Fetzima

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 )] Increased Risk of 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 )] Sexual Dysfunction [see Warnings and Precautions ( 5.12 )] The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) are: nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, ejaculation disorder, tachycardia, vomiting, and palpitations ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie 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 e xposure The safety of FETZIMA was evaluated in 3,317 patients (18 to 78 years of age) diagnosed with MDD who participated in clinical studies, representing 1,186 patient-years of exposure. Among the 3,317 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 3,317 patients exposed to at least one dose of FETZIMA, 895 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 mg to 120 mg once daily and was given without regard to food. Adverse r eacti ons r eported as r easons for discontinuation of t reatment In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who 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 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 a dverse r eactions in p lacebo- c ontrolled MDD s tudies The most commonly observed adverse reactions 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, ejaculation disorder, 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 in 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 Tachycardia a 2 6 Palpitations 1 5 Reproductive system and breast disorders b Erectile dysfunction c 1 6 Testicular pain d <1 4 Ejaculation disorder e <1 5 Investigations Heart rate increased f 1 6 Blood pressure increased g 1 3 Renal and urinary disorders Urinary hesitation 0 4 Skin and s ubcutaneous t issue d isorders Hyperhidrosis 2 9 Rash h 0 2 Vascular disorders Hot flush 1 3 Hypotension i 1 3 Hypertension j 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 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 Dose- r elated a dverse r eactions 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 mg to 120 mg once daily, with the exception of erectile dysfunction and urinary 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 dysfunction a 2 6 8 10 a Percentage is relative to the number of male patients. N = number of patients in the Safety Population 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 6.2 Post m arketing Experience The following adverse reaction has been identified during post-approval use of FETZIMA or other selective serotonin and norepinephrine reuptake inhibitors. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac disorders : Takotsubo cardiomyopathy

4 CONTRAINDICATIONS FETZIMA is contraindicated: in patients with hypersensitivity to levomilnacipran, milnacipran HCl, or to any excipient in the formulation. with 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 ). 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 ).

11 DESCRIPTION Fetzima contains levomilnacipran, a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in the form of hydrochloride salt with the chemical name of levomilnacipran hydrochloride is (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride. Its empirical formula is C 15 H 2 2 N 2 O∙HCl and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial US approval: 2013) is the 1S,2R-enantiomer of milnacipran. The chemical structure of levomilnacipran hydrochloride is: FETZIMA extended-release capsules are intended for oral administration. Each FETZIMA capsule contains 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 ethylcellulose, hypromellose, povidone, sugar spheres, talc, titanium dioxide, and triethyl citrate. Inactive ingredients also include black iron oxide, red iron oxide (80 mg and 120 mg capsules only), shellac glaze, and yellow iron oxide (20 mg and 40 mg capsules only). The chemical structure 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.

2 DOSAGE AND ADMINISTRATION Recommended dosage: 40 mg to 120 mg once daily with or without food ( 2.1 ). Initial dosage is 20 mg once daily for 2 days and then increase to 40 mg once daily ( 2.1 ). Based on clinical response and tolerability, increase dose in increments of 40 mg at intervals of 2 or more days ( 2.1 ). The maximum recommended dosage is 120 mg once daily ( 2.1 ). Take capsules whole; do not open, chew or crush ( 2.1 ) Renal impairment ( 2.3 ) : Severe renal impairment: Maximum recommended dosage is 40 mg once daily. Moderate renal impairment: Maximum recommended dosage is 80 mg once daily. Discontinuation: Reduce dose gradually whenever possible ( 2.4 ) 2.1 Recommended Dosage The recommended dosage range for FETZIMA is 40 mg to 120 mg once daily, with or without food. FETZIMA should be initiated at 20 mg once daily for 2 days and then increased to 40 mg once daily. Based on clinical response and tolerability, FETZIMA may be increased in increments of 40 mg at intervals of 2 or more days. The maximum recommended dosage is 120 mg once daily. Take FETZIMA at approximately the same time each day. Swallow FETZIMA whole; do not open, chew, or crush the capsule. 2.2 Screen for Bipolar Disorder Prior to Starting FETZIMA Prior to initiating treatment with FETZIMA or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.8 ) ] . 2. 3 Dosage Recommendations for Patients with Renal Impairment End stage renal disease (ESRD): FETZIMA is not recommended; Severe renal impairment (creatinine clearance of 15 to 29 mL/min), the dosage should not exceed 40 mg once daily; Moderate renal impairment (creatinine clearance of 30 to 59 mL/min), the dosage should not exceed 80 mg once daily; Mild renal impairment (creatinine clearance of 60 to 89 mL/min): no dosage adjustment recommended [see Use in Specific Populations ( 8.7 )]. 2.4 Discontinuing Treatment with FETZIMA Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as FETZIMA. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing FETZIMA. If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate [see Warnings and Precautions ( 5.10 )] . 2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days must elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with FETZIMA. Conversely, at least 7 days should be allowed after stopping FETZIMA before starting an MAOI antidepressant [see Contraindications ( 4 )] . 2.6 Dosage Recommendations for Use with Strong CYP3A4 Inhibitors The maximum recommended dosage of FETZIMA should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors [ s ee Drug Interactions ( 7.1 )]

1 INDICATIONS AND USAGE FETZIMA ® is indicated for the treatment of major depressive disorder (MDD) in adults [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) in adults ( 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 ).

9.2 Abuse 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 not possible to predict on the basis of clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of FETZIMA (e.g., development of tolerance or drug-seeking behavior).

9.1 Controlled Substance FETZIMA is not a controlled substance.

9.3 Dependence FETZIMA has not been systematically studied in animals or humans for its potential for dependence.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance FETZIMA is not a controlled substance. 9.2 Abuse 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 not possible to predict on the basis of clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of FETZIMA (e.g., development of tolerance or drug-seeking behavior). 9.3 Dependence FETZIMA has not been systematically studied in animals or humans for its potential for dependence.

10 OVERDOSAGE 10.1 Human Experience 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. 10.2 Management of Overdose 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 drug involvement. 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.

7 DRUG INTERACTIONS Strong CYP3A4 inhibitors : Maximum recommended dosage is 80 mg once daily ( 7 ). 7.1 Drugs Having Clinically Important Interactions with FETZIMA 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: With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with FETZIMA. Within 14 days of stopping an MAOI intended to treat psychiatric disorders In a patient who is being treated with linezolid or intravenous methylene blue [see Dosage and Administration ( 2.5 , 2.6 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )] . 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 ( 2.5 , 2.6 ) , Contraindications ( 4 ) , and Warnings and Precautions ( 5.2 ) ] . Examples: other SNRIs, SSRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, 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 ( 5.5 )] . Examples: NSAIDs, aspirin, and warfarin Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of FETZIMA with strong CYP3A4 inhibitors increases levomilnacipran exposure [see Pharmacokinetics ( 12.3 )] . Intervention: The dose of FETZIMA should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors [see Dosage and Administration ( 2.7 ). 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 ( 12.3 )] .

12 CLINICAL PHARMACOLOGY Figure_EN_071213 Figure_IN_071213 12.1 Mechanism of Action The exact mechanism of the antidepressant action of levomilnacipran is unknown, but is thought to 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 studies have shown that levomilnacipran is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). 12.2 Pharmacodynamics 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 other receptors, ion channels or transporters tested in vitro , including serotonergic (5HT1-7), α- and β- adrenergic, muscarinic, or histaminergic receptors and Ca 2+ , Na+, K+ or Cl- channels. Levomilnacipran did not inhibit monoamine oxidase (MAO). Cardiovascular Electrophysiology At a dose 2.5 times the maximum recommended dose, levomilnacipran does not prolong QTc to any clinically relevant extent. 12.3 Pharmacokinetics The concentration of levomilnacipran at steady state is proportional to dose when administered from 25 mg to 300 mg (2.5 times the maximum recommended dosage of FETZIMA) once daily. Following an oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h. Steady-state concentrations of levomilnacipran are predictable from single-dose data. The apparent terminal elimination half-life of levomilnacipran is approximately 12 hours. After daily dosing of FETZIMA 120 mg, the mean C max value is 341 ng/mL, and the mean steady-state AUC value is 5196 ng·h/mL. Interconversion between levomilnacipran and its stereoisomer does not occur in humans. Absorption The relative bioavailability of levomilnacipran after administration of FETZIMA was 92% when compared to oral solution. The median time to peak concentration (T max ) of levomilnacipran is 6-8 hours after oral administration. Effect of Food Levomilnacipran concentration was not significantly affected when FETZIMA was administered with food. Distribution 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. Elimination Metabolism Levomilnacipran undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran. Both oxidative metabolites undergo further conjugation with glucuronide to form conjugates. The desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2. Excretion Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose. Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%). The metabolites are inactive [see Dosage and Administration ( 2.3 )] . Drug Interaction Studies Clinical Studies The drug interaction studies for levomilnacipran are summarized in Figure 1. Figure 1. PK Interactions between Levomilnacipran (LVM) and Other Drugs In vitro Studies 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. 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. Alcohol An in vitro study indicated increases of levomilnacipran release from FETZIMA extended-release capsules (20, 40, 80, and 120 mg) at 2 hours by approximately 9.5%, 23%, and 56% in the presence of 5%, 20%, and 40% (v/v) alcohol, respectively. Effect of 40% alcohol resulted in nearly complete drug release in 4 hours. There is no in vivo study conducted for the effect of alcohol on drug exposure. Speci fic Populations The effect of intrinsic patient factors on the pharmacokinetics of levomilnacipran is presented in Figure 2. Figure 2 Effect of Intrinsic Factors on Levomilnacipran PK

12.1 Mechanism of Action The exact mechanism of the antidepressant action of levomilnacipran is unknown, but is thought to 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 studies have shown that levomilnacipran is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).

12.2 Pharmacodynamics 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 other receptors, ion channels or transporters tested in vitro , including serotonergic (5HT1-7), α- and β- adrenergic, muscarinic, or histaminergic receptors and Ca 2+ , Na+, K+ or Cl- channels. Levomilnacipran did not inhibit monoamine oxidase (MAO). Cardiovascular Electrophysiology At a dose 2.5 times the maximum recommended dose, levomilnacipran does not prolong QTc to any clinically relevant extent.

12.3 Pharmacokinetics The concentration of levomilnacipran at steady state is proportional to dose when administered from 25 mg to 300 mg (2.5 times the maximum recommended dosage of FETZIMA) once daily. Following an oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h. Steady-state concentrations of levomilnacipran are predictable from single-dose data. The apparent terminal elimination half-life of levomilnacipran is approximately 12 hours. After daily dosing of FETZIMA 120 mg, the mean C max value is 341 ng/mL, and the mean steady-state AUC value is 5196 ng·h/mL. Interconversion between levomilnacipran and its stereoisomer does not occur in humans. Absorption The relative bioavailability of levomilnacipran after administration of FETZIMA was 92% when compared to oral solution. The median time to peak concentration (T max ) of levomilnacipran is 6-8 hours after oral administration. Effect of Food Levomilnacipran concentration was not significantly affected when FETZIMA was administered with food. Distribution 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. Elimination Metabolism Levomilnacipran undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran. Both oxidative metabolites undergo further conjugation with glucuronide to form conjugates. The desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2. Excretion Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose. Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%). The metabolites are inactive [see Dosage and Administration ( 2.3 )] . Drug Interaction Studies Clinical Studies The drug interaction studies for levomilnacipran are summarized in Figure 1. Figure 1. PK Interactions between Levomilnacipran (LVM) and Other Drugs In vitro Studies 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. 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. Alcohol An in vitro study indicated increases of levomilnacipran release from FETZIMA extended-release capsules (20, 40, 80, and 120 mg) at 2 hours by approximately 9.5%, 23%, and 56% in the presence of 5%, 20%, and 40% (v/v) alcohol, respectively. Effect of 40% alcohol resulted in nearly complete drug release in 4 hours. There is no in vivo study conducted for the effect of alcohol on drug exposure. Speci fic Populations The effect of intrinsic patient factors on the pharmacokinetics of levomilnacipran is presented in Figure 2. Figure 2 Effect of Intrinsic Factors on Levomilnacipran PK

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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 ).

Fetzima LEVOMILNACIPRAN HYDROCHLORIDE LEVOMILNACIPRAN HYDROCHLORIDE levomilnacipran SUCROSE ETHYLCELLULOSE, UNSPECIFIED TALC POVIDONE, UNSPECIFIED TRIETHYL CITRATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE SHELLAC FERROSOFERRIC OXIDE FERRIC OXIDE YELLOW Yellow White FL;20 CAPSULE Fetzima LEVOMILNACIPRAN HYDROCHLORIDE LEVOMILNACIPRAN HYDROCHLORIDE levomilnacipran SUCROSE ETHYLCELLULOSE, UNSPECIFIED TALC POVIDONE, UNSPECIFIED TRIETHYL CITRATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE SHELLAC FERROSOFERRIC OXIDE FERRIC OXIDE YELLOW Yellow FL;40 CAPSULE Fetzima LEVOMILNACIPRAN HYDROCHLORIDE LEVOMILNACIPRAN HYDROCHLORIDE levomilnacipran SUCROSE ETHYLCELLULOSE, UNSPECIFIED TALC POVIDONE, UNSPECIFIED TRIETHYL CITRATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE SHELLAC FERROSOFERRIC OXIDE FERRIC OXIDE RED Pink White FL;80 CAPSULE Fetzima LEVOMILNACIPRAN HYDROCHLORIDE LEVOMILNACIPRAN HYDROCHLORIDE levomilnacipran SUCROSE ETHYLCELLULOSE, UNSPECIFIED TALC POVIDONE, UNSPECIFIED TRIETHYL CITRATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE SHELLAC FERROSOFERRIC OXIDE FERRIC OXIDE RED Pink FL;120 CAPSULE Fetzima LEVOMILNACIPRAN HYDROCHLORIDE Fetzima LEVOMILNACIPRAN HYDROCHLORIDE levomilnacipran hydrochloride levomilnacipran SUCROSE ETHYLCELLULOSE, UNSPECIFIED TALC POVIDONE, UNSPECIFIED TRIETHYL CITRATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE SHELLAC FERROSOFERRIC OXIDE FERRIC OXIDE YELLOW yellow white FL;20 CAPSULE Fetzima LEVOMILNACIPRAN HYDROCHLORIDE levomilnacipran hydrochloride levomilnacipran SUCROSE ETHYLCELLULOSE, UNSPECIFIED TALC POVIDONE, UNSPECIFIED TRIETHYL CITRATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE SHELLAC FERROSOFERRIC OXIDE FERRIC OXIDE YELLOW yellow FL;40 CAPSULE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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/m 2 basis. Tg.rasH2 mice received levomilnacipran at doses up to 150 mg/kg/day. Mutagenesis 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. Impairment of Fertility 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/m 2 basis.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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/m 2 basis. Tg.rasH2 mice received levomilnacipran at doses up to 150 mg/kg/day. Mutagenesis 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. Impairment of Fertility 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/m 2 basis.

NDA204168

Fetzima

LEVOMILNACIPRAN HYDROCHLORIDE

0456-2220

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL Rx o nly NDC 0456-2220-30 Fetzima ® levomilnacipran extended-release capsules 20 mg per capsule Dispense the accompanying Medication Guide to each patient. 30 capsules PRINCIPAL DISPLAY PANEL Rx only NDC 0456-2220-30 Fetzima® levomilnacipran extended-release capsules 20 mg per capsule Dispense the accompanying Medication Guide to each patient. 30 capsules

Dosage and Administration, Use of FETZIMA with Other MAOIs such as Linezolid or Methylene Blue - Removed ( 2.6 ) 3/2023 Warnings and Precautions, Elevated Blood Pressure ( 5.3 ) 3/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Suicide Thoughts and Behaviors 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 ( 5.1 ) ] . Dosing and Administration 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. Concomitant Medication 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 ( 4 ) ] . 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 ( 7.1 ) ] . Allergic Reactions Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [ see Contraindications ( 4 ) ] . Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of FETZIMA with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, amphetamines, tryptophan, buspirone, and St. John’s Wort supplements) [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.1 )] . Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome. E levated Blood Pressure and Heart Rate Advise patients that they should have regular monitoring of blood pressure and heart rate when taking FETZIMA [ see Warnings and Precautions ( 5.3 , 5.4 ) ] . Increased Risk of Bleeding 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 ( 5.5 )] . Angle Closure Glaucoma 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 ( 5.6 )] . Urinary Hesitation or Retention 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 ( 5.7 ) ] . Activation of Mania/Hypomania Advise patients and their caregivers to look for signs of activation of mania/hypomania [ see Warnings and Precautions ( 5.8 ) ] . Seizures Caution patients about using FETZIMA if they have a history of a seizure disorder [see Warnings and Precautions ( 5.9 )] . Discontinuation Syndrome 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 ( 5.10 ) ] . Hyponatremia 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 ( 5.11 ) ] . Sexual Dysfunction 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 ( 5.12 )] . Alcohol Advise patients to avoid consumption of alcohol while taking FETZIMA [see Drug Interactions ( 7.1 ) , Clinical Pharmacology ( 12.3 ) ] . Pregnancy Advise pregnant females to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with FETZIMA. Advise patients that FETZIMA use in late pregnancy may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding. Advise patient that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FETZIMA during pregnancy [see Use in Specific Populations ( 8.1 )] Lactation 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 ( 8.2 )]. Interference with Cognitive and Motor Performance 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. Distributed by: AbbVie, Inc. 1 N Waukegan Rd. North Chicago, IL 60064 ©2023 AbbVie. All rights reserved. FETZIMA ® is a registered trademark of Pierre Fabre Medicaments S.A.S. Licensed from Pierre Fabre Medicament. Patented: See: www.Allergan.com/patents Licensed from Pierre Fabre Medicament. All trademarks are the property of their respective owners. v4.0USPI2220

MEDICATION GUIDE 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: Increased risk of suicidal thoughts and actions . FETZIMA and other antidepressant medicines may increase suicidal thoughts and actions in some people 24 years and younger, especially within the first few months of treatment or when the dose is changed. FETZ IMA is not for use in children. Depression or other mental illnesses are the most important causes of suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions? Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings or if you develop suicidal thoughts or actions. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. 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 the y are new, worse, or worry you: ● attempts to commit suicide ● acting on dangerous impulses ● acting aggressive, being angry or violent ● thoughts about suicide or dying ● new or worse depression ● new or worsening anxiety ● panic attacks ● feeling very agitated or restless ● new or worse irritability ● trouble sleeping ● an extreme increase in activity or talking (mania) ● other unusual changes in behavior or mood 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: are allergic to levomilnacipran, milnacipran HCl, or any of the ingredients in FETZIMA. See the end of this Medication Guide for a complete list of ingredients in FETZIMA. are taking or have taken within the last 14 days, a medicine called a monoamine oxidase inhibitor (MAOI), including the antibiotic linezolid or intravenous methylene blue. 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 : have or have a family history of suicide, depression, bipolar disorder, mania, or hypomania have high blood pressure have or had heart problems, including fast heartbeat, or stroke have or had bleeding problems have glaucoma (high pressure in the eye) have or had problems urinating (hesitation) or emptying your bladder (retention) have or had seizures (convulsions) have low sodium levels in your blood have or had kidney problems drink alcohol are pregnant or plan to become pregnant. FETZIMA may harm your unborn baby. Taking FETZIMA during your third trimester of pregnancy may cause you to have an increased risk of bleeding after your delivery and may also cause your baby to be at increased risk for withdrawal symptoms, or breathing, temperature control, feeding or other problems at birth. Talk to your healthcare provider about the risks to you and your baby if you take FETZIMA during pregnancy. ◦ Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with FETZIMA. ◦ There is a pregnancy registry for women who are exposed to FETZIMA during pregnancy. The purpose of the registry is to collect information about the health of women exposed to FETZIMA and their baby. If you become pregnant during treatment with FETZIMA, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visit online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. are breastfeeding or plan to breastfeed. It is not known if FETZIMA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with FETZIMA. ◦ If you breastfeed during treatment with FETZIMA, call you 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: MAOIs medicines used to treat migraine headache known as triptans tricyclic antidepressants fentanyl lithium tramadol tryptophan buspirone amphetamines St. John’s Wort medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and warfarin diuretics medicines used to treat mood, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) 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? Take FETZIMA exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking FETZIMA without first talking to your healthcare provider. Your healthcare provider may need to change the dose of FETZIMA until it is the right dose for you. Take FETZIMA 1 time each day at about the same time each day. Take FETZIMA with or without food. Swallow FETZIMA capsules whole. Do not open, chew, or crush the FETZIMA capsule. If you miss a dose of FETZIMA, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take 2 doses of FETZIMA at the same time. If you take too much FETZIMA, call your healthcare provider or poison control center at 1-800-222-1222, or go to the nearest hospital emergency room right away. What should I avoid while taking FETZIMA? Do not drive, operate heavy machinery, or do other dangerous activities until you know how FETZIMA affects you. FETZIMA can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. Avoid drinking alcohol during treatment with FETZIMA. What are the possible side effects of FETZIMA? FETZIMA may cause serious side effects, including: See “What is the most important information I should know about FETZIMA?” Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when FETZIMA is taken with certain other medicines. See “ Do not take FETZIMA if you. ” Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome: ○ agitation ○ seeing or hearing things that are not real (hallucinations) ○ confusion ○ coma ○ fast heartbeat ○ blood pressure changes ○ dizziness ○ sweating ○ flushing ○ high body temperature (hyperthermia) ○ tremors, stiff muscles, or muscle twitching ○ loss of coordination ○ seizures ○ nausea, vomiting, diarrhea High blood pressure (hypertension). Your healthcare provider should check your blood pressure before you start and during treatment with FETZIMA. If you have high blood pressure, it should be controlled before you start treatment with FETZIMA. Increased heart rate. Your healthcare provider should check your heart rate before you start and during treatment with FETZIMA. If you have heart problems or problems with an abnormal heartbeat, your problems should be treated before you start treatment with FETZIMA. Increased risk of bleeding. Taking FETZIMA with aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin or blood thinners may add to this risk. Tell your healthcare provider right away about any unusual bleeding or bruising. Eye problems (angle-closure glaucoma). FETZIMA may cause a type of eye problem called angle-closure glaucoma in people with certain eye problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have changes in your vision, eye pain, or swelling or redness in or around the eye. Problems with urination. FETZIMA may cause you to have problems with urination including decreased urine flow and being unable to pass any urine. Tell your healthcare provider if you develop any problems with urine flow during treatment with FETZIMA. Manic episodes. Manic episodes may happen in people with bipolar disorder who take FETZIMA. Symptoms may include: ○ greatly increased energy ○ severe trouble sleeping ○ racing thoughts ○ reckless behavior ○ unusually grand ideas ○ excessive happiness or irritability ○ talking more or faster than usual Seizures (convulsions). Discontinuation syndrome. Suddenly stopping FETZIMA may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: ○ changes in your mood ○ headache ○ irritability and agitation ○ tiredness ○ dizziness ○ problems sleeping ○ electric shock sensation (paresthesia) ○ hypomania ○ anxiety ○ ringing in your ears (tinnitus) ○ confusion ○ seizures Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood that may be serious and may cause death can happen during treatment with FETZIMA. Elderly people and people who take certain medicines may be at greater risk for this. Signs and symptoms may include: ○ headache ○ difficulty concentrating ○ memory changes ○ confusion ○ weakness and unsteadiness on your feet which can lead to falls In more severe or more sudden cases, signs and symptoms include: ○ hallucinations (seeing or hearing things that are not real) ○ fainting ○ seizures ○ coma ○ stopping breathing (respiratory arrest) Sexual problems (dysfunction). Taking FETZIMA may cause sexual problems. Symptoms in males may include: ○ delayed ejaculation or inability to have an ejaculation ○ problems getting or keeping an erection ○ decreased sex drive Symptoms in females may include: ○ decreased sex drive ○ delayed orgasm or inability to have an orgasm 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 si de effects of FETZIMA, include: ● nausea ● problems getting or keeping an erection ● constipation ● delayed ejaculation or inability to have an ejaculation ● sweating ● vomiting ● increased heart rate ● fast or irregular heartbeat (palpitations) 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? Store FETZIMA at room temperature between 68°F to 77°F (20°C to 25°C). Keep FETZIMA and all medicines out of the reach of children. 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) Distributed by: AbbVie, Inc. 1 N Waukegan Rd. North Chicago, IL 60064 ©2023 AbbVie. All rights reserved. For more information, go to www.FETZIMA.com or call 1-800-678-1605. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 3/2023 v4.0MG2220

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 e xposure The safety of FETZIMA was evaluated in 3,317 patients (18 to 78 years of age) diagnosed with MDD who participated in clinical studies, representing 1,186 patient-years of exposure. Among the 3,317 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 3,317 patients exposed to at least one dose of FETZIMA, 895 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 mg to 120 mg once daily and was given without regard to food. Adverse r eacti ons r eported as r easons for discontinuation of t reatment In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who 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 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 a dverse r eactions in p lacebo- c ontrolled MDD s tudies The most commonly observed adverse reactions 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, ejaculation disorder, 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 in 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 Tachycardia a 2 6 Palpitations 1 5 Reproductive system and breast disorders b Erectile dysfunction c 1 6 Testicular pain d <1 4 Ejaculation disorder e <1 5 Investigations Heart rate increased f 1 6 Blood pressure increased g 1 3 Renal and urinary disorders Urinary hesitation 0 4 Skin and s ubcutaneous t issue d isorders Hyperhidrosis 2 9 Rash h 0 2 Vascular disorders Hot flush 1 3 Hypotension i 1 3 Hypertension j 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 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 Dose- r elated a dverse r eactions 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 mg to 120 mg once daily, with the exception of erectile dysfunction and urinary 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 dysfunction a 2 6 8 10 a Percentage is relative to the number of male patients. N = number of patients in the Safety Population 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

8. 5 Geriatric Use No dose adjustment is recommended on the basis of age [ see Clinical Pharmacology ( 12.3 ) ] . 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 ( 2.3 ) ] . 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 ( 5.11 )].

8. 4 Pediatric Use 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 ( 6.1 )]. 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 ( 5.3 )]. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [ see Boxed Warning, Warnings and Precautions ( 5.1 ), and Adverse Reactions ( 6.1 ) ] . Juvenile Animal Toxicity Data 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.

8.1 Pregnancy Pregnancy Exposure Registry 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-and-researchprograms/pregnancyregistry/antidepressants. Risk Summary The available data on FETZIMA use in pregnant women are insufficient to evaluate for a drug-associated 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/m 2 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. Clinical Considerations 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 SNRIs in late pregnancy may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.5 )]. 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 ( 5.2 and 5.10 )]. Data 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/m 2 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/m 2 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/m 2 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/m 2 basis.

8 USE IN SPECIFIC POPULATIONS Pregnancy : Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry 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-and-researchprograms/pregnancyregistry/antidepressants. Risk Summary The available data on FETZIMA use in pregnant women are insufficient to evaluate for a drug-associated 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/m 2 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. Clinical Considerations 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 SNRIs in late pregnancy may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.5 )]. 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 ( 5.2 and 5.10 )]. Data 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/m 2 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/m 2 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/m 2 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/m 2 basis. 8.2 Lactation Risk Summary 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. Clinical Considerations Infants exposed to FETZIMA should be monitored for agitation, irritability, poor feeding and poor weight gain. Data 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. 8. 4 Pediatric Use 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 ( 6.1 )]. 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 ( 5.3 )]. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [ see Boxed Warning, Warnings and Precautions ( 5.1 ), and Adverse Reactions ( 6.1 ) ] . Juvenile Animal Toxicity Data 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. 8. 5 Geriatric Use No dose adjustment is recommended on the basis of age [ see Clinical Pharmacology ( 12.3 ) ] . 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 ( 2.3 ) ] . 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 ( 5.11 )]. 8. 6 Hepatic Impairment 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 ( 12.3 )]. 8. 7 Renal Impairment 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 ( 2.3 ) and Clinical Pharmacology ( 12.3 ) ] . Dose adjustment is not recommended for patients with mild (creatinine clearance of 60 to 89 mL/min) renal impairment [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 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 Storage and Handling 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] .

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [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 thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.1 ) . FETZIMA is not approved for use in pediatric patients ( 8.4 ).