Milnacipran

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

DOSAGE AND ADMINISTRATION Milnacipran hydrochloride tablets are given orally with or without food. Taking milnacipran hydrochloride tablets with food may improve the tolerability of the drug. • Administer milnacipran hydrochloride tablets in two divided doses per day (2.1) . • Based on efficacy and tolerability, dosing may be titrated according to the following schedule (2.1) : Day 1: 12.5 mg once Days 2 to 3: 25 mg/day (12.5 mg twice daily) Days 4 to 7: 50 mg/day (25 mg twice daily) After Day 7: 100 mg/day (50 mg twice daily) • Recommended dose is 100 mg/day (2.1) . • May be increased to 200 mg/day based on individual patient response (2.1) . • Adjust dose in patients with severe renal impairment (2.2) . 2.1 Recommended Dosing The recommended dose of milnacipran hydrochloride tablet is 100 mg/day (50 mg twice daily). Based on efficacy and tolerability dosing may be titrated according to the following schedule: Day 1: 12.5 mg once Days 2 to 3: 25 mg/day (12.5 mg twice daily) Days 4 to 7: 50 mg/day (25 mg twice daily) After Day 7: 100 mg/day (50 mg twice daily) Based on individual patient response, the dose may be increased to 200 mg/day (100 mg twice daily). Doses above 200 mg/day have not been studied. Taper milnacipran hydrochloride tablets and do not abruptly discontinue after extended use [see Dosage and Administration (2.4) , Warnings and Precautions (5.7) ]. 2.2 Patients with Renal Insufficiency No dosage adjustment is necessary in patients with mild renal impairment. Use milnacipran hydrochloride tablets with caution in patients with moderate renal impairment. For patients with severe renal impairment (indicated by an estimated creatinine clearance of 5 to 29 mL/min), reduce the maintenance dose by 50% to 50 mg/day (25 mg twice daily). Based on individual patient response, the dose may be increased to 100 mg/day (50 mg twice daily). Milnacipran hydrochloride tablets are not recommended for patients with end-stage renal disease. 2.3 Patients with Hepatic Insufficiency No dosage adjustment is necessary for patients with hepatic impairment. As with any drug, exercise caution in patients with severe hepatic impairment. 2.4 Discontinuing Milnacipran Hydrochloride Tablets Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other serotonin and norepinephrine re-uptake inhibitors (SNRIs) and selective serotonin re-uptake inhibitors (SSRIs). Monitor patients for these symptoms when discontinuing treatment. Taper milnacipran hydrochloride tablets and do not abruptly discontinue after extended use [see Warnings and Precautions (5.7) ] . 2.5 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with milnacipran hydrochloride tablets. Conversely, allow at least 5 days after stopping milnacipran hydrochloride tablets before starting a MAOI intended to treat psychiatric disorders [see Contraindications (4.1) ] . 2.6 Use of Milnacipran Hydrochloride Tablets with other MAOIs such as Linezolid or Methylene Blue Do not start milnacipran hydrochloride tablets in a patient being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, consider other interventions, including hospitalization [see Contraindications (4.1) ]. In some cases, a patient already receiving milnacipran hydrochloride tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, discontinue milnacipran hydrochloride tablets promptly, and consider administering linezolid or intravenous methylene blue. Monitor the patient for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with milnacipran hydrochloride tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2) ]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with milnacipran hydrochloride 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) ] .

WARNINGS AND PRECAUTIONS Suicidality : Monitor for worsening of depressive symptoms and suicide risk ( 5.1 ). Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue SAVELLA and any other serotonergic agents, and initiate supportive treatment ( 5.2 ). Elevated B lood P ressure and H eart R ate : SAVELLA may increase blood pressure and heart rate. Measure blood pressure and heart rate prior to initiating treatment with SAVELLA and monitor periodically throughout treatment ( 5.3 , 5.4 ). Seizures : Cases have been reported with SAVELLA therapy. Prescribe SAVELLA with care in patients with a history of seizure disorder ( 5.5 ). Hepatotoxicity : SAVELLA may cause elevations of ALT and AST. Avoid concomitant use of SAVELLA in patients with substantial alcohol use or chronic liver disease ( 5.6 ). Discontinuation : Withdrawal symptoms have been reported in patients when discontinuing treatment with SAVELLA. A gradual dose reduction is recommended ( 5.7 ). Increased Risk of Bleeding : SAVELLA may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of SAVELLA and NSAIDs, aspirin, or other drugs that affect coagulation ( 5.9 ). History of Dysuria : Male patients with a history of obstructive uropathies may experience higher rates of genitourinary adverse events ( 5.11 ). Sexual Dysfunction : SAVELLA use may cause symptoms of sexual dysfunction ( 5.12 ). 5.1 Suicide Risk SAVELLA is a 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 a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have a 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 a history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with SAVELLA 100 mg/day, and 1.3% in patients treated with SAVELLA 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1 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 18-24) 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 a 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 a total of 24 short-term trials of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk 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 1000 patients treated) are provided in Table 1 . Table 1: Risk Differences (Drug – Placebo) in the number of Cases of Suicidality, per 1000 patients treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric 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 a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, 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 non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients 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 patient’s 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 ), 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 SAVELLA 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 Selective-serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including SAVELLA, can precipitate serotonin syndrome, a potentially life-

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

DRUG INTERACTIONS Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%) and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that milnacipran hydrochloride is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations (12.3)] . • Milnacipran hydrochloride is unlikely to be involved in clinically significant pharmacokinetic drug interactions (7) . • Pharmacodynamic interactions of milnacipran hydrochloride with other drugs can occur (7) . 7.1 Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of SSRIs and SNRIs, including milnacipran hydrochloride, with MAOIs increases the risk of serotonin syndrome. The use of MAOIs intended to treat psychiatric disorders with milnacipran hydrochloride or within 5 days of stopping treatment with milnacipran hydrochloride is contraindicated. The use of milnacipran hydrochloride within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. In addition, do not initiate milnacipran hydrochloride in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking milnacipran hydrochloride, discontinue milnacipran hydrochloride before initiating treatment with the MAOI [see Dosage and Administration (2.5, 2.6), Contraindications (4), Drug Interactions (7.1)]. 7.2 Serotonergic Drugs Serotonin syndrome can occur with use of milnacipran hydrochloride and other serotonergic drugs (other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort), or with drugs that impair metabolism of serotonin (i.e., monoamine oxidase inhibitors). Advise patients of the signs and symptoms associated with serotonin syndrome and to seek medical care immediately if they experience these symptoms [see Dosage and Administration (2.5, 2.6), Warnings and Precautions (5.2)]. 7.3 Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of milnacipran hydrochloride with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.2)]. 7.4 Catecholamines Milnacipran hydrochloride inhibits the reuptake of norepinephrine. Therefore, concomitant use of milnacipran hydrochloride 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 hydrochloride, use caution when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action. Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to milnacipran hydrochloride. 7.6 Clinically Important Interactions with Select Cardiovascular Agents Digoxin: Use of milnacipran hydrochloride concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Avoid co-administration of milnacipran hydrochloride and intravenous digoxin [see Warnings and Precautions (5.3 , 5.4) ] . Clonidine: Because milnacipran hydrochloride inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine’s anti-hypertensive effect. 7.7 Drugs that Interfere with Hemostasis Concomitant use of milnacipran hydrochloride with an antiplatelet or anticoagulant drug (e.g., NSAIDs, aspirin, and warfarin) may potentiate the risk of bleeding. This may be due to the effect of milnacipran hydrochloride on the release of serotonin by platelets. Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when milnacipran hydrochloride is initiated or discontinued [see Warnings and Precautions (5.9)].

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 Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patient Exposure Milnacipran hydrochloride was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with milnacipran hydrochloride and 652 patients treated with placebo) for a treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions Leading to Discontinuation In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with milnacipran hydrochloride 100 mg/day, 26% of patients treated with milnacipran hydrochloride 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 hydrochloride 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 hydrochloride 200 mg/day compared to milnacipran hydrochloride 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 hydrochloride were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Table 4 lists all adverse reactions that occurred in at least 2% of patients treated with milnacipran hydrochloride 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 Hydrochloride-Treated Patients and Occurring More Frequently in Either Milnacipran Hydrochloride Treatment Group Than in the Placebo Treatment Group) System Organ Class– Preferred Term Milnacipran Hydrochloride 100 mg/day (n = 623) % Milnacipran Hydrochloride 200 mg/day (n = 934) % All Milnacipran Hydrochloride (n = 1557) % Placebo (n = 652) % Cardiac Disorders Palpitations 8 7 7 2 Tachycardia 3 2 2 1 Eye Disorders Vision blurred 1 2 2 1 Gastrointestinal Disorders Nausea 35 39 37 20 Constipation 16 15 16 4 Vomiting 6 7 7 2 Dry mouth 5 5 5 2 Abdominal pain 3 3 3 2 General Disorders Chest pain 3 2 2 2 Chills 1 2 2 0 Chest discomfort 2 1 1 1 Infections Upper respiratory tract infection 7 6 6 6 Investigations Heart rate increased 5 6 6 1 Blood pressure increased 3 3 3 1 Metabolism and Nutrition Disorders Decreased appetite 1 2 2 0 Nervous System Disorders Headache 19 17 18 14 Dizziness 11 10 10 6 Migraine 6 4 5 3 Paresthesia 2 3 2 2 Tremor 2 2 2 1 Hypoesthesia 1 2 1 1 Tension headache 2 1 1 1 Psychiatric Disorders Insomnia 12 12 12 10 Anxiety 5 3 4 4 Respiratory Disorders Dyspnea 2 2 2 1 Skin Disorders Hyperhidrosis 8 9 9 2 Rash 3 4 3 2 Pruritus 3 2 2 2 Vascular Disorders Hot flush 11 12 12 2 Hypertension 7 4 5 2 Flushing 2 3 3 1 Weight Changes In placebo-controlled fibromyalgia clinical trials, patients treated with milnacipran hydrochloride for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the milnacipran hydrochloride 100 mg/day and the milnacipran hydrochloride 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients. Genitourinary Adverse Reactions in Males In the placebo-controlled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with milnacipran hydrochloride, and occurred at a rate greater than in placebo-treated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased. Other Adverse Reactions Observed During Clinical Trials of Milnacipran Hydrochloride in Fibromyalgia Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with milnacipran for periods up to 68 weeks. The listing does not include those events already listed in Table 4 , those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section (5) . Gastrointestinal Disorders ― diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension General Disorders ― fatigue, peripheral edema, irritability, pyrexia Infections ― urinary tract infection, cystitis Injury, Poisoning, and Procedural Complications ― contusion, fall Investigations ― weight decreased or increased Metabolism and Nutrition Disorders ― hypercholesterolemia Nervous System Disorders ― somnolence, dysgeusia Psychiatric Disorders ― depression, stress Skin Disorders ― night sweats 6.2 Postmarketing Experience The following additional adverse reactions have been identified from spontaneous reports of milnacipran hydrochloride received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to milnacipran hydrochloride. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include: Blood and Lymphatic System Disorders ― leukopenia, neutropenia, thrombocytopenia Cardiac Disorders ― supraventricular tachycardia, Takotsubo cardiomyopathy Eye Disorders ― accommodation disorder Endocrine Disorders ― hyperprolactinemia Gastrointestinal Disorders ― acute pancreatitis Hepatobiliary Disorders ― hepatitis Metabolism and Nutrition Disorders ― anorexia, hyponatremia Musculoskeletal and Connective Tissue Disorders ― rhabdomyolysis Nervous System Disorders ― anosmia, convulsions (including grand mal), hyposmia, loss of consciousness, Parkinsonism Psychiatric Disorders ― aggression, anger, delirium, hallucination, homicidal ideation Renal and Urinary Disorders ― acute renal failure Reproductive Syste

Mechanism of Action The exact mechanism of the central pain inhibitory action of milnacipran and its ability to improve the symptoms of fibromyalgia in humans are unknown. Preclinical studies have shown that milnacipran is a potent inhibitor of neuronal norepinephrine and serotonin reuptake; milnacipran inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters. Milnacipran has no significant affinity for serotonergic (5-HT1-7), α- and β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and γ-aminobutyric acid (GABA) receptors in vitro . Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Milnacipran has no significant affinity for Ca++, K+, Na+ and Cl– channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.