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Milnacipran Hydrochloride

Class: Fibromyalgia Agents
VA Class: CN609
Chemical Name: (±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride
Molecular Formula: C15H22N2O•HCl
CAS Number: 101152-94-7
Brands: Savella

Warning(s)

  • Suicidality
  • Milnacipran, an SNRI, is similar to some drugs used for treatment of depression and other psychiatric disorders.1 Antidepressants increased risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need.1 32 33 Milnacipran is not approved for treating major depressive disorder.1 Milnacipran is also not approved for use in pediatric patients <18 years of age.1 (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.1 32 33

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.1 32 33 34

  • Appropriately monitor and closely observe all patients who are started on milnacipran therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.1 32 33 34 (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

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

Uses for Milnacipran Hydrochloride

Fibromyalgia

Management of fibromyalgia.1 2 3 4 5 7

Major Depressive Disorder

Has been used in the treatment of major depressive disorder and is approved for treating depression in some countries;4 6 17 18 37 55 this indication is not an FDA-labeled use.1

Slideshow: Fighting the Fight: Fibromylagia Explained

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

Milnacipran Hydrochloride Dosage and Administration

General

  • Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor intended to treat psychiatric disorders and initiation of milnacipran and allow at least 5 days to elapse between discontinuance of milnacipran and initiation of MAO inhibitor therapy intended to treat psychiatric disorders.1 (See Contraindications and Serotonin Syndrome under Cautions and also see Specific Drugs under Interactions.)

  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.1 32 33 34 (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Avoid abrupt discontinuance after extended use.1 6 Taper dosage gradually and monitor for withdrawal symptoms.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 (See Withdrawal of Therapy under Cautions.)

Administration

Oral Administration

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

Dosage

Available as milnacipran hydrochloride; dosage expressed in terms of the salt.1

Adults

Fibromyalgia
Oral

Titrate dosage, based on efficacy and tolerability, according to the following schedule:1 initially, 12.5 mg as a single dose on the first day of therapy.1 Increase to 12.5 mg twice daily (25 mg daily) on days 2 and 3, then increase to 25 mg twice daily (50 mg daily) on days 4–7.1 After day 7, recommended maintenance dosage is 50 mg twice daily (100 mg daily).1

Based on individual patient response, may increase dosage to 100 mg twice daily (200 mg daily).1

Prescribing Limits

Adults

Fibromyalgia
Oral

Safety and efficacy of dosages >200 mg daily not evaluated.1

Special Populations

Hepatic Impairment

No dosage adjustment necessary.1 44 Use with caution in patients with severe hepatic impairment.1 Generally should not be prescribed to patients with substantial alcohol use or evidence of chronic hepatic disease.1 (See Hepatic Effects under Cautions and see also Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary in mild renal impairment.1 Use with caution in patients with moderate renal impairment.1 In patients with severe renal impairment (Clcr of 5–29 mL/minute), reduce usual maintenance dosage by 50% to 50 mg daily (given as 25 mg twice daily).1 Based on individual patient response, may increase dosage to 100 mg daily (given as 50 mg twice daily).1 Not recommended in patients with end-stage renal disease.1

Geriatric Patients

No specific dosage recommendations at this time, but consider possibility of age-related decreases in renal function when selecting dosage.1 (See Renal Impairment under Dosage and Administration.)

Cautions for Milnacipran Hydrochloride

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

Worsening of Depression and Suicidality Risk

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

Serotonin Syndrome

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

Elevated Blood Pressure

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

Elevated Heart Rate

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

Seizures

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

Hepatic Effects

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 of Therapy

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

Hyponatremia/SIADH

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

Abnormal Bleeding

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/Hypomania

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

Patients with History of Dysuria

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

Angle-closure Glaucoma

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.)

Concomitant Use with Alcohol

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

Pregnancy

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

Lactation

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

Pediatric Use

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.)

Geriatric Use

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.)

Hepatic Impairment

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.)

Renal Impairment

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

Interactions for Milnacipran Hydrochloride

Minimally metabolized by CYP isoenzymes.1 Does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; does not induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4/5 in vitro.1 43 53 Pharmacokinetic interactions unlikely with drugs metabolized by CYP isoenzymes or with CYP enzyme inducers or inhibitors.1 53

Drugs Associated with Serotonin Syndrome

Potentially serious, sometimes fatal serotonin syndrome with other serotonergic drugs.1 If concomitant use of other serotonergic drugs with milnacipran is clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases.1

If serotonin syndrome occurs, immediately discontinue milnacipran and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment.1 (See Serotonin Syndrome under Cautions.)

Drugs that Increase Blood Pressure and Heart Rate

Concurrent use of milnacipran with other drugs that increase BP and heart rate not evaluated; use with caution.1 (See Elevated Blood Pressure and Elevated Heart Rate under Cautions.)

Drugs Affecting Hemostasis

Potential increased risk of bleeding if used concomitantly with drugs that affect coagulation or bleeding; use with caution.1 (See Abnormal Bleeding under Cautions.)

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1 (See Distribution under Pharmacokinetics.)

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible increased risk of hepatotoxicity (see Hepatic Effects under Cautions)1

Avoid use in patients with substantial alcohol consumption1

Anticoagulants (e.g., warfarin)

Potential increased risk of bleeding1

Warfarin: Steady-state milnacipran did not affect the pharmacokinetics or pharmacodynamics (i.e., INR) of a single dose of warfarin; milnacipran pharmacokinetics also not affected by warfarin1

Use anticoagulants concomitantly with caution1

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) or other SNRIs (e.g., desvenlafaxine, duloxetine, levomilnacipran, venlafaxine)

Potentially life-threatening serotonin syndrome1 28

Fluoxetine: Pharmacokinetic interaction unlikely when switching patients from fluoxetine to milnacipran without a washout period 1 40

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1

If serotonin syndrome occurs, immediately discontinue milnacipran and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Antidepressants, tricyclics (TCAs)

Potentially life-threatening serotonin syndrome1

Clomipramine: No clinically important changes in pharmacokinetics of milnacipran;1 possible increased adverse effects (e.g., euphoria, postural hypotension) when switching from clomipramine to milnacipran1

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1

If serotonin syndrome occurs, immediately discontinue milnacipran, the TCA, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Monitor patients when switching from clomipramine to milnacipran1

Aspirin

Potential increased risk of bleeding1

Use concomitantly with caution1

Buspirone

Potentially life-threatening serotonin syndrome1

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1

If serotonin syndrome occurs, immediately discontinue milnacipran, buspirone, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Carbamazepine

Clinically important pharmacokinetic interactions unlikely1

Clonidine

Possible reduced antihypertensive effect of clonidine1

CNS drugs

Potential pharmacologic interaction1

Use concomitantly with caution1

Digoxin

Possible potentiation of adverse hemodynamic effects; postural hypotension and tachycardia reported with concomitant milnacipran and IV digoxin1

Pharmacokinetic interaction not observed with concurrent use of milnacipran and oral digoxin capsules (Lanoxicaps)1

Avoid concomitant therapy with milnacipran and IV digoxin1

Diuretics

Possible increased risk of hyponatremia1

Epinephrine

Possible paroxysmal hypertension and cardiac arrhythmias1

Use concomitantly with caution1

Fentanyl

Potentially life-threatening serotonin syndrome1

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1

If serotonin syndrome occurs, immediately discontinue milnacipran, fentanyl, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

5-HT1 receptor agonists (triptans) (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan)

Potentially life-threatening serotonin syndrome1 36

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1 36

If serotonin syndrome occurs, immediately discontinue milnacipran, the triptan, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Linezolid

Potentially life-threatening serotonin syndrome1 57 58

Do not use concurrently;1 57 consider availability of alternative anti-infectives and weigh benefit of linezolid against risk of serotonin syndrome1 57

If emergency use of linezolid is considered necessary, immediately discontinue milnacipran; monitor for symptoms of CNS toxicity for 5 days or until 24 hours after the last linezolid dose, whichever comes first1 57

May resume milnacipran 24 hours after last linezolid dose1 57

Do not initiate milnacipran in patients receiving linezolid1 57

If urgent treatment of a psychiatric condition is necessary, consider other interventions, including hospitalization; may initiate milnacipran 24 hours after last linezolid dose1 57

Lithium

No effect on pharmacokinetics of lithium1

Potentially life-threatening serotonin syndrome1

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1

If serotonin syndrome occurs, immediately discontinue milnacipran, lithium, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Lorazepam

Pharmacokinetic interaction unlikely1

MAO inhibitors

Potentially life-threatening serotonin syndrome1

Concomitant use is contraindicated1

Allow at least 14 days between discontinuance of an MAO inhibitor intended to treat psychiatric disorders and initiation of milnacipran and at least 5 days between discontinuance of milnacipran and initiation of MAO inhibitor therapy1

Methylene blue

Potentially life-threatening serotonin syndrome1 59 60

Most cases occurred when methylene blue (1–8 mg/kg IV) was used as a diagnostic (visualizing) dye during parathyroid surgery; 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 drugs1 59 60

Generally should not use methylene blue in patients receiving milnacipran;59 consider availability of alternative interventions and weigh benefits of IV methylene blue against risk of serotonin syndrome1 59

If emergency use of IV methylene blue is considered necessary, immediately discontinue milnacipran and monitor for symptoms of CNS toxicity for 5 days or until 24 hours after last methylene blue dose, whichever comes first1 59

May resume milnacipran 24 hours after last dose of IV methylene blue1 59

Do not initiate milnacipran in patients receiving IV methylene blue1 59

If urgent treatment of a psychiatric condition is necessary, consider other interventions, including hospitalization; may initiate milnacipran 24 hours after last IV methylene blue dose1 59

Norepinephrine

Possible paroxysmal hypertension and cardiac arrhythmias1

Use concomitantly with caution1

NSAIAs

Increased risk of bleeding1

Use concomitantly with caution1

Pregabalin

No clinically important change in the steady-state pharmacokinetics of milnacipran and pregabalin during concurrent administration1

In an open-label study, addition of milnacipran to pregabalin in patients with fibromyalgia was generally well tolerated and did not appear to exacerbate adverse effects associated with either drug67

St. John's wort (Hypericum perforatum)

Potentially life-threatening serotonin syndrome1

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1

If serotonin syndrome occurs, immediately discontinue milnacipran, St. John's wort, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Tramadol

Potentially life-threatening serotonin syndrome1

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1

If serotonin syndrome occurs, immediately discontinue milnacipran, tramadol, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Tryptophan

Potentially life-threatening serotonin syndrome1

If concomitant use clinically warranted, advise patients of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases1

If serotonin syndrome occurs, immediately discontinue milnacipran, tryptophan, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Milnacipran Hydrochloride Pharmacokinetics

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

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Milnacipran is a racemic mixture of the 1S,2R and 1R,2S enantiomers;1 the more active 1S,2R enantiomer of milnacipran, levomilnacipran, is used in the treatment of major depressive disorder.61 Also pharmacologically related to duloxetine, desvenlafaxine, and venlafaxine.1 6 8 9 10

  • Exact mechanisms of central pain inhibitory action and ability to improve symptoms of fibromyalgia not fully elucidated; apparently related to inhibitory effect on reuptake of both serotonin and norepinephrine.1 4 6

  • Antidepressant activity demonstrated in clinical studies, presumably due to potentiation of serotonergic and noradrenergic activity in CNS.4 6 7 8 9 10

  • Inhibits reuptake of norepinephrine with approximately threefold greater potency than serotonin in vitro without directly affecting uptake of dopamine or other neurotransmitters.1 3 4 6

  • Substantial affinity not demonstrated for serotonergic (5-HT1–7), α- and β-adrenergic, muscarinic (M1–5), histaminergic (H1–4), dopaminergic (D1–5), opiate, benzodiazepine, and GABA receptors in vitro.1 4 6 18

  • No appreciable affinity for calcium, potassium, sodium, or chloride ion channels.1

  • Does not inhibit human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.1

Advice to Patients

  • Importance of providing copy of written patient information (medication guide) each time milnacipran 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 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), TCAs, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort (Hypericum perforatum) and with drugs that impair serotonin metabolism, particularly 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 BP, diarrhea, coma, nausea, vomiting, confusion).1 36

  • Importance of instructing patients not to take milnacipran concurrently with 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 Cautions.)

  • Risk of increased BP and heart rate; importance of advising patients that their BP and heart rate should be measured prior to initiating milnacipran and periodically during therapy.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 NSAIAs, warfarin, or other drugs that affect coagulation.1

  • Potential for drug to impair mental alertness or physical coordination; importance of using caution when driving or operating machinery until effects on individual are known.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.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;1 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 informing women about the existence of and encouraging enrollment in the Savella Pregnancy Registry (see Pregnancy under Cautions).1

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

Preparations

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.

Milnacipran Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Titration Pack

5 Tablets, film-coated, Milnacipran Hydrochloride 12.5 mg (Savella)

8 Tablets, film-coated, Milnacipran Hydrochloride 25 mg (Savella)

42 Tablets, film-coated, Milnacipran Hydrochloride 50 mg (Savella)

Savella Titration Pack (available as blister package for first month of therapy)

Forest

Tablets, film-coated

12.5 mg

Savella

Forest

25 mg

Savella

Forest

50 mg

Savella

Forest

100 mg

Savella

Forest

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 06/2015. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Savella 100MG Tablets (FOREST): 100/$239.98 or 300/$701.00

Savella 12.5MG Tablets (FOREST): 60/$145.79 or 180/$406.07

Savella 50MG Tablets (FOREST): 60/$144.24 or 180/$408.71

AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions June 1, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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