ADVERSE REACTIONS SECTION.


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 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 treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, treatment-emergent adverse reaction of the type listed. 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 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 TermMilnacipran 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 8772Tachycardia 3221Eye Disorders Vision blurred 1221Gastrointestinal Disorders Nausea 35393720Constipation 1615164Vomiting 6772Dry mouth 5552Abdominal pain 3332General Disorders Chest pain 3222Chills 1220Chest discomfort 2111Infections Upper respiratory tract infection 7666Investigations Heart rate increased 5661Blood pressure increased 3331Metabolism and Nutrition Disorders Decreased appetite 1220Nervous System Disorders Headache 19171814Dizziness 1110106Migraine 6453Paresthesia 2322Tremor 2221Hypoesthesia 1211Tension headache 2111Psychiatric Disorders Insomnia 12121210Anxiety 5344Respiratory Disorders Dyspnea 2221Skin Disorders Hyperhidrosis 8992Rash 3432Pruritus 3222Vascular Disorders Hot flush 1112122Hypertension 7452Flushing 2331Weight Changes In placebo-controlled fibromyalgia clinical trials, patients treated with milnacipran HCl for up to months experienced 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 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 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 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 drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have 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 Postmarketing 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 combination of seriousness, frequency of reporting, or potential causal connection to milnacipran HCl. However, because these adverse reactions were reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 Skin Disorders erythema multiforme, Stevens Johnson syndrome Vascular Disorders hypertensive crisis.

BOXED WARNING SECTION.


WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Milnacipran HCl is 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 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 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 DRUGSSee 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). 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).

CLINICAL PHARMACOLOGY SECTION.


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 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), and -adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and -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. Cardiovascular Electrophysiology The effect of milnacipran HCl on the QTcF interval was measured in double-blind placebo-and positive-controlled parallel study in 88 healthy subjects using 600 mg/day milnacipran HCl (3 to times the recommended therapeutic dose for fibromyalgia). After baseline and placebo adjustment, the maximum mean QTcF change was ms (2-sided 90% CI, 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 terminal elimination half-life of about to 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 longer elimination half-life (8 to 10 hours) than the l-enantiomer (4 to hours). There is no interconversion between the enantiomers. Absorption and Distribution Milnacipran HCl is absorbed following oral administration with maximum concentrations (Cmax) reached within to hours post dose. Absorption of milnacipran HCl is not affected by food. The absolute bioavailability is approximately 85% to 90%. The mean volume of distribution of milnacipran following single intravenous dose to healthy subjects is approximately 400 L. Plasma protein binding is 13%. Metabolism and Elimination Milnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-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. Pharmacokinetics in Special Populations 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 to 29 mL/min) renal impairment and to healthy subjects (CLcr 80 mL/min). The mean AUC0- 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. Caution should be exercised in patients with moderate renal impairment. Dose adjustment is necessary in severe renal impairment patients [see Dosage and Administration (2.2)]. 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. AUC0- and 1/2 were similar in healthy subjects and subjects with mild and moderate hepatic impairment. However, subjects with severe hepatic impairment had 31% higher AUC0- and 55% higher 1/2 than healthy subjects. Caution should be exercised in patients with severe hepatic impairment. Elderly Cmax 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)]. Gender Cmax and AUC parameters of milnacipran were about 20% higher in female subjects compared with male subjects. Dosage adjustment based on gender is not necessary. Lactation study In pharmacokinetic study, 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 maximum estimated 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. In most patients, peak concentrations of milnacipran in breast milk were seen within hours after the maternal dose. Because of the limited data regarding infant exposure to milnacipran HCl, caution should be exercised when milnacipran HCl is administered to nursing woman. Drug-Drug Interactions 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 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. 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 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 day) to milnacipran (100 mg/day) without 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 day), strong inhibitor of CYP2D6 and moderate inhibitor of CYP2C19, to milnacipran (100 mg/day) without 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 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 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 single dose of 25 mg warfarin. The pharmacokinetics of milnacipran HCl was not altered by warfarin.

CLINICAL STUDIES SECTION.


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 months and pain present at 11 or more of the 18 specific tender point sites). Approximately 35% of patients had history of depression. Study was six months in duration and Study was three months in duration. larger proportion of patients treated with milnacipran HCl than with placebo experienced 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, 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 minimum mean baseline pain score of >= 50 mm on 100 mm visual analog scale (VAS) ranging from (no pain) to 100 (worst possible pain). The mean baseline pain score in this trial was 69. The efficacy results for Study are summarized in Figure 1. Figure 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 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 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 1Study 2: This 3-month study compared total daily doses of milnacipran HCl 100 mg and 200 mg to placebo. Patients were enrolled with minimum mean baseline pain score of >= 40 mm on 100-mm VAS ranging from (no pain) to 100 (worst possible pain). The mean baseline pain score in this trial was 65. The efficacy results for Study are summarized in Figure 2. Figure 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 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 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 2In both studies, some patients who rated themselves as globally much or very much improved experienced decrease in pain as early as week of treatment with stable dose of milnacipran HCl that persisted throughout these studies. 7baf123f-figure-02. 7baf123f-figure-03.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with milnacipran HCl or within 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 patient who is being treated with linezolid or intravenous methylene blue (4.1, 5.2). Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with milnacipran HCl or within 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 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 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 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)].

DESCRIPTION SECTION.


11 DESCRIPTION Milnacipran hydrochloride is selective norepinephrine and serotonin reuptake inhibitor; it inhibits norepinephrine uptake with greater potency than serotonin. It is 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 white to off-white crystalline powder with melting point of 179C. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and sparingly soluble in diethyl ether. It has an empirical formula of C15H23ClN2O and 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 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.

DOSAGE & ADMINISTRATION SECTION.


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 to 3: 25 mg/day (12.5 mg twice daily) Days 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). Dose should be adjusted in patients with severe renal impairment (2.2). 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): Recommended dose is 100 mg/day (2.1). May be increased to 200 mg/day based on individual patient response (2.1). Dose should be adjusted 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 to 3: 25 mg/day (12.5 mg twice daily) Days 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.Milnacipran HCl tablets should be tapered and not abruptly discontinued 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. Milnacipran HCl tablets should be used with caution in patients with moderate renal impairment. For patients with severe renal impairment (indicated by an estimated creatinine clearance of to 29 mL/min), the maintenance dose should be reduced 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, caution should be exercised 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). Patients should be monitored for these symptoms when discontinuing treatment. Milnacipran HCl tablets should be tapered and not abruptly discontinued after extended use [see Warnings and Precautions (5.7)]. 2.5 Switching Patient to or from Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders. At least 14 days should elapse between discontinuation of MAOI intended to treat psychiatric disorders and initiation of therapy with milnacipran HCl tablets. Conversely, at least days should be allowed after stopping milnacipran HCl tablets before starting 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 patient being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In patient who requires more urgent treatment of psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)]. In some cases, 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 particular patient, milnacipran HCl tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 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 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)].

DOSAGE FORMS & STRENGTHS SECTION.


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.[see Description (11) and How Supplied/ Storage and Handling (16)]. Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg (3) Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg (3).

DRUG ABUSE AND DEPENDENCE SECTION.


9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance. Milnacipran is not 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, milnacipran HCl should be tapered and not abruptly discontinued after extended use [see Warnings and Precautions (5.7)].

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has 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). 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 postmarketing reports of serotonin syndrome with use of an SSRI and triptan. If concomitant treatment of milnacipran HCl with 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, caution should be used when it is taken in combination with other centrally acting drugs, including those with similar mechanism of action. Clomipramine: In 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). Co-administration of milnacipran HCl and intravenous digoxin should be avoided [see Warnings and Precautions (5.3, 5.4)]. Clonidine: Because milnacipran HCl inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidines anti-hypertensive effect.

HOW SUPPLIED SECTION.


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 65162-093-06Bottles of 500: NDC 65162-093-50Milnacipran 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 65162-094-06Bottles of 500: NDC 65162-094-50 Storage 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 INDICATIONSAND 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). 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).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION See Medication Guide Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with milnacipran HCl and should counsel them in its appropriate use. patient Medication Guide is available for milnacipran HCl. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking milnacipran HCl: Clinical Worsening and Suicide Risk Patients and their families and caregivers should be advised that milnacipran HCl is selective norepinephrine and serotonin reuptake inhibitor and therefore belongs to the same class of drugs as antidepressants. Patients, their families, and their caregivers should be advised 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 new medication. Patients, their families, and their caregivers should be encouraged 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. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patients prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patients presenting symptoms [see Boxed Warning and Warnings and Precautions (5.1)]. Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with concomitant use of milnacipran HCl with 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 (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.2)]. Patients should be advised of the signs and symptoms associated with serotonin syndrome that 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 changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms. Elevated Blood Pressure and Heart Rate Patients should be advised 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)]. Abnormal Bleeding Patients should be cautioned about the concomitant use of milnacipran HCl and NSAIDs, aspirin, or other drugs that affect coagulation, since the combined use of agents that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding [see Warnings and Precautions (5.9)]. Angle Closure Glaucoma Patients should be advised that taking milnacipran HCl can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. 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. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.12)].Ability to Drive and Use Machinery Milnacipran HCl might diminish mental and physical capacities necessary to perform certain tasks such as operating machinery, including motor vehicles. Patients should be cautioned about operating machinery or driving motor vehicles until they are reasonably certain that milnacipran HCl treatment does not affect their ability to engage in such activities. Alcohol Patients should talk to their healthcare provider about their alcohol intake prior to initiating treatment with milnacipran HCl [see Warnings and Precautions (5.6, 5.13)]. DiscontinuationPatients should be advised that withdrawal symptoms can occur when discontinuing treatment with milnacipran HCl, particularly when discontinuation is abrupt [see Warnings and Precautions (5.7)]. Missing Dose Patients should be advised that if they miss dose, they should skip the missed dose and take the next dose at their regular time. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during milnacipran HCl therapy [see Use in Specific Populations (8.1)].Nursing Advise patients to notify their physician if they are breast feeding [see Use in Specific Populations (8.3)].Manufactured by:Amneal Pharmaceuticals Pvt. Ltd.Ahmedabad 382220, INDIA Distributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807Rev. 05-2018-01.

NONCLINICAL TOXICOLOGY SECTION.


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 mg/m2 basis) for years caused statistically significant increase in the incidence of thyroid C-cell adenomas and combined adenomas and carcinomas in males. carcinogenicity study was conducted in Tg.rasH2 mice for 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/m2 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 EffectsChronic administration (2 years) of milnacipran to rats at 15 mg/kg (0.6 times the MRHD on an mg/m2 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 mg/m2 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 mg/m2 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.

OVERDOSAGE SECTION.


10 OVERDOSAGE 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 postmarketing 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. An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with 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 should be considered as soon as possible for patients who experience 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, the possibility of multiple drug involvement should be considered. The physician should consider contacting 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).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. 1. . 1. . 1. . 1.

SPL MEDGUIDE SECTION.


MEDICATION GUIDE FDA-Approved Medication Guide Milnacipran Hydrochloride (mil na si pran hye droe klor ide) TabletsMilnacipran 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 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 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. Your blood pressure and heart rate should be checked 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), 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 problemseye painchanges in visionswelling or redness in or around eyeOnly 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 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 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 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. 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 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 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 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 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 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 should know about milnacipran HCl tablets The most common side effects of milnacipran HCl tablets include: nauseaheadacheconstipationdizziness trouble sleepinghot flushincreased sweatingvomitingirregular 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 store milnacipran HCl tablets Store at room temperature between 68 to 77F (20 to 25C). 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 Medication Guide. Do not use milnacipran HCl tablets for 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 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 LLCBridgewater, NJ 08807Rev. 05-2018-01. 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. 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. 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 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. itching right upper abdominal pain dark urine yellowing of your skin or eyes enlarged liver increased liver enzymes headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual decreased urine flow unable to pass any urine eye pain. changes in vision. swelling or redness in or around eye. anxiety, irritability, or confusion feeling tired or problems sleeping headache, dizziness, seizures electric shock-like sensations, ringing in ears take 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 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) Do not take an MAOI within 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) high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) 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. 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 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 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 times each day. On the first day of treatment, you will take 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 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 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. 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 should know about milnacipran HCl tablets nausea. headache. constipation. dizziness trouble sleeping. hot flush. increased sweating. vomiting. irregular heartbeat (palpitations) heart rate increased dry mouth high blood pressure (hypertension) Store at room temperature between 68 to 77F (20 to 25C).

SPL UNCLASSIFIED SECTION.


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 to 3: 25 mg/day (12.5 mg twice daily) Days 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.Milnacipran HCl tablets should be tapered and not abruptly discontinued after extended use [see Dosage and Administration (2.4) and Warnings and Precautions (5.7)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1). Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy. Pregnancy Category Risk Summary There are no adequate or well-controlled studies in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as milnacipran HCl), or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery. Reproduction studies have been performed in rats, rabbits and mice. Milnacipran was shown to increase embryo fetal and perinatal lethality in rats and the incidence of 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 mg/m2 basis. No effects were seen in mice when treated with milnacipran during the period of organogenesis at doses up to times the MRHD on mg/m2 basis. Because animal reproduction studies are not always predictive of human response, milnacipran HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Consideration Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery and require prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Monitor neonates for reported clinical findings such as respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either direct toxic effect of these classes of drugs 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)]. 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 mg/kg/day (0.25 times the MRHD on mg/m2 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 mg/m2 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 mg/m2 basis). With peri- and postnatal exposure to oral milnacipran in rats, decreases in viability and body weight were observed on Postpartum Day at dose of mg/kg/day (approximately 0.25 times the MRHD on mg/m2 basis). The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on mg/m2 basis). 8.3 Nursing Mothers. Milnacipran is present in the milk of lactating women treated with milnacipran HCl. In pharmacokinetic study, 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 maximum estimated 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. In most patients, peak concentrations of milnacipran in breast milk were seen within hours after the maternal dose. Because of the limited data regarding infant exposure to milnacipran HCl, caution should be exercised when milnacipran HCl is administered to nursing woman. 8.4 Pediatric Use. Safety and effectiveness of milnacipran HCl in 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)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Suicidality: Monitor for worsening of depressive symptoms and suicide risk (5.1). Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including milnacipran HCl, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St. Johns Wort). If such symptoms occur, discontinue milnacipran HCl and initiate supportive treatment. If concomitant use of milnacipran HCl with other serotonergic drugs is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment and dose increases (5.2). Elevated blood pressure and heart rate: Milnacipran HCl may increase blood pressure and heart rate. In an ambulatory blood pressure monitoring study, substantially higher proportion of milnacipran HCl-treated patients experienced clinically significant blood pressure and heart rate elevations as compared with placebo-treated patients. Measure blood pressure and heart rate prior to initiating treatment with milnacipran HCl and monitor periodically throughout treatment (5.3, 5.4). Seizures: Cases have been reported with milnacipran HCl therapy. Prescribe milnacipran HCl with care in patients with history of seizure disorder (5.5). Hepatotoxicity: More patients treated with milnacipran HCl than with placebo experienced mild elevations of ALT and AST. Rarely, fulminant hepatitis has been reported in patients treated with milnacipran HCl tablets. Avoid concomitant use of milnacipran HCl in patients with substantial alcohol use or chronic liver disease (5.6). Discontinuation: Withdrawal symptoms have been reported in patients when discontinuing treatment with milnacipran HCl. gradual dose reduction is recommended (5.7). Abnormal Bleeding: Milnacipran HCl may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of milnacipran HCl and NSAIDs, aspirin, or other drugs that affect coagulation (5.9). Male patients with history of obstructive uropathies may experience higher rates of genitourinary adverse events (5.11). Suicidality: Monitor for worsening of depressive symptoms and suicide risk (5.1). Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including milnacipran HCl, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St. Johns Wort). If such symptoms occur, discontinue milnacipran HCl and initiate supportive treatment. If concomitant use of milnacipran HCl with other serotonergic drugs is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment and dose increases (5.2). Elevated blood pressure and heart rate: Milnacipran HCl may increase blood pressure and heart rate. In an ambulatory blood pressure monitoring study, substantially higher proportion of milnacipran HCl-treated patients experienced clinically significant blood pressure and heart rate elevations as compared with placebo-treated patients. Measure blood pressure and heart rate prior to initiating treatment with milnacipran HCl and monitor periodically throughout treatment (5.3, 5.4). Seizures: Cases have been reported with milnacipran HCl therapy. Prescribe milnacipran HCl with care in patients with history of seizure disorder (5.5). Hepatotoxicity: More patients treated with milnacipran HCl than with placebo experienced mild elevations of ALT and AST. Rarely, fulminant hepatitis has been reported in patients treated with milnacipran HCl tablets. Avoid concomitant use of milnacipran HCl in patients with substantial alcohol use or chronic liver disease (5.6). Discontinuation: Withdrawal symptoms have been reported in patients when discontinuing treatment with milnacipran HCl. gradual dose reduction is recommended (5.7). Abnormal Bleeding: Milnacipran HCl may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of milnacipran HCl and NSAIDs, aspirin, or other drugs that affect coagulation (5.9). Male patients with history of obstructive uropathies may experience higher rates of genitourinary adverse events (5.11). 5.1 Suicide Risk. Milnacipran HCl is selective serotonin and norepinephrine re-uptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Patients, both adult and pediatric, with depression or other psychiatric disorders may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these medications, and this risk may persist until significant remission occurs. Suicide is known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with milnacipran HCl 100 mg/day, and 1.3% in patients treated with milnacipran HCl 200 mg/day. No suicides occurred in the short-term or longer-term (up to year) fibromyalgia trials. Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included total of 24 short-term trials of drugs used to treat depression in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included total of 295 short-term trials (median duration of months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1: Risk Differences (Drug Placebo) in the number of Cases of Suicidality, per 1,000 patients treatedAge Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated 18 14 additional cases 18 to 24 additional cases Decreases Compared to Placebo25 to 64 fewer case >= 65 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e. beyond several months.However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who may experience worsening depressive symptoms, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patients presenting symptoms. If the decision has been made to discontinue treatment due to worsening depressive symptoms or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can produce withdrawal symptoms [see Dosage and Administration (2.1, 2.4) and Warnings and Precautions (5.7)]. Families and caregivers of patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for milnacipran HCl should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 5.2 Serotonin Syndrome. The development of potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including milnacipran HCl, alone but particularly 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 (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of milnacipran HCl with MAOIs intended to treat psychiatric disorders is contraindicated. Milnacipran HCl should also not be started in patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of mg/kg to mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in patient taking milnacipran HCl. Milnacipran HCl should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1), Dosage and Administration (2.5, 2.6)]. If concomitant use of milnacipran HCl with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. Johns Wort is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with milnacipran HCl and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated. 5.3 Elevated Blood Pressure. double-blind, placebo-controlled ambulatory blood pressure monitoring (ABPM) study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients. Among fibromyalgia patients who were normotensive at baseline, an analysis of the blood pressure findings demonstrated substantially higher proportion of milnacipran HCl-treated patients had hypertensive blood pressure measurement at the Week 4, 50 mg BID steady-state visit (17.7% [n=21/119]) and the Week 7, 100 mg BID steady-state visit (14.3% [n=15/105]) as compared to placebo-treated patients (3.7% [n=2/54] and 0% [0/49] at the Week and Week visits, respectively). Hypertension was defined as mean systolic blood pressure (SBP) >= 140 mmHg and change from baseline in mean SBP >= 10 mmHg or mean diastolic blood pressure (DBP) >= 90 mmHg and change from baseline in mean DBP >= mmHg for the 12-hour period post AM study drug measurement at that visit. Furthermore, 1.9% (4/210) of milnacipran HCl-treated and 0.9% (1/111) of placebo patients discontinued treatment for increases in blood pressure. The increased risk of blood pressure measurements in the hypertensive range in milnacipran HCl-treated patients is supported by substantial increases in mean SBP and DBP measurements observed in the ABPM study. Table shows that, following treatment with milnacipran HCl 50 mg BID for three weeks in patients who were normotensive at baseline, the mean increase from baseline was mmHg in systolic blood pressure (SBP) and diastolic blood pressure (DBP). After further treatment with milnacipran HCl 100 mg BID for two weeks, the mean increase from baseline in SBP and DBP was mmHg. Similar elevations occurred in milnacipran HCl-treated patients who were hypertensive at baseline.Table 2: Mean (Standard Error) Change from Baseline in Mean 24-hour Systolic and Diastolic Blood Pressure (mmHg) of Milnacipran or Placebo following Weeks of Treatment (50mg BID) and Subsequent Weeks of Treatment (100mg BID)NormotensiveHypertensivenSystolicDiastolicnSystolicDiastolicPlacebo390(2)-1(1)500(2)0(2)50 mg BID 925(1)5(1)845(2)4(1)Placebo370(2)-1(1)47-1(2)0(1)100 mg BID 826(1)6(1)805(2)4(1)Blood pressure measurements made after weeks of milnacipran 50mg BID Blood pressure measurements made after weeks of milnacipran 100mg BID Similar patterns of treatment-emergent blood pressure elevations were observed in Phase and clinical pharmacology studies as manifested by an increased risk of new onset hypertension or substantial increases in end of study blood pressure measurements in patients with hypertension at baseline (Table 3).Table 3: Blood pressure changes in Phase randomized controlled trialsMilnacipran 50 mg BIDMilnacipran 100 mg BIDPlaceboFM patients normotensive at baseline who became hypertensive (defined as SBP >= 140 mmHg or DBP >= 90 mmHg on three consecutive post-baseline visits) 20%17%7%FM patients with sustained increases in SBP (increase of >= 15 mmHg on three consecutive post-baseline visits) 9%6%2%FM patients with sustained increases in DBP (increase of >= 10 mmHg on three consecutive post-baseline visits) 13%10 %4%FM patients hypertensive at baseline who had increases in SBP >= 15 mmHg at end of study 10%7%4%FM patients hypertensive at baseline who had increases in DBP >= 10 mmHg at end of study 8%6%3%Sustained increases in blood pressure may have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported. Concomitant use of milnacipran HCl with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution [see Drug Interactions (7)]. Effects of milnacipran HCl on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Milnacipran HCl should be used with caution in these patients.Measure blood pressure prior to initiating treatment and periodically monitor blood pressure throughout milnacipran HCl treatment. Treat pre-existing hypertension and other cardiovascular disease before starting therapy with milnacipran HCl. For patients who experience sustained increase in blood pressure while receiving milnacipran HCl, either reduce the dose or discontinue treatment with milnacipran HCl if clinically warranted. 5.4 Elevated Heart Rate. double-blind, placebo-controlled ABPM study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients [see Warnings and Precautions (5.3)]. Information on heart rate was also collected. Following treatment with milnacipran HCl 50 mg BID for three weeks in patients who were normotensive at baseline, the mean increase in mean 24-hour heart rate from baseline was 13 beats per minute. After further treatment with milnacipran HCl 100 mg BID for two weeks, the mean increase from baseline in heart rate was 13 beats per minute. Similar trends were observed in the clinical trials where milnacipran HCl treatment was associated with mean increases in heart rate of approximately to beats per minute [see Adverse Reactions (6.1)]. Increases in heart rate >= 20 beats per minute occurred more frequently in milnacipran HCl-treated patients when compared to placebo (8% in the milnacipran HCl 50 mg BID and 100 mg BID treatment arms versus 0.3% in the placebo arm). Milnacipran HCl has not been systematically evaluated in patients with cardiac rhythm disorder. Measure heart rate prior to initiating treatment and periodically monitor the heart rate throughout milnacipran HCl treatment. Treat pre-existing tachyarrhythmias and other cardiac disease before starting therapy with milnacipran HCl. For patients who experience sustained increase in heart rate while receiving milnacipran HCl, either reduce the dose or discontinue treatment with milnacipran HCl if clinically warranted. 5.5 Seizures. Milnacipran HCl has not been systematically evaluated in patients with seizure disorder. In clinical trials evaluating milnacipran HCl in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with milnacipran HCl for disorders other than fibromyalgia. Milnacipran HCl should be prescribed with care in patients with history of seizure disorder. 5.6 Hepatotoxicity. In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with milnacipran HCl with mild elevations of ALT or AST (1 to times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with milnacipran HCl 100 mg/day (6%) and milnacipran HCl 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving milnacipran HCl 100 mg/day (0.2%) had an increase in ALT greater than times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with milnacipran HCl 100 mg/day (3%) and milnacipran HCl 200 mg/day (5%) compared to the patients treated with placebo (2%).The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant. No case met the criteria of elevated ALT 3x ULN and associated with an increase in bilirubin >= 2x ULN. There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe liver injury, there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Milnacipran HCl should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with milnacipran HCl should not be resumed unless another cause can be established. Milnacipran HCl should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 5.7 Discontinuation of Treatment with Milnacipran HCl. Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs. During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when discontinuation is abrupt. The adverse events include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with milnacipran HCl. Milnacipran HCl should be tapered and not abruptly discontinued after extended use. If intolerable symptoms occur following decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at more gradual rate [see Dosage and Administration (2.4)]. 5.8 Hyponatremia. Hyponatremia may occur as result of treatment with SSRIs and SNRIs, including milnacipran HCl. In many cases, this 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 SNRIs, SSRIs, or milnacipran HCl. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use (8.5)]. Discontinuation of milnacipran HCl should be considered in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.9 Abnormal Bleeding. SSRIs and SNRIs, including milnacipran HCl, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants 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 use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of milnacipran HCl and NSAIDs, aspirin, or other drugs that affect coagulation. 5.10 Activation of Mania. No activation of mania or hypomania was reported in the clinical trials evaluating effects of milnacipran HCl in patients with fibromyalgia. However those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, milnacipran HCl should be used cautiously in patients with history of mania. 5.11 Patients with History of Dysuria. Because of their noradrenergic effect, SNRIs including milnacipran HCl, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with milnacipran HCl (1%) than in placebo-treated patients (0.5%). Caution is advised in use of milnacipran HCl in patients with history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention, and may experience testicular pain or ejaculation disorders. 5.12 Angle Closure Glaucoma. The pupillary dilation that occurs following use of SNRI drugs including milnacipran HCl may trigger an angle closure attack in patient with anatomically narrow angles who does not have patent iridectomy. 5.13 Concomitant Use with Alcohol. In clinical trials, more patients treated with milnacipran HCl developed elevated transaminases than did placebo treated patients [see Warnings and Precautions (5.6)]. Because it is possible that milnacipran may aggravate pre-existing liver disease, milnacipran HCl should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

RECENT MAJOR CHANGES SECTION.


fgfg. Warnings and Precautions (5.12) 09/2021. Warnings and Precautions (5.12) 09/2021.