Milnacipran HCl

6 ADVERSE REACTIONS The most frequently occurring adverse reactions (≥ 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. (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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patient Exposure Milnacipran HCl was evaluated in three double-blind placebo-controlled trials involving 2,209 fibromyalgia patients (1,557 patients treated with milnacipran HCl and 652 patients treated with placebo) for a treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions Leading to Discontinuation In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with milnacipran HCl 100 mg/day, 26% of patients treated with milnacipran HCl 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in ≥ 1% of patients in the milnacipran HCl treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with milnacipran HCl 200 mg/day compared to milnacipran HCl 100 mg/day. Most Common Adverse Reactions in Placebo Controlled Trials In the placebo-controlled fibromyalgia patient trials, the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence ≥ 5% and twice placebo) in patients treated with milnacipran HCl were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Table 4 lists all adverse reactions that occurred in at least 2% of patients treated with milnacipran HCl at either 100 or 200 mg/day and at an incidence greater than that of placebo. Table 4: Treatment-Emergent Adverse Reaction Incidence in Placebo Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Milnacipran HCl-Treated Patients and Occurring More Frequently in Either Milnacipran HCl Treatment Group Than in the Placebo Treatment Group) System Organ Class– Preferred Term Milnacipran HCl 100 mg/day (n = 623) % Milnacipran HCl 200 mg/day (n = 934) % All Milnacipran HCl (n = 1,557) % Placebo (n = 652) % Cardiac Disorders Palpitations 8 7 7 2 Tachycardia 3 2 2 1 Eye Disorders Vision blurred 1 2 2 1 Gastrointestinal Disorders Nausea 35 39 37 20 Constipation 16 15 16 4 Vomiting 6 7 7 2 Dry mouth 5 5 5 2 Abdominal pain 3 3 3 2 General Disorders Chest pain 3 2 2 2 Chills 1 2 2 0 Chest discomfort 2 1 1 1 Infections Upper respiratory tract infection 7 6 6 6 Investigations Heart rate increased 5 6 6 1 Blood pressure increased 3 3 3 1 Metabolism and Nutrition Disorders Decreased appetite 1 2 2 0 Nervous System Disorders Headache 19 17 18 14 Dizziness 11 10 10 6 Migraine 6 4 5 3 Paresthesia 2 3 2 2 Tremor 2 2 2 1 Hypoesthesia 1 2 1 1 Tension headache 2 1 1 1 Psychiatric Disorders Insomnia 12 12 12 10 Anxiety 5 3 4 4 Respiratory Disorders Dyspnea 2 2 2 1 Skin Disorders Hyperhidrosis 8 9 9 2 Rash 3 4 3 2 Pruritus 3 2 2 2 Vascular Disorders Hot flush 11 12 12 2 Hypertension 7 4 5 2 Flushing 2 3 3 1 Weight Changes In placebo-controlled fibromyalgia clinical trials, patients treated with milnacipran HCl for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the milnacipran HCl 100 mg/day and the milnacipran HCl 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients. Genitourinary Adverse Reactions in Males In the placebo-controlled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with milnacipran HCl, and occurred at a rate greater than in placebo-treated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased. Other Adverse Reactions Observed During Clinical Trials of Milnacipran HCl in Fibromyalgia Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1,824 fibromyalgia patients treated with milnacipran HCl for periods up to 68 weeks. The listing does not include those events already listed in Table 4 , those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section (5) . Gastrointestinal Disorders - diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension General Disorders - fatigue, peripheral edema, irritability, pyrexia Infections - urinary tract infection, cystitis Injury, Poisoning, and Procedural Complications - contusion, fall Investigations - weight decreased or increased Metabolism and Nutrition Disorders - hypercholesterolemia Nervous System Disorders - somnolence, dysgeusia Psychiatric Disorders - depression, stress Skin Disorders - night sweats 6.2 Post-marketing Experience The following additional adverse reactions have been identified from spontaneous reports of milnacipran HCl received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to milnacipran HCl. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include: Blood and Lymphatic System Disorders - leukopenia, neutropenia, thrombocytopenia Cardiac Disorders - supraventricular tachycardia, Takotsubo cardiomyopathy Eye Disorders - accommodation disorder Endocrine Disorders - hyperprolactinemia Gastrointestinal Disorders - acute pancreatitis Hepatobiliary Disorders - hepatitis Metabolism and Nutrition Disorders - anorexia, hyponatremia Musculoskeletal and Connective Tissue Disorders - rhabdomyolysis Nervous System Disorders - convulsions (including grand mal), loss of consciousness, Parkinsonism Psychiatric Disorders - aggression, anger, delirium, hallucination, homicidal ideation Renal and Urinary Disorders - acute renal failure Reproductive System and Breast Disorders - galactorrhea, decreased libido, delayed or absent orgasm Skin Disorders - erythema multiforme, Stevens Johnson syndrome Vascular Disorders - hypertensive crisis

4 CONTRAINDICATIONS Serotonin Syndrome and MAOIs : Do not use MAOIs intended to treat psychiatric disorders with milnacipran HCl or within 5 days of stopping treatment with milnacipran HCl. Do not use milnacipran HCl within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start milnacipran HCl in a patient who is being treated with linezolid or intravenous methylene blue. (4.1, 5.2) 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with milnacipran HCl or within 5 days of stopping treatment with milnacipran HCl is contraindicated because of an increased risk of serotonin syndrome. The use of milnacipran HCl within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.5) , Warnings and Precautions (5.2) ] . Starting milnacipran HCl in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.6) , Warnings and Precautions (5.2) ] .

11 DESCRIPTION Milnacipran hydrochloride is a selective norepinephrine and serotonin reuptake inhibitor; it inhibits norepinephrine uptake with greater potency than serotonin. It is a racemic mixture with the chemical name: (±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride. The structural formula is: Milnacipran hydrochloride is a white to off-white crystalline powder with a melting point of 179°C. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and sparingly soluble in diethyl ether. It has an empirical formula of C 15 H 23 C l N 2 O and a molecular weight of 282.8 g/mol. Milnacipran HCl is available for oral administration as film-coated tablets containing 12.5 mg, 25 mg, 50 mg and 100 mg milnacipran hydrochloride. Each tablet also contains carboxymethylcellulose calcium, dibasic calcium phosphate dihydrate, magnesium stearate, povidone, silicon dioxide and talc as inactive ingredients. The film coat contains the following additional inactive ingredients: 12.5 mg: Erythrosine dye, FD&C Blue #1 Aluminum Lake, hypromellose, polyethylene glycol and titanium dioxide 25 mg: Hypromellose, polyethylene glycol, talc and titanium dioxide 50 mg: Hypromellose, polyethylene glycol, talc and titanium dioxide 100 mg: FD&C Red #40 Aluminum Lake, hypromellose, polyethylene glycol, talc and titanium dioxide 7baf123f-figure-01

2 DOSAGE AND ADMINISTRATION Milnacipran HCl tablets are given orally with or without food. Taking milnacipran HCl tablets with food may improve the tolerability of the drug. Administer milnacipran HCl tablets in two divided doses per day. (2.1) Based on efficacy and tolerability, dosing may be titrated according to the following schedule (2.1) : Day 1: 12.5 mg once Days 2 to 3: 25 mg/day (12.5 mg twice daily) Days 4 to 7: 50 mg/day (25 mg twice daily) After Day 7: 100 mg/day (50 mg twice daily) Recommended dose is 100 mg/day. (2.1) May be increased to 200 mg/day based on individual patient response. (2.1) Adjust dose in patients with severe renal impairment. (2.2) 2.1 Recommended Dosing The recommended dose of milnacipran HCl tablets is 100 mg/day (50 mg twice daily). Based on efficacy and tolerability dosing may be titrated according to the following schedule: Day 1: 12.5 mg once Days 2 to 3: 25 mg/day (12.5 mg twice daily) Days 4 to 7: 50 mg/day (25 mg twice daily) After Day 7: 100 mg/day (50 mg twice daily) Based on individual patient response, the dose may be increased to 200 mg/day (100 mg twice daily). Doses above 200 mg/day have not been studied. Taper milnacipran HCl tablets and do not abruptly discontinue after extended use [see Dosage and Administration (2.4) and Warnings and Precautions (5.7) ] . 2.2 Patients with Renal Insufficiency No dosage adjustment is necessary in patients with mild renal impairment. Use milnacipran HCl tablets with caution in patients with moderate renal impairment. For patients with severe renal impairment (indicated by an estimated creatinine clearance of 5 to 29 mL/min), reduce the maintenance dose by 50% to 50 mg/day (25 mg twice daily). Based on individual patient response, the dose may be increased to 100 mg/day (50 mg twice daily). Milnacipran HCl tablets are not recommended for patients with end-stage renal disease. 2.3 Patients with Hepatic Insufficiency No dosage adjustment is necessary for patients with hepatic impairment. As with any drug, exercise caution in patients with severe hepatic impairment. 2.4 Discontinuing Milnacipran HCl Tablets Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other serotonin and norepinephrine re-uptake inhibitors (SNRIs) and selective serotonin re-uptake inhibitors (SSRIs). Monitor patients for these symptoms when discontinuing treatment. Taper milnacipran HCl tablets and do not abruptly discontinue after extended use [see Warnings and Precautions (5.7) ] . 2.5 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with milnacipran HCl tablets. Conversely, allow at least 5 days after stopping milnacipran HCl tablets before starting a MAOI intended to treat psychiatric disorders [see Contraindications (4.1) ] . 2.6 Use of Milnacipran HCl Tablets with other MAOIs such as Linezolid or Methylene Blue Do not start milnacipran HCl tablets in a patient being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, consider other interventions, including hospitalization [see Contraindications (4.1) ] . In some cases, a patient already receiving milnacipran HCl tablets 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 a particular patient, discontinue milnacipran HCl tablets promptly, and consider administering linezolid or intravenous methylene blue. Monitor the patient for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with milnacipran HCl tablets 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 1 mg/kg with milnacipran HCl tablets are 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) ] .

1 INDICATIONS AND USAGE Milnacipran HCl tablets are indicated for the management of fibromyalgia. Milnacipran HCl tablets are not approved for use in pediatric patients [see Use in Specific Populations (8.4) ] . Milnacipran HCl tablets are selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the management of fibromyalgia. (1) Milnacipran HCl tablets are not approved for use in pediatric patients. (1)

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Milnacipran is not a controlled substance. 9.2 Abuse Milnacipran did not produce behavioral signs indicative of abuse potential in animal or human studies. 9.3 Dependence Milnacipran produces physical dependence, as evidenced by the emergence of withdrawal symptoms following drug discontinuation, similar to other SNRIs and SSRIs. These withdrawal symptoms can be severe. Thus, taper milnacipran HCl and do not abruptly discontinue after extended use [see Warnings and Precautions (5.7) ] .

10 OVERDOSAGE Clinical Presentation There is limited clinical experience with milnacipran HCl overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg, alone or in combination with other drugs, were reported with none being fatal. In post-marketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with milnacipran HCl only. The most common signs and symptoms included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes. Management of Overdose There is no specific antidote to milnacipran HCl, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. Ensure adequate airway, oxygenation, and ventilation and monitor cardiac rhythm and vital signs. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Because there is no specific antidote for milnacipran HCl, symptomatic care and treatment with gastric lavage and activated charcoal as soon as possible for patients who experience a milnacipran HCl overdose. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

7 DRUG INTERACTIONS Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that milnacipran HCl is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations (12.3) ] . Milnacipran HCl is unlikely to be involved in clinically significant pharmacokinetic drug interactions. (7) Pharmacodynamic interactions of milnacipran HCl with other drugs can occur. (7) 7.1 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration (2.5 and 2.6) , Contraindications (4.1) , Warnings and Precautions (5.2) ]. 7.2 Serotonergic Drugs [See Dosage and Administration (2.5 and 2.6) , Contraindications (4.1) , Warnings and Precautions (5.2) ]. 7.3 Triptans There have been rare post-marketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of milnacipran HCl with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.2) ] . 7.4 Catecholamines Milnacipran HCl inhibits the reuptake of norepinephrine. Therefore, concomitant use of milnacipran HCl with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [see Warnings and Precautions (5.3, 5.4) ] . 7.5 CNS-active drugs Given the primary CNS effects of milnacipran HCl, use caution when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action. Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to milnacipran HCl. 7.6 Clinically Important Interactions with Select Cardiovascular Agents Digoxin: Use of milnacipran HCl concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Avoid co-administration of milnacipran HCl and intravenous digoxin [see Warnings and Precautions (5.3, 5.4) ] . Clonidine: Because milnacipran HCl inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine’s anti-hypertensive effect.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The exact mechanism of the central pain inhibitory action of milnacipran and its ability to improve the symptoms of fibromyalgia in humans are unknown. Preclinical studies have shown that milnacipran is a potent inhibitor of neuronal norepinephrine and serotonin reuptake; milnacipran inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters. Milnacipran has no significant affinity for serotonergic (5-HT1-7), α- and β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and γ-aminobutyric acid (GABA) receptors in vitro . Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Milnacipran has no significant affinity for Ca++, K+, Na+ and Cl– channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of milnacipran HCl on the QTcF interval was measured in a double-blind placebo-and positive-controlled parallel study in 88 healthy subjects using 600 mg/day milnacipran HCl (3 to 6 times the recommended therapeutic dose for fibromyalgia). After baseline and placebo adjustment, the maximum mean QTcF change was 8 ms (2-sided 90% CI, 3 to 12 ms). This increase is not considered to be clinically significant. 12.3 Pharmacokinetics Milnacipran is well absorbed after oral administration with an absolute bioavailability of approximately 85% to 90%. The exposure to milnacipran increased proportionally within the therapeutic dose range. It is excreted predominantly unchanged in urine (55%) and has a terminal elimination half-life of about 6 to 8 hours. Steady-state levels are reached within 36 to 48 hours and can be predicted from single-dose data. The active enantiomer, d -milnacipran, has a longer elimination half-life (8 to 10 hours) than the l -enantiomer (4 to 6 hours). There is no interconversion between the enantiomers. Absorption Milnacipran HCl is absorbed following oral administration with maximum concentrations (C max ) reached within 2 to 4 hours post dose. Absorption of milnacipran HCl is not affected by food. The absolute bioavailability is approximately 85% to 90%. Distribution The mean volume of distribution of milnacipran following a single intravenous dose to healthy subjects is approximately 400 L. Plasma protein binding is 13%. Elimination Metabolism Milnacipran and its metabolites are eliminated primarily by renal excretion. Excretion Following oral administration of 14 C-milnacipran hydrochloride, approximately 55% of the dose was excreted in urine as unchanged milnacipran (24% as l -milnacipran and 31% as d -milnacipran). The l -milnacipran carbamoyl-O-glucuronide was the major metabolite excreted in urine and accounted for approximately 17% of the dose; approximately 2% of the dose was excreted in urine as d -milnacipran carbamoyl-O-glucuronide. Approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite. Specific Populations Geriatric Patients C max and AUC parameters of milnacipran were about 30% higher in elderly (> 65 years) subjects compared with young subjects due to age-related decreases in renal function. No dosage adjustment is necessary based on age unless renal function is severely impaired [see Dosage and Administration (2.2)] . Male and Female Patients C max and AUC parameters of milnacipran were about 20% higher in female subjects compared with male subjects. Dosage adjustment based on gender is not necessary. Patients with Renal Impairment Milnacipran pharmacokinetics were evaluated following single oral administration of 50 mg milnacipran HCl to subjects with mild (creatinine clearance [CLcr] 50 to 80 mL/min), moderate (CLcr 30 to 49 mL/min), and severe (CLcr 5 to 29 mL/min) renal impairment and to healthy subjects (CLcr > 80 mL/min). The mean AUC 0-∞ increased by 16%, 52%, and 199%, and terminal elimination half-life increased by 38%, 41%, and 122% in subjects with mild, moderate, and severe renal impairment, respectively, compared with healthy subjects. No dosage adjustment is necessary for patients with mild renal impairment. Exercise caution in patients with moderate renal impairment. Dose adjustment is necessary in severe renal impairment patients [see Dosage and Administration (2.2)] . Patients with Hepatic Impairment Milnacipran pharmacokinetics were evaluated following single oral administration of 50 mg milnacipran HCl to subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment and to healthy subjects. AUC 0-∞ and T ½ were similar in healthy subjects and subjects with mild and moderate hepatic impairment. However, subjects with severe hepatic impairment had a 31% higher AUC 0-∞ and a 55% higher T ½ than healthy subjects. Exercise caution in patients with severe hepatic impairment. Drug Interaction Studies In Vitro Studies In general, milnacipran, at concentrations that were at least 25 times those attained in clinical trials, did not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 or induce human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 enzyme systems, indicating a low potential of interactions with drugs metabolized by these enzymes. In vitro studies have shown that the biotransformation rate of milnacipran by human hepatic microsomes and hepatocytes was low. A low biotransformation was also observed following incubation of milnacipran with cDNA-expressed human CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isozymes. In Vivo Studies The drug interaction studies described in this section were conducted in healthy adult subjects. Carbamazepine - There were no clinically significant changes in the pharmacokinetics of milnacipran following co-administration of milnacipran HCl (100 mg/day) and carbamazepine (200 mg twice a day). No changes were observed in the pharmacokinetics of carbamazepine or its epoxide metabolite due to co-administration with milnacipran HCl. Clomipramine - Switching from clomipramine (75 mg once a day) to milnacipran (100 mg/day) without a washout period did not lead to clinically significant changes in the pharmacokinetics of milnacipran. Because an increase in adverse events (e.g., euphoria and postural hypotension) was observed after switching from clomipramine to milnacipran, monitoring of patients during treatment switch is recommended. Digoxin - There was no pharmacokinetic interaction between milnacipran HCl (200 mg/day) and digoxin (0.2 mg/day Lanoxicaps) following multiple-dose administration to healthy subjects. Fluoxetine - Switching from fluoxetine (20 mg once a day), a strong inhibitor of CYP2D6 and a moderate inhibitor of CYP2C19, to milnacipran (100 mg/day) without a washout period did not affect the pharmacokinetics of milnacipran. Lithium - Multiple doses of milnacipran HCl (100 mg/day) did not affect the pharmacokinetics of lithium. Lorazepam - There was no pharmacokinetic interaction between a single dose of milnacipran HCl (50 mg) and lorazepam (1.5 mg). Pregabalin - There were no clinically significant changes in the steady-state pharmacokinetics of milnacipran or pregabalin following twice a day co-administration of 50 mg milnacipran and 150 mg pregabalin. Warfarin - Steady-state milnacipran (200 mg/day) did not affect the pharmacokinetics of R-warfarin and S-warfarin or the pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of 25 mg warfarin. The pharmacokinetics of milnacipran HCl were not altered by warfarin.

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12

3 DOSAGE FORMS AND STRENGTHS Film-coated, immediate-release tablets available in four strengths: 12.5 mg, 25 mg, 50 mg, and 100 mg of milnacipran hydrochloride. Milnacipran HCl tablets, 12.5 mg are blue color, round shaped, biconvex, film-coated tablets, debossed with "AN" on one side and "091" on the other side. Milnacipran HCl tablets, 25 mg are white to off-white, round shaped, biconvex, film-coated tablets, debossed with "AN" on one side and "092" on the other side. Milnacipran HCl tablets, 50 mg are white to off-white, oval shaped, biconvex, film-coated tablets, debossed with "AN" on one side and "093" on the other side. Milnacipran HCl tablets, 100 mg are pink color, oval shaped, biconvex, film-coated tablets, debossed with "AN" on one side and "094" on the other side. Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg (3)

Milnacipran HCl Milnacipran HCl MILNACIPRAN HYDROCHLORIDE MILNACIPRAN CARBOXYMETHYLCELLULOSE CALCIUM CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE MAGNESIUM STEARATE POVIDONE SILICON DIOXIDE TALC FD&C RED NO. 3 FD&C BLUE NO. 1 HYPROMELLOSES POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE AN;091 Milnacipran HCl Milnacipran HCl MILNACIPRAN HYDROCHLORIDE MILNACIPRAN CARBOXYMETHYLCELLULOSE CALCIUM CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE MAGNESIUM STEARATE POVIDONE SILICON DIOXIDE TALC HYPROMELLOSES POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE off-white AN;092 Milnacipran HCl Milnacipran HCl MILNACIPRAN HYDROCHLORIDE MILNACIPRAN CARBOXYMETHYLCELLULOSE CALCIUM CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE MAGNESIUM STEARATE POVIDONE SILICON DIOXIDE TALC HYPROMELLOSES POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE off-white AN;093 Milnacipran HCl Milnacipran HCl MILNACIPRAN HYDROCHLORIDE MILNACIPRAN CARBOXYMETHYLCELLULOSE CALCIUM CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE MAGNESIUM STEARATE POVIDONE SILICON DIOXIDE TALC HYPROMELLOSES POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE FD&C RED NO. 40 AN;094

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Dietary administration of milnacipran to rats at doses of 50 mg/kg/day (2 times the MRHD on a mg/m 2 basis) for 2 years caused a statistically significant increase in the incidence of thyroid C-cell adenomas and combined adenomas and carcinomas in males. A carcinogenicity study was conducted in Tg.rasH2 mice for 6 months at oral gavage doses of up to 125 mg/kg/day. Milnacipran did not induce tumors in Tg.rasH2 mice at any dose tested. Mutagenesis Milnacipran was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or in the L5178Y TK +/-mouse lymphoma forward mutation assay. Milnacipran was also not clastogenic in an in vitro chromosomal aberration test in human lymphocytes or in the in vivo mouse micronucleus assay. Impairment of Fertility Although administration of milnacipran to male and female rats had no statistically significant effect on mating or fertility at doses up to 80 mg/kg/day (4 times the MRHD on an mg/m 2 basis), there was an apparent dose-related decrease in the fertility index at clinically relevant doses based on body surface area. 13.2 Animal Toxicology and/or Pharmacology Hepatic Effects Chronic administration (2 years) of milnacipran to rats at 15 mg/kg (0.6 times the MRHD on an mg/m 2 basis) and higher doses showed increased incidences of centrilobular vacuolation of the liver in male rats and eosinophilic foci in male and female rats in the absence of any change in hepatic enzymes. The clinical significance of the finding is not known. Chronic (1 year) administration in the primate at doses up to 25 mg/kg (2 times the MRHD on a mg/m 2 basis) did not demonstrate similar evidence of hepatic changes. Ocular Effects Chronic (2 years) administration of milnacipran to rats at 15 mg/kg (0.6 times the MRHD on a mg/m 2 basis) and higher doses showed increased incidence of keratitis of the eye. One-year studies in the rat and primate did not show this response.

ANDA205081

Milnacipran HCl

Milnacipran HCl

65162-093

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 65162-091-06 Milnacipran HCl tablets, 12.5 mg Rx only 60 Tablets Amneal Pharmaceuticals LLC 12.5 NDC 65162-092-06 Milnacipran HCl tablets, 25 mg Rx only 60 Tablets Amneal Pharmaceuticals LLC 25 NDC 65162-093-06 Milnacipran HCl tablets, 50 mg Rx only 60 Tablets Amneal Pharmaceuticals LLC 50 NDC 65162-094-06 Milnacipran HCl tablets, 100 mg Rx only 60 Tablets Amneal Pharmaceuticals LLC 100

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Advise patients of the following issues and to alert their prescriber if these occur while taking milnacipran HCl: Clinical Worsening and Suicide Risk Advise patients, their families, and their caregivers that patients with depression may be at increased risk for clinical worsening and/or suicidal ideation if they stop taking anti-depressant medication, change the dose, or start a new medication. Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, or other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during treatment with milnacipran HCl or other drugs that inhibit the reuptake of norepinephrine and/or serotonin, and when the dose is adjusted up or down. Advise families and caregivers to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt and to report such symptoms to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms [see Boxed Warning and Warnings and Precautions (5.1)] . Serotonin Syndrome Inform patients about the risk of serotonin syndrome with use of milnacipran HCl as well as the increased risk when taken concomitantly with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.2)] . Advise patients of the signs and symptoms associated with serotonin syndrome and to seek medical care immediately if they experience these symptoms. Elevated Blood Pressure and Heart Rate Advise patients that milnacipran HCl may increase their blood pressure and heart rate and that they should have their blood pressure and heart rate monitored at regular intervals when receiving treatment with milnacipran HCl [see Warnings and Precautions (5.3, 5.4)] . Increased Risk of Bleeding Advise Patients that the concomitant use of drugs that interfere with serotonin reuptake, including milnacipran HCl, and NSAIDs, aspirin, or anticoagulants has been associated with an increased risk of abnormal bleeding [see Warnings and Precautions (5.9)] . Angle Closure Glaucoma Advise patients that taking milnacipran HCl can cause mild pupillary dilation which, in susceptible individuals, can lead to an episode of angle closure glaucoma [see Warnings and Precautions (5.13)] . Ability to Drive and Use Machinery Advise patients not to operate machinery or drive motor vehicles until they are reasonably certain that milnacipran HCl treatment does not affect their ability to engage in such activities. Alcohol Inform patients of the risks associated with drinking alcohol while taking milnacipran HCl [see Warnings and Precautions (5.6, 5.14)] . Sexual Dysfunction Advise patients that use of milnacipran HCl may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.12)] . Discontinuation Advise patients that withdrawal symptoms can occur when discontinuing treatment with milnacipran HCl, particularly when discontinuation is abrupt [see Warnings and Precautions (5.7)] . Missing a Dose Advise patients that if they miss a dose, they should skip the missed dose and take the next dose at their regular time. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to milnacipran HCl during pregnancy [see Use in Specific Populations (8.1)]. Pregnancy Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with milnacipran HCl. Advise patients that milnacipran HCl 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, and tube feeding. Lactation Advise breastfeeding women using milnacipran 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)] . Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Ahmedabad 382220, INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 03-2023-04

FDA-Approved Medication Guide MEDICATION GUIDE Milnacipran Hydrochloride (mil naʹ si pran hyeʺ droe klorʹ ide) Tablets Milnacipran HCl tablets are not used to treat depression, but it acts like medicines that are used to treat depression (antidepressants) and other psychiatric disorders. Read the Medication Guide that comes with milnacipran HCl tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about milnacipran HCl tablets? Milnacipran HCl tablets and antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: Milnacipran HCl tablets and antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: New or sudden changes, in mood, behavior, thoughts, or feelings, especially if severe. Pay particular attention to such changes when milnacipran HCl tablets are started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away or go to the nearest hospital emergency room if you 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 worse anxiety or panic attacks feeling agitated, restless, angry or irritable trouble sleeping (insomnia) an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Call your healthcare provider right away or go to the nearest hospital emergency room if you have any symptoms of the serious side effects listed below: 2. Serotonin Syndrome. This condition can be life-threatening, symptoms may include: agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) sweating or fever diarrhea muscle rigidity dizziness tremor Symptoms such as racing heartbeat, high or low blood pressure, nausea, vomiting, and flushing are common with milnacipran HCl tablets. Call your healthcare provider right away if you get these symptoms and they are severe or if they happen with any of the symptoms of serotonin syndrome listed above. 3. Increase in blood pressure or heart rate: Milnacipran HCl tablets may increase your blood pressure or heart rate. Check your blood pressure and heart rate before you start and during treatment with milnacipran HCl tablets. Before taking milnacipran HCl tablets, tell your healthcare provider if you have high blood pressure or problems with your heart or blood vessels (cardiovascular disease). 4. Seizures or convulsions. 5. Liver problems. Symptoms of liver problems may include: itching right upper abdominal pain dark urine yellowing of your skin or eyes enlarged liver increased liver enzymes 6. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 7. Abnormal bleeding: Milnacipran HCl tablets and other similar medicines (antidepressants) may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin, Jantoven), a nonsteroidal anti-inflammatory drug (NSAID), or aspirin. 8. Manic episodes greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 9. Problems with urination decreased urine flow unable to pass any urine Men may be more likely to have these symptoms, and may develop pain in their testicles or have problems with ejaculation. 10. Visual problems eye pain changes in vision swelling or redness in or around eye 11. Sexual problems (dysfunction). Taking serotonin and norepinephrine reuptake inhibitors (SNRIs), including milnacipran HCl, may cause sexual problems. Symptoms in males may include Delayed ejaculation or inability to have an ejaculation Decreased sex drive Problems getting or keeping an erection Symptoms in females may include Decreased sex drive Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with milnacipran HCl. There may be treatments your healthcare provider can suggest. Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Do not stop milnacipran HCl tablets without first talking to your healthcare provider. Stopping milnacipran HCl tablets too quickly may cause symptoms, some serious, including: anxiety, irritability, or confusion feeling tired or problems sleeping headache, dizziness, seizures electric shock-like sensations, ringing in ears What are milnacipran HCl tablets? Milnacipran HCl tablets are prescription medicine used to manage fibromyalgia. It is important to talk with your healthcare provider about the risks of treating fibromyalgia and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. It is not known if milnacipran HCl tablets are safe and effective in children. Who should not take milnacipran HCl tablets? Do not take milnacipran HCl tablets if you: take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 5 days of stopping milnacipran HCl tablets unless your healthcare provider tells you to. Do not start milnacipran HCl tablets if you stopped taking an MAOI in the last 14 days unless your healthcare provider tells you to. People who take milnacipran HCl tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) What should I tell my healthcare provider before taking milnacipran HCl tablets? Before starting milnacipran HCl tablets, tell your healthcare provider if you: have heart problems or high blood pressure have liver problems have kidney problems have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have or had bleeding problems drink alcohol. Talk to your healthcare provider about how often and how much alcohol you drink. have any other medical conditions are pregnant or plan to become pregnant. It is not known if milnacipran HCl tablets will harm your unborn baby. Pregnancy registry: There is a pregnancy registry for women who take milnacipran HCl during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. You may talk to your healthcare provider about how you can take part in this registry, or you may call the Registry directly at X-XXX-XXX-XXXX or go to www.XXXXXXXXXXXXX.com. are breastfeeding or plan to breastfeed. Milnacipran HCl can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby while taking milnacipran HCl tablets. Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Milnacipran HCl tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects when taken together. Your healthcare provider or pharmacist can tell you if it is safe to take milnacipran HCl tablets with your other medicines. Do not start or stop any medicine while taking milnacipran HCl tablets without talking to your healthcare provider first. How should I take milnacipran HCl tablets? Take milnacipran HCl tablets exactly as your healthcare provider tells you. Your healthcare provider will slowly increase your dose to find the dose that is right for you. On the first day of treatment, you will take 1 dose of milnacipran HCl tablets as prescribed. After your first dose, your healthcare provider will tell you how much milnacipran HCl tablets to take and when to take it, usually 2 times each day. You may take milnacipran HCl tablets with or without food. Taking milnacipran HCl tablets with food may help you tolerate it better. If you miss a dose, skip the missed dose and take the next dose at your regular time. Tell your healthcare provider if you feel that your condition is not improving during treatment with milnacipran HCl tablets. If you take too much milnacipran HCl tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What should I avoid while taking milnacipran HCl tablets? Do not drive or operate machinery until you know how milnacipran HCl tablets affect you. Milnacipran HCl tablets may make you less alert and affect your reaction time. What are the possible side effects of milnacipran HCl tablets? Milnacipran HCl tablets may cause side effects, some serious, including: See “What is the most important information I should know about milnacipran HCl tablets?” The most common side effects of milnacipran HCl tablets include: nausea headache constipation dizziness trouble sleeping hot flush increased sweating vomiting irregular heartbeat (palpitations) heart rate increased dry mouth high blood pressure (hypertension) Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of milnacipran HCl tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store milnacipran HCl tablets? Store at room temperature between 68° to 77°F (20° to 25°C). Keep milnacipran HCl tablets and all medicines out of the reach of children. General information about the safe and effective use of milnacipran HCl tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use milnacipran HCl tablets for a condition for which it was not prescribed. Do not give milnacipran HCl tablets to other people, even if they have the same condition. It may harm them. You may ask your healthcare provider or pharmacist for information about milnacipran HCl tablets that is written for health professionals. For more information call 1-877-835-5472 or go to www.amneal.com. What are the ingredients in milnacipran HCl tablets? Active ingredient: milnacipran hydrochloride Inactive ingredients: carboxymethylcellulose calcium, dibasic calcium phosphate dihydrate, magnesium stearate, povidone, silicon dioxide and talc. The film coat contains the inactive ingredients: 12.5 mg tablets: Erythrosine dye, FD&C Blue #1 Aluminum Lake, hypromellose, polyethylene glycol and titanium dioxide 25 mg tablets: Hypromellose, polyethylene glycol, talc and titanium dioxide 50 mg tablets: Hypromellose, polyethylene glycol, talc and titanium dioxide 100 mg tablets: FD&C Red #40 Aluminum Lake, hypromellose, polyethylene glycol, talc and titanium dioxide This Medication Guide has been approved by the U.S. Food and Drug Administration. *All trademarks are the property of their respective owners. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Ahmedabad 382220, INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 03-2023-04 Dispense with Medication Guide available at: documents.amneal.com/mg/milnacipran-hcl.pdf

14 CLINICAL STUDIES Management of Fibromyalgia The efficacy of milnacipran HCl for the management of fibromyalgia was established in two double-blind, placebo-controlled, multicenter studies in adult patients (18 to 74 years of age). Enrolled patients met the American College of Rheumatology (ACR) criteria for fibromyalgia (a history of widespread pain for 3 months and pain present at 11 or more of the 18 specific tender point sites). Approximately 35% of patients had a history of depression. Study 1 was six months in duration and Study 2 was three months in duration. A larger proportion of patients treated with milnacipran HCl than with placebo experienced a simultaneous reduction in pain from baseline of at least 30% (VAS) and also rated themselves as much improved or very much improved based on the patient global assessment (PGIC). In addition, a larger proportion of patients treated with milnacipran HCl met the criteria for treatment response, as measured by the composite endpoint that concurrently evaluated improvement in pain (VAS), physical function (SF-36 PCS), and patient global assessment (PGIC), in fibromyalgia as compared to placebo. Study 1: This 6-month study compared total daily doses of milnacipran HCl 100 mg and 200 mg to placebo. Patients were enrolled with a minimum mean baseline pain score of ≥ 50 mm on a 100 mm visual analog scale (VAS) ranging from 0 (“no pain”) to 100 (“worst possible pain”). The mean baseline pain score in this trial was 69. The efficacy results for Study 1 are summarized in Figure 1 . Figure 1 shows the proportion of patients achieving various degrees of improvement in pain from baseline to the 3-month time point and who concurrently rated themselves globally improved (PGIC score of 1 or 2). Patients who did not complete the 3-month assessment were assigned 0% improvement. More patients in the milnacipran HCl treatment arms experienced at least a 30% reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than did patients in the placebo arm. Treatment with milnacipran HCl 200 mg/day did not confer greater benefit than treatment with milnacipran HCl 100 mg/day. Figure 1: Patients Achieving Various Levels of Pain Relief with Concurrent Ratings of Being Much or Very Much Improved on the PGIC - Study 1 Study 2: This 3-month study compared total daily doses of milnacipran HCl 100 mg and 200 mg to placebo. Patients were enrolled with a minimum mean baseline pain score of ≥ 40 mm on a 100-mm VAS ranging from 0 (“no pain”) to 100 (“worst possible pain”). The mean baseline pain score in this trial was 65. The efficacy results for Study 2 are summarized in Figure 2 . Figure 2 shows the proportion of patients achieving various degrees of improvement in pain from baseline to the 3-month time point and who concurrently rated themselves globally improved (PGIC score of 1 or 2). Patients who did not complete the 3-month assessment were assigned 0% improvement. More patients in the milnacipran HCl treatment arms experienced at least a 30% reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than did patients in the placebo arm. Treatment with milnacipran HCl 200 mg/day did not confer greater benefit than treatment with milnacipran HCl 100 mg/day. Figure 2: Patients Achieving Various Levels of Pain Relief with Concurrent Ratings of Being Much or Very Much Improved on the PGIC - Study 2 In both studies, some patients who rated themselves as globally “much” or “very much” improved experienced a decrease in pain as early as week 1 of treatment with a stable dose of milnacipran HCl that persisted throughout these studies. 7baf123f-figure-02 7baf123f-figure-03

8 USE IN SPECIFIC POPULATIONS Pregnancy: Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate. (8.1) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to milnacipran HCl during pregnancy. Physicians are advised to recommend that pregnant patients taking milnacipran HCl enroll in the milnacipran HCl Pregnancy Registry. Enrollment is voluntary and may be initiated by pregnant patients or their healthcare providers by contacting the registry at X-XXX-XXX-XXXX or by email at xxxxxxxx@xxxxxx.com. Data forms may also be downloaded from the registry website at www.xxxxxxxxxxxx.com. Risk Summary The available data on milnacipran HCl use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with exposure to serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including milnacipran HCl, during pregnancy (see Clinical Considerations) . Animal reproduction studies have been performed in rats, rabbits and mice. Milnacipran was shown to increase embryofetal and perinatal lethality in rats and the incidence of a minor skeletal variation in rabbits at doses below (rat) or approximately equal to (rabbit) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis. No effects were seen in mice when treated with milnacipran during the period of organogenesis at doses up to 3 times the MHRD on a mg/m 2 basis (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Consideration Maternal adverse reactions Use of SNRIs in late pregnancy may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.9)] . Fetal/Neonatal adverse reactions Neonates exposed to SNRIs or SSRIs, including milnacipran, 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 a direct toxic effect of SSRIs and SNRIs or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2, 5.7) ] . Data Animal Data Studies were conducted in rats, rabbits and mice with dosing of milnacipran during the period of organogenesis. In rats, milnacipran was shown to increase embryo fetal lethality at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m 2 basis). In rabbits, dose-dependent increases in the incidence of the skeletal variation of an extra single rib were observed in several pups from multiple litters in the absence of maternal toxicity at 15 mg/kg/day (1.5 times the MRHD on a mg/m 2 basis). The clinical significance of this finding is unknown. In mice, no embryotoxic or teratogenic effects were seen at doses up to 125 mg/kg/day (3 times the MRHD on a mg/m 2 basis). With peri- and postnatal exposure to oral milnacipran in rats, decreases in viability and body weight were observed on Postpartum Day 4 at a dose of 5 mg/kg/day (approximately 0.25 times the MRHD on a mg/m 2 basis). The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Milnacipran is present in human milk [see Data] . There are no reports on the effects of milnacipran on the breastfed child and on milk production/excretion. However, there are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to SSRIs or SNRIs through breast milk (see Clinical Considerations) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for milnacipran and any potential adverse effects on the breastfed child from milnacipran or from the underlying maternal conditions. Clinical Considerations Monitor infants exposed to milnacipran for agitation, irritability, poor feeding and poor weight gain. Data Human Data Milnacipran is present in the milk of lactating women treated with milnacipran. In a lactation pharmacokinetic study with milnacipran, a single, oral dose of 50 mg milnacipran HCl tablet was administered to 8 lactating women who were at least 12 weeks postpartum and weaning their infants. The milk/plasma AUC ratio of milnacipran was 1.85 ± 0.38. The maximum estimated weight adjusted daily infant dose for milnacipran from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 5% of the maternal dose based on peak plasma concentrations. 8.4 Pediatric Use Safety and effectiveness of milnacipran HCl in a fibromyalgia pediatric population below the age of 18 have not been established [see Boxed Warning , Indications and Usage (1) , and Warnings and Precautions (5.1) ] . The use of milnacipran HCl is not recommended in pediatric patients. 8.5 Geriatric Use In controlled clinical studies of milnacipran HCl, 402 patients were 60 years or older, and no overall differences in safety and efficacy were observed between these patients and younger patients. In view of the predominant excretion of unchanged milnacipran via kidneys and the expected decrease in renal function with age, renal function should be considered prior to use of milnacipran HCl in the elderly [see Dosage and Administration (2.2) ] . SNRIs, SSRIs, and milnacipran HCl, 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 (5.8) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Milnacipran HCl tablets, 12.5 mg are supplied as blue color, round shaped, biconvex, film-coated tablets, debossed with “AN” on one side and “091” on the other side. Bottles of 60: NDC 65162-091-06 Milnacipran HCl tablets, 25 mg are supplied as white to off-white, round shaped, biconvex, film-coated tablets, debossed with “AN” on one side and “092” on the other side. Bottles of 60: NDC 65162-092-06 Milnacipran HCl tablets, 50 mg are supplied as white to off-white, oval-shaped, biconvex, film-coated tablets, debossed with “AN” on one side and “093” on the other side. Bottles of 60: NDC 65162-093-06 Bottles of 500: NDC 65162-093-50 Milnacipran HCl tablets, 100 mg are supplied as pink color, oval-shaped, biconvex, film-coated tablets, debossed with “AN” on one side and “094” on the other side. Bottles of 60: NDC 65162-094-06 Bottles of 500: NDC 65162-094-50 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Milnacipran HCl is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on milnacipran HCl should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Milnacipran HCl is not approved for use in the treatment of major depressive disorder. Milnacipran HCl is not approved for use in pediatric patients [see Indications and Usage (1) , Warnings and Precautions (5.1) , Use in Specific Populations (8.4) ] . WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning. Increased risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders. ( 5.1 ) Milnacipran HCl is not approved for use in pediatric patients. ( 1 , 8.4 )