 3.2 |
| Sustained Hypertension, % of patients | ||
| Broad Criteria: SBP ≥ 140 mm Hg and an increase ≥15 mm Hg OR DBP ≥ 90 mm Hg and an increase ≥ 10 mm Hg for at least 3 consecutive visits | 1.2 | 1.8 |
| Strict Criteria: SBP ≥ 140 mm He and an increase ≥15 mm Ha AND DBP ≥ 90 mm Hg and an increase ≥ 10 mm Hg for at least 3 consecutive visits | 0.1 | 0.3 |
| Upward Shifts in Hypertensive Statusa, % of patients | ||
| Normal/ Pre-hypertensive → Stage I/ Stage II | 7.1 | 10.4 |
| a Normal Blood Pressure: SBP < 120 mm Hg and DBP < 80 mm Hg Pre-hypertension: SBP ≥ 120 mm Hg and ≤ 139 mm Hg or DBP ≥ 80 mm Hg and ≤ 89 mm Hg Stage I hypertension: SBP ≥ 140 mm Hg and ≤ 159 mm Hg or DBP ≥ 90 mm Hg and ≤ 99 mm Hg Stage II hypertension: SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg |
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In the short-term, placebo-controlled MDD studies in adults, the mean increase from initiation of treatment in systolic BP was 3 mm Hg and diastolic BP was 3.2 mm Hg, as compared to no change in the placebo group. There were no dose-related changes in systolic and diastolic blood pressure observed.
In adult patients exposed to one-year, open-label treatment of FETZIMA (doses range from 40- 120 mg once daily), the mean change from initiation of treatment in systolic BP was 3.9 mm Hg and diastolic BP was 3.1 mm Hg.
In short-term, placebo- and active-controlled MDD studies in pediatric patients 7 years to less than 18 years of age, treatment with FETZIMA was associated with the occurrence of new-onset hypertension (two systolic and/or diastolic BP measurements in the stage I hypertension range and/or one measurement in the stage II range) in 36.2% of treated patients compared with 20.7% of patients randomized to placebo. Elevations in either systolic or diastolic BP leading to measures at or above the stage II hypertension threshold occurred in 12.1% of pediatric patients treated with FETZIMA and 7.5% of patients randomized to placebo. Sustained hypertension (three or more consecutive systolic or diastolic BP measurements at or above the stage I hypertension threshold) occurred in 15% of pediatric patients treated with FETZIMA and 4% of patients randomized to placebo. The safety and effectiveness of FETZIMA have not been established in pediatric patients for the treatment of MDD.
In the short-term, placebo-controlled studies in adults, 11.6% of patients met orthostatic hypotension criteria (SBP or DBP) in the FETZIMA group compared to 9.7% in the placebo group. Orthostatic reductions of blood pressure ≥ 10 mm Hg in DBP occurred in 5.8%, 6.1%, and 9.8% of FETZIMA-treated patients with doses of 40, 80, and 120 mg/day respectively, compared to 6.2% of placebo-treated patients.
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. Effects of FETZIMA on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. FETZIMA should be used with caution in these patients.
SNRIs, including FETZIMA, have been associated with increased heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Preexisting tachyarrhythmias and other cardiac disease should be treated before starting therapy with FETZIMA. For patients who experience a sustained increase in heart rate while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered.
In short-term clinical studies, FETZIMA treatment was associated with a mean increase in heart rate of 7.4 beats per minute (bpm) compared to a mean decrease of 0.3 bpm in placebo-treated patients. Heart rate increase in FETZIMA-treated patients receiving doses of 40 mg, 80 mg, and 120 mg was 7.2, 7.2, and 9.1 bpm.
FETZIMA has not been systematically evaluated in patients with a cardiac rhythm disorder.
Drugs that interfere with serotonin reuptake, including FETZIMA, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use In Specific Populations]. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Inform patients about the increased risk of bleeding associated with the concomitant use of FETZIMA and NSAIDs, aspirin, or other drugs that affect coagulation [see DRUG INTERACTIONS].
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. Avoid use of antidepressants, including FETZIMA, in patients with anatomically narrow angles.
The noradrenergic effect of SNRIs including FETZIMA, can affect urethral resistance. In the controlled short-term studies, urinary hesitation occurred in 4%, 5%, and 6% of FETZIMAtreated patients receiving doses of 40, 80, and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised in the use of FETZIMA in patients prone to obstructive urinary disorders. If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with FETZIMA, consideration should be given to the possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered.
Symptoms of mania/hypomania were reported in 0.2% of FETZIMA-treated patients and 0.2% of placebo-treated patients in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other antidepressants. Prior to initiating treatment with FETZIMA, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.
One case of seizure has been reported in pre-marketing clinical studies with FETZIMA. FETZIMA has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. FETZIMA should be prescribed with caution in patients with a seizure disorder.
There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Monitor patients for these symptoms when discontinuing FETZIMA. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate [see DOSAGE AND ADMINISTRATION].
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including FETZIMA. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. FETZIMA should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Use of SNRIs, including FETZIMA, may cause symptoms of sexual dysfunction [see ADVERSE REACTIONS]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.
It is important for prescribers to inquire about sexual function prior to initiation of FETZIMA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Advise patients that FETZIMA should be swallowed whole and should not be chewed, crushed, or opened.
Advise patients that FETZIMA can be taken with or without food.
Instruct patients if they miss a dose, to take the missed dose as soon as they remember. If it is almost time for the next dose, instruct them to skip the missed dose and take their next dose at the regular time. Advise them not to take two doses of FETZIMA at the same time.
Instruct patients not to take FETZIMA with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping FETZIMA before starting an MAOI [see CONTRAINDICATIONS]. Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for drug-drug interactions [see DRUG INTERACTIONS].
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see CONTRAINDICATIONS].
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of FETZIMA with other serotonergic agents (including triptans, tricyclic antidepressants, opioids, lithium, amphetamines, tryptophan, buspirone, and St. John’s Wort supplements) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.
Advise patients that they should have regular monitoring of blood pressure and heart rate when taking FETZIMA [see WARNINGS AND PRECAUTIONS].
Caution patients about the concomitant use of FETZIMA and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation because combined use has been associated with an increased risk of bleeding. Advise patients to inform their healthcare provider if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see WARNINGS AND PRECAUTIONS].
Patients should be advised that taking FETZIMA can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma [see WARNINGS AND PRECAUTIONS].
Caution patients about the risk of urinary hesitation and retention while taking FETZIMA, particularly in patients prone to obstructive urinary disorders. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see WARNINGS AND PRECAUTIONS].
Advise patients and their caregivers to look for signs of activation of mania/hypomania [see WARNINGS AND PRECAUTIONS].
Caution patients about using FETZIMA if they have a history of a seizure disorder [see WARNINGS AND PRECAUTIONS].
Advise patients not to abruptly stop taking FETZIMA without first talking with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping FETZIMA and they should monitor for discontinuation symptoms [see WARNINGS AND PRECAUTIONS].
Advise patients that hyponatremia has been reported as a result of treatment with FETZIMA. Advise patients of the signs and symptoms of hyponatremia [see WARNINGS AND PRECAUTIONS].
Advise patients that use of FETZIMA may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients to avoid consumption of alcohol while taking FETZIMA [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Advise breastfeeding patients using FETZIMA to monitor infants for sedation, agitation, irritability, poor feeding, and poor weight gain and to seek medical care if they notice these signs [see Use In Specific Populations].
Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that FETZIMA therapy does not adversely affect their ability to engage in such activities.
Levomilnacipran administered by oral gavage to rats for 2 years and Tg.rasH2 mice for 6 months did not increase the incidence of tumors in either study.
Rats received levomilnacipran at doses up to 90/70 mg/kg/day (the dose was lowered in males after 45 weeks of dosing). The 90 mg/kg/day dose is 7 times the maximum recommended human dose (MRHD) of 120 mg on a mg/m² basis.
Tg.rasH2 mice received levomilnacipran at doses up to 150 mg/kg/day.
Levomilnacipran was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vivo micronucleus assay in rats. Additionally, levomilnacipran was not genotoxic in the in vitro mouse lymphoma (L5178Y TK+/-) cell forward mutation assay.
When levomilnacipran was administered orally to male and female rats before mating, through mating and up to Day 7 of gestation at doses up to 100 mg/kg/day, no effects were observed on fertility. This dose is 8 times the MRHD on a mg/m² basis.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-andresearchprograms/ pregnancyregistry/antidepressants.
Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see WARNINGS AND PRECAUTIONS and Clinical Considerations].
The available data on FETZIMA use in pregnant women are insufficient to evaluate for a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including FETZIMA, during pregnancy (see Clinical Considerations).
In animal reproduction studies, levomilnacipran was not associated with malformations in rats or rabbits when given during the period of organogenesis at doses up to 8 or 16 times the maximum recommended human dose (MRHD) of 120 mg on a mg/m² basis, respectively. However, an increase in early post-natal rat pup mortality was seen at a dose equivalent to 5 times the MRHD given during pregnancy and lactation (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Maternal Adverse Reactions
Use of FETZIMA in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see WARNINGS AND PRECAUTIONS].
Fetal/Neonatal Adverse Reactions
Neonates exposed to SNRIs or SSRIs, including FETZIMA, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either direct toxic effect of SSRIs and SNRIs or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS AND PRECAUTIONS].
Animal Data
No malformations were observed when levomilnacipran was administered to pregnant rats or rabbits during the period of organogenesis at oral doses up to 100 mg/kg/day. This dose is 8 and 16 times (in rats and rabbits, respectively) the maximum recommended human dose (MRHD) of 120 mg on a mg/m² basis. Fetal body weights were reduced in rats, and skeletal ossification was delayed in both rats and rabbits at this dose; these effects were not observed in either species at doses up to 30 mg/kg/day, 2.4 times the MRHD in rats or 5 times the MRHD in rabbits on a mg/m² basis.
When levomilnacipran was administered to pregnant rats at an oral dose of 60 mg/kg/day, 5 times the MRHD, during organogenesis and throughout pregnancy and lactation, there was an increase in early postnatal pup mortality; no pup mortality was seen at 20 mg/kg/day, 1.6 times the MRHD on a mg/m² basis. Among the surviving pups, pre- and post-weaning pup weight gain was reduced up to at least 8 weeks of age; however, physical and functional development, including reproductive performance of the progeny, was not affected. The effects on body weight gain were not seen at 7 mg/kg/day, 0.6 times the MRHD on a mg/m² basis.
There are no available data on the presence of levomilnacipran in human milk; however, racemic milnacipran is present in human milk (see Data). There are no reports on the effects of levomilnacipran or milnacipran on the breastfed infant or the effects on milk production. However, there are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to SSRIs or SNRIs through breast milk (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FETZIMA and any potential adverse effects on the breastfed child from FETZIMA or from the underlying maternal conditions.
Infants exposed to FETZIMA should be monitored for agitation, irritability, poor feeding and poor weight gain.
Milnacipran, a racemic mixture that contains levomilnacipran (the 1S,2R-enantiomer of milnacipran), is present in the milk of lactating women treated with milnacipran. In a lactation pharmacokinetic study with milnacipran, a single, oral dose of 50 mg milnacipran HCl tablet was administered to 8 lactating women who were at least 12 weeks postpartum and weaning their infants. The milk/plasma AUC ratio of milnacipran was 1.85 ± 0.38. The maximum estimated weight-adjusted daily infant dose for milnacipran from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 5% of the maternal weight-adjusted dose based on peak plasma concentrations.
The safety and effectiveness of FETZIMA have not been established in pediatric patients for the treatment of major depressive disorder (MDD).
The safety and efficacy of FETZIMA were evaluated in two randomized, double-blind, placebo- and active-controlled 8-week trials in pediatric patients with MDD, one in patients 7 to 17 years of age  (flexible-dose study) and the other in patients 12 to 17 years of age (fixed-dose study). The primary efficacy endpoint for both studies was the change from baseline to week 8 in the Children’s Depression Rating Scale-Revised (CDRS-R) total score. The CDRS-R assesses the severity of depression and change in depressive symptoms in children and adolescents with depression. FETZIMA was not superior to placebo in either study. The most commonly observed adverse reactions in pediatric patients 7 to 17 years of age randomized to FETZIMA were similar to those observed in adults [see ADVERSE REACTIONS].
FETZIMA was associated with an increase in blood pressure in placebo- and active-controlled trials in pediatric patients with MDD. Increases in blood pressure in pediatric patients treated with FETZIMA led to a higher proportion of pediatric patients developing new-onset and sustained hypertension when compared to adults [see WARNINGS AND PRECAUTIONS].
Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS].
In a juvenile animal study, male and female rats were treated with 10, 35, or 120 mg/kg/day of levomilnacipran by oral gavage from post-natal day 21 to 90. At 120 mg/kg/day, there was a decrease in bone mineral density in both males and females and a decrease in mean tibia length in females. These effects were not completely resolved at the end of the recovery period. There was a delay in sexual maturation in females treated with 120 mg/kg/day; however, there was no effect on fertility. The no observed adverse effect level (NOAEL) for all these findings was 35 mg/kg/day.
No dose adjustment is recommended on the basis of age [see CLINICAL PHARMACOLOGY].
Of the total number of patients in the 8-week clinical studies of FETZIMA, 2.8% of patients were age 65 or older.
Because levomilnacipran is predominantly excreted by the kidney, renal clearance of levomilnacipran should be considered when determining the dose [see DOSAGE AND ADMINISTRATION].
SNRIs, including FETZIMA, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see WARNINGS AND PRECAUTIONS].
Dose adjustment is not recommended in patients with mild (Child-Pugh score of 1-6), moderate (Child-Pugh score of 7-9), or severe (Child-Pugh score of 10-13) hepatic impairment [see CLINICAL PHARMACOLOGY].
Renal excretion plays a predominant role in the elimination of levomilnacipran.
FETZIMA is not recommended for use in patients with end stage renal disease.
Dosing adjustment is recommended for patients with moderate (creatinine clearance of 30 to 59 mL/min) or severe (creatinine clearance of 15 to 29 mL/min) renal impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Dose adjustment is not recommended for patients with mild (creatinine clearance of 60 to 89 mL/min) renal impairment [see CLINICAL PHARMACOLOGY].
There is limited clinical experience with FETZIMA overdose in humans. In clinical studies,cases of ingestions up to 360 mg daily were reported with none being fatal.
No specific antidotes for FETZIMA are known. In managing overdose, provide supportive care,including close medical supervision and monitoring, and consider the possibility of multiple druginvolvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222)for up-to-date guidance and advice. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in reducing levomilnacipran plasma concentrations.
FETZIMA is contraindicated:
Starting FETZIMA in a patient who is being treated with MAOIs such as linezolid orintravenous methylene blue is also contraindicated because of an increased risk ofserotonin syndrome [see DOSAGE AND ADMINISTRATION and WARNINGS ANDPRECAUTIONS].
The exact mechanism of the antidepressant action of levomilnacipran is unknown, but is thoughtto be related to the potentiation of serotonin and norepinephrine in the central nervous system,through inhibition of reuptake at serotonin and norepinephrine transporters. Non-clinical studieshave shown that levomilnacipran is a potent and selective serotonin and norepinephrine reuptakeinhibitor (SNRI).
Levomilnacipran binds with high affinity to the human serotonin (5-HT) and norepinephrine(NE) transporters (Ki = 11 and 91 nM, respectively) and potently inhibits 5-HT and NE reuptake(IC50 = 16-19 and 11 nM, respectively). Levomilnacipran lacks significant affinity for any otherreceptors, ion channels or transporters tested in vitro, including serotonergic (5HT1-7), α- and β-adrenergic, muscarinic, or histaminergic receptors and Ca2+, Na+, K+ or Cl- channels.Levomilnacipran did not inhibit monoamine oxidase (MAO).
At a dose 2.5 times the maximum recommended dose, levomilnacipran does not prolong QTc toany clinically relevant extent.
The concentration of levomilnacipran at steady state is proportional to dose when administeredfrom 25 mg to 300 mg (2.5 times the maximum recommended dosage of FETZIMA) once daily.Steady-state concentrations of levomilnacipran are predictable from single-dose data. After dailydosing of FETZIMA 120 mg, the mean Cmax value is 341 ng/mL, and the mean steady-state AUCvalue is 5196 ng·h/mL. Interconversion between levomilnacipran and its stereoisomer does notoccur in humans.
The relative bioavailability of levomilnacipran after administration of FETZIMA was 92% whencompared to oral solution. The median time to peak concentration (Tmax) of levomilnacipran is 6-8 hours after oral administration.
Effect Of Food
Levomilnacipran concentration was not significantly affected when FETZIMA was administeredwith food.
Levomilnacipran is widely distributed with an apparent volume of distribution of 387-473 L;plasma protein binding is 22% over concentration range of 10 to 1000 ng/mL.
Following an oral administration, the mean apparent total clearance of levomilnacipran is 21-29L/h. The apparent terminal elimination half-life of levomilnacipran is approximately 12 hours.
Levomilnacipran undergoes desethylation to form desethyllevomilnacipran and hydroxylation toform p-hydroxy-levomilnacipran. Both oxidative metabolites undergo further conjugation withglucuronide to form conjugates. The desethylation is catalyzed primarily by CYP3A4 with minorcontribution by CYP2C8, 2C19, 2D6, and 2J2.
Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oraladministration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted inurine as unchanged levomilnacipran. N-desethyllevomilnacipran is the major metaboliteexcreted in the urine and accounted for approximately 18% of the dose. Other identifiablemetabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyllevomilnacipran glucuronide (3%), p-hydroxylevomilnacipran glucuronide (1%), and p-hydroxylevomilnacipran (1%). The metabolites are inactive [see DOSAGE AND ADMINISTRATION].
The drug interaction studies for levomilnacipran are summarized in Figure 1.
Figure 1: PK Interactions between Levomilnacipran (LVM) and Other Drugs
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In vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimalcontributions to metabolism of levomilnacipran. In addition, levomilnacipran is not a substrate ofBCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 and is a weak substrate of P-gp.
In vitro studies have shown that levomilnacipran is not an inhibitor of CYP1A2, CYP2A6,CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3,or OCT2.
An in vitro study indicated increases of levomilnacipran release from FETZIMA extendedreleasecapsules (20, 40, 80, and 120 mg) at 2 hours by approximately 9.5%, 23%, and 56% inthe presence of 5%, 20%, and 40% (v/v) alcohol, respectively. Effect of 40% alcohol resulted innearly complete drug release in 4 hours. There is no in vivo study conducted for the effect ofalcohol on drug exposure.
The effect of intrinsic patient factors on the pharmacokinetics of levomilnacipran is presented inFigure 2.
Figure 2 :Effect of Intrinsic Factors on Levomilnacipran PK
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The efficacy of FETZIMA for the treatment of major depressive disorder (MDD) wasestablished in three 8-week randomized, double-blind, placebo-controlled studies (at doses 40-120 mg once daily) in adult (18 - 78 years of age) outpatients who met the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. Two of the studies werefixed dose (Study 1 and Study 2) and one study was flexible dose (Study 3).
In Study 1, patients received 40 mg (n = 178), 80 mg (n = 179), or 120 mg (n = 180) ofFETZIMA once daily, or placebo (n = 176). In Study 2, patients received either 40 mg (n = 188)or 80 mg (n = 188) of FETZIMA once daily, or placebo (n = 186). In the flexible-dose study(Study 3), patients received 40 to 120 mg (n = 217) of FETZIMA once daily, or placebo (n =217) with 21%, 34%, and 44% of FETZIMA patients on 40 mg, 80 mg, and 120 mg, respectivelyat the end of their treatment.
In all three studies, FETZIMA demonstrated superiority over placebo in the improvement ofdepressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) total score (see Table 6). FETZIMA also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale (SDS) functional impairment total score.
Table 6 :Summary of Results for the Primary Efficacy Endpoint MADRS
| Study Number | Treatment Group | Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Differencea (95% CI) |
| Study 1 (fixed dose) | FETZIMA (ER 40 mg/day)* | 36.0 (4.1) | -14.8 (1.0) | -3.2 (-5.9, -0.5) |
| FETZIMA (ER 80 mg/day)* | 36.1 (3.9) | -15.6 (1.0) | -4.0 (-6.7, -1.3) | |
| FETZIMA (ER 120 mg/day)* | 36.0 (3.9) | -16.5 (1.0) | -4.9 (-7.6, -2.1) | |
| Placebo | 35.6 (4.5) | -11.6 (1.0) | -- | |
| Study 2 (fixed-dose) | FETZIMA (ER 40 mg/day)* | 30.8 (3.4) | -14.6 (0.8) | -3.3 (-5.5, -1.1) |
| FETZIMA (ER 80 mg/day)* | 31.2 (3.5) | -14.4 (0.8) | -3.1 (-5.3, -1.0) | |
| Placebo | 31.0 (3.8) | -11.3 (0.8) | -- | |
| Study 3 (flexible-dose) | FETZIMA (ER 40 - 120 mg/day)* | 35.0 (3.6) | -15.3 (0.8) | -3.1 (-5.3, -0.9) |
| Placebo | 35.2 (3.8) | -12.2 (0.8) | -- | |
| SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval unadjusted for multiplicity. a Difference (drug minus placebo) in least-squares mean change from baseline to endpoint (Week 8). * Doses statistically significantly superior to placebo. |
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Post-hoc analyses of the relationships between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
In a maintenance study (Study 4; NCT02288325), adult patients meeting DSM-5 criteria for MDD received flexibly dosed FETZIMA (40 mg, 80 mg, or 120 mg) once daily for 8 weeks. Responders in the initial 8-week treatment period were eligible to enter a 12-week, open-label, fixed-dose stabilization phase. At the end of stabilization, approximately half of the subjects were receiving 120 mg once daily. Three hundred twenty-four (324) patients who met the response criteria (MADRS total score ≤12) after 20 weeks of open-label treatment were randomized to the double-blind treatment phase with FETZIMA or placebo for 26 weeks. The primary efficacy endpoint was the time from randomization to first relapse during the doubleblindphase. Relapse of depressive episode was defined as a MADRS total score ≥ 18 at two consecutive visits or insufficient therapeutic response as judged by the investigator. Patients on FETZIMA experienced a statistically significantly longer time to relapse than patients on placebo (Figure 3).
Figure 3: Kaplan-Meier Estimated Proportion of Patients with Relapse for Adults withMDD (Study 4)
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FETZIMA®
(fet-ZEE-muh)
(levomilnacipran)extended-release capsules, for oral use
What is the most important information I should know about FETZIMA?
FETZIMA may cause serious side effects, including:
How can I watch for and try to prevent suicidal thoughts and actions?
Call your healthcare provider or get emergency medical help right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you:
What is FETZIMA?
FETZIMA is a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD) in adults.
It is not known if FETZIMA is safe and effective for use in children.
It is not known if FETZIMA is safe and effective for the management of fibromyalgia. FETZIMA is not for use for the management of fibromyalgia.
Do not take FETZIMA if you:
Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue.
Do not start taking an MAOI for at least 7 days after you stop treatment with FETZIMA.
Before taking FETZIMA, tell your healthcare provider about all your medical conditions, including if you:
If you breastfeed during treatment with FETZIMA, call your healthcare provider if your baby develops sleepiness or fussiness, or is not feeding or gaining weight well.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
FETZIMA and other medicines may affect each other causing possible serious side effects.
FETZIMA may affect the way other medicines work and other medicines may affect the way FETZIMA works.
Especially tell your healthcare provider if you take:
Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take FETZIMA with your other medicines.
Do not start or stop any other medicines during treatment with FETZIMA without talking to your healthcare provider first. Stopping FETZIMA suddenly may cause you to have serious side effects. See, “What are the possible side effects of FETZIMA?”
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take FETZIMA?
What should I avoid while taking FETZIMA?
What are the possible side effects of FETZIMA?
FETZIMA may cause serious side effects, including:
In more severe or more sudden cases, signs and symptoms include:
Sexual problems (dysfunction). Taking FETZIMA may cause sexual problems.
Symptoms in males may include:
Symptoms in females may include:
Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with FETZIMA. There may be treatments your healthcare provider can suggest.
The most common side effects of FETZIMA, include:
These are not all the possible side effects of FETZIMA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store FETZIMA?
General information about the safe and effective use of FETZIMA
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FETZIMA for a condition for which it was not prescribed. Do not give FETZIMA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about FETZIMA that is written for healthcare professionals.
What are the ingredients in FETZIMA?
Active ingredient:levomilnacipran hydrochloride
Inactive ingredients:ethylcellulose, hypromellose, povidone, sugar spheres, talc, titanium dioxide, triethyl citrate, black iron oxide, red iron oxide (80 mg and 120 mg capsules only) shellac glaze, yellow iron oxide (20 mg and 40 mg capsules only)
This Medication Guide has been approved by the U.S. Food and Drug Administration.
