AHFS Class:

• Fibromyalgia Agents 28:40

Generic Name(s):

• Milnacipran Hydrochloride

Chemical Name:

• (±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride

Molecular Formula:

• C₁₅H₂₂N₂O•HCl

Milnacipran hydrochloride is a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI).1,2,3,4,5,6 The drug is a fibromyalgia agent.1,2,3,4,5,6

Fibromyalgia

Milnacipran hydrochloride is used for the management of fibromyalgia in adults.1,2,3,4,5,7

Fibromyalgia, which is estimated to affect from 2-4% of the population in the US, is a complex syndrome associated with chronic widespread musculoskeletal pain and a reduced pain threshold, with hyperalgesia and allodynia (pain-related behavior in response to normally innocuous stimuli).2,3,4,6,19,20,21,22,26,27,28,38,39,42,47 Some associated clinical features include fatigue, depression and other mood disorders, anxiety, sleep disturbances, headache (including migraine), changes in bowel habits (including irritable bowel syndrome), diffuse abdominal pain, and urinary frequency.38,47,64,65,68

The American College of Rheumatology (ACR) initially published criteria for the classification of fibromyalgia in 1990, which included a history of widespread pain for at least 3 months and the presence of pain in at least 11 of 18 specific tender point sites.19,64,65 In 2010, the ACR developed new diagnostic criteria for fibromyalgia that no longer included tender point counts and focused more on patient symptoms, including use of a widespread pain index (WPI) and symptom severity (SS) scale.64,65 According to the 2010 diagnostic criteria, a diagnosis of fibromyalgia can be made if a patient has a WPI of 7 or greater and SS scale score of 5 or greater or a WPI of 3-6 and SS scale score of 9 or greater;64,65 symptoms must have been present at a similar level for at least 3 months and the patient should not have a disorder that would otherwise explain the pain.64,65 Due to the complex nature of the fibromyalgia syndrome, optimal treatment often requires a combination of nonpharmacologic therapy (e.g., cognitive behavioral therapy, education, exercise and other forms of physical therapy) and pharmacologic therapy (e.g., selective serotonin-reuptake inhibitors [SSRIs], SNRIs, tricyclic antidepressants, other agents [e.g., pregabalin], topical and systemic analgesics).2,19,20,26,27,28,38,47

Efficacy of milnacipran for the management of fibromyalgia has principally been established in 2 double-blind, placebo-controlled, multicenter studies conducted in the US in 2084 adults with a diagnosis of fibromyalgia based on the 1990 ACR criteria.1,2,3 Approximately 35% of the patients in these studies had a history of depression.1,2,3 Study 1 was of 6 months' duration and study 2 was of 3 months' duration; both studies compared total daily milnacipran hydrochloride dosages of 100 mg and 200 mg with placebo.1,2,3 In these studies, a larger proportion of patients treated with milnacipran than those treated with placebo experienced a simultaneous reduction in pain from baseline of at least 30% on the visual analog scale (VAS) and rated themselves as much improved or very much improved on the Patient Global Impression of Change (PGIC) scale.1,2,3 In addition, a larger proportion of patients treated with milnacipran met the criteria for treatment response as measured by the composite endpoint that concurrently evaluated improvement in pain (VAS), physical function (Short Form-36 Physical Component Summary), and the PGIC.1,2,3 In both studies, some patients who rated themselves as much or very much improved experienced a decrease in pain as early as week 1 of treatment with a stable milnacipran dosage, and the pain reduction persisted throughout the studies.1,2,3 Neither study demonstrated an additional therapeutic benefit of 200 mg of milnacipran hydrochloride daily compared with 100 mg daily.1,2,3

A multicenter, randomized, blinded extension of study 1, which was of 6 months' duration, subsequently demonstrated that continuing milnacipran therapy (100 or 200 mg daily) for an additional 6 months provides sustained efficacy for up to 1 year and generally is well tolerated in patients with fibromyalgia.5

Fatigue is one of the core symptoms associated with fibromyalgia and affects patients both physically and mentally.68 In a pooled analysis of 3 randomized, placebo-controlled clinical trials of milnacipran (100 or 200 mg daily) in patients with fibromyalgia, milnacipran-treated patients experienced substantial and clinically important reductions in fatigue as measured by the Multidimensional Fatigue Inventory (MFI; a scale that assesses physical, mental, and psychosocial aspects of fatigue).68 The improvement in fatigue observed in the milnacipran-treated patients could not be completely attributed to indirect effects of the drug on pain reduction.68

Major Depressive Disorder

Although milnacipran has been used in the treatment of major depressive disorder† and is approved for treating depression in some countries outside the US,4,6,17,18,37,55 this indication is not an FDA-labeled use.1 Levomilnacipran hydrochloride (Fetzima^®), the 1 S ,2 R -enantiomer of milnacipran, is labeled by the FDA for the treatment of major depressive disorder.61

There are insufficient data, to date, to determine if the efficacy and tolerability of milnacipran as an antidepressant are superior, inferior, or equal to that of other antidepressant agents for the acute phase treatment of major depressive disorder.37 However, some studies indicate improved tolerability with milnacipran when compared with tricyclic antidepressants.17,37

Administration

Milnacipran hydrochloride is administered orally twice daily in divided doses without regard to meals; however, taking the drug with food may improve tolerability.1

The manufacturer states that at least 2 weeks must elapse between discontinuance of a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders and initiation of milnacipran therapy and that at least 5 days must elapse between discontinuance of milnacipran and initiation of MAO inhibitor therapy intended to treat psychiatric disorders.1 (See Contraindications, Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions, and Drug Interactions: Monoamine Oxidase Inhibitors.)

Patients receiving milnacipran for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, particularly during initial therapy or following any change (increase or decrease) in dosage.1,32,33,34 (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Dosage

Dosage of milnacipran hydrochloride is expressed in terms of the salt.1

Fibromyalgia

For the management of fibromyalgia in adults, the recommended maintenance dosage of milnacipran hydrochloride is 100 mg daily (given as 50 mg twice daily).1 The manufacturer states that the dosage should be titrated based on efficacy and tolerability, beginning with 12.5 mg administered once on the first day of therapy, 25 mg daily (given as 12.5 mg twice daily) on days 2 and 3, and 50 mg daily (given as 25 mg twice daily) on days 4 through 7.1 After day 7, the usual maintenance dosage of 100 mg daily (given as 50 mg twice daily) should be given.1 Based upon individual patient response, the dosage may be increased to 200 mg daily (given as 100 mg twice daily).1 Safety and efficacy of milnacipran hydrochloride dosages above 200 mg daily have not been evaluated.1

Discontinuance of Therapy

Because withdrawal effects may occur, abrupt discontinuance of milnacipran should be avoided after extended use.1,6 When milnacipran therapy is discontinued, dosage should be tapered gradually and the patient monitored to reduce the risk of withdrawal symptoms.1,6 If intolerable symptoms occur following dosage reduction or upon discontinuance of treatment, reinstitution of milnacipran therapy at the previously prescribed dosage may be considered until symptoms abate.1 Clinicians may resume dosage reductions at that time but at a more gradual rate.1 (See Withdrawal of Therapy under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Special Populations

Dosage adjustment is not necessary in patients with mild renal impairment.1 Milnacipran should be used with caution in patients with moderate renal impairment.1 In patients with severe renal impairment (creatinine clearance of 5-29 mL/minute), the usual maintenance dosage should be reduced by 50% to 50 mg daily (given as 25 mg twice daily).1 Based on individual patient response, the dosage may be increased to 100 mg daily (given as 50 mg twice daily).1 Milnacipran is not recommended in patients with end-stage renal disease.1

Dosage adjustment is not necessary in patients with hepatic impairment.1,44 However, the drug should be used with caution in patients with severe hepatic impairment.1 In addition, the manufacturer states that milnacipran generally should not be prescribed to patients with substantial alcohol use or evidence of chronic hepatic disease.1 (See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Specific Populations under Cautions: Warnings/Precautions.)

The manufacturer does not recommend routine dosage adjustment in geriatric patients; however, possible age-related decreases in renal function should be considered.1 Dosage adjustment is necessary in geriatric patients with severely impaired renal function.1

Dosage adjustment based on gender is not necessary.1

Contraindications

Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders.1 Use of an MAO inhibitor intended to treat psychiatric disorders within 5 days of milnacipran discontinuance.1 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Initiation of milnacipran therapy in patients receiving MAO inhibitors such as linezolid or IV methylene blue.1 (See Drug Interactions: Linezolid and also see Drug Interactions: Methylene Blue.)

Warnings/Precautions

Warnings

Worsening of Depression and Suicidality Risk

Milnacipran is a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) and is similar to some drugs used for the treatment of depression and other psychiatric disorders.1

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Pediatric Use under Cautions: Specific Populations) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.1,32,33,34,35 This risk may persist until clinically important remission occurs.1,33 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1,32,33,34 However, there has been a long-standing concern 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.1,33,55 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.1,32,33 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older.1,32,33

In controlled trials of adults with fibromyalgia, the incidence of suicidal ideation among patients with a history of depression at treatment initiation was 0% in patients receiving milnacipran 100 mg daily, 1.3% in patients receiving milnacipran 200 mg daily, and 0.5% in patients receiving placebo.1 No suicides occurred in the short-term or longer-term (up to 1 year) fibromyalgia trials.1

All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1,32,33,34 Families and caregivers of such patients also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.1,33,34

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania 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.1,33,34 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy 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, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.1,33 The manufacturer also recommends that milnacipran be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1

Other Warnings and Precautions

Serotonin Syndrome

Potentially life-threatening serotonin syndrome has been reported with SSRIs and SNRIs, including milnacipran, when used alone, but particularly with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”], tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, St. John's wort [ Hypericum perforatum ]) and with drugs that impair the metabolism of serotonin (particularly MAO inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue).1,36 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, 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 GI symptoms (e.g., nausea, vomiting, diarrhea).1,36 Patients receiving milnacipran should be monitored for the development of serotonin syndrome.1

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated.1 Use of an MAO inhibitor intended to treat psychiatric disorders within 5 days of milnacipran discontinuance also is contraindicated.1 (See Contraindications and also see Drug Interactions: Monoamine Oxidase Inhibitors.) Milnacipran also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue.1 (See Drug Interactions: Linezolid and also see Drug Interactions: Methylene Blue.)

If concurrent therapy with milnacipran and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased.1 (See Drug Interactions.)

If manifestations of serotonin syndrome occur, treatment with milnacipran and any concurrently administered serotonergic agents should be immediately discontinued and supportive and symptomatic treatment initiated.1

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Elevated Blood Pressure

SNRIs, including milnacipran, have been associated with increases in blood pressure.1,62 In a double-blind, placebo-controlled ambulatory blood pressure monitoring study conducted in 321 patients with fibromyalgia, a greater percentage of milnacipran-treated patients who were normotensive at baseline had a hypertensive blood pressure measurement at weeks 4 (50 mg twice daily steady-state visit) and 7 (100 mg twice daily steady-state visit) compared with those who received placebo (17.7% versus 3.7% and 14.3% versus 0% at weeks 4 and 7, respectively).1,62 Mean 24-hour systolic and diastolic blood pressure increased by 5-6 mm Hg and 4-6 mm Hg, respectively, following 4-6 weeks of milnacipran therapy.1,62 Increases in blood pressure were similar between milnacipran-treated patients who were hypertensive at baseline and those who were normotensive at baseline.1,62

Similar patterns of treatment-emergent blood pressure elevations were observed in phase 3 and clinical pharmacology studies with milnacipran.1 In controlled studies in fibromyalgia, approximately twice as many milnacipran-treated patients (about 17-20%) who were not hypertensive at baseline became hypertensive by the end of the study compared with patients receiving placebo (approximately 7%).1 In addition, a greater percentage of milnacipran-treated patients who were hypertensive at baseline experienced increases in systolic and diastolic blood pressure of more than 15 and 10 mm Hg, respectively, compared with placebo recipients.1

Sustained increases in blood pressure also have been reported.1 In controlled fibromyalgia studies, sustained increases in systolic and diastolic blood pressure occurred in 6-9 and 10-13% of milnacipran-treated patients, respectively, compared with 2 and 4% of placebo recipients, respectively.1 Sustained blood pressure increases may have adverse consequences in patients receiving the drug.1 Some cases of elevated blood pressure requiring immediate treatment have been reported with milnacipran.1

Concurrent use of milnacipran with other drugs that increase blood pressure and heart rate has not been evaluated, and the manufacturer recommends that such combinations be used with caution.1 (See Drug Interactions: Epinephrine and Norepinephrine and also see Drug Interactions: Drugs that Increase Blood Pressure and Heart Rate.)

Effects of milnacipran on blood pressure in patients with clinically important hypertension or cardiovascular disease have not been systematically evaluated; the drug should be used with caution in such patients.1

The manufacturer states that preexisting hypertension and other cardiovascular disease should be treated before initiating milnacipran therapy.1 In addition, blood pressure should be measured prior to initiating milnacipran and then periodically throughout treatment.1 For patients who experience a sustained increase in blood pressure during milnacipran therapy, the dosage should be reduced or the drug discontinued, if clinically warranted.1

Elevated Heart Rate

SNRIs, including milnacipran, have been associated with increases in heart rate.1,62 In a double-blind, placebo-controlled ambulatory blood pressure monitoring study, patients with fibromyalgia who were normotensive at baseline had a mean increase in 24-hour heart rate of 13 beats per minute at week 4 (50 mg twice daily steady-state visit) and also at week 7 (100 mg twice daily steady-state visit).1,62

In clinical trials, relative to placebo, milnacipran was associated with similar mean increases in heart rate of approximately 7-8 beats per minute.1 Increases in heart rate of at least 20 beats per minute were reported in 8% of milnacipran-treated patients compared with 0.3% of placebo recipients.1

Concurrent use of milnacipran with other drugs that increase blood pressure and heart rate has not been evaluated, and the manufacturer recommends that such combinations be used with caution.1 (See Drug Interactions: Epinephrine and Norepinephrine and also see Drug Interactions: Drugs that Increase Blood Pressure and Heart Rate.)

Milnacipran has not been systematically evaluated in patients with cardiac rhythm disorders.1

The manufacturer states that preexisting tachyarrhythmias and other cardiovascular disease should be treated before initiating milnacipran therapy.1 In addition, heart rate should be measured prior to initiating milnacipran and periodically throughout treatment.1 For patients who experience a sustained increase in heart rate during milnacipran therapy, the dosage should be reduced or the drug discontinued, if clinically warranted.1

Seizures

Milnacipran has not been systematically evaluated in patients with seizure disorders.1 Seizures were not reported during clinical trials of milnacipran for fibromyalgia; however, seizures have been reported infrequently in patients receiving the drug for other conditions.1 The manufacturer states that milnacipran should be used with caution in patients with a history of a seizure disorder.1

Hepatic Effects

In fibromyalgia clinical trials, mild elevations in serum ALT (SGPT) or AST (SGOT) concentrations were reported more frequently in milnacipran-treated patients (6-7% and 3-5%, respectively) than in those receiving placebo (3 and 2%, respectively).1 An elevation in ALT of more than 5 times the upper limit of normal but not exceeding 10 times the upper limit of normal was reported in one patient who received the drug (0.2%).1 Increases in serum bilirubin concentrations reported in these trials were not found to be clinically significant.1

Cases of elevated serum transaminase concentrations and severe hepatic injury, including fulminant hepatitis, have been reported during foreign postmarketing surveillance.1 In the cases of severe hepatic injury, there were significant underlying clinical conditions and/or concomitant use of multiple medications.1

Milnacipran should be discontinued in any patient who develops jaundice or other evidence of hepatic dysfunction; therapy should not be resumed unless another cause for the hepatic dysfunction can be established.1

Milnacipran should not ordinarily be prescribed to patients with a history of substantial alcohol consumption or evidence of chronic hepatic disease.1 (See Concomitant Use with Alcohol under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Withdrawal of Therapy

Withdrawal symptoms have been observed in clinical trials following discontinuance of milnacipran, other SNRIs, and SSRIs; there also have been spontaneous reports of adverse effects indicative of withdrawal and physical dependence during marketing of these drugs, particularly when discontinuance was abrupt.1 These withdrawal effects include 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.1 While these events generally are self-limiting, there have been severe cases.1

Patients should be monitored for possible withdrawal symptoms when discontinuing milnacipran therapy.1 A gradual reduction in dosage rather than abrupt cessation is recommended after extended use.1,6 If intolerable symptoms occur following dosage reduction or discontinuance of milnacipran, reinstituting the previously prescribed dosage until symptoms abate may be considered; subsequently, resuming dosage reductions at a more gradual rate may be considered.1 (See Dosage and Administration: Dosage.)

Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion

Treatment with SSRIs and SNRIs, including milnacipran, may result in hyponatremia.1,48,49,51,54 In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).1,48,54 Cases with serum sodium concentrations lower than 110 mmol/L have been reported.1 Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia.1,49,50,54 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death.1 Drug discontinuance should be considered in patients with symptomatic hyponatremia.1,51,54

Abnormal Bleeding

SSRIs and SNRIs, including milnacipran, may increase the risk of bleeding events.1 Concurrent use of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, and other anticoagulants may add to this risk.1 Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding.1 Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1 The manufacturer recommends that patients be advised of the risk of bleeding associated with the concomitant use of milnacipran and aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.1 (See Drug Interactions: Drugs Affecting Hemostasis.)

Activation of Mania/Hypomania

Activation of mania or hypomania was not reported in clinical trials evaluating milnacipran for fibromyalgia; however, patients with a current major depressive episode were excluded from participating in those trials.1 Activation of mania and hypomania have been reported in patients with mood disorders treated with other similar drugs for major depressive disorder.1 Milnacipran should be used with caution in patients with a history of mania.1

Patients with History of Dysuria

Because of their noradrenergic effect, SNRIs, including milnacipran, may affect urethral resistance and micturition.1 In controlled fibromyalgia trials, dysuria occurred in 1% of milnacipran-treated patients compared with 0.5% of those receiving placebo.1 The manufacturer recommends exercising caution if milnacipran is used in patients with a history of dysuria, particularly in males with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders.1 Male patients are more likely to experience adverse genitourinary effects, such as dysuria and urinary retention; they may also experience testicular pain or ejaculation disorders.1

Angle-closure Glaucoma

The pupillary dilation (mydriasis) that occurs following the use of SNRIs, including milnacipran, may trigger an acute attack of angle-closure glaucoma (narrow-angle glaucoma) in patients with anatomically narrow angles who do not have a patent iridectomy.1 (See Advice to Patients.)

Concomitant Use with Alcohol

In clinical trials, more milnacipran-treated patients developed elevated serum transaminases than did those receiving placebo.1 Because it is possible that milnacipran may aggravate preexisting hepatic disease, the drug should not be prescribed to patients with substantial alcohol consumption or evidence of chronic hepatic disease.1 (See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

The Savella Pregnancy Registry may be contacted at 877-643-3010 (for clinicians and patients); registry information also is available on the website [Web] or by e-mail at pregnancyregistries2@INCResearch.com.1,66

Some neonates exposed to SNRIs or SSRIs late in the third trimester of pregnancy have developed complications, which have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries.1,11,12,13,14,15,16 Such complications may arise immediately upon delivery and usually last several days or up to 2-4 weeks.1,11,12,13,15,16 Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying.1,11,12,13,14,15,16 These clinical features appear to be consistent with either a direct toxic effect of the SNRI or SSRI or, possibly, a drug withdrawal syndrome.1,11,12,13,14,15,16 In some cases, the clinical picture was consistent with serotonin syndrome (see Serotonin Syndrome under Warnings/Precautions, in Cautions).1,12

Lactation

Milnacipran is distributed into human milk. 1 In a pharmacokinetic study in lactating women given a single, 50-mg dose of the drug, the maximum estimated daily infant dose from breast milk was 5% of the maternal dose based on peak plasma concentrations.1 In most patients, peak concentrations of milnacipran in breast milk occurred within 4 hours after the maternal dose.1 Because data regarding infant exposure to milnacipran are limited, caution should be exercised when milnacipran is administered to a nursing woman.1

Pediatric Use

The manufacturer states that safety and effectiveness of milnacipran in pediatric patients younger than 18 years of age with fibromyalgia have not been established and that the drug is not recommended for use in such patients.1 Fibromyalgia in children and adolescents has not been as well studied as in adults to date; however, the syndrome appeared to be characterized by diffuse pain and sleep disturbances in one pediatric patient series.46

Milnacipran is an SNRI and is similar to some drugs used for the treatment of depression and other psychiatric disorders.1 FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants).1,33 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.35 No suicides occurred in these pediatric trials.1,33,35

These findings should be carefully considered when assessing potential benefits and risks of milnacipran in a child or adolescent for any clinical use.1,33,34,35 (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

In controlled trials of milnacipran, 402 patients were 60 years of age or older; no overall differences in efficacy or safety were observed between these patients and younger adults.1

Because milnacipran and its metabolites are eliminated principally by renal excretion1,4,6,18 and because of expected decreases in renal function with increasing age, renal function should be considered prior to using the drug in geriatric patients.1 (See Dosage and Administration: Special Populations.)

SSRIs and SNRIs, including milnacipran, have been associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.1,48,49,50,51,54 (See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.1,32,33 (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Hepatic Impairment

Pharmacokinetics of milnacipran are not substantially affected by mild to moderate hepatic impairment.1,44,45 However, patients with severe hepatic impairment had 31% higher area under the plasma concentration-time curve (AUC) and 55% longer elimination half-lives compared with healthy individuals.1,45 Milnacipran should be used with caution in patients with severe hepatic impairment.1 (See Dosage and Administration: Special Populations.)

Renal Impairment

The elimination half-life of milnacipran is increased in patients with renal impairment compared with healthy individuals.1,56 The drug should be used with caution in patients with moderate renal impairment.1 Dosage adjustment is necessary in patients with severe renal impairment (creatinine clearance of 5-29 mL/minute).1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in at least 5% of patients with fibromyalgia receiving milnacipran and at an incidence greater than that reported with placebo in controlled studies include nausea,1,21,28,41 vomiting,1,28,41 constipation,1,21,28,41 headache,1,28,41 insomnia,1,28 dizziness,1,28,41 hot flushes,1,21,28,41 hyperhidrosis,1,28,41 palpitations,1,21,28,41 increased heart rate,1,41 hypertension,1,41 dry mouth,1,28,41 and migraine.1

In vitro and in vivo studies suggest that milnacipran is unlikely to be involved in clinically important pharmacokinetic drug interactions.1,53

Drugs Metabolized by Hepatic Microsomal Enzymes

Milnacipran generally does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro, nor does it induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4/5 in vitro.1,43,53

Drugs Affecting Hepatic Microsomal Enzymes

Milnacipran undergoes minimal CYP-related metabolism.1

Inhibitors or inducers of CYP isoenzymes: clinically important pharmacokinetic interaction is unlikely.1,53

Drugs Affecting Hemostasis

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs were administered concurrently with warfarin.1

Steady-state milnacipran (200 mg daily) did not affect the pharmacokinetics or pharmacodynamics (assessed by measurement of prothrombin international normalized ratio [INR]) of a single 25-mg dose of warfarin.1 Warfarin did not affect the pharmacokinetics of milnacipran.1

The risk of bleeding may be increased if milnacipran is used concurrently with aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs).1 Patients should be advised of the risk of bleeding associated with the concomitant use of milnacipran and aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.1

CNS-active Drugs

Because of the CNS effects of milnacipran, use caution when administered concurrently with other centrally-acting drugs, including those with a similar mechanism of action.1

Monoamine Oxidase Inhibitors

Concomitant use of SSRIs and SNRIs (e.g., milnacipran) and monoamine oxidase (MAO) inhibitors is associated with a risk of serious, sometimes fatal, serotonin syndrome.1 Concomitant use of MAO inhibitors intended to treat psychiatric disorders with milnacipran is contraindicated.1 In addition, at least 2 weeks should elapse between discontinuance of an MAO inhibitor intended to treat psychiatric disorders and initiation of milnacipran and at least 5 days should elapse between discontinuance of milnacipran and initiation of an MAO inhibitor intended to treat psychiatric disorders.1 (See Contraindications and also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Serotonergic Drugs

Concomitant use of milnacipran and other serotonergic drugs, including selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort ( Hypericum perforatum ), is associated with a risk of serious, sometimes fatal, serotonin syndrome.1,36 If concomitant use of milnacipran and other serotonergic drugs is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients).1 If serotonin syndrome manifestations occur, treatment with milnacipran and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.1 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Clomipramine

Switching from clomipramine (75 mg once daily) to milnacipran (100 mg daily) without a washout period did not result in clinically important changes in the pharmacokinetics of milnacipran.1 However, because an increase in adverse effects (e.g., euphoria, postural hypotension) was observed after switching from clomipramine to milnacipran therapy, the manufacturer of milnacipran recommends monitoring patients during the treatment switch.1

Fluoxetine

Switching patients from fluoxetine (20 mg once daily) to milnacipran (100 mg daily) without a washout period did not substantially affect the pharmacokinetics of milnacipran.1,40

Lithium

Multiple-dose administration of milnacipran (100 mg daily) did not affect the pharmacokinetics of lithium.1

Drugs that Increase Blood Pressure and Heart Rate

Concurrent use of milnacipran with other drugs that increase blood pressure and heart rate has not been evaluated; such combinations should be used with caution.1

Alcohol

Because milnacipran may possibly aggravate preexisting hepatic disease, the drug should not be prescribed to patients with substantial alcohol consumption or evidence of chronic hepatic disease.1 (See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Carbamazepine

Carbamazepine (200 mg twice daily) given concomitantly with milnacipran (100 mg daily) did not result in clinically important changes in the pharmacokinetics of milnacipran.1 The pharmacokinetics of carbamazepine or its epoxide metabolite also were not substantially affected during concomitant milnacipran administration.1

Clonidine

Because milnacipran inhibits norepinephrine reuptake, concurrent administration with clonidine may inhibit clonidine's antihypertensive effect.1

Digoxin

Concomitant milnacipran and digoxin administration may be associated with potentiation of adverse hemodynamic effects.1 Postural hypotension and tachycardia have been reported in patients receiving combined milnacipran and IV digoxin (1 mg).1 The manufacturer of milnacipran therefore recommends avoiding combined milnacipran and IV digoxin therapy.1

There was no pharmacokinetic interaction between milnacipran (200 mg daily) and digoxin (200 mcg daily given as Lanoxicaps^®) following multiple-dose oral administration to healthy individuals.1

Diuretics

Concomitant use of milnacipran and diuretics may increase the risk of hyponatremia.1 (See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Epinephrine and Norepinephrine

Because milnacipran inhibits norepinephrine reuptake, concurrent administration with epinephrine or norepinephrine may be associated with paroxysmal hypertension and possible cardiac arrhythmias.1

Linezolid

Linezolid, an anti-infective agent that is also a reversible MAO inhibitor, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs and SNRIs.1,57,58 Because of this potential risk, linezolid generally should not be used in patients receiving serotonergic drugs such as milnacipran.57 However, the manufacturer of milnacipran and the US Food and Drug Administration (FDA) state that certain life-threatening or urgent situations may necessitate immediate linezolid treatment in a patient receiving a serotonergic drug such as milnacipran.1,57 In such emergency situations, the availability of alternative anti-infectives should be considered and the benefits of linezolid should be weighed against the risk of serotonin syndrome.1,57 If linezolid is indicated in such emergency situations, milnacipran must be immediately discontinued and the patient monitored for symptoms of CNS toxicity for 5 days or until 24 hours after the last linezolid dose, whichever comes first.1 Treatment with milnacipran may be resumed 24 hours after the last linezolid dose.1

Treatment with milnacipran should not be initiated in a patient receiving linezolid.1,57 In patients who require more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.1 Milnacipran may be started 24 hours after the last linezolid dose.1,57 (See Contraindications and also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Lorazepam

There was no pharmacokinetic interaction between a single dose of milnacipran 50 mg and lorazepam 1.5 mg.1

Methylene Blue

Methylene blue, a potent and reversible inhibitor of MAO-A, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs and SNRIs.1,59,60 Most of these cases occurred when methylene blue (1-8 mg/kg IV) was used as a diagnostic (visualizing) dye† during parathyroid surgery; it is unclear whether there is a risk of serotonin syndrome when methylene blue is administered by other routes or in lower IV doses in patients receiving serotonergic drugs.1,59,60 Because of this potential risk, methylene blue generally should not be used in patients receiving serotonergic drugs such as milnacipran.59 However, the manufacturer of milnacipran and the FDA state that certain life-threatening or urgent situations may necessitate immediate IV methylene blue use in a patient receiving a serotonergic drug such as milnacipran.1,59 In such emergency situations, the availability of alternative interventions should be considered and the benefits of methylene blue should be weighed against the risk of serotonin syndrome.1,59 If methylene blue is indicated in such emergency situations, milnacipran must be immediately discontinued and the patient monitored for symptoms of CNS toxicity for 5 days or until 24 hours after the last methylene blue dose, whichever comes first.1 Treatment with milnacipran may be resumed 24 hours after the last methylene blue dose.1,59

Treatment with milnacipran should not be initiated in a patient receiving IV methylene blue.1,59 In patients who require more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.1 Milnacipran may be started 24 hours after the last IV methylene blue dose.1,59 (See Contraindications and also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

The manufacturer of milnacipran states that the risk of administering methylene blue by non-IV routes (e.g., oral tablets, local injection) or in IV doses much lower than 1 mg/kg in patients receiving milnacipran is unclear.1 Clinicians should be aware of the possibility of the emergent symptoms of serotonin syndrome with concomitant use.1

Pregabalin

Concomitant administration of milnacipran (50 mg twice daily) and pregabalin (150 mg twice daily) did not have a clinically important effect on the steady-state pharmacokinetics of either drug.1 In an open-label study, the addition of milnacipran to pregabalin therapy in patients with fibromyalgia was generally well tolerated and did not appear to exacerbate adverse effects associated with either drug.67

Description

Milnacipran hydrochloride is a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI).1,2,3,4,5,6 The drug is pharmacologically related to duloxetine, desvenlafaxine, and venlafaxine.1,6,8,9,10 Milnacipran is a racemic mixture of the 1 S ,2 R and 1 R ,2 S enantiomers1 ; the more active 1 S ,2 R enantiomer of milnacipran, levomilnacipran, is used in the treatment of major depressive disorder.61

The exact mechanisms of the central pain inhibitory action of milnacipran hydrochloride and its ability to improve the symptoms of fibromyalgia have not been fully elucidated, but appear to be related to the drug's inhibitory effect on the reuptake of both serotonin and norepinephrine.1,4,6 Like other SNRIs, milnacipran has demonstrated antidepressant activity in clinical studies, presumably also due to potentiation of serotonergic and noradrenergic activity in the CNS.4,6,7,8,9,10 The drug inhibits the reuptake of norepinephrine with approximately threefold greater potency than serotonin in vitro without directly affecting the uptake of dopamine or other neurotransmitters.1,3,4,6 Milnacipran hydrochloride has not demonstrated substantial affinity for serotonergic (5-HT_1-7), α- and β-adrenergic, muscarinic (M_1-5), histaminergic (H_1-4), dopaminergic (D_1-5), opiate, benzodiazepine, and γ-aminobutyric acid (GABA) receptors in vitro.1,4,6,18 The drug does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.1

Milnacipran hydrochloride is principally metabolized via glucuronide conjugation and, to a lesser extent, N -dealkylation.1,4,6 The drug generally does not inhibit the cytochrome P-450 (CYP) 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 isoenzymes and does not induce the CYP1A2, 2B6, 2C8, 2C9, 2C19, or 3A4/5 isoenzymes.1,6,53 The drug exhibits a low degree of protein binding (13%) and has a mean elimination half-life of approximately 6-8 hours.1,4,6 Milnacipran and its metabolites are eliminated principally (90%) by renal excretion.1,4,6,18 Following administration of a single radiolabeled dose of milnacipran hydrochloride, approximately 55% of the dose is eliminated unchanged in urine, approximately 17% is eliminated as the l -milnacipran carbamoyl-O-glucuronide, approximately 2% as the d -milnacipran carbamoyl-O-glucuronide, and approximately 8% as the N -desmethyl milnacipran metabolite.1

Advice to Patients

Importance of providing copy of written patient information (medication guide) each time milnacipran hydrochloride is dispensed.1,32,33,34 Importance of advising patients to read the patient information before taking milnacipran and each time the prescription is refilled.1

Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.1,32,33,34 (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Importance of informing patients of potential risk of serotonin syndrome, particularly with concurrent use of milnacipran and other serotonergic agents, including 5-HT₁ receptor agonists (triptans), tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort ( Hypericum perforatum ), and with drugs that impair serotonin metabolism, particularly monoamine oxidase (MAO) inhibitors, both those used to treat psychiatric disorders and others (e.g., linezolid).1,36,57,58 Importance of immediately contacting clinician if manifestations of serotonin syndrome develop (e.g., restlessness, hallucinations, delirium, loss of coordination, tachycardia, increased body temperature, sweating, muscle stiffness, labile blood pressure, diarrhea, coma, nausea, vomiting, confusion).1,36

Importance of instructing patients not to take milnacipran with an MAO inhibitor or within 14 days of stopping an MAO inhibitor, and to allow 5 days after stopping milnacipran before starting therapy with an MAO inhibitor.1

Possible increased risk of hepatotoxicity in patients with a history of substantial alcohol use.1 Importance of advising patients to discuss their alcohol intake with their clinician prior to initiating milnacipran therapy.1 (See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions and also see Drug Interactions: Alcohol.)

Risk of increased blood pressure and heart rate; importance of advising patients that their blood pressure and heart rate should be measured prior to initiating milnacipran and periodically during therapy.1

Risk that milnacipran may diminish mental and physical capacities necessary to drive motor vehicles or operate machinery; importance of cautioning patients about not operating machinery or driving motor vehicles until patients are reasonably certain that milnacipran therapy does not adversely affect their ability to engage in such activities.1

Importance of advising patients not to stop taking milnacipran without first talking with their clinician.1 Importance of patients being aware that discontinuance effects may occur when stopping milnacipran, especially with abrupt discontinuance of the drug.1

If a dose of milnacipran is missed, importance of advising patients that the missed dose should be skipped and the next dose should be taken at the regularly scheduled time.1

Importance of informing patients that if they receive diuretics, are otherwise volume depleted, or are elderly, that they may be at greater risk of developing hyponatremia during milnacipran therapy.1

Importance of advising patients that milnacipran can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals.1 Possible symptoms include eye pain, vision changes, and swelling or redness in or around the eye.1 Preexisting glaucoma is almost always open-angle glaucoma since angle-closure glaucoma can be treated definitively with iridectomy when diagnosed; open-angle glaucoma is not a risk factor for angle-closure glaucoma.1 Patients may wish to be examined to determine whether they are susceptible to angle-closure glaucoma and have a prophylactic procedure (e.g., iridectomy) if they are susceptible.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the Savella Pregnancy Registry (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease, liver disease, glaucoma) or personal or family history of suicidality or bipolar disorder.1 Importance of advising patients about the risk of bleeding associated with concomitant use of milnacipran with aspirin or other nonsteroidal anti-inflammatory agents, warfarin, or other drugs that affect coagulation.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Forest Laboratories, Inc. Savella^® (milnacipran hydrochloride) tablets prescribing information. New York, NY; 2015 Jan.

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