Generic Name: 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

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 <17 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.)

REMS:

FDA approved a REMS for milnacipran hydrochloride to ensure that the benefits outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

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

Uses for Savella

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: View Frightful (But Dead Serious) Drug Side Effects

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

Savella Dosage and Administration

General

  • Allow at least 14 days to elapse between discontinuance of an MAO inhibitor and initiation of milnacipran, and at least 5 days to elapse between discontinuance of milnacipran and initiation of an MAO inhibitor.1 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautions.)

  • 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 To avoid withdrawal effects, taper dosage gradually and monitor the patient.1 6 If intolerable symptoms occur following dosage reduction or upon drug discontinuance, consider reinstituting previously prescribed dosage until symptoms abate, then may 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 to 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, usual 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 Savella

Contraindications

  • Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.1 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautions.)

  • Uncontrolled narrow-angle glaucoma.1 (See Controlled Narrow-angle Glaucoma under Cautions.)

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 or Neuroleptic Malignant Syndrome (NMS)-like Reactions

Potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions reported with SNRIs and SSRIs alone, including milnacipran, but particularly during concurrent therapy with other serotonergic drugs (e.g., 5-HT1 receptor agonists [“triptans”]), drugs that impair serotonin metabolism (e.g., MAO inhibitors), or antipsychotics or other dopamine antagonists.1 (See Contraindications under Cautions and see Interactions.)

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1

Severe serotonin syndrome may resemble NMS, which is characterized by hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.1

Monitor patients receiving milnacipran for the development of serotonin syndrome or NMS-like signs and symptoms.1 If such symptoms occur, immediately discontinue milnacipran and any concurrently administered serotonergic or antidopaminergic agents, including antipsychotic agents, and initiate supportive and symptomatic treatment.1

Effects on Blood Pressure

Possible increased BP with SNRIs, including milnacipran.1 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 Specific Drugs under 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, consider milnacipran dosage reduction or discontinuance.1

Effects on Heart Rate

Increased heart rate reported with SNRIs, including milnacipran.1 Use in patients with cardiac rhythm disorders not evaluated.1

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

Monitor heart rate prior to and periodically during therapy.1 Treat preexisting tachyarrhythmias and other cardiovascular disease before initiating therapy.1 If sustained increase in heart rate occurs during therapy, consider milnacipran dosage reduction or discontinuance.1

Seizures

Seizures not reported during clinical trials of milnacipran for fibromyalgia; seizures reported infrequently in patients receiving the drug for other conditions.1 Milnacipran not systematically evaluated in patients with seizure disorders;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, then resume more gradual dosage reductions.1 (See General under Dosage and Administration.)

Hyponatremia or SIADH

Possible hyponatremia or SIADH.1 48 49 51 54 Increased risk in patients who are volume-depleted, elderly, or taking diuretics.1 49 50 54 Initiate appropriate medical intervention and 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.)

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

Controlled Narrow-angle Glaucoma

Mydriasis reported; use with caution in patients with controlled narrow-angle glaucoma.1 Do not use in patients with uncontrolled narrow-angle glaucoma.1 (See Contraindications.)

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 registries@kendle.com.1

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

Lactation

Milnacipran or its metabolites distributed into milk in animals; not known whether distributed into human milk.1 Use not recommended.1

Pediatric Use

Safety and efficacy not established in pediatric patients <17 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 or 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 Savella

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 Affecting Hemostasis

Potential pharmacologic interaction (increased risk of bleeding) with concomitant use of drugs that affect coagulation; use with caution.1 (See Abnormal Bleeding under Cautions.)

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions) with serotonergic agents; avoid concomitant use or use with caution.1 28 (See Contraindications and see Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautions.)

Possible pharmacodynamic interaction (e.g., hypertension, coronary artery vasoconstriction) when milnacipran is used concomitantly with other serotonergic agents.1

Protein-bound Drugs

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

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 Effects on Blood Pressure and Effects on Heart Rate under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Alcohol

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

Avoid alcohol use during milnacipran therapy1

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

Potentially life-threatening serotonin syndrome or NMS-like reactions1 28

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

Concomitant use not recommended1

Antipsychotic agents

Potentially life-threatening serotonin syndrome or NMS-like reactions1

Use concomitantly with caution1

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue milnacipran and any concurrently administered antidopaminergic or serotonergic agents; initiate supportive and symptomatic treatment1

Carbamazepine

Clinically important pharmacokinetic interactions unlikely1

Clomipramine

No clinically important changes in pharmacokinetics of milnacipran1

Possible increase in adverse effects (e.g., euphoria, postural hypotension) when switching from clomipramine to milnacipran1

Monitor patients when switching from clomipramine to milnacipran1

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

Dopamine antagonists

Potentially life-threatening serotonin syndrome or NMS-like reactions1

Use concomitantly with caution1

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue milnacipran and any concurrently administered antidopaminergic or serotonergic agents; initiate supportive and symptomatic treatment1

Epinephrine

Possible paroxysmal hypertension and cardiac arrhythmias1

Use concomitantly with caution1

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

Potentially life-threatening serotonin syndrome or NMS-like reactions 1 36

Use concomitantly with caution1

Observe carefully if used concomitantly, particularly during treatment initiation, dosage increases, or when another serotonergic agent is initiated1 36

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue milnacipran and any concurrently administered antidopaminergic or serotonergic agents; initiate supportive and symptomatic treatment1

Linezolid

Potentially life-threatening serotonin syndrome or NMS-like reactions1

Use concomitantly with caution1

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue milnacipran and any concurrently administered antidopaminergic or serotonergic agents; initiate supportive and symptomatic treatment1

Lithium

No effect on pharmacokinetics of lithium1

Potentially life-threatening serotonin syndrome or NMS-like reactions1

Use concomitantly with caution1

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue milnacipran and any concurrently administered antidopaminergic or serotonergic agents; initiate supportive and symptomatic treatment1

Lorazepam

Pharmacokinetic interaction unlikely1

MAO inhibitors

Potentially life-threatening serotonin syndrome or NMS-like reactions1

Concomitant use is contraindicated1

Allow at least 14 days between discontinuance of an MAO inhibitor and initiation of milnacipran and at least 5 days between discontinuance of milnacipran and initiation of MAO inhibitor therapy1

Norepinephrine

Possible paroxysmal hypertension and cardiac arrhythmias1

Use concomitantly with caution1

NSAIAs (e.g., aspirin)

Increased risk of bleeding1

Use concomitantly with caution1

Sibutramine (no longer commercially available in US)

Potentially life-threatening serotonin syndrome or NMS-like reactions1 36

Use concomitantly with caution1 36

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue milnacipran and any concurrently administered serotonergic or antidopaminergic agents; initiate supportive and symptomatic treatment36

St. John's Wort (Hypericum perforatum)

Potentially life-threatening serotonin syndrome or NMS-like reactions1

Use concomitantly with caution1

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue milnacipran and any concurrently administered serotonergic or antidopaminergic agents; initiate supportive and symptomatic treatment1

Tramadol

Potentially life-threatening serotonin syndrome or NMS-like reactions1

Use concomitantly with caution1

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue milnacipran and any concurrently administered antidopaminergic or serotonergic agents; initiate supportive and symptomatic treatment1

Tryptophan and other serotonin precursors

Potentially life-threatening serotonin syndrome or NMS-like reactions1

Concomitant use not recommended1

Warfarin and other anticoagulants

Pharmacokinetic interaction with warfarin unlikely1

Pharmacodynamics (i.e., INR) of warfarin not affected by milnacipran1

Increased risk of bleeding1

Use concomitantly with caution1

Savella 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

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

  • 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 and neuroleptic malignant syndrome (NMS)-like reactions, particularly with concurrent use of milnacipran and 5-HT1 receptor agonists (also called triptans), tramadol, tryptophan, other serotonergic agents, or antipsychotic agents.1 36 Importance of immediately contacting clinician if signs and symptoms of these syndromes develop (e.g., restlessness, hallucinations, loss of coordination, fast heart beat, increased body temperature, muscle stiffness, increased BP, diarrhea, coma, nausea, vomiting, confusion).1 36

  • 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 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

  • 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

  • Importance of avoiding alcohol during milnacipran therapy.1

  • 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

  • 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

  • Importance of advising patients with elevated IOP or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) that mydriasis (prolonged abnormal dilatation of the pupil of the eye) has been reported with milnacipran and that they should be monitored during therapy.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.

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 02/2014. 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, 2004-2014, Selected Revisions March 29, 2012. 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

1. Forest Laboratories, Inc. Savella (milnacipran hydrochloride) tablets prescribing information. New York, NY; 2010 May.

2. Mease PJ, Clauw DJ, Gendreau RM et al. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009; 36:398-409. [PubMed 19132781]

3. Clauw DJ, Mease P, Palmer RH et al. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther. 2008; 30:1988-2004. [PubMed 19108787]

4. Owen RT. Milnacipran hydrochloride: its efficacy, safety and tolerability profile in fibromyalgia syndrome. Drugs Today (Barc). 2008; 44:653-60. [PubMed 19137120]

5. Arnold LM, Goldenberg D, Clauw DJ et al. One-year durability of response to milnacipran treatment for fibromyalgia. Ann Rheum Dis. 2008; 67(Suppl II):249. Abstr. No. THU0359.

6. Leo RJ, Brooks VL. Clinical potential of milnacipran, a serotonin and norepinephrine reuptake inhibitor, in pain. Curr Opin Investig Drugs. 2006; 7:637-42. [PubMed 16869117]

7. Gendreau RM, Thorn MD, Gendreau JF et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol. 2005; 32:1975-85. [PubMed 16206355]

8. Wyeth Laboratories Inc. Pristiq (desvenlafaxine succinate) extended-release tablets prescribing information. Philadelphia, PA; 2009 Feb.

9. Eli Lilly and Company. Cymbalta (duloxetine hydrochloride) delayed-release capsules prescribing information. Indianaopolis, IN; 2009 Feb 16.

10. Wyeth Pharmaceuticals Inc. Effexor (venlafaxine hydrochloride) tablets prescribing information. Philadelphia, PA: 2009 Feb.

11. Morag I, Batash D, Keidar R et al. Paroxetine use throughout pregnancy: does it pose any risk to the neonate?. J Toxicol Clin Toxicol. 2004; 42:97-100. [PubMed 15083945]

12. Haddad PM, Pal BR, Clarke P et al. Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome?. J Psychopharmacol. 2005; 19:554-7. [PubMed 16166193]

13. Moses-Kolko EL, Bogen D, Perel J et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005; 293:2372-85. [PubMed 15900008]

14. Sanz EJ, De-Las-Cuevas C, Kiuru A et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet. 2005; 365:482-7. [IDIS 527994] [PubMed 15705457]

15. Nordeng H, Lindemann R, Perminov KV et al. Neonatal withdrawal syndrome after in utero exposure to selective serotonin-reuptake inhibitors. Acta Paediatr. 2001; 90:288-91. [PubMed 11332169]

16. Dahl ML, Olhager E, Ahlner J. Paroxetine withdrawal syndrome in a neonate. Br J Psychiatry. 1997; 171:391-2. [IDIS 395472] [PubMed 9373435]

17. Nakagawa A, Watanabe N, Omori IM et al. Efficacy and tolerability of milnacipran in the treatment of major depression in comparison with other antidepressants: a systematic review and meta-analysis. CNS Drugs. 2008; 22:587-602. [PubMed 18547127]

18. Mediline LTD. Ixel (milnacipran hydrochloride) hard capsule summary of product characteristics. Israel; undated.

19. Wolfe F, Smythe HA, Yunus MB et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990; 33:160-72. [PubMed 2306288]

20. Lawson K. Treatment options and patient perspectives in the management of fibromyalgia: future trends. Neuropsychiatr Dis Treat. 2008; 4:1059-71. [PubMed 19337451]

21. Harris RE, Clauw DJ. Newer treatments for fibromyalgia syndrome. Ther Clin Risk Manag. 2008; 4:1331-42. [PubMed 19337439]

22. Moret C, Briley M. Antidepressants in the treatment of fibromyalgia. Neuropsychiatr Dis Treat. 2006; 2:537-48. [PubMed 19412502]

23. Vargas-Alarcón G, Fragoso JM, Cruz-Robles D et al. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res Ther. 2007; 9:R110. [PubMed 17961261]

24. Buskila D, Sarzi-Puttini P, Ablin JN. The genetics of fibromyalgia syndrome. Pharmacogenomics. 2007; 8:67-74. [PubMed 17187510]

25. Ablin JN, Cohen H, Buskila D. Mechanisms of disease: genetics of fibromyalgia. Nat Clin Pract Rheumatol. 2006; 2:671-8. [PubMed 17133252]

26. Rooks DS. Fibromyalgia treatment update. Curr Opin Rheumatol. 2007; 19:111-7. [PubMed 17278924]

27. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA. 2004; 292:2388-95. [PubMed 15547167]

28. Anon. Milnacipran (Savella) for fibromyalgia. Med Lett Drugs Ther. 2009; 51:45-6.

29. Offenbaecher M, Bondy B, de Jonge S et al. Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum. 1999; 42:2482-8. [PubMed 10555044]

30. Gürsoy S, Erdal E, Herken H et al. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int. 2003; 23:104-7. [PubMed 12739038]

31. Gürsoy S, Erdal E, Herken H et al. Association of T102C polymorphism of the 5-HT2A receptor gene with psychiatric status in fibromyalgia syndrome. Rheumatol Int. 2001; 21:58-61. [PubMed 11732859]

32. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site: .

33. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2.

34. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site: .

35. Bridge JA, Iyengar S, Salary CB et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007; 297:1683-96. [PubMed 17440145]

36. Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website: ( ). Accessed 2009 Oct 14.

37. Nakagawa A, Watanabe N, Omori IM et al. Milnacipran versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2009; :CD006529.

38. Carville SF, Arendt-Nielsen S, Bliddal H et al. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis. 2008; 67:536-41. [PubMed 17644548]

39. Uçeyler N, Häuser W, Sommer C. A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome. Arthritis Rheum. 2008; 59:1279-98. [PubMed 18759260]

40. Puozzo C, Hermann P, Chassard D. Lack of pharmacokinetic interaction when switching from fluoxetine to milnacipran. Int Clin Psychopharmacol. 2006; 21:153-8. [PubMed 16528137]

41. Hussar DA. New drugs: milnacipran hydrochloride, fesoterodine fumarate, and silodosin. J Am Pharm Assoc (2003). 2009 Mar-Apr; 49:347-50.

42. Perrot S, Dickenson AH, Bennett RM. Fibromyalgia: harmonizing science with clinical practice considerations. Pain Pract. 2008 May-Jun; 8:177-89.

43. Paris BL, Ogilvie BW, Scheinkoenig JA et al. In vitro inhibition and induction of human liver cytochrome P450 (CYP) enzymes by milnacipran. Drug Metab Dispos. 2009 Jul 16; :[epub ahead of print].

44. Puozzo C, Albin H, Vinçon G et al. Pharmacokinetics of milnacipran in liver impairment. Eur J Drug Metab Pharmacokinet. 1998; 23:273-9. [PubMed 9725493]

45. Cada DJ, Levien TL, Baker DE. Milnacipran. Hosp Pharm. 2009; 44:604-18.

46. Siegel DM, Janeway D, Baum J. Fibromyalgia syndrome in children and adolescents: clinical features at presentation and status at follow-up. Pediatrics. 1998; 101:377-82. [PubMed 9481000]

47. Mease PJ, Clauw DJ, Arnold LM et al. Fibromyalgia syndrome. J Rheumatol. 2005; 32:2270-7. [PubMed 16265715]

48. Hull M, Kottlors M, Braune S. Prolonged coma caused by low sodium and hypo-osmolarity during treatment with citalopram. J Clin Psychopharmacol. 2002; 22:337-8. [IDIS 481146] [PubMed 12006908]

49. Odeh M, Beny A, Oliven A. Severe symptomatic hyponatremia during citalopram therapy. Am J Med Sci. 2001; 321:159-60. [IDIS 459269] [PubMed 11217819]

50. Wilkinson TJ, Begg EJ, Winter AC et al. Incidence and risk factors for hyponatremia following treatment with fluoxetine or paroxetine in elderly people. Br J Clin Pharmacol. 1999; 47:211-7. [IDIS 424778] [PubMed 10190657]

51. Krüger S, Lindstaeadt M. Duloxetine and hyponatremia: a report of 5 cases. J Clin Psychopharmacol. 2007; 27:101-4. [PubMed 17224730]

52. Meijer WEE, Heerdink ER, Nolen WA et al. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med. 2004; 164:2367-70. [PubMed 15557417]

53. Puozzo C, Lens S, Reh C et al. Lack of interaction of milnacipran with the cytochrome p450 isoenzymes frequently involved in the metabolism of antidepressants. Clin Pharmacokinet. 2005; 44:977-88. [PubMed 16122284]

54. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006; 40:1618-22. [PubMed 16896026]

55. Avedisova A, Borodin V, Zakharova K et al. Effect of milnacipran on suicidality in patients with mild to moderate depressive disorder. Neuropsych Dis Treat. 2009; 5:415-20.

56. Puozzo C, Pozet N, Deprez D et al. Pharmacokinetics of milnacipran in renal impairment. Eur J Drug Metab Pharmacokinet. 1998; 23:280-6. [PubMed 9725494]

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