Milnacipran Drug Information

Generic name: MILNACIPRAN HYDROCHLORIDE

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Uses of Milnacipran

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

Dosage & Administration of Milnacipran

  • 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) ] .

Side Effects of Milnacipran

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 . 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

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 System and Breast Disorders ― galactorrhea, decreased libido, delayed or absent orgasm Skin Disorders ― erythema multiforme, Stevens Johnson syndrome Vascular Disorders ― hypertensive crisis

Warnings & Cautions for Milnacipran

  • 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 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was 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 to 24 5 additional cases Decreases Compared to Placebo 25 to 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 milnacipran hydrochloride 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 milnacipran hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin i.e., MAOIs [see Contraindications (4 ), Drug Interactions (7) ] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of milnacipran hydrochloride with MAOIs is 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 an MAOI such as linezolid or intravenous methylene blue in a patient taking milnacipran hydrochloride, discontinue milnacipran hydrochloride before initiating treatment with the MAOI [see Contraindications (4.1) , Dosage and Administration (2.5 , 2.6) , Drug Interactions (7.1) ] . Monitor all patients taking milnacipran hydrochloride for the emergence of serotonin syndrome. Discontinue treatment with milnacipran hydrochloride and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. If concomitant use of milnacipran hydrochloride with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Elevated Blood Pressure A double-blind, placebo-controlled ambulatory blood pressure monitoring (ABPM) study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients. Among fibromyalgia patients who were normotensive at baseline, an analysis of the blood pressure findings demonstrated a substantially higher proportion of milnacipran hydrochloride -treated patients had a hypertensive blood pressure measurement at the Week 4, 50 mg BID steady state visit (17.7% [n=21/119]) and the Week 7, 100 mg BID steady state visit (14.3% [n=15/105]) as compared to placebo-treated patients (3.7% [n=2/54] and 0% [0/49] at the Week 4 and Week 7 visits, respectively). Hypertension was defined as mean systolic blood pressure (SBP) ≥140 mmHg and change from baseline in mean SBP ≥10 mmHg or mean diastolic blood pressure (DBP) ≥90 mmHg and change from baseline in mean DBP ≥5 mmHg for the 12-hour period post AM study drug measurement at that visit. Furthermore, 1.9% (4/210) of milnacipran hydrochloride -treated and 0.9% (1/111) of placebo patients discontinued treatment for increases in blood pressure. The increased risk of blood pressure measurements in the hypertensive range in milnacipran hydrochloride -treated patients is supported by substantial increases in mean SBP and DBP measurements observed in the ABPM study. Table 2 shows that, following treatment with milnacipran hydrochloride 50 mg BID for three weeks in patients who were normotensive at baseline, the mean increase from baseline was 5 mmHg in systolic blood pressure (SBP) and diastolic blood pressure (DBP). After further treatment with milnacipran hydrochloride 100 mg BID for two weeks, the mean increase from baseline in SBP and DBP was 6 mmHg. Similar elevations occurred in milnacipran hydrochloride -treated patients who were hypertensive at baseline. Table 2: Mean (Standard Error) Change from Baseline in Mean 24-hour Systolic and Diastolic Blood Pressure (mmHg) of Milnacipran or Placebo following 4 Weeks of Treatment (50 mg BID) and a Subsequent 2 Weeks of Treatment (100 mg BID) Normotensive Hypertensive n Systolic Diastolic n Systolic Diastolic Placebo 39 0(2) -1(1) 50 0(2) 0(2) 50 mg BID* 92 5(1) 5(1) 84 5(2) 4(1) Placebo 37 0(2) -1(1) 47 -1(2) 0(1) 100 mg BID^ 82 6(1) 6(1) 80 5(2) 4(1) *Blood pressure measurements made after 3 weeks of milnacipran 50 mg BID ^Blood pressure measurements made after 2 weeks of milnacipran 100 mg BID Similar patterns of treatment-emergent blood pressure elevations were observed in Phase 3 and clinical pharmacology studies as manifested by an increased risk of new onset hypertension or substantial increases in end of study blood pressure measurements in patients with hypertension at baseline (Table 3) . Table 3: Blood pressure changes in Phase 3 randomized controlled trials Milnacipran 50 mg BID Milnacipran 100 mg BID Placebo FM patients normotensive at baseline who became hypertensive (defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg on three consecutive post-baseline visits) 20% 17% 7% FM patients with sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits) 9% 6% 2% FM patients with sustained increases in DBP (increase of ≥ 10 mmHg on three consecutive post-baseline visits) 13% 10 % 4% FM patients hypertensive at baseline who had increases in SBP ≥ 15 mmHg at end of study 10% 7% 4% FM patients hypertensive at baseline who had increases in DBP ≥ 10 mmHg at end of study 8% 6% 3% Sustained increases in blood pressure may have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported. Concomitant use of milnacipran hydrochloride with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution [see Drug Interactions (7) ] . Effects of milnacipran hydrochloride on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Milnacipran hydrochloride should be used with caution in these patients. Measure blood pressure prior to initiating treatment and periodically monitor blood pressure throughout milnacipran hydrochloride treatment. Treat pre-existing hypertension and other cardiovascular disease before starting therapy with milnacipran hydrochloride. For patients who experience a sustained increase in blood pressure while receiving milnacipran hydrochloride, either reduce the dose or discontinue treatment with milnacipran hydrochloride if clinically warranted. 5.4 Elevated Heart Rate A double-blind, placebo-controlled ABPM study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients [see Warnings and Precautions (5.3) ] . Information on heart rate was also collected. Following treatment with milnacipran hydrochloride 50 mg BID for three weeks in patients who were normotensive at baseline, the mean increase in mean 24-hour heart rate from baseline was 13 beats per minute. After further treatment with milnacipran hydrochloride 100 mg BID for two weeks, the mean increase from baseline in heart rate was 13 beats per minute. Similar trends were observed in the clinical trials where milnacipran hydrochloride treatment was associated with mean increases in heart rate of approximately 7 to 8 beats per minute [see Adverse Reactions (6.1) ] . Increases in heart rate ≥ 20 beats per minute occurred more frequently in milnacipran hydrochloride -treated patients when compared to placebo (8% in the milnacipran hydrochloride 50 mg BID and 100 mg BID treatment arms versus 0.3% in the placebo arm). Milnacipran hydrochloride has not been systematically evaluated in patients with a cardiac rhythm disorder. Measure heart rate prior to initiating treatment and periodically monitor the heart rate throughout milnacipran hydrochloride treatment. Treat pre-existing tachyarrhythmias and other cardiac disease before starting therapy with milnacipran hydrochloride. For patients who experience a sustained increase in heart rate while receiving milnacipran hydrochloride, either reduce the dose or discontinue treatment with milnacipran hydrochloride if clinically warranted. 5.5 Seizures Milnacipran hydrochloride has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating milnacipran hydrochloride in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with milnacipran hydrochloride for disorders other than fibromyalgia. Milnacipran hydrochloride should be prescribed with care in patients with a history of a seizure disorder. 5.6 Hepatotoxicity In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with milnacipran hydrochloride with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with milnacipran hydrochloride 100 mg/day (6%) and milnacipran hydrochloride 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving milnacipran hydrochloride 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with milnacipran hydrochloride 100 mg/day (3%) and milnacipran hydrochloride 200 mg/day (5%) compared to the patients treated with placebo (2%). The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant. No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin ≥ 2x ULN. There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe liver injury, there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Discontinue milnacipran hydrochloride in patients who develop jaundice or other evidence of liver dysfunction. Treatment with milnacipran hydrochloride should not be resumed unless another cause can be established. Milnacipran hydrochloride should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 5.7 Discontinuation of Treatment with Milnacipran Hydrochloride Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs. During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when discontinuation is abrupt. The adverse events include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Monitor patients for these symptoms when discontinuing treatment with milnacipran hydrochloride. Milnacipran hydrochloride should be tapered after extended use. Do not abruptly discontinue. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.4) ]. 5.8 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including milnacipran hydrochloride. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs, SSRIs, or milnacipran hydrochloride. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use (8.5)] . Consider discontinuation of milnacipran hydrochloride in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.9 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake, including milnacipran hydrochloride, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. 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 Use in Specific Populations (8.1)] . Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of milnacipran hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.7)]. 5.10 Activation of Mania No activation of mania or hypomania was reported in the clinical trials evaluating effects of milnacipran hydrochloride in patients with fibromyalgia. However, those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, use milnacipran hydrochloride cautiously in patients with a history of mania. 5.11 Patients with a History of Dysuria Because of their noradrenergic effect, SNRIs including milnacipran hydrochloride, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with milnacipran hydrochloride (1%) than in placebo-treated patients (0.5%). Caution is advised in use of milnacipran hydrochloride in patients with a history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention, and may experience testicular pain or ejaculation disorders. 5.12 Sexual Dysfunction Use of SNRIs, including milnacipran hydrochloride, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1 , 6.2) ]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of milnacipran hydrochloride and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment. 5.13 Angle Closure Glaucoma The pupillary dilation that occurs following use of SNRI drugs including milnacipran hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.14 Concomitant Use with Alcohol In clinical trials, more patients treated with milnacipran hydrochloride developed elevated transaminases than did placebo treated patients [see Warnings and Precautions (5.6)] . Because it is possible that milnacipran may aggravate pre-existing liver disease, milnacipran hydrochloride should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

Drug Interactions with Milnacipran

  • 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 Safety for Milnacipran

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. 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% to 4% and 15% to 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. 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 . 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 of Milnacipran

Pediatric Use Safety and effectiveness of milnacipran hydrochloride in a fibromyalgia pediatric population below the age of 18 have not been established . The use of milnacipran hydrochloride is not recommended in pediatric patients.

Contraindications for Milnacipran

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 . 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.

Overdosage Information for Milnacipran

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).

Clinical Studies of Milnacipran

Management of Fibromyalgia The efficacy of milnacipran hydrochloride for the management of fibromyalgia was established in two double-blind, placebo-controlled, multicenter studies in adult patients (18 to 74 years of age). Enrolled patients met the American College of Rheumatology (ACR) criteria for fibromyalgia (a history of widespread pain for 3 months and pain present at 11 or more of the 18 specific tender point sites). Approximately 35% of patients had a history of depression. Study 1 was six months in duration and Study 2 was three months in duration. A larger proportion of patients treated with milnacipran hydrochloride than with placebo experienced a simultaneous reduction in pain from baseline of at least 30% (VAS) and also rated themselves as much improved or very much improved based on the patient global assessment (PGIC). In addition, a larger proportion of patients treated with milnacipran hydrochloride met the criteria for treatment response, as measured by the composite endpoint that concurrently evaluated improvement in pain (VAS), physical function (SF-36 PCS), and patient global assessment (PGIC), in fibromyalgia as compared to placebo.

Study 1: This 6-month study compared total daily doses of milnacipran hydrochloride 100 mg and 200 mg to placebo. Patients were enrolled with a minimum mean baseline pain score of ≥ 50 mm on a 100 mm visual analog scale (VAS) ranging from 0 (“no pain”) to 100 (“worst possible pain”). The mean baseline pain score in this trial was 69. The efficacy results for Study 1 are summarized in Figure 1. Figure 1 shows the proportion of patients achieving various degrees of improvement in pain from baseline to the 3-month time point and who concurrently rated themselves globally improved (PGIC score of 1 or 2). Patients who did not complete the 3-month assessment were assigned 0% improvement. More patients in the milnacipran hydrochloride treatment arms experienced at least a 30% reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than did patients in the placebo arm.

Treatment with milnacipran hydrochloride 200 mg/day did not confer greater benefit than treatment with milnacipran hydrochloride 100 mg/day. Figure 1: Patients Achieving Various Levels of Pain Relief with Concurrent Ratings of Being Much or Very Much Improved on the PGIC ― Study 1 Study 2: This 3-month study compared total daily doses of milnacipran hydrochloride 100 mg and 200 mg to placebo. Patients were enrolled with a minimum mean baseline pain score of ≥ 40 mm on a 100 mm VAS ranging from 0 (“no pain”) to 100 (“worst possible pain”). The mean baseline pain score in this trial was 65. The efficacy results for Study 2 are summarized in Figure 2. Figure 2 shows the proportion of patients achieving various degrees of improvement in pain from baseline to the 3-month time point and who concurrently rated themselves globally improved (PGIC score of 1 or 2). Patients who did not complete the 3-month assessment were assigned 0% improvement.

More patients in the milnacipran hydrochloride treatment arms experienced at least a 30% reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than did patients in the placebo arm. Treatment with milnacipran hydrochloride 200 mg/day did not confer greater benefit than treatment with milnacipran hydrochloride 100 mg/day. Figure 2: Patients Achieving Various Levels of Pain Relief with Concurrent Ratings of Being Much or Very Much Improved on the PGIC ― Study 2 In both studies, some patients who rated themselves as globally “much” or “very much” improved experienced a decrease in pain as early as week 1 of treatment with a stable dose of milnacipran hydrochloride that persisted throughout these studies. milnacipran-hydrochloride-tabletsfigure1 milnacipran-hydrochloride-tabletsfigure2

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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