Milnacipran Hydrochloride

A selective serotonin- and norepinephrine-reuptake inhibitor (SNRI); a fibromyalgia agent.1 2 3 4 5 6

Contraindications

• Concurrent or recent (i.e., within 2 weeks) therapy with an 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 Cautions and also see Specific Drugs under Interactions.)

• Initiation of milnacipran in patients receiving MAO inhibitors such as linezolid or IV methylene blue.1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.1 32 33 34 35 (See Boxed Warning and also see Pediatric Use under Cautions.) However, 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 In clinical trials, no suicides were reported in adult fibromyalgia patients treated with milnacipran.1

Appropriately monitor and closely observe patients receiving milnacipran for any reason 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

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.1 33 34 Consider changing or discontinuing therapy in patients whose depression is persistently worse and in those with emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of the patient’s presenting symptoms.1 33 If decision is made to discontinue therapy, taper milnacipran dosage as rapidly as is feasible but consider risks of abrupt discontinuance.1 (See Withdrawal of Therapy under Cautions.)

Prescribe in smallest quantity consistent with good patient management, to reduce risk of overdosage.1

Other Warnings and Precautions

Potentially life-threatening serotonin syndrome reported with SNRIs and SSRIs, including milnacipran, when used alone, but particularly during concurrent therapy with other serotonergic drugs (e.g., 5-HT1 receptor agonists [“triptans”], TCAs, 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 (See Contraindications under Cautions and also see Interactions.)

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, 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

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 contraindicated.1 Do not initiate milnacipran in patients treated with other MAO inhibitors such as linezolid or IV methylene blue.1 (See Specific Drugs under Interactions.)

If concurrent therapy with other serotonergic drugs is clinically warranted, advise patient of potentially increased risk for serotonin syndrome, particularly during initiation of therapy and dosage increases.1

Monitor patients receiving milnacipran for the development of serotonin syndrome.1 If manifestations occur, immediately discontinue milnacipran and any concurrently administered serotonergic agents and initiate supportive and symptomatic treatment.1

Possible increased BP with SNRIs, including milnacipran.1 62 In an ambulatory blood pressure monitoring study, a substantially greater percentage of milnacipran-treated patients experienced clinically important BP elevations compared with placebo recipients.1 62 Sustained hypertension (i.e., treatment-emergent increases in SBP of ≥15 mm Hg and DBP of ≥10 mm Hg for 3 consecutive visits) reported; potential adverse consequences.1 Elevated BP requiring immediate treatment also reported.1 Effects of milnacipran on BP in patients with significant hypertension or cardiovascular disease not evaluated; use with caution.1

Concurrent use of milnacipran with other drugs that increase BP and heart rate not evaluated; use with caution.1 (See Interactions.)

Monitor BP prior to and periodically during therapy.1 Treat preexisting hypertension and other cardiovascular disease before initiating milnacipran therapy.1 If sustained increase in BP occurs during therapy, reduce milnacipran dosage or discontinue the drug, if clinically warranted.1

Increased heart rate reported with SNRIs, including milnacipran.1 62 In an ambulatory blood pressure monitoring study, a substantially greater percentage of milnacipran-treated patients experienced clinically important increases in heart rate compared with placebo recipients.1 62 Use in patients with cardiac rhythm disorders not systematically evaluated.1

Concurrent use of milnacipran with other drugs that increase BP and heart rate not evaluated; use with caution.1 (See Interactions.)

Treat preexisting tachyarrhythmias and other cardiovascular disease before initiating milnacipran therapy.1

Monitor heart rate prior to and periodically during therapy.1 If sustained increase in heart rate occurs during therapy, reduce milnacipran dosage or discontinue the drug, if clinically warranted.1

Milnacipran not systematically evaluated in patients with seizure disorders.1 Seizures not reported during clinical trials of milnacipran for fibromyalgia; seizures reported infrequently in patients receiving the drug for other conditions.1 Use with caution in patients with a history of seizure disorder.1

Increased serum transaminase (ALT, AST) concentrations and severe hepatic injury, including fulminant hepatitis, reported.1 Clinically important increases in serum bilirubin concentrations not reported.1

Discontinue milnacipran in any patient who develops jaundice or other evidence of hepatic dysfunction; do not resume therapy unless another cause for the hepatic dysfunction established.1

Use not generally recommended in patients with a history of substantial alcohol consumption or evidence of chronic hepatic disease.1

Withdrawal effects (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances [e.g., paresthesias, such as electric shock sensation], anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, seizures) reported following discontinuance of milnacipran, other SNRIs, and SSRIs, particularly when discontinuance was abrupt.1 Events generally self-limiting, but severe cases reported.1

Taper dosage gradually; monitor patients for withdrawal symptoms when discontinuing therapy.1 6 If intolerable symptoms occur following dosage reduction or discontinuance, consider reinstituting previously prescribed dosage until symptoms abate, then resume more gradual dosage reductions.1

Treatment with SSRIs and SNRIs, including milnacipran, may cause hyponatremia; in many cases, SIADH is apparent cause.1 48 49 51 54 Increased risk in patients who are volume-depleted, elderly, or taking diuretics.1 49 50 54 Consider drug discontinuance in patients with symptomatic hyponatremia.1 51 54

Possible increased risk of bleeding with SSRIs and SNRIs, including milnacipran; events ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1 Concomitant use of aspirin, NSAIAs, warfarin, or other anticoagulants may increase risk.1 (See Drugs Affecting Hemostasis and Specific Drugs under Interactions and also see Advice to Patients.)

Activation of mania or hypomania not reported in fibromyalgia clinical trials, but has been reported with similar drugs in patients with major depressive disorder.1 5 Use with caution in patients with a history of mania.1

May affect urethral resistance and micturition.1 Increased risk of adverse GU effects (e.g., dysuria, urinary retention, testicular pain, ejaculation disorders) in male patients.1 Use with caution in patients with a history of dysuria, particularly in males with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders.1

Pupillary dilation (mydriasis) occurs with SNRIs, including milnacipran, and 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.)

Possible hepatotoxicity when milnacipran and alcohol are used together.1 Avoid concomitant milnacipran use in patients with substantial alcohol consumption or evidence of chronic hepatic disease.1 (See Hepatic Effects under Cautions.)

Specific Populations

Category C.1

Pregnancy registry at 1-877-643-3010; registry information also available at or by email at pregnancyregistries2@INCResearch.com.1 66

Possible complications, sometimes severe and requiring prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care, in neonates exposed to SSRIs or SNRIs late in the third trimester; may arise immediately upon delivery.1 11 12 13 14 15 16

Distributed into milk; use with caution in nursing women.1 (See Distribution under Pharmacokinetics.)

Safety and efficacy not established in pediatric patients <18 years of age; not recommended for use in such patients.1

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 others).1 33 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <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

Carefully consider these findings when assessing potential benefits and risks of milnacipran in a child or adolescent for any clinical use.1 33 34 35 (See Boxed Warning and Worsening of Depression and Suicidality Risk under Cautions.)

No overall differences in safety or efficacy relative to younger adults.1 Consider possible reduced renal clearance of the drug in geriatric patients.1 (See Geriatric Patients under Dosage and Administration and see Pharmacokinetics.)

Clinically important hyponatremia reported in geriatric patients.1 48 49 50 51 54 (See Hyponatremia/SIADH under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.1 32 33 (See Boxed Warning and see Worsening of Depression and Suicidality Risk under Cautions.)

Pharmacokinetics not substantially affected by mild to moderate hepatic impairment.1 44 45 Use with caution in patients with severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration and see Pharmacokinetics.)

Use with caution in patients with moderate renal impairment.1 Dosage adjustment necessary in severe renal impairment (Clcr of 5–29 mL/minute).1 Use not recommended in patients with end-stage renal disease.1 (See Renal Impairment under Dosage and Administration and see Pharmacokinetics.)

Common Adverse Effects

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 migraine.1

Absorption

Bioavailability

Well absorbed following oral administration; absolute bioavailability approximately 85–90%.1

Exposure is dose-proportional over the therapeutic dosage range.1

Peak plasma concentrations reached within 2–4 hours following a single dose and steady-state concentrations achieved within 36–48 hours.1

Food

Food does not affect absorption.1

Special Populations

AUC is increased by 31% in patients with severe hepatic impairment.1 45

Mean AUC increased by 16, 52, and 199% in individuals with mild, moderate, and severe renal impairment, respectively.1

Peak plasma milnacipran concentrations and AUC were approximately 30% higher in patients >65 years of age compared with younger adults.1

Distribution

Extent

Distributes into milk.1 In lactating women given a single, 50-mg dose, the maximum estimated daily infant dose from breast milk was 5% of the maternal dose based on peak plasma concentrations.1 Peak concentrations in breast milk occurred within 4 hours after the maternal dose in most patients.1

Plasma Protein Binding

13%.1

Elimination

Metabolism

Principally metabolized via glucuronide conjugation and, to a lesser extent, N-dealkylation.1 4 6

Elimination Route

Milnacipran and metabolites eliminated principally (90%) by renal excretion.1 4 6 18 Majority (approximately 55%) of a dose excreted as unchanged drug in urine.1

Half-life

Milnacipran: Terminal elimination half-life of about 6–8 hours.1

d-Milnacipran (the active enantiomer): 8–10 hours.1

l-Milnacipran: 4–6 hours.1

Special Populations

Elimination half-life increased by 55% in patients with severe hepatic impairment.1 45

Elimination half-life increased by 38, 41, and 122% in individuals with mild, moderate, and severe renal impairment, respectively.1 56

Storage

Oral

25°C (may be exposed to 15–30°C).1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.