DRUG ABUSE AND DEPENDENCE SECTION.

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

ADVERSE REACTIONS SECTION.

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)] 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)] 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 Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 exposureThe safety of levomilnacipran 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 levomilnacipran-treated patients, 1,583 were exposed to levomilnacipran in short-term, placebo-controlled studies. There were 825 patients who continued from short-term studies into one-year, open-label extension study. Of the 3,317 patients exposed to at least one dose of levomilnacipran, 895 patients were exposed to levomilnacipran for at least months and 367 were exposed for one year. In these studies, levomilnacipran was given at doses ranging from 40 mg to 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 levomilnacipran (40 mg to 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 levomilnacipran-treated patients in the short-term placebo-controlled studies was nausea (1.5%). Common adverse reactions in placebo-controlled MDD studiesThe most commonly observed adverse events in levomilnacipran-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 shows the incidence of adverse reactions that occurred in >= 2% of levomilnacipran-treated MDD patients and at least twice the rate of placebo in the placebo-controlled studies.Table 3: Adverse Reactions Occurring in >= 2% of Levomilnacipran-treated Patients and at Least Twice the rate of Placebo-treated PatientsSystem Organ Class Preferred TermPlacebo(N =1,040)%Levomilnacipran40 to 120 mg/d(N 1,583)%Gastrointestinal disordersNausea617Constipation39Vomiting15Cardiac disorders Tachycardiaa 26Palpitations15Reproductive system and breast disordersb Erectile dysfunctionc 16Testicular paind <14Ejaculation disordere <15InvestigationsHeart rate increasedf 16Blood pressure increasedg 13Renal and urinary disordersUrinary hesitation04Skin and subcutaneous tissue disordersHyperhidrosis29Rashh 02Vascular disordersHot flush13Hypotensioni 13Hypertensionj 13Metabolism and nutrition disordersDecreased appetite13a Tachycardia also includes: sinus tachycardia and postural orthostatic tachycardia syndromeb Percentage is relative to the number of patients in the associated demographic sex category. Fewer than 2% of levomilnacipran-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 dysfunctiond Testicular pain includes: testicular pain, epididymitis, and seminal vesiculitise Ejaculation disorder includes: ejaculation disorder, ejaculation delayed, ejaculation failure, and premature ejaculationf Heart rate increased also includes: orthostatic heart rate response increasedg Blood pressure increased also includes: blood pressure systolic increased, blood pressure diastolic increased and blood pressure orthostatic increasedh Rash also includes: rash generalized, rash maculo-papular, rash erythematous and rash maculari Hypotension also includes: orthostatic hypotension and dizziness posturalj Hypertension also includes: labile hypertensionN number of patients in the Safety PopulationDose-related adverse reactionsIn 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 levomilnacipran 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 ReactionsSystem Organ Class Preferred Term Placebo(N 362)%Levomilnacipran40 mg/d(N 366)%80 mg/d(N 367)%120 mg/d(N 180)%Urinary hesitation 0456Erectile dysfunctiona 26810a Percentage is relative to the number of male patients.N number of patients in the Safety PopulationOther adverse reactions observed in clinical studiesOther infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of 2% in MDD patients treated with levomilnacipran 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 Postmarketing Experience. The following adverse reaction has been identified during post-approval use of levomilnacipran or other selective serotonin and norepinephrine reuptake inhibitors. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiac disorders: Takotsubo cardiomyopathy.

BOXED WARNING SECTION.

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)]. Levomilnacipran is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].. WARNING: SUICIDAL THOUGHTS AND BEHAVIORSSee 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). Levomilnacipran is not approved for use in pediatric patients (8.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Levomilnacipran administered by oral gavage to rats for years and Tg.rasH2 mice for 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 times the maximum recommended human dose (MRHD) of 120 mg on mg/m2 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 of gestation at doses up to 100 mg/kg/day, no effects were observed on fertility. This dose is times the MRHD on mg/m2 basis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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 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 to 19 and 11 nM, respectively). Levomilnacipran lacks significant affinity for any other receptors, ion channels or transporters tested in vitro, including serotonergic (5HT1-7), and -adrenergic, muscarinic, or histaminergic receptors and Ca2+, Na+, K+ or Cl- channels. Levomilnacipran did not inhibit monoamine oxidase (MAO). Cardiovascular Electrophysiology At 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 once daily. Following an oral administration, the mean apparent total clearance of levomilnacipran is 21 to 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 levomilnacipran 120 mg, the mean Cmax 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 levomilnacipran extended-release capsules was 92% when compared to oral solution. Levomilnacipran concentration was not significantly affected when levomilnacipran extended-release capsule was administered with food. The median time to peak concentration (Tmax) of levomilnacipran is to hours after oral administration. Distribution Levomilnacipran is widely distributed with an apparent volume of distribution of 387 to 473 L; plasma protein binding is 22% over concentration range of 10 to 1000 ng/mL. EliminationMetabolismLevomilnacipran 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 [see Drug Interactions (7.4, 7.5)].ExcretionLevomilnacipran 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 StudiesThe drug interaction studies for levomilnacipran are summarized in Figure 1.Figure 1. PK Interactions between Levomilnacipran (LVM) and Other Drugs-- In vitro StudiesIn vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimal contributions to metabolism of levomilnacipran. In addition, levomilnacipran is not substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 and is 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 levomilnacipran extended-release capsules (20, 40, 80, and 120 mg) at 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 hours. There is no in vivo study conducted for the effect of alcohol on drug exposure.Special Populations The effect of intrinsic patient factors on the pharmacokinetics of levomilnacipran is presented in Figure 2.Figure Effect of Intrinsic Factors on Levomilnacipran PK. 1. 2.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Treatment of Major Depressive Disorder. The efficacy of levomilnacipran for the treatment of major depressive disorder (MDD) was established in three 8-week randomized, double-blind, placebo-controlled studies (at doses 40 mg to 120 mg once daily) in adult (18 to 78 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. Two of the studies were fixed dose (Study and Study 2) and one study was flexible dose (Study 3). In Study 1, patients received 40 mg (n 178), 80 mg (n 179), or 120 mg (n 180) of levomilnacipran once daily, or placebo (n 176). In Study 2, patients received either 40 mg (n 188) or 80 mg (n 188) of levomilnacipran once daily, or placebo (n 186). In the flexible-dose study (Study 3), patients received 40 mg to 120 mg (n 217) of levomilnacipran once daily, or placebo (n 217) with 21%, 34%, and 44% of levomilnacipran patients on 40 mg, 80 mg, and 120 mg, respectively at the end of their treatment.In all three studies, levomilnacipran demonstrated superiority over placebo in the improvement of depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) total score (see Table 6). Levomilnacipran also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale (SDS) functional impairment total score.Table 6: Summary of Results for the Primary Efficacy Endpoint MADRSStudy Number Treatment GroupMean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Differencea (95% CI)Study (fixed dose) Levomilnacipran (extended-release 40 mg/day)36.0 (4.1)-14.8 (1.0)-3.2 (-5.9, -0.5)Levomilnacipran (extended-release 80 mg/day)36.1 (3.9)-15.6 (1.0)-4.0 (-6.7, -1.3)Levomilnacipran (extended-release 120 mg/day)36.0 (3.9)-16.5 (1.0)-4.9 (-7.6, -2.1)Placebo35.6 (4.5)-11.6 (1.0)--Study (fixed-dose) Levomilnacipran (extended-release 40 mg/day)30.8 (3.4)-14.6 (0.8)-3.3 (-5.5, -1.1)Levomilnacipran (extended-release 80 mg/day)31.2 (3.5)-14.4 (0.8)-3.1 (-5.3, -1.0)Placebo31.0 (3.8)-11.3 (0.8)--Study (flexible-dose) Levomilnacipran (extended-release 40 to 120 mg/day)35.0 (3.6)-15.3 (0.8)-3.1 (-5.3, -0.9)Placebo35.2 (3.8)-12.2 (0.8)--SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval unadjusted for multiplicity. Difference (drug minus placebo) in least-squares mean change from baseline to endpoint (Week 8). Doses statistically significantly superior to placebo.Post-hoc analyses of the relationships between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.In maintenance study (Study 4; NCT02288325), adult patients meeting DSM-5 criteria for MDD received flexibly dosed levomilnacipran (40 mg, 80 mg, or 120 mg) once daily for weeks. Responders in the initial 8-week treatment period were eligible to enter 12-week, open-label, fixed-dose stabilization phase. At the end of stabilization, approximately half of the subjects were receiving 120 mg once daily. Three hundred twenty-four (324) patients who met the response criteria (MADRS total score <=12) after 20 weeks of open-label treatment were randomized to the double-blind treatment phase with levomilnacipran or placebo for 26 weeks. The primary efficacy endpoint was the time from randomization to first relapse during the double-blind phase. Relapse of depressive episode was defined as MADRS total score >= 18 at two consecutive visits or insufficient therapeutic response as judged by the investigator. Patients on levomilnacipran experienced statistically significantly longer time to relapse than patients on placebo (Figure 3).Figure 3. Kaplan-Meier Estimated Proportion of Patients with Relapse for Adults with MDD (Study 4)Note: The estimated hazard ratio (95% CI) of levomilnacipran relative to Placebo based on Cox proportional hazards model was 0.56 (95% CI: 0.33, 0.92). 1.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Hypersensitivity to levomilnacipran, milnacipran HCl or to any excipient in the formulation. The use of MAOIs intended to treat psychiatric disorders with levomilnacipran or within days of stopping treatment with levomilnacipran is contraindicated because of an increased risk of serotonin syndrome. The use of levomilnacipran 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 levomilnacipran in 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 to any excipient in the formulation. The use of MAOIs intended to treat psychiatric disorders with levomilnacipran or within days of stopping treatment with levomilnacipran is contraindicated because of an increased risk of serotonin syndrome. The use of levomilnacipran 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)]. Hypersensitivity to levomilnacipran, milnacipran HCl, or any excipient in the levomilnacipran extended-release capsules formulation (4).Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with levomilnacipran or within days of stopping treatment with levomilnacipran. Do not use levomilnacipran within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start levomilnacipran in patient who is being treated with linezolid or intravenous methylene blue (4).. Hypersensitivity to levomilnacipran, milnacipran HCl, or any excipient in the levomilnacipran extended-release capsules formulation (4).. Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with levomilnacipran or within days of stopping treatment with levomilnacipran. Do not use levomilnacipran within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start levomilnacipran in patient who is being treated with linezolid or intravenous methylene blue (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Levomilnacipran extended-release capsules contains levomilnacipran hydrochloride, selective serotonin and norepinephrine reuptake inhibitor (SNRI). The chemical name of levomilnacipran hydrochloride is (1S,2R)-2(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride; its molecular formula is C15H23ClN2O and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial U.S. approval: 2013) is the 1S,2R-enantiomer of milnacipran. The chemical structure of levomilnacipran hydrochloride is:Levomilnacipran extended-release capsules are intended for oral administration. Each levomilnacipran extended-release capsule contains extended-release beads with 23, 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, red iron oxide (80 mg and 120 mg), sugar sphere [sucrose, starch (Biological source: maize) and purified water], talc, triethyl citrate, titanium dioxide and yellow iron oxide (20 mg and 40 mg). Each capsule is imprinted with black pharmaceutical ink which contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.. 12.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dose: 40 mg to 120 mg once daily with or without food (2.1). Initiate dose at 20 mg once daily for days and then increase to 40 mg once daily (2.1). Based on efficacy and tolerability, increase dose in increments of 40 mg at intervals of or more days (2.1).The maximum recommended dose is 120 mg once daily (2.1). Take capsules whole; do not open, chew or crush (2.1).Renal Impairment: Do not exceed 80 mg once daily for moderate impairment. Do not exceed 40 mg once daily for severe renal impairment (2.3). Discontinuation: Reduce dose gradually whenever possible (2.4) Recommended dose: 40 mg to 120 mg once daily with or without food (2.1). Initiate dose at 20 mg once daily for days and then increase to 40 mg once daily (2.1). Based on efficacy and tolerability, increase dose in increments of 40 mg at intervals of or more days (2.1).. The maximum recommended dose is 120 mg once daily (2.1). Take capsules whole; do not open, chew or crush (2.1).. Renal Impairment: Do not exceed 80 mg once daily for moderate impairment. Do not exceed 40 mg once daily for severe renal impairment (2.3). Discontinuation: Reduce dose gradually whenever possible (2.4) 2.1General Instruction for Use. The recommended dose range for levomilnacipran extended-release capsule is 40 mg to 120 mg once daily, with or without food. Levomilnacipran extended-release capsules should be initiated at 20 mg once daily for days and then increased to 40 mg once daily. Based on efficacy and tolerability, levomilnacipran extended-release capsules may then be increased in increments of 40 mg at intervals of or more days. The maximum recommended dose is 120 mg once daily. Levomilnacipran extended-release capsules should be taken at approximately the same time each day. Levomilnacipran extended-release capsules should be swallowed whole. Do not open, chew or crush the capsule. 2.2 Screen for Bipolar Disorder Prior to Starting Levomilnacipran Extended-release Capsules. Prior to initiating treatment with levomilnacipran extended-release capsules or another antidepressant, screen patients for personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.8)].. 2.3 SpecialPopulations. Renal Impairment: Dose adjustment is not recommended in patients with mild renal impairment (creatinine clearance of 60 to 89 mL/min). For patients with moderate renal impairment (creatinine clearance of 30 to 59 mL/min), the maintenance dose should not exceed 80 mg once daily. For patients with severe renal impairment (creatinine clearance of 15 to 29 mL/min), the maintenance dose should not exceed 40 mg once daily. Levomilnacipran extended-release capsules are not recommended for patients with end stage renal disease [see Use in Specific Populations (8.7)].. 2.4 Discontinuing Treatment. Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as levomilnacipran extended-release capsules. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing levomilnacipran extended-release capsules. If intolerable symptoms occur following dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at more gradual rate [see Warnings and Precautions (5.10)]. 2.5 Switchinga Patient To or From Monoamine Oxidase Inhibitor (MAOI) Intended to TreatPsychiatric Disorders. At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with levomilnacipran extended-release capsules. Conversely, at least days should be allowed after stopping levomilnacipran extended-release capsules before starting an MAOI antidepressant [see Contraindications (4)]. 2.6Use of Levomilnacipran with Other MAOIs such as Linezolid or Methylene Blue. Do not start levomilnacipran extended-release capsules in patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In patient who requires more urgent treatment of psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)]. In some cases, patient already receiving levomilnacipran extended-release capsules therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in particular patient, levomilnacipran extended-release capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with levomilnacipran extended-release capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than mg/kg with levomilnacipran extended-release capsule is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].. 2.7Use of Levomilnacipran with Strong Inhibitors of Cytochrome P450 (CYP3A4)Enzyme. The dose of levomilnacipran extended-release capsules should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir) [see Drug Interactions (7.4)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Levomilnacipran extended-release capsules are available as 20 mg, 40 mg, 80 mg and 120 mg extended-release capsules.Levomilnacipran extended-release capsules, 20 mg are supplied as size capsules, imprinted with AN on yellow cap and 411 on white body of the capsules with black ink, filled with off-white to pale yellow pellets.Levomilnacipran extended-release capsules, 40 mg are supplied as size capsules, imprinted with AN on yellow cap and 414 on yellow body of the capsules with black ink, filled with off-white to pale yellow pellets.Levomilnacipran extended-release capsules, 80 mg are supplied as size capsules, imprinted with AN on pink cap and 437 on white body of the capsules with black ink, filled with off-white to pale yellow pellets.Levomilnacipran extended-release capsules, 120 mg are supplied as size capsules, imprinted with AN on pink cap and 455 on pink body of the capsules with black ink, filled with off-white to pale yellow pellets.. Extended-release capsules: 20 mg, 40 mg, 80 mg and 120 mg (3).. Extended-release capsules: 20 mg, 40 mg, 80 mg and 120 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP3A4 inhibitors such as ketoconazole: Do not exceed 80 mg once daily (7).. Strong CYP3A4 inhibitors such as ketoconazole: Do not exceed 80 mg once daily (7).. 7.1Clinically Important Drug Interactions with Levomilnacipran. Table includes clinically important drug interactions with levomilnacipran.Table 5: Clinically Important Drug Interactions with LevomilnacipranMonoamine Oxidase Inhibitors (MAOIs)Clinical Impact:Concomitant use of SSRIs and SNRIs including levomilnacipran with MAOIs increases the risk of serotonin syndrome.Intervention:Concomitant use of levomilnacipran is contraindicated:. With an MAOI intended to treat psychiatric disorders or within days of stopping treatment with levomilnacipran.. Within 14 days of stopping an MAOI intended to treat psychiatric disorders. In 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 blueOther Serotonergic DrugsClinical Impact:Concomitant use of levomilnacipran with other serotonergic drugs increases the risk of serotonin syndrome.Intervention:Monitor for symptoms of serotonin syndrome when levomilnacipran is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, immediately discontinue levomilnacipran 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. Johns WortDrugs that Interfere with HemostasisClinical Impact:Concomitant use of levomilnacipran with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of levomilnacipran on the release of serotonin by platelets.Intervention:Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when levomilnacipran is initiated or discontinued [see Warnings and Precautions 5.5 )].Examples:NSAIDs, aspirin, and warfarinStrong CYP3A4 InhibitorsClinical Impact:Concomitant use of levomilnacipran with strong CYP3A4 inhibitors increases levomilnacipran exposure [see Pharmacokinetics 12.3 )].Intervention:The dose of levomilnacipran should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors [see Dosage and Administration 2.7 ). Examples:Ketoconazole, itraconazole, clarithromycinAlcoholClinical Impact:Concomitant use of levomilnacipran and alcohol may result in accelerated release of levomilnacipran.Intervention:Avoid concomitant use of levomilnacipran and alcohol [see Clinical Pharmacology 12.3 )].

GERIATRIC USE SECTION.

8.5 Geriatric Use. No dose adjustment is recommended on the basis of age (see Figure 2). In multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had slightly higher exposure (Cmax by 24% and AUC by 26%) of levomilnacipran than younger subjects (18 to 45 years). Of the total number of subjects in the 8-week clinical studies of levomilnacipran, 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 levomilnacipran, 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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Levomilnacipran extended-release capsules are supplied in the following configurations: Levomilnacipran Extended-release Capsules, 20 mg are supplied as size capsules, imprinted with AN on yellow cap and 411 on white body of the capsules with black ink, filled with off-white to pale yellow pellets.They are available as follows:Bottles of 30: NDC 65162-411-03Levomilnacipran Extended-release Capsules, 40 mg are supplied as size capsules, imprinted with AN on yellow cap and 414 on yellow body of the capsules with black ink, filled with off-white to pale yellow pellets.They are available as follows:Bottles of 30: NDC 65162-960-03Levomilnacipran Extended-release Capsules, 80 mg are supplied as size capsules, imprinted with AN on pink cap and 437 on white body of the capsules with black ink, filled with off-white to pale yellow pellets.They are available as follows:Bottles of 30: NDC 65162-437-03Levomilnacipran Extended-release Capsules, 120 mg are supplied as size capsules, imprinted with AN on pink cap and 455 on pink body of the capsules with black ink, filled with off-white to pale yellow pellets.They are available as follows:Bottles of 30: NDC 65162-455-03Storage and HandlingAll package configurations: Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Levomilnacipran is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)]. Limitation of Use: Levomilnacipran extended-release capsules are not approved for the management of fibromyalgia. The efficacy and safety of levomilnacipran extended-release capsules for the management of fibromyalgia have not been established.. Levomilnacipran is serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of Major Depressive Disorder (MDD) in adults (1).Limitation of Use: Levomilnacipran extended-release capsules are not approved for the management of fibromyalgia. The efficacy and safety of levomilnacipran extended-release capsules for the management of fibromyalgia have not been established (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Suicide Thoughts and BehaviorsAdvise 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 [see Box Warning and Warnings and Precautions (5.1)]. Dosing and AdministrationAdvise patients that levomilnacipran extended-release capsules should be swallowed whole and should not be chewed, crushed or opened. Advise patients that levomilnacipran extended-release capsules can be taken with or without food. Instruct patients if they miss 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 levomilnacipran at the same time. Concomitant MedicationInstruct patients not to take levomilnacipran with an MAOI or within 14 days of stopping an MAOI and to allow days after stopping levomilnacipran before starting an MAOI [see Contraindications (4)]. Allergic ReactionsAdvise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Contraindications (4)].Serotonin SyndromeCaution patients about the risk of serotonin syndrome, particularly with the concomitant use of levomilnacipran with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, amphetamines, tryptophan, buspirone, and St. Johns Wort supplements) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Effect on Blood Pressure and Heart RateAdvise patients that they should have regular monitoring of blood pressure and heart rate when taking levomilnacipran [see Warnings and Precautions (5.3, 5.4)]. Increased Risk of BleedingCaution patients about the concomitant use of levomilnacipran and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding [see Warnings and Precautions (5.5)]. Angle Closure GlaucomaPatients should be advised that taking levomilnacipran 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 RetentionCaution patients about the risk of urinary hesitation and retention while taking levomilnacipran, particularly in patients prone to obstructive urinary disorders [see Warnings and Precautions (5.7)]. Activation of Mania/HypomaniaAdvise patients and their caregivers to observe for signs of activation of mania/hypomania [see Warnings and Precautions (5.8)]. SeizuresCaution patients about using levomilnacipran if they have history of seizure disorder [see Warnings and Precautions (5.9)]. Patients with history of seizures were excluded from clinical studies.Discontinuation SyndromeAdvise patients not to stop taking levomilnacipran without first talking with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping levomilnacipran [see Warnings and Precautions (5.10)]. HyponatremiaAdvise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking levomilnacipran [see Warnings and Precautions (5.11)]. AlcoholAdvise patients to avoid consumption of alcohol while taking levomilnacipran [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. PregnancyAdvise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with levomilnacipran.Advise patients that levomilnacipran 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 women that there is risk of relapse with discontinuation of antidepressants.Advise patient that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to levomilnacipran during pregnancy [see Use in Specific Populations (8.1)] LactationAdvise breastfeeding women using levomilnacipran 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 levomilnacipran therapy does not adversely affect their ability to engage in such activities. Manufactured by:Amneal Pharmaceuticals Pvt. Ltd. Ahmedabad 382220, INDIA Distributed by:Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 04-2020-01. Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with levomilnacipran.. Advise patients that levomilnacipran 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 women that there is risk of relapse with discontinuation of antidepressants.. Advise patient that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to levomilnacipran during pregnancy [see Use in Specific Populations (8.1)].

MECHANISM OF ACTION SECTION.

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 potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Levomilnacipran administered by oral gavage to rats for years and Tg.rasH2 mice for 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 times the maximum recommended human dose (MRHD) of 120 mg on mg/m2 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 of gestation at doses up to 100 mg/kg/day, no effects were observed on fertility. This dose is times the MRHD on mg/m2 basis.

NURSING MOTHERS SECTION.

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 mothers clinical need for levomilnacipran and any potential adverse effects on the breastfed child from levomilnacipran or from the underlying maternal conditions. Clinical ConsiderationsInfants exposed to levomilnacipran should be monitored for agitation, irritability, poor feeding and poor weight gain. Data Milnacipran, racemic mixture that contains levomilnacipran (the 1S,2R-enantiomer of milnacipran), is present in the milk of lactating women treated with milnacipran. In lactation pharmacokinetic study with milnacipran, single, oral dose of 50 mg milnacipran HCl tablet was administered to 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. 10.1Human Experience. There is limited clinical experience with levomilnacipran 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 levomilnacipran 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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 65162-411-03Levomilnacipran Extended-Release Capsules, 20 mgRx only30 CapsulesAmneal Pharmaceuticals LLC NDC 65162-960-03Levomilnacipran Extended-Release Capsules, 40 mgRx only30 CapsulesAmneal Pharmaceuticals LLC NDC 65162-437-03Levomilnacipran Extended-Release Capsules, 80 mgRx only30 CapsulesAmneal Pharmaceuticals LLC NDC 65162-455-03Levomilnacipran Extended-Release Capsules, 120 mgRx only30 CapsulesAmneal Pharmaceuticals LLC 12. 13. 13. 15.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Clinical studies on the use of levomilnacipran in pediatric patients have not been conducted; therefore, the safety and effectiveness of levomilnacipran in the pediatric population have not been established. Levomilnacipran is not approved for use in pediatric patients [see Boxed Warning and Warnings and Precautions (5.1)].

PHARMACODYNAMICS SECTION.

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 to 19 and 11 nM, respectively). Levomilnacipran lacks significant affinity for any other receptors, ion channels or transporters tested in vitro, including serotonergic (5HT1-7), and -adrenergic, muscarinic, or histaminergic receptors and Ca2+, Na+, K+ or Cl- channels. Levomilnacipran did not inhibit monoamine oxidase (MAO). Cardiovascular Electrophysiology At dose 2.5 times the maximum recommended dose, levomilnacipran does not prolong QTc to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The concentration of levomilnacipran at steady state is proportional to dose when administered from 25 mg to 300 mg once daily. Following an oral administration, the mean apparent total clearance of levomilnacipran is 21 to 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 levomilnacipran 120 mg, the mean Cmax 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 levomilnacipran extended-release capsules was 92% when compared to oral solution. Levomilnacipran concentration was not significantly affected when levomilnacipran extended-release capsule was administered with food. The median time to peak concentration (Tmax) of levomilnacipran is to hours after oral administration. Distribution Levomilnacipran is widely distributed with an apparent volume of distribution of 387 to 473 L; plasma protein binding is 22% over concentration range of 10 to 1000 ng/mL. EliminationMetabolismLevomilnacipran 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 [see Drug Interactions (7.4, 7.5)].ExcretionLevomilnacipran 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 StudiesThe drug interaction studies for levomilnacipran are summarized in Figure 1.Figure 1. PK Interactions between Levomilnacipran (LVM) and Other Drugs-- In vitro StudiesIn vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimal contributions to metabolism of levomilnacipran. In addition, levomilnacipran is not substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 and is 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 levomilnacipran extended-release capsules (20, 40, 80, and 120 mg) at 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 hours. There is no in vivo study conducted for the effect of alcohol on drug exposure.Special Populations The effect of intrinsic patient factors on the pharmacokinetics of levomilnacipran is presented in Figure 2.Figure Effect of Intrinsic Factors on Levomilnacipran PK. 1. 2.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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-research-programs/pregnancyregistry/antidepressants/. Risk Summary The available data on levomilnacipran use in pregnant women are insufficient to evaluate for 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 levomilnacipran, 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 or 16 times the maximum recommended human dose (MRHD) of 120 mg on mg/m2 basis, respectively. However, an increase in early post-natal rat pup mortality was seen at dose equivalent to 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 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 relapse of major depression than women who continued antidepressants. This finding is from prospective, longitudinal study that followed 201 pregnant women with 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 reactionsNeonates exposed to SNRIs or SSRIs, including levomilnacipran, 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, 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)]. DataAnimal 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 and 16 times (in rats and rabbits, respectively) the maximum recommended human dose (MRHD) of 120 mg on 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 times the MRHD in rabbits on mg/m2 basis. When levomilnacipran was administered to pregnant rats at an oral dose of 60 mg/kg/day, 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 mg/m2 basis. Among the surviving pups, pre- and post-weaning pup weight gain was reduced up to at least 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 mg/kg/day, 0.6 times the MRHD on mg/m2 basis.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions (5.1) 10/2019 Warnings and Precautions (5.2) 10/2019 Warnings and Precautions (5.5) 10/2019 Warnings and Precautions (5.6) 10/2019 Warnings and Precautions (5.11) 10/2019. Warnings and Precautions (5.1) 10/2019 Warnings and Precautions (5.2) 10/2019 Warnings and Precautions (5.5) 10/2019 Warnings and Precautions (5.6) 10/2019 Warnings and Precautions (5.11) 10/2019.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. Levomilnacipran (lee voe mil na si pran) Extended-Release CapsulesWhat is the most important information should know about levomilnacipran extended-release capsules Levomilnacipran extended-release capsules may cause serious side effects, including: Increased risk of suicidal thoughts or actions in some children, adolescents, and young adults. Levomilnacipran extended-release capsules and other antidepressant medicines may increase suicidal thoughts or actions in some children and young adults, especially within the first few months of treatment or when the dose is changed. Levomilnacipran extended-release capsules are not for use in children.Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have higher risk of having suicidal thoughts or actions. These include people who have (or have family history of) depression, bipolar illness (also called manic-depressive illness) or have history of suicidal thoughts or actions. How can watch for and try to prevent suicidal thoughts and actionsPay 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. 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 they 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 moodWhat are levomilnacipran extended-release capsulesLevomilnacipran extended-release capsules are prescription medicine used to treat certain type of depression called Major Depressive Disorder (MDD) in adults. It is not known if levomilnacipran extended-release capsules are safe and effective for use in children. It is not known if levomilnacipran extended-release capsules are safe and effective for the management of fibromyalgia. Levomilnacipran extended-release capsules are not for use for the management of fibromyalgia. Who should not take levomilnacipran extended-release capsulesDo not take levomilnacipran extended-release capsules if you: are allergic to levomilnacipran, milnacipran HCl, or any of the ingredients in levomilnacipran extended-release capsules. See the end of this Medication Guide for complete list of ingredients in levomilnacipran extended-release capsules. take Monoamine Oxidase Inhibitor (MAOI) have stopped taking an MAOI in the last 14 days are being treated with the antibiotic linezolid or intravenous methylene blueAsk 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 days after you stop treatment with levomilnacipran extended-release capsules. Before taking levomilnacipran extended-release capsules, tell your healthcare provider about all your medical conditions, including if you: have or have family history of suicide, depression, bipolar disorder, mania or hypomaniahave high blood pressure have or had heart problems or stroke have or had bleeding problemshave glaucoma (high pressure in the eye) have or had problems urinating (hesitation) or empting 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. Levomilnacipran extended-release capsules may harm your unborn baby. Taking levomilnacipran extended-release capsules during your third trimester of pregnancy may cause an increased risk of bleeding after delivery and may cause harm to your baby. Talk to your healthcare provider about the risks to you and your baby if you take levomilnacipran extended-release capsules during pregnancy.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with levomilnacipran extended-release capsules.There is pregnancy registry for females who are exposed to levomilnacipran extended-release capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to levomilnacipran extended-release capsules and their baby. If you become pregnant during treatment with levomilnacipran extended-release capsules, 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 levomilnacipran passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with levomilnacipran extended-release capsules. If you breastfeed during treatment with levomilnacipran extended-release capsules, call you healthcare provider right away 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.Levomilnacipran extended-release capsules and other medicines may affect each other causing possible serious side effects.Levomilnacipran extended-release capsules may affect the way other medicines work and other medicines may affect the way levomilnacipran extended-release capsules works.Especially tell your healthcare provider if you take: MAOIsmedicines used to treat migraine headache known as triptanstricyclic antidepressantsfentanyllithiumtramadoltryptophanbuspironeamphetaminesSt. Johns Wortmedicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and warfarindiureticsmedicines 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 levomilnacipran extended-release capsules with your other medicines.Do not start or stop any other medicines during treatment with levomilnacipran extended-release capsules without talking to your healthcare provider first. Stopping levomilnacipran extended-release capsules suddenly may cause you to have serious side effects. See, What are the possible side effects of levomilnacipran extended-release capsules Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take levomilnacipran extended-release capsules Take levomilnacipran extended-release capsules exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking levomilnacipran extended-release capsules without first talking to your healthcare provider. Your healthcare provider may need to change the dose of levomilnacipran extended-release capsules until it is the right dose for you. Take levomilnacipran extended-release capsules one time each day at about the same time each day.Take levomilnacipran extended-release capsules with or without food. Swallow levomilnacipran extended-release capsules whole. Do not open, chew, or crush the levomilnacipran extended-release capsules capsule. If you miss dose of levomilnacipran extended-release capsules, 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 doses of levomilnacipran extended-release capsules at the same time. If you take too much levomilnacipran extended-release capsules, 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 avoid while taking levomilnacipran extended-release capsules Do not drive, operate heavy machinery, or do other dangerous activities until you know how levomilnacipran extended-release capsules affects you. Levomilnacipran extended-release capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. Avoid drinking alcohol during treatment with levomilnacipran extended-release capsules. What are the possible side effects of levomilnacipran extended-release capsules Levomilnacipran extended-release capsules may cause serious side effects, including: See, What is the most important information should know about levomilnacipran extended-release capsules Serotonin syndrome. potentially life-threatening problem called serotonin syndrome can happen when levomilnacipran extended-release capsules is taken with certain other medicines. See, Who should not take levomilnacipran extended-release capsules Stop taking levomilnacipran extended-release capsules and call you 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:agitationseeing or hearing things that are not real (hallucinations)confusioncomafast heart beatblood pressure changesdizzinesssweatingflushinghigh body temperature (hyperthermia)tremors, stiff muscles, or muscle twitchingloss of coordinationseizuresnausea, vomiting, diarrheaHigh blood pressure (hypertension). Your healthcare provider should check your blood pressure before you start and during treatment with levomilnacipran extended-release capsules. If you have high blood pressure, it should be controlled before you start treatment with levomilnacipran extended-release capsules.Increased heart rate. Your healthcare provider should check your heart rate before you start and during treatment with levomilnacipran extended-release capsules. If you have heart problems or problems with an abnormal heartbeat, your problems should be treated before you start treatment with levomilnacipran extended-release capsules.Increased risk of bleeding. Taking levomilnacipran extended-release capsules 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). Many antidepressant medicines, including levomilnacipran extended-release capsules, may cause certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have changes in your vision or eye pain.Problems with urination. Levomilnacipran extended-release capsules 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 levomilnacipran extended-release capsules. Manic episodes. Manic episodes may happen in people with bipolar disorder who take levomilnacipran extended-release capsules. Symptoms may include:greatly increased energysevere trouble sleepingracing thoughtsreckless behaviorunusually grand ideasexcessive happiness or irritabilitytalking more or faster than usualSeizures (convulsions). Discontinuation syndrome. Suddenly stopping levomilnacipran extended-release capsules may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:changes in your moodheadacheirritability and agitationtirednessdizzinessproblems sleeping electric shock sensation (paresthesia)hypomania anxietyringing in your ears (tinnitus) confusionseizures Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood may be serious and may cause death. Elderly people may be at greater risk for this. Signs and Symptoms of low sodium levels in your blood may include:headache difficulty concentrating memory changes confusion weakness and unsteadiness on your feet which can lead to fallsIn severe or more sudden cases, signs and symptoms include:hallucinations (seeing or hearing things that are not real)fainting seizurescomarespiratory arrestdeathThe most common side effects of levomilnacipran extended-release capsules, include:nauseaconstipationsweatingabnormal heartbeaterectile dysfunctionvomitingThese are not all the possible side effects of levomilnacipran extended-release capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store levomilnacipran extended-release capsules Store levomilnacipran extended-release capsules at room temperature between 68 to 77F (20 to 25C). Keep levomilnacipran extended-release capsules and all medicines out of the reach of children.General information about the safe and effective use of levomilnacipran extended-release capsules Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use levomilnacipran extended-release capsules for condition for which it was not prescribed. Do not give levomilnacipran extended-release capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about levomilnacipran extended-release capsules that is written for healthcare professionals. What are the ingredients in levomilnacipran extended-release capsules Active ingredient: levomilnacipran hydrochlorideInactive ingredients: ethylcellulose, hypromellose, povidone, red iron oxide (80 mg and 120 mg), sugar sphere [sucrose, starch (Biological source: maize) and purified water], talc, triethyl citrate, titanium dioxide and yellow iron oxide (20 mg and 40 mg). Each capsule is imprinted with black pharmaceutical ink which contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.For more information, go to www.amneal.com or call 1-877-835-5472.This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by:Amneal Pharmaceuticals Pvt. Ltd. Ahmedabad 382220, INDIADistributed by:Amneal Pharmaceuticals LLC Bridgewater, NJ 08807Rev. 04-2020-01. Increased risk of suicidal thoughts or actions in some children, adolescents, and young adults. Levomilnacipran extended-release capsules and other antidepressant medicines may increase suicidal thoughts or actions in some children and young adults, especially within the first few months of treatment or when the dose is changed. Levomilnacipran extended-release capsules are not for use in children.. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have higher risk of having suicidal thoughts or actions. These include people who have (or have family history of) depression, bipolar illness (also called manic-depressive illness) or have history of suicidal thoughts or 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. 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. 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. are allergic to levomilnacipran, milnacipran HCl, or any of the ingredients in levomilnacipran extended-release capsules. See the end of this Medication Guide for complete list of ingredients in levomilnacipran extended-release capsules. take Monoamine Oxidase Inhibitor (MAOI) have stopped taking an MAOI in the last 14 days are being treated with the antibiotic linezolid or intravenous methylene blue. have or have family history of suicide, depression, bipolar disorder, mania or hypomania. have high blood pressure have or had heart problems or stroke have or had bleeding problems. have glaucoma (high pressure in the eye) have or had problems urinating (hesitation) or empting 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. Levomilnacipran extended-release capsules may harm your unborn baby. Taking levomilnacipran extended-release capsules during your third trimester of pregnancy may cause an increased risk of bleeding after delivery and may cause harm to your baby. Talk to your healthcare provider about the risks to you and your baby if you take levomilnacipran extended-release capsules during pregnancy.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with levomilnacipran extended-release capsules.There is pregnancy registry for females who are exposed to levomilnacipran extended-release capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to levomilnacipran extended-release capsules and their baby. If you become pregnant during treatment with levomilnacipran extended-release capsules, 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/. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with levomilnacipran extended-release capsules.. There is pregnancy registry for females who are exposed to levomilnacipran extended-release capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to levomilnacipran extended-release capsules and their baby. If you become pregnant during treatment with levomilnacipran extended-release capsules, 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 levomilnacipran passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with levomilnacipran extended-release capsules. If you breastfeed during treatment with levomilnacipran extended-release capsules, call you healthcare provider right away if your baby develops sleepiness or fussiness, or is not feeding or gaining weight well.. MAOIs. medicines used to treat migraine headache known as triptans. tricyclic antidepressants. fentanyl. lithium. tramadol. tryptophan. buspirone. amphetamines. St. Johns 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). Take levomilnacipran extended-release capsules exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking levomilnacipran extended-release capsules without first talking to your healthcare provider. Your healthcare provider may need to change the dose of levomilnacipran extended-release capsules until it is the right dose for you. Take levomilnacipran extended-release capsules one time each day at about the same time each day.. Take levomilnacipran extended-release capsules with or without food. Swallow levomilnacipran extended-release capsules whole. Do not open, chew, or crush the levomilnacipran extended-release capsules capsule. If you miss dose of levomilnacipran extended-release capsules, 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 doses of levomilnacipran extended-release capsules at the same time. If you take too much levomilnacipran extended-release capsules, call your healthcare provider or poison control center at 1-800-222-1222, or go to the nearest hospital emergency room right away. Do not drive, operate heavy machinery, or do other dangerous activities until you know how levomilnacipran extended-release capsules affects you. Levomilnacipran extended-release capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. Avoid drinking alcohol during treatment with levomilnacipran extended-release capsules. See, What is the most important information should know about levomilnacipran extended-release capsules Serotonin syndrome. potentially life-threatening problem called serotonin syndrome can happen when levomilnacipran extended-release capsules is taken with certain other medicines. See, Who should not take levomilnacipran extended-release capsules Stop taking levomilnacipran extended-release capsules and call you 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 heart beat. 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 levomilnacipran extended-release capsules. If you have high blood pressure, it should be controlled before you start treatment with levomilnacipran extended-release capsules.. Increased heart rate. Your healthcare provider should check your heart rate before you start and during treatment with levomilnacipran extended-release capsules. If you have heart problems or problems with an abnormal heartbeat, your problems should be treated before you start treatment with levomilnacipran extended-release capsules.. Increased risk of bleeding. Taking levomilnacipran extended-release capsules 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). Many antidepressant medicines, including levomilnacipran extended-release capsules, may cause certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have changes in your vision or eye pain.. Problems with urination. Levomilnacipran extended-release capsules 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 levomilnacipran extended-release capsules. Manic episodes. Manic episodes may happen in people with bipolar disorder who take levomilnacipran extended-release capsules. 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 levomilnacipran extended-release capsules 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 may be serious and may cause death. Elderly people may be at greater risk for this. Signs and Symptoms of low sodium levels in your blood may include:. headache difficulty concentrating memory changes confusion weakness and unsteadiness on your feet which can lead to falls. hallucinations (seeing or hearing things that are not real). fainting seizures. coma. respiratory arrest. death. nausea. constipation. sweating. abnormal heartbeat. erectile dysfunction. vomiting. Store levomilnacipran extended-release capsules at room temperature between 68 to 77F (20 to 25C). Keep levomilnacipran extended-release capsules and all medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.

2.1General Instruction for Use. The recommended dose range for levomilnacipran extended-release capsule is 40 mg to 120 mg once daily, with or without food. Levomilnacipran extended-release capsules should be initiated at 20 mg once daily for days and then increased to 40 mg once daily. Based on efficacy and tolerability, levomilnacipran extended-release capsules may then be increased in increments of 40 mg at intervals of or more days. The maximum recommended dose is 120 mg once daily. Levomilnacipran extended-release capsules should be taken at approximately the same time each day. Levomilnacipran extended-release capsules should be swallowed whole. Do not open, chew or crush the capsule.

USE IN SPECIFIC POPULATIONS SECTION.

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). 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 RegistryThere is 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-research-programs/pregnancyregistry/antidepressants/. Risk Summary The available data on levomilnacipran use in pregnant women are insufficient to evaluate for 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 levomilnacipran, 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 or 16 times the maximum recommended human dose (MRHD) of 120 mg on mg/m2 basis, respectively. However, an increase in early post-natal rat pup mortality was seen at dose equivalent to 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 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 relapse of major depression than women who continued antidepressants. This finding is from prospective, longitudinal study that followed 201 pregnant women with 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 reactionsNeonates exposed to SNRIs or SSRIs, including levomilnacipran, 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, 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)]. DataAnimal 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 and 16 times (in rats and rabbits, respectively) the maximum recommended human dose (MRHD) of 120 mg on 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 times the MRHD in rabbits on mg/m2 basis. When levomilnacipran was administered to pregnant rats at an oral dose of 60 mg/kg/day, 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 mg/m2 basis. Among the surviving pups, pre- and post-weaning pup weight gain was reduced up to at least 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 mg/kg/day, 0.6 times the MRHD on mg/m2 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 mothers clinical need for levomilnacipran and any potential adverse effects on the breastfed child from levomilnacipran or from the underlying maternal conditions. Clinical ConsiderationsInfants exposed to levomilnacipran should be monitored for agitation, irritability, poor feeding and poor weight gain. Data Milnacipran, racemic mixture that contains levomilnacipran (the 1S,2R-enantiomer of milnacipran), is present in the milk of lactating women treated with milnacipran. In lactation pharmacokinetic study with milnacipran, single, oral dose of 50 mg milnacipran HCl tablet was administered to 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. Clinical studies on the use of levomilnacipran in pediatric patients have not been conducted; therefore, the safety and effectiveness of levomilnacipran in the pediatric population have not been established. Levomilnacipran 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 multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had slightly higher exposure (Cmax by 24% and AUC by 26%) of levomilnacipran than younger subjects (18 to 45 years). Of the total number of subjects in the 8-week clinical studies of levomilnacipran, 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 levomilnacipran, 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 to 6), moderate (Child-Pugh score of to 9), or severe (Child-Pugh score of 10 to 13) hepatic impairment (see Figure 2).. 8.7 Renal Impairment. Renal excretion plays predominant role in the elimination of levomilnacipran. Dose adjustment is not recommended for patients with mild (creatinine clearance of 60 to 89 mL/min) renal impairment. 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 Figure 2). Levomilnacipran is not recommended for patients with end stage renal disease [see Dosage and Administration (2.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue levomilnacipran and initiate supportive treatment (5.2).Elevated Blood Pressure and Heart Rate: Control hypertension before initiating therapy with levomilnacipran. Monitor blood pressure regularly during treatment (5.3, 5.4).Increased Risk of Bleeding: Concomitant use of NSAIDs, aspirin, other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk (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 levomilnacipran 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 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).. Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue levomilnacipran and initiate supportive treatment (5.2).. Elevated Blood Pressure and Heart Rate: Control hypertension before initiating therapy with levomilnacipran. Monitor blood pressure regularly during treatment (5.3, 5.4).. Increased Risk of Bleeding: Concomitant use of NSAIDs, aspirin, other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk (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 levomilnacipran 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 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. In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult PatientsAge RangeDrug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients TreatedIncreases Compared to Placebo<18 years old14 additional patients18 to 24 years old5 additional patientsDecreases Compared to Placebo25 to 64 years old1 fewer patient>=65 years old6 fewer patientsIt is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e. beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is risk factor for suicidal thoughts and behaviors.Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing levomilnacipran, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.. 5.2 Serotonin Syndrome. Selective-serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including levomilnacipran, can precipitate serotonin syndrome, potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. Johns Wort) and with drugs that impair metabolism of serotonin, i.e. MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone.Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of levomilnacipran with MAOIs is contraindicated. In addition, do not initiate levomilnacipran in patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with MAOI such as linezolid or intravenous methylene blue in patient taking levomilnacipran, discontinue levomilnacipran before initiating treatment with the MAOI [see Dosage and Administration (2.5, 2.6) and Contraindications (4), Drug Interactions (7.1)].Monitor all patients taking levomilnacipran for the emergence of serotonin syndrome. Discontinue treatment with levomilnacipran and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. If concomitant use of levomilnacipran with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.. 5.3 Elevated Blood Pressure. SNRIs, including levomilnacipran, have been associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically throughout levomilnacipran treatment. Pre-existing hypertension should be controlled before initiating treatment with levomilnacipran. 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 sustained increase in blood pressure while receiving levomilnacipran, discontinuation or other appropriate medical intervention should be considered. Table shows the mean changes in blood pressure, sustained hypertension, and upward shifts in hypertensive status that were observed in levomilnacipran-treated patients in the short-term placebo-controlled studies.Table 2: Blood Pressure Mean Changes, Sustained Hypertension, and Upward Shifts in Hypertensive StatusPlaceboLevomilnacipran40 to 120 mg/dayMean change from baseline to end of treatment, mm HgSystolic blood pressure (SBP)-0.43.0Diastolic blood pressure (DBP)-0.03.2Sustained Hypertension, of patientsBroad 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 consecutive visits1.21.8Strict 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 consecutive visits0.10.3Upward Shifts in Hypertensive Statusa, of patientsNormal/ Pre-hypertensive -> Stage I/ Stage II7.110.4a Normal Blood Pressure: SBP 120 mm Hg and DBP 80 mm HgPre-hypertension: SBP >= 120 mm Hg and <= 139 mm Hg or DBP >= 80 mm Hg and <= 89 mm HgStage hypertension: SBP >= 140 mm Hg and <= 159 mm Hg or DBP >= 90 mm Hg and <= 99 mm HgStage II hypertension: SBP >= 160 mm Hg or DBP >= 100 mm HgIn the short-term, placebo-controlled MDD studies, the mean increase from initiation of treatment in systolic BP was 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 levomilnacipran (doses range from 40 mg to 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 levomilnacipran 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 levomilnacipran-treated patients with doses of 40, 80 and 120 mg/day respectively, compared to 6.2% of placebo-treated patients. Concomitant use of levomilnacipran with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. Effects of levomilnacipran on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Levomilnacipran should be used with caution in these patients.. 5.4 Elevated Heart Rate. SNRIs including levomilnacipran have been associated with increased heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout levomilnacipran treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with levomilnacipran. For patients who experience sustained increase in heart rate while receiving levomilnacipran, discontinuation or other appropriate medical intervention should be considered.In short-term clinical studies, levomilnacipran treatment was associated with mean increase in heart rate of 7.4 beats per minute (bpm) compared to mean decrease of 0.3 bpm in placebo-treated patients. Heart rate increase in levomilnacipran-treated patients receiving doses of 40 mg, 80 mg and 120 mg was 7.2, 7.2, and 9.1 bpm. Levomilnacipran has not been systematically evaluated in patients with cardiac rhythm disorder.. 5.5 Increased Risk of Bleeding. Drugs that interfere with serotonin reuptake, including levomilnacipran, 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.Inform patients about the risk of bleeding associated with the concomitant use of levomilnacipran and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.1)].. 5.6 Angle Closure Glaucoma. The pupillary dilation that occurs following use of many antidepressant drugs including levomilnacipran may trigger an angle closure attack in patient with anatomically narrow angles who does not have patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not risk factor for angle closure glaucoma.. 5.7Urinary Hesitation or Retention. The noradrenergic effect of SNRIs including levomilnacipran, can affect urethral resistance. In the controlled short-term studies, urinary hesitation occurred in 4%, 5% and 6% of levomilnacipran-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 levomilnacipran in patients prone to obstructive urinary disorders. If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with levomilnacipran, consideration should be given to the possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered.. 5.8Activation of Mania/Hypomania. Symptoms of mania/hypomania were reported in 0.2% of levomilnacipran-treated patients and 0.2% of placebo-treated patients in clinical studies. Activation of mania/hypomania has also been reported in small proportion of patients with mood disorders who were treated with other antidepressants. As with all antidepressants, use levomilnacipran cautiously in patients with history or family history of bipolar disorder, mania, or hypomania.. 5.9Seizures. Levomilnacipran has not been systematically evaluated in patients with seizure disorder. Patients with history of seizures were excluded from clinical studies. Levomilnacipran should be prescribed with caution in patients with seizure disorder. One case of seizure has been reported in pre-marketing clinical studies with levomilnacipran.. 5.10Discontinuation 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 levomilnacipran. Reduce the dose gradually whenever possible. If intolerable symptoms occur following decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at more gradual rate [see Dosage and Administration (2.4)].. 5.11Hyponatremia. Hyponatremia may occur as result of treatment with SSRIs and SNRIs, including levomilnacipran. 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. Levomilnacipran 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.