Milnacipran Hydrochloride

Milnacipran hydrochloride is indicated for the management of fibromyalgia. Milnacipran hydrochloride is not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )] .

• Milnacipran hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the management of fibromyalgia ( 1 ).
• Milnacipran hydrochloride is not approved for use in pediatric patients ( 1 ).

Film-coated, immediate-release tablets in four strengths: 12.5 mg, 25 mg, 50 mg, and 100 mg of milnacipran hydrochloride. 12.5 mg tablets are round, blue, "F" on one side, "L" on the reverse side; 25 mg tablets are round, white, "FL" on one side, "25" on the reverse side; 50 mg tablets are oval, white, "FL" on one side, "50" on the reverse side; 100 mg tablets are oval, pink, "FL" on one side, "100" on the reverse side.

• Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg ( 3 )

• 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 )] .

• 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 milnacipran hydrochloride and any other serotonergic agents, and initiate supportive treatment ( 5.2 ).
• Elevated Blood Pressure and Heart Rate : Milnacipran hydrochloride may increase blood pressure and heart rate. Measure blood pressure and heart rate prior to initiating treatment with milnacipran hydrochloride and monitor periodically throughout treatment ( 5.3 , 5.4 ).
• Seizures : Cases have been reported with milnacipran hydrochloride therapy. Prescribe milnacipran hydrochloride with care in patients with a history of seizure disorder ( 5.5 ).
• Hepatotoxicity : milnacipran hydrochloride may cause elevations of ALT and AST. Avoid concomitant use of milnacipran hydrochloride 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 hydrochloride. A gradual dose reduction is recommended ( 5.7 ).
• Increased Risk of Bleeding : Milnacipran hydrochloride may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of milnacipran hydrochloride 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 : Milnacipran hydrochloride use may cause symptoms of sexual dysfunction ( 5.12 ).

5.1 Suicide Risk Milnacipran hydrochloride 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 milnacipran hydrochloride 100 mg/day, and 1.3% in patients treated with milnacipran hydrochloride 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. […]

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 Glenmark Pharmaceuticals Inc., USA at 1-888-721-7115 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 hydrochloride 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. […]

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 )] .

• Pregnancy: Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8.1 ).

8.1 Pregnancy Risk Summary Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.2 )] . The available data on milnacipran hydrochloride use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with exposure to serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including milnacipran hydrochloride, during pregnancy (see Clinical Considerations). Animal reproduction studies have been performed in rats, rabbits and mice. Milnacipran was shown to increase embryofetal and perinatal lethality in rats and the incidence of a minor skeletal variation in rabbits at doses below (rat) or approximately equal to (rabbit) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis. No effects were seen in mice when treated with milnacipran during the period of organogenesis at doses up to 3 times the MHRD on a mg/m 2 basis (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Clinical Consideration Maternal adverse reactions Use of milnacipran hydrochloride in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.9 )]. Fetal/Neonatal adverse reactions Neonates exposed to SNRIs or SSRIs, including milnacipran hydrochloride, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either direct toxic effect of SSRIs and SNRIs or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ( 5.2 , 5.7 )]. Data Animal Data Studies were conducted in rats, rabbits and mice with dosing of milnacipran during the period of organogenesis. In rats, milnacipran was shown to increase embryofetal lethality at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m 2 basis). In rabbits, dose-dependent increases in the incidence of the skeletal variation of an extra single rib were observed in several pups from multiple litters in the absence of maternal toxicity at 15 mg/kg/day (1.5 times the MRHD on a mg/m 2 basis). The clinical significance of this finding is unknown. In mice, no embryotoxic or teratogenic effects were seen at doses up to 125 mg/kg/day (3 times the MHRD on a mg/m 2 basis). With peri- and postnatal exposure to oral milnacipran in rats, decreases in viability and body weight were observed on Postpartum Day 4 at a dose of 5 mg/kg/day (approximately 0.25 times the MRHD on a mg/m 2 basis). The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m 2 basis).

8.2 Lactation Risk Summary Milnacipran is present in human milk [see Data] . There are no reports on the effects of milnacipran on the breastfed child and on milk production/excretion. However, there are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to SSRIs or SNRIs through breast milk (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for milnacipran hydrochloride and any potential adverse effects on the breastfed child from milnacipran hydrochloride or from the underlying maternal conditions. Clinical Considerations Monitor infants exposed to milnacipran for agitation, irritability, poor feeding and poor weight gain. Data Human Data Milnacipran is present in the milk of lactating women treated with milnacipran. In a lactation pharmacokinetic study with milnacipran, a single, oral dose of 50 mg milnacipran HCl tablet was administered to 8 lactating women who were at least 12 weeks postpartum and weaning their infants. The milk/plasma AUC ratio of milnacipran was 1.85 ± 0.38. The maximum estimated weight adjusted daily infant dose for milnacipran from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 5% of the maternal dose based on peak plasma concentrations.

8.4 Pediatric Use Safety and effectiveness of milnacipran hydrochloride in a fibromyalgia pediatric population below the age of 18 have not been established [see Boxed Warning , Indications and Usage ( 1 ), and Warnings and Precautions ( 5.1 )] . The use of milnacipran hydrochloride is not recommended in pediatric patients.

8.5 Geriatric Use In controlled clinical studies of milnacipran hydrochloride, 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 hydrochloride in the elderly [see Dosage and Administration ( 2.2 )] . SNRIs, SSRIs, and milnacipran hydrochloride, 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 )] .

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.