Milnacipran Hydrochloride
Tablet, Film Coated · Oral
Uses
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 ).
Dosage and administration
Milnacipran hydrochloride is given orally with or without food. Taking milnacipran hydrochloride with food may improve the tolerability of the drug.
• Administer Milnacipran hydrochloride 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 2-3: 25 mg/day (12.5 mg twice daily) Days 4-7: 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 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 2-3: 25 mg/day (12.5 mg twice daily) Days 4-7: 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 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 with caution in patients with moderate renal impairment. For patients with severe renal impairment (indicated by an estimated creatinine clearance of 5-29 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 is 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 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 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. Conversely, allow at least 5 days after stopping milnacipran hydrochloride before starting a MAOI intended to treat psychiatric disorders [see Contraindications ( 4.1 )] . 2.6 Use of Milnacipran hydrochloride with other MAOIs such as Linezolid or Methylene Blue Do not start milnacipran hydrochloride 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 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 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 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 is unclear. The clinician should nevertheless be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions ( 5.2 )] .
Dosage forms and strengths
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 )
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 )] .
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 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.
Side effects
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.
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 )] .
Use in specific populations
• Pregnancy: Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8.1 ). 8.1 Pregnancy 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.
Pregnancy
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).
Pediatric use
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.
Geriatric use
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 )] .
Overdosage
Clinical Presentation There is limited clinical experience with milnacipran hydrochloride 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 hydrochloride 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 hydrochloride, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. Ensure adequate airway, oxygenation, and ventilation and monitor cardiac rhythm and vital signs. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Because there is no specific antidote for milnacipran hydrochloride, consider symptomatic care and treatment with gastric lavage and activated charcoal as soon as possible for patients who experience a milnacipran hydrochloride overdose. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
Description
Milnacipran hydrochloride is a selective norepinephrine and serotonin reuptake inhibitor; it inhibits norepinephrine uptake with greater potency than serotonin. It is a racemic mixture with the chemical name: (±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride. The structural formula is: Milnacipran hydrochloride is a white to off-white crystalline powder with a melting point of 179°C. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and sparingly soluble in diethyl ether. It has an empirical formula of C15H23ClN2O and a molecular weight of 282.8 g/mol. Milnacipran hydrochloride 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 dibasic calcium phosphate, povidone, carboxymethylcellulose calcium, colloidal silicon dioxide, magnesium stearate, and talc as inactive ingredients. The film coat contains the following additional inactive ingredients: 12.5 mg: FD&C Blue #2 Aluminum Lake, polyvinyl alcohol, polyethylene glycol, titanium dioxide 25 mg: Polyvinyl alcohol, polyethylene glycol, titanium dioxide 50 mg: Polyvinyl alcohol, polyethylene glycol, titanium dioxide 100 mg: FD&C Red #40 Aluminum Lake, polyvinyl alcohol, polyethylene glycol, titanium dioxide structure
Mechanism of action
12.1 Mechanism of Action The exact mechanism of the central pain inhibitory action of milnacipran and its ability to improve the symptoms of fibromyalgia in humans are unknown. Preclinical studies have shown that milnacipran is a potent inhibitor of neuronal norepinephrine and serotonin reuptake; milnacipran inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters. Milnacipran has no significant affinity for serotonergic (5-HT1-7), α- and β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and γ-aminobutyric acid (GABA) receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Milnacipran has no significant affinity for Ca++, K+, Na+ and Cl– channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.
How supplied
12.5-mg tablets: Blue, round, film-coated tablets, debossed with “F” on one side and “L” on the reverse side Bottles of 60: NDC 68462-763-60 25-mg tablets: White, round, film-coated tablets, debossed with “FL” on one side and “25” on the reverse side Bottles of 60: NDC 68462-764-60 50-mg tablets: White, oval-shaped, film-coated tablets, debossed with “FL” on one side and “50” on the reverse side Bottles of 60: NDC 68462-765-60 100-mg tablets: Pink, oval-shaped, film-coated tablets, debossed with “FL” on one side and “100” on the reverse side Bottles of 60: NDC 68462-766-60 Storage Store at 25°C (77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F) [See USP Controlled Room Temperature] .
Patient information
Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Advise patients of the following issues and to alert their prescriber if these occur while taking milnacipran hydrochloride: Clinical Worsening and Suicide Risk Advise patients, their families, and their caregivers that patients with depression may be at increased risk for clinical worsening and/or suicidal ideation if they stop taking anti-depressant medication, change the dose, or start a new medication. Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, or other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during treatment with milnacipran hydrochloride or other drugs that inhibit the reuptake of norepinephrine and/or serotonin, and when the dose is adjusted up or down. Advise families and caregivers to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt and to report such symptoms to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms [see Boxed Warning and Warnings and Precautions ( 5.1 )] . Serotonin Syndrome Inform patients about the risk of serotonin syndrome with use of milnacipran hydrochloride as well as the increased risk when taken concomitantly with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.2 )] . Advise patients of the signs and symptoms associated with serotonin syndrome and to seek medical care immediately if they experience these symptoms. Elevated Blood Pressure and Heart Rate Advise patients that milnacipran hydrochloride 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 hydrochloride [see Warnings and Precautions ( 5.3 , 5.4 )] . Increased Risk of Bleeding Advise patients that the concomitant use of drugs that interfere with serotonin reuptake, including milnacipran hydrochloride, and NSAIDs, aspirin, or anticoagulants has been associated with an increased risk of abnormal bleeding [see Warnings and Precautions ( 5.9 )] . Angle Closure Glaucoma Advise patients that taking milnacipran hydrochloride can cause mild pupillary dilation which, in susceptible individuals, can lead to an episode of angle closure glaucoma. [see Warnings and Precautions ( 5.13 )] . Ability to Drive and Use Machinery Advise patients not to operate machinery or drive motor vehicles until they are reasonably certain that milnacipran hydrochloride treatment does not affect their ability to engage in such activities. Alcohol Inform patients of the risks associated with drinking alcohol while taking milnacipran hydrochloride [see Warnings and Precautions ( 5.6 , 5.14 )] . Sexual Dysfunction Advise patients that use of milnacipran hydrochloride may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions ( 5.12 )]. Discontinuation Advise patients that withdrawal symptoms can occur when discontinuing treatment with milnacipran hydrochloride, particularly when discontinuation is abrupt [see Warnings and Precautions ( 5.7 )] . Missing a Dose Advise patients that if they miss a dose, they should skip the missed dose and take the next dose at their regular time. Pregnancy
• Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with milnacipran hydrochloride.
• Advise patients that milnacipran hydrochloride may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Lactation Advise breastfeeding women using milnacipran hydrochloride to monitor infants for sedation, agitation, irritability, poor feeding, and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )] . Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com © 2025 AbbVie. All rights reserved. Revised: September 2025 IN0763-01 glenmarklogo1
Label text from the FDA structured product label by Glenmark Pharmaceuticals Inc., USA (revised Mar 19, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Milnacipran Hydrochloride in 16 products
Milnacipran Hydrochloride NDC products (17)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 51991-876 | Milnacipran Hydrochloride 25 mg/1 Tablet | Breckenridge Pharmaceutical, Inc. | ANDA |
| 51991-037 | Milnacipran Hydrochloride 100 mg/1 Tablet | Breckenridge Pharmaceutical, Inc. | ANDA |
| 51991-036 | Milnacipran Hydrochloride 50 mg/1 Tablet | Breckenridge Pharmaceutical, Inc. | ANDA |
| 51991-034 | Milnacipran Hydrochloride 12.5 mg/1 Tablet | Breckenridge Pharmaceutical, Inc. | ANDA |
| 31722-847 | Milnacipran Hydrochloride 25 mg/1 Tablet, Film Coated | Camber Pharmaceuticals, Inc. | ANDA |
| 31722-848 | Milnacipran Hydrochloride 50 mg/1 Tablet, Film Coated | Camber Pharmaceuticals, Inc. | ANDA |
| 31722-849 | Milnacipran Hydrochloride 100 mg/1 Tablet, Film Coated | Camber Pharmaceuticals, Inc. | ANDA |
| 31722-880 | Kit | Camber Pharmaceuticals, Inc. | ANDA |
| 31722-846 | Milnacipran Hydrochloride 12.5 mg/1 Tablet, Film Coated | Camber Pharmaceuticals, Inc. | ANDA |
| 33342-372 | Milnacipran Hydrochloride 100 mg/1 Tablet | Macleods Pharmaceuticals Limited | ANDA |
| 33342-371 | Milnacipran Hydrochloride 50 mg/1 Tablet | Macleods Pharmaceuticals Limited | ANDA |
| 33342-370 | Milnacipran Hydrochloride 25 mg/1 Tablet | Macleods Pharmaceuticals Limited | ANDA |
| 33342-369 | Milnacipran Hydrochloride 12.5 mg/1 Tablet | Macleods Pharmaceuticals Limited | ANDA |
| 68462-763 | Milnacipran Hydrochloride 12.5 mg/1 Tablet, Film Coated | Glenmark Pharmaceuticals Inc., USA | NDA AUTHORIZED GENERIC |
| 68462-764 | Milnacipran Hydrochloride 25 mg/1 Tablet, Film Coated | Glenmark Pharmaceuticals Inc., USA | NDA AUTHORIZED GENERIC |
| 68462-765 | Milnacipran Hydrochloride 50 mg/1 Tablet, Film Coated | Glenmark Pharmaceuticals Inc., USA | NDA AUTHORIZED GENERIC |
| 68462-766 | Milnacipran Hydrochloride 100 mg/1 Tablet, Film Coated | Glenmark Pharmaceuticals Inc., USA | NDA AUTHORIZED GENERIC |
Frequently asked questions
What is Milnacipran Hydrochloride used for?
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…
What are the side effects of Milnacipran Hydrochloride?
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.… See the full label for the complete list.
Who makes Milnacipran Hydrochloride?
Milnacipran Hydrochloride is listed by 4 labelers in the FDA NDC directory, including Breckenridge Pharmaceutical, Inc., Camber Pharmaceuticals, Inc., Macleods Pharmaceuticals Limited, Glenmark Pharmaceuticals Inc., USA.