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 (5.1)]. 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 (5.1)]. FETZIMA is not approved for use in pediatric patients [see Use in Specific Populations (8.4)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants (5.1). Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1). FETZIMA is not approved for use in pediatric patients (8.4).
| Contraindications - removed uncontrolled narrow-angle glaucoma (4) |
| 07/2014 |
| Warnings and Precautions - Angle Closure Glaucoma (5.6) || 07/2014 |
1 INDICATIONS AND USAGE FETZIMA, a serotonin and norepinephrine reuptake inhibitor (SNRI) is indicated for the treatment of major depressive disorder (MDD). The efficacy of FETZIMA was established in three 8-week, randomized, double-blind, placebo-controlled studies in adult patients with a diagnosis of MDD [ see Clinical Studies (14)]. Limitation of Use: FETZIMA is not approved for the management of fibromyalgia. The efficacy and safety of FETZIMA for the management of fibromyalgia have not been established. FETZIMA is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of Major Depressive Disorder (MDD) (1). Limitation of Use: FETZIMA is not approved for the management of fibromyalgia. The efficacy and safety of FETZIMA for the management of fibromyalgia have not been established (1).
3 DOSAGE FORMS AND STRENGTHS FETZIMA (levomilnacipran) is available as 20 mg, 40 mg, 80 mg and 120 mg extended-release capsules. 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 Extended-release capsules: 20 mg, 40 mg, 80 mg and 120 mg (3).
4 CONTRAINDICATIONS 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 because of 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 [see Dosage and Administration (2.5) and Warnings and Precautions (5.2)]. Starting FETZIMA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.6) and Warnings and Precautions (5.2)]. Hypersensitivity to levomilnacipran, milnacipran HCl, or any excipient in the FETZIMA formulation (4). Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA. Do not use FETZIMA within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start FETZIMA in a patient who is being treated with linezolid or intravenous methylene blue (4).
5 WARNINGS AND PRECAUTIONS Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Monitor patients for clinical worsening and suicidal thinking or behavior (5.1). Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclics, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's Wort). If such symptoms occur, discontinue FETZIMA and initiate supportive treatment. If concomitant use of FETZIMA with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2). Elevated Blood Pressure and Heart Rate: Measure heart rate and blood pressure prior to initiating treatment and periodically throughout treatment. Control pre-existing hypertension before initiating therapy with FETZIMA (5.3, 5.4). Abnormal Bleeding: Treatment can increase the risk of bleeding. Caution patients about the risk of bleeding associated with the use of NSAIDs, aspirin, or other drugs that affect coagulation (5.5). Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.6). Urinary Hesitation or Retention: Can occur. If such symptoms occur, discontinue FETZIMA or consider other appropriate medical intervention (5.7). Activation of Mania/Hypomania: Screen patients for bipolar disorder, Caution patients about risk of activation of mania/hypomania (5.8). Seizures: Can occur. Use with caution in patients with a seizure disorder (5.9). Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms (5.10). Hyponatremia: Can occur in association with SIADH (5.11). 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phase of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 . Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4) and Warnings and Precautions (5.10) for a description of the risks of discontinuation of FETZIMA]. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. 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. Screening patients for bipolar disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that FETZIMA is not approved for use in treating bipolar depression. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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). 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). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of FETZIMA with MAOIs intended to treat psychiatric disorders is contraindicated. FETZIMA should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking FETZIMA. FETZIMA should be discontinued before initiating treatment with the MAOI [ see Dosage and Administration (2.5, 2.6) and Contraindications (4)]. If concomitant use of FETZIMA with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with FETZIMA and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.3 Elevated Blood Pressure 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 patients in the short-term placebo-controlled studies. Table 2 Blood Pressure Mean Changes, Sustained Hypertension, and Upward Shifts in Hypertensive Status 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 Placebo FETZIMA 40-120 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 Hg and an increase ≥15 mm Hg 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 In the short-term, placebo-controlled MDD studies, 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 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 the short-term, placebo-controlled studies, 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. 5.4 Elevated Heart Rate SNRIs including FETZIMA have been associated with increased 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 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. 5.5 Abnormal Bleeding SSRIs and SNRIs, 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. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of FETZIMA and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. 5.6 Angle Closure Glaucoma 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. 5.7 Urinary Hesitation or Retention 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 FETZIMA-treated 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. 5.8 Activation of Mania/Hypomania 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. As with all antidepressants, use FETZIMA cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. 5.9 Seizures 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. One case of seizure has been reported in pre-marketing clinical studies with FETZIMA. 5.10 Discontinuation Syndrome 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 (2.4)]. 5.11 Hyponatremia Although no adverse events of hyponatremia were reported for FETZIMA-treated patients in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. 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.
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity [see Contraindications (4)] Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1)] Serotonin Syndrome [see Warnings and Precautions (5.2)] Elevated Blood Pressure [see Warnings and Precautions (5.3)] Elevated Heart Rate [see Warnings and Precautions (5.4)] Abnormal Bleeding [see Warnings and Precautions (5.5)] Angle Closure Glaucoma [see Warnings and Precautions (5.6)] Urinary Hesitation or Retention [see Warnings and Precautions (5.7)] Activation of Mania/Hypomania [see Warnings and Precautions (5.8)] Seizure [see Warnings and Precautions (5.9)] Discontinuation Syndrome [see Warnings and Precautions (5.10)] Hyponatremia [see Warnings and Precautions (5.11)] The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) are: nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, tachycardia, vomiting, and palpitations (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Forest Pharmaceuticals, Inc. at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Patient exposure The safety of FETZIMA was evaluated in 2,673 patients (18-78 years of age) diagnosed with MDD who participated in clinical studies, representing 942 patient-years of exposure. Among the 2,673 FETZIMA-treated patients, 1,583 were exposed to FETZIMA in short-term, placebo-controlled studies. There were 825 patients who continued from short-term studies into a one-year, open-label extension study. Of the 2,673 patients exposed to at least one dose of FETZIMA, 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 40-120 mg once daily and was given without regard to food. Adverse reactions reported as reasons for discontinuation of treatment In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who received FETZIMA (40-120 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,040 placebo-treated patients in those studies. The most common adverse reaction leading to discontinuation in at least 1% of the FETZIMA-treated patients in the short-term placebo-controlled studies was nausea (1.5%). Common adverse reactions in placebo-controlled MDD studies The most commonly observed adverse events in FETZIMA-treated MDD patients in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were: nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, tachycardia, vomiting, and palpitations. Table 3 shows the incidence of adverse reactions that occurred in ≥ 2% of FETZIMA-treated MDD patients and at least twice the rate of placebo in the placebo-controlled studies. Table 3 Adverse Reactions Occurring in ≥ 2% of FETZIMA-treated Patients and at Least Twice the rate of Placebo-treated Patients 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 clinical studies reported adverse events related to sexual function. c erectile dysfunction includes: erectile dysfunction, organic erectile dysfunction and psychogenic 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 pressure diastolic increased and blood pressure orthostatic increased h Rash also includes: rash generalized, rash maculo-papular, rash erythematous and rash macular i Hypotension also includes: orthostatic hypotension and dizziness postural j Hypertension also includes: labile hypertension N = number of patients in the Safety Population System Organ Class Preferred Term Placebo (N =1040) % FETZIMA 40-120 mg/d (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 disorders b 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 Dose-related adverse reactions In pooled data from the short-term placebo-controlled fixed-dose studies, there were no dose-related adverse reactions (greater than 2% overall incidence) in patients treated with FETZIMA across the dose range 40-120 mg once daily, with the exception of erectile dysfunction and urinary hesitation (see Table 4 ). Table 4 Dose-Related Adverse Reactions a Percentage is relative to the number of male patients. N = number of patients in the Safety Population System Organ Class Preferred Term Placebo (N = 362) % FETZIMA 40 mg/d (N = 366) % 80 mg/d (N = 367) % 120 mg/d (N = 180) % Urinary hesitation 0 4 5 6 Erectile dysfunctiona 2 6 8 10 Other adverse reactions observed in clinical studies Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence 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
7 DRUG INTERACTIONS Other than CYP3A4 drug interactions, FETZIMA is predicted, based on in vitro studies, to have a low potential to be involved in clinically significant pharmacokinetic drug interactions. Strong CYP3A4 inhibitors such as ketoconazole: Do not exceed 80 mg once daily (7). 7.1 Monoamine Oxidase Inhibitors (MAOIs) [see Dosage and Administration (2.5, 2.6), Contraindications (4), and Warnings and Precautions (5.2)] 7.2 Serotonergic Drugs [see Dosage and Administration (2.5, 2.6), Contraindications (4), and Warnings and Precautions (5.2)] 7.3 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when FETZIMA is initiated or discontinued [see Warnings and Precautions (5.5)]. 7.4 Potential for Other Drugs to Affect FETZIMA Dose adjustment is recommended when FETZIMA is co-administered with strong inhibitors of CYP3A4 (e.g. ketoconazole) [see Dosage and Administration (2.7)]. An in vivo study showed a clinically meaningful increase in levomilnacipran exposure when FETZIMA was co-administered with the CYP3A4 inhibitor ketoconazole (see Figure 1 ). No dose adjustment of FETZIMA is needed when co-administered with a CYP3A4 inducer or substrate. In vivo studies showed no clinically meaningful change in levomilnacipran exposure when co-administered with the CYP3A4 inducer carbamazepine or the CYP3A4 substrate alprazolam (see Figure 1 ). No dose adjustment of FETZIMA is needed when co-administered with inhibitors of CYP2C8 , CYP2C19, CYP2D6, CYP2J2, P-glycoprotein, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. In vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimal contributions to metabolism of levomilnacipran. In addition, levomilnacipran is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 and is a weak substrate of P-gp. Figure 1 PK Interactions between Levomilnacipran (LVM) and Other Drugs Figure 1 7.5 Potential for FETZIMA to Affect Other Drugs No dose adjustment of the concomitant medication is recommended when FETZIMA is administered with a substrate of CYP3A4, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. 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. Concomitant use of FETZIMA with alprazolam or carbamazepine, substrates of CYP3A4, had no significant effect on alprazolam or carbamazepine plasma concentrations (see Figure 1 ). 7.6 Central Nervous System (CNS)-Active Agents The risk of using FETZIMA in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when FETZIMA is prescribed in combination with other CNS-active drugs, including those with a similar mechanism of action. Alcohol In an in vitro study, alcohol interacted with the extended-release properties of FETZIMA. If FETZIMA is taken with alcohol, a pronounced accelerated drug release may occur. It is recommended that FETZIMA extended-release capsules not be taken with alcohol.
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of FETZIMA in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as FETZIMA), or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery. Levomilnacipran was not teratogenic 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. FETZIMA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Neonates exposed to SSRIs or SNRIs, 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 features are consistent with either a direct toxic effect of these classes of drugs 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 (5.2)]. A prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Animal Data No teratogenic effects 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. 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. 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. 8.3 Nursing Mothers It is not known if FETZIMA is present in human milk. Studies have shown that levomilnacipran is present in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FETZIMA, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Clinical studies on the use of FETZIMA in pediatric patients have not been conducted; therefore, the safety and effectiveness of FETZIMA in the pediatric population have not been established. FETZIMA is not approved for use in pediatric patients [see Boxed Warning and Warnings and Precautions (5.1)]. 8.5 Geriatric Use No dose adjustment is recommended on the basis of age (see Figure 2 ). In a multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had a slightly higher exposure (Cmax by 24% and AUC by 26%) of levomilnacipran than younger subjects (18-45 years). Of the total number of subjects in clinical studies of FETZIMA, 2.8% of patients were age 65 or older. Because levomilnacipran is predominately excreted by the kidney, renal clearance of levomilnacipran should be considered when determining the dose [see Dosage and Administration (2.3)]. SSRIs and SNRIs, including FETZIMA, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.11)]. 8.6 Hepatic Impairment Hepatic elimination of levomilnacipran is low. Dose adjustment is not recommended in subjects 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 Figure 2 ). 8.7 Renal Impairment Renal excretion plays a predominant role in the elimination of levomilnacipran. Dose adjustment is not recommended for patients with mild (creatinine clearance of 60-89 ml/min) renal impairment. Dosing adjustment is recommended for patients with moderate (creatinine clearance of 30-59 ml/min) or severe (creatinine clearance of 15-29 ml/min) renal impairment (see Figure 2 ). FETZIMA is not recommended for patients with end stage renal disease [see Dosage and Administration (2.3)]. 8.8 Gender Dose adjustment based on gender is not recommended (see Figure 2 ). Figure 2 Effect of Intrinsic Factors on Levomilnacipran PK Figure 2