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Fetzima

Generic Name: Levomilnacipran Hydrochloride
Class: Selective Serotonin- and Norepinephrine-reuptake Inhibitors
VA Class: CN609
Chemical Name: (1S,2R)-2-(Aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride (1:1)
Molecular Formula: C15H22N2O•HCl
CAS Number: 175131-60-9

Warning(s)

  • Suicidality
  • Antidepressants increased risk of suicidal thinking and behavior (suicidality) compared with placebo 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 12 14 Levomilnacipran is not approved for use in pediatric patients.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 12 14

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.1 12 14 15

  • Appropriately monitor and closely observe all patients who are started on levomilnacipran therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.1 12 14 15 (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Antidepressant; selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) and 1S,2R-enantiomer of racemic milnacipran.1 2 3 4 5 7 8 9 10 21

Uses for Fetzima

Major Depressive Disorder

Treatment of major depressive disorder in adults.1 2 3 4 5 7 8

APA states that effectiveness of antidepressants is generally comparable between and within classes of medications, including SSRIs, SNRIs, TCAs, MAO inhibitors, and other antidepressants (e.g., bupropion, mirtazapine, trazodone).29 Choose antidepressant based mainly on the following factors: patient preference; nature of prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, actions on CYP isoenzymes, other drug interactions); and cost.29 For most patients, an SSRI, SNRI, mirtazapine, or bupropion is considered optimal.29 Consult APA’s Practice Guidelines for the Treatment of Patients with Major Depressive Disorder (at ) for additional information.29

Fibromyalgia

Levomilnacipran is the more active 1S,2R-enantiomer of racemic milnacipran (Savella), which is FDA-labeled for use in the management of fibromyalgia.1 10 11

Manufacturer states that levomilnacipran (Fetzima) is not approved for the management of fibromyalgia; efficacy and safety of the drug for this use not established.1

Fetzima 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 levomilnacipran and allow at least 7 days to elapse between discontinuance of levomilnacipran and initiation of MAO inhibitor therapy.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 12 14 15 (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Avoid abrupt discontinuance whenever possible.1 Taper dosage gradually and monitor for withdrawal symptoms.1 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 extended-release capsules orally once daily, with or without food, at approximately the same time each day.1 Swallow extended-release capsules whole; do not open, chew, cut, or crush.1

Dosage

Available as levomilnacipran hydrochloride; dosage expressed in terms of levomilnacipran.1

Adults

Major Depressive Disorder
Oral

Initially, 20 mg once daily for 2 days, followed by an increase to 40 mg once daily.1 Depending on efficacy and tolerability, may increase daily dosage in 40-mg increments at intervals of ≥2 days.1 May use the levomilnacipran (Fetzima) titration pack for initial 1-month titration period.1 In a short-term, flexible-dose clinical study, 21, 34, and 44% of the patients were receiving 40, 80, or 120 mg of levomilnacipran once daily, respectively, at the end of the treatment period; the mean daily dosage was approximately 73 mg.1 4

If used with a potent CYP3A4 inhibitor, dosage should not exceed 80 mg once daily.1 (See Interactions.)

Optimum duration not established; may require several months or longer of sustained antidepressant therapy.1 29 Manufacturer states that long-term efficacy (i.e., >8 weeks) not established.1 Periodically reassess need for continued maintenance therapy and appropriateness of dosage.1

Prescribing Limits

Adults

Major Depressive Disorder
Oral

120 mg once daily.1

Special Populations

Hepatic Impairment

Mild (Child-Pugh score of 1–6), moderate (Child-Pugh score of 7–9), or severe (Child-Pugh score of 10–13) hepatic impairment: Dosage adjustment not necessary.1

Renal Impairment

Mild renal impairment (Clcr 60–89 mL/minute): Dosage adjustment not necessary.1

Moderate renal impairment (Clcr 30–59 mL/minute): Maintenance dosage should not exceed 80 mg once daily.1

Severe renal impairment (Clcr 15–29 mL/minute): Maintenance dosage should not exceed 40 mg once daily.1

End-stage renal disease: Use not recommended.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Routine dosage adjustment not necessary; however, consider renal clearance of levomilnacipran when determining dosage.1

Gender

Dosage adjustment based on gender not necessary.1

Cautions for Fetzima

Contraindications

  • Known hypersensitivity to levomilnacipran, milnacipran, or any ingredient in the formulation.1

  • 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 7 days of levomilnacipran discontinuance.1 (See Serotonin Syndrome under Cautions and also see Specific Drugs under Interactions.)

  • Initiation of levomilnacipran 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 12 14 15 28 (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 12 14 15

Appropriately monitor and closely observe patients receiving levomilnacipran for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 12 14 15

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.1 14 15 Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or were not part of the patient’s presenting symptoms.1 14 If a decision is made to discontinue therapy, taper levomilnacipran dosage as rapidly as is feasible but consider risks of abrupt discontinuance.1 14 (See Withdrawal of Therapy under Cautions.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.1 14

Other Warnings and Precautions

Serotonin Syndrome

Potentially life-threatening serotonin syndrome reported with SSRIs and SNRIs 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 18 31 (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 18 31

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated.1 Do not initiate levomilnacipran 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 levomilnacipran for the development of serotonin syndrome.1 If manifestations occur, immediately discontinue levomilnacipran and any concurrently administered serotonergic agents and initiate supportive and symptomatic treatment.1

Elevated Blood Pressure

Possible increased BP with SNRIs, including levomilnacipran.1 Orthostatic hypotension also reported.1 Effects of levomilnacipran on BP in patients with clinically important hypertension or cardiovascular disease not evaluated; use with caution.1

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

Control preexisting hypertension before initiating levomilnacipran therapy.1 Monitor BP prior to and periodically during treatment.1 Use caution in treating patients with preexisting hypertension, cardiovascular conditions, or cerebrovascular conditions that might be compromised by BP increases.1

If sustained increase in BP occurs during therapy, consider levomilnacipran discontinuance or other appropriate medical intervention.1

Elevated Heart Rate

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

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

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

Monitor heart rate prior to and periodically during therapy.1 If sustained increase in heart rate occurs during therapy, consider levomilnacipran discontinuance or other appropriate medical intervention.1

Abnormal Bleeding

Possible increased risk of bleeding with SSRIs and SNRIs, including levomilnacipran; events ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1 Concurrent 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.)

Angle-closure Glaucoma

Pupillary dilation (mydriasis) occurs with many antidepressants, including levomilnacipran, 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.)

Urinary Hesitation and Retention

SNRIs, including levomilnacipran, may affect urethral resistance.1 Use with caution in patients prone to obstructive urinary disorders.1

If symptoms of urinary hesitation, urinary retention, or dysuria develop, consider possibility of drug-related effects.1 Also consider drug discontinuance or other appropriate medical intervention.1

Activation of Mania/Hypomania

Possible activation of mania and hypomania; use with caution in patients with personal or family history of bipolar disorder, mania, or hypomania.1

Seizures

Levomilnacipran has not been systematically evaluated in patients with seizure disorders; use with caution in patients with a history of seizure disorder.1

Withdrawal of Therapy

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

Taper dosage gradually; monitor patients for withdrawal symptoms when discontinuing therapy.1 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

Although not reported with levomilnacipran therapy, treatment with SSRIs and SNRIs may cause hyponatremia; in many cases, SIADH is apparent cause.1 Increased risk in patients who are volume-depleted, elderly, or taking diuretics.1 Discontinue levomilnacipran and institute appropriate medical intervention in patients with symptomatic hyponatremia.1

Specific Populations

Pregnancy

Category C.1

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 22 23 24 25 26 27

Consult joint APA and ACOG guidelines (at ) for additional information on management of depression in women prior to conception and during pregnancy, including treatment algorithms.32

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients; not recommended for use in such patients.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 14 However, a later 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.28 No suicides occurred in these pediatric trials.1 14 28

Carefully consider these findings when assessing potential benefits and risks of levomilnacipran in a child or adolescent for any clinical use.1 14 15 28 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

In clinical trials with levomilnacipran, 2.8% of patients were ≥65 years of age.1

Slightly higher exposure possible in geriatric patients.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Because levomilnacipran is eliminated principally by renal excretion, consider renal function when determining dosage in geriatric patients.1 (See Geriatric Patients under Dosage and Administration.)

SSRIs and SNRIs, including levomilnacipran, associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.1 (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 12 14 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Hepatic Impairment

Hepatic elimination of levomilnacipran is low; pharmacokinetics not substantially affected by hepatic impairment.1 Dosage adjustment not necessary in patients with mild (Child-Pugh score of 1–6), moderate (Child-Pugh score of 7–9), or severe (Child-Pugh score of 10–13) hepatic impairment.1

Renal Impairment

Levomilnacipran is primarily eliminated by renal excretion.1

Dosage adjustment not necessary in mild renal impairment.1 However, dosage adjustment is recommended in moderate or severe renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Use not recommended in patients with end-stage renal disease.1

Because of levomilnacipran's large volume of distribution, hemodialysis not expected to reduce plasma concentrations of the drug.1

Common Adverse Effects

Nausea,1 2 3 4 constipation,1 2 3 4 hyperhidrosis,1 2 3 4 increased heart rate,1 2 3 erectile dysfunction,1 2 3 tachycardia (including sinus tachycardia and postural orthostatic tachycardia syndrome),1 2 4 vomiting,1 2 4 palpitations.1 2 Incidence of erectile dysfunction was dose related in a pooled analysis of studies.1

Interactions for Fetzima

Primarily metabolized by CYP isoenzyme 3A4 with minor contributions by CYP isoenzymes 2C8, 2C19, 2D6, and 2J2.1 Other than CYP3A4-mediated drug interactions, clinically important pharmacokinetic drug interactions unlikely.1

Levomilnacipran is not a substrate or inhibitor of breast cancer resistance protein (BCRP), organic anion-transporting polypeptides (OATP) 1B1 and 1B3, organic cation transporter (OCT) 2, and organic anion transporters (OAT) 1 and 3.1 No dosage adjustment is necessary when levomilnacipran is used concomitantly with a substrate or inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma levomilnacipran concentrations).1 Levomilnacipran dosage should not exceed 80 mg once daily if administered concomitantly with potent CYP3A4 inhibitors.1 (See Specific Drugs under Interactions.)

Inhibitors of CYP isoenzymes 2C8, 2C19, 2D6, and 2J2: Clinically important pharmacokinetic interaction unlikely; dosage adjustment of levomilnacipran not necessary.1

CYP3A4 inducers: No dosage adjustment of levomilnacipran necessary.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Drugs metabolized by CYP3A4, 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, or 2E1: Clinically important pharmacokinetic interaction unlikely; dosage adjustment of concomitantly administered substrates of these isoenzymes not necessary.1

Drugs Affecting P-glycoprotein (P-gp) Transport

Levomilnacipran is a weak substrate of P-gp, but does not inhibit P-gp.1 No dosage adjustment of concomitantly administered P-gp substrates recommended.1

Drugs Associated with Serotonin Syndrome

Potentially serious, sometimes fatal serotonin syndrome with other serotonergic drugs.1 If concomitant use of other serotonergic drugs with levomilnacipran 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 levomilnacipran and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment.1 (See Serotonin Syndrome under Cautions.)

Drugs Affecting Hemostasis

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

Drugs that Increase Blood Pressure and Heart Rate

Concurrent use of levomilnacipran 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.)

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potential for pronounced accelerated drug release from extended-release capsules of levomilnacipran 1

Avoid alcohol use during levomilnacipran therapy1

Alprazolam

No clinically important change in levomilnacipran exposure with concomitant use of alprazolam (a CYP3A4 substrate)1

No dosage adjustment of levomilnacipran necessary1

Anticoagulants (e.g., warfarin)

Potential increased risk of bleeding1

Carefully monitor patients receiving warfarin during initiation and discontinuance of levomilnacipran1

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

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 levomilnacipran and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Antidepressants, tricyclics (TCAs)

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 levomilnacipran, the TCA, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

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 levomilnacipran, buspirone, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Carbamazepine

No clinically important change in levomilnacipran exposure with concomitant use of carbamazepine (a CYP3A4 inducer)1

No dosage adjustment necessary1

Clarithromycin

Possible increased levomilnacipran exposure with concomitant use of potent CYP3A4 inhibitors, including clarithromycin1

Levomilnacipran dosage should not exceed 80 mg once daily during concomitant use1

CNS drugs

Potential pharmacologic interaction1

Use concomitantly with caution1

Diuretics

Possible increased risk of hyponatremia1

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 levomilnacipran, 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 18

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 levomilnacipran, the triptan, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Ketoconazole

Substantial increase in levomilnacipran exposure when used concomitantly with ketoconazole (a potent CYP3A4 inhibitor)1

Levomilnacipran dosage should not exceed 80 mg once daily during concomitant use1

Linezolid

Potentially life-threatening serotonin syndrome1 16 17

Do not use concurrently;1 consider availability of alternative anti-infectives and weigh benefit of linezolid against risk of serotonin syndrome1 16

If emergency use of linezolid is considered necessary, immediately discontinue levomilnacipran; monitor for symptoms of CNS toxicity for 2 weeks or until 24 hours after the last linezolid dose, whichever comes first1 16

May resume levomilnacipran 24 hours after last linezolid dose1 16

If nonemergency use of linezolid is planned, withhold levomilnacipran for at least 2 weeks prior to initiating linezolid16

Do not initiate levomilnacipran in patients receiving linezolid1 16

If urgent treatment of a psychiatric condition is necessary, consider other interventions, including hospitalization; may initiate levomilnacipran 24 hours after last linezolid dose1 16

Lithium

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 levomilnacipran, lithium, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

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 levomilnacipran and at least 7 days between discontinuance of levomilnacipran and initiation of MAO inhibitor therapy1

Methylene blue

Potentially life-threatening serotonin syndrome1 19 20

Most cases occurred when methylene blue was used as a diagnostic (visualizing) dye (1–8 mg/kg IV) 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 19 20

Generally should not use methylene blue in patients receiving levomilnacipran;19 consider availability of alternative interventions and weigh benefits of IV methylene blue against risk of serotonin syndrome1 19

If emergency use of IV methylene blue is considered necessary, immediately discontinue levomilnacipran and monitor for symptoms of CNS toxicity for 2 weeks or until 24 hours after last methylene blue dose, whichever comes first1 19

May resume levomilnacipran 24 hours after last dose of IV methylene blue1 19

If nonemergency use of methylene blue is planned, withhold levomilnacipran for at least 2 weeks prior to initiating methylene blue19

Do not initiate levomilnacipran in patients receiving IV methylene blue1 19

If urgent treatment of a psychiatric condition is necessary, consider other interventions, including hospitalization; may initiate levomilnacipran 24 hours after last IV methylene blue dose1 19

Ritonavir

Possible increased levomilnacipran exposure with concomitant use of potent CYP3A4 inhibitors, including ritonavir1

Levomilnacipran dosage should not exceed 80 mg once daily during concomitant use1

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 levomilnacipran, 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 levomilnacipran, 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 levomilnacipran, tryptophan, and any concurrently administered serotonergic agents; initiate supportive and symptomatic treatment1

Fetzima Pharmacokinetics

Absorption

Bioavailability

Relative oral bioavailability of levomilnacipran extended-release capsules is 92% compared with oral solution.1

Median time to achieve peak plasma concentrations is 6–8 hours after oral administration.1

Interconversion between levomilnacipran and its stereoisomer does not appear to occur in humans.1

Food

Administration with food does not substantially affect levomilnacipran concentrations.1

Special Populations

Exposure increases with increasing severity of renal impairment.1

Slightly higher exposure in geriatric individuals >65 years of age (peak concentrations increased by 24% and AUC increased by 26%) than in younger individuals (18–45 years of age).1

Distribution

Extent

Widely distributed.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

22%.1

Elimination

Metabolism

Undergoes desethylation, catalyzed primarily by CYP3A4 with minor contributions by CYP isoenzymes 2C8, 2C19, 2D6, and 2J2, to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran.1 Both of these oxidative metabolites further undergo glucuronide conjugation.1

Elimination Route

Levomilnacipran and metabolites primarily eliminated by renal excretion.1 Approximately 58% excreted in urine as unchanged drug.1 Approximately 18% excreted in urine as N-desethyl levomilnacipran, the principal metabolite.1 Other metabolites excreted in urine include levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%).1 All metabolites are inactive.1

Half-life

Approximately 12 hours.1

Special Populations

Pharmacokinetics not substantially affected by mild, moderate, or severe hepatic impairment.1

Because of large volume of distribution, hemodialysis not expected to reduce plasma concentrations.1

Stability

Storage

Oral

Extended-release Capsules

25°C (may be exposed to 15–30°C).1

Actions

  • An SNRI antidepressant; levomilnacipran is the more active 1S,2R enantiomer of the SNRI milnacipran, which is a racemic mixture of the 1S,2R and 1R,2S enantiomers used in the management of fibromyalgia.1 8 9 10 21

  • Precise mechanism of antidepressant action not fully elucidated, but thought to be related to potentiation of serotonin and norepinephrine activity in the CNS through selective inhibition of serotonin and norepinephrine reuptake.1

  • Potently and selectively inhibits reuptake of serotonin and norepinephrine, with preferential activity at norepinephrine transporters.1 9 21 Demonstrated a twofold preference for norepinephrine- over serotonin-reuptake inhibition in vitro.9 21

  • Lacks substantial affinity for other receptors, ion channels, or transporters tested, including serotonergic (5HT1–7), α- and β-adrenergic, muscarinic, and histaminergic receptors and calcium, sodium, potassium, and chloride channels in vitro.1

  • Does not inhibit monoamine oxidase (MAO).1 9

Advice to Patients

  • Importance of providing copy of written patient information (medication guide) each time levomilnacipran is dispensed.1 Importance of advising patients to read the patient information before taking levomilnacipran 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 12 14 15 (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Importance of informing patients of potential risk of serotonin syndrome, particularly with concurrent use of levomilnacipran and 5-HT1 receptor agonists (also called triptans), tramadol, tryptophan, other serotonergic agents, or antipsychotic agents.1 18 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 18

  • Importance of instructing patients not to take levomilnacipran with or within 14 days of discontinuing an MAO inhibitor and to allow 7 days after discontinuing levomilnacipran before initiating an MAO inhibitor.1

  • Importance of advising patients that levomilnacipran can be taken with or without food.1 Importance of advising patients to swallow extended-release capsules of levomilnacipran whole and not to chew, cut, crush, or open the capsules.1 Importance of also informing patients that dosage of levomilnacipran should be titrated when initiating therapy.1

  • If a dose of levomilnacipran is missed, it should be taken as soon as it is remembered.1 However, if it is almost time for the next scheduled dose, skip the missed dose and take the next dose at the regularly scheduled time.1 Do not take 2 doses of levomilnacipran at the same time.1

  • Risk of seizures; importance of cautioning patients about use of levomilnacipran if they have a history of a seizure disorder.1

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

  • Risk of cognitive and motor impairment; importance of patients exercising caution while operating hazardous machinery, including driving a motor vehicle, until they are reasonably certain that levomilnacipran therapy does not adversely affect their ability to engage in such activities.1

  • Importance of avoiding alcohol during levomilnacipran 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 levomilnacipran and periodically during therapy.1

  • Importance of advising patients that levomilnacipran 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

  • Risk of urinary hesitation and retention while taking levomilnacipran, particularly in patients prone to obstructive urinary disorders.1

  • Importance of advising patients to notify their clinician if any signs or symptoms of an allergic reaction develop during therapy (e.g., rash, hives, swelling, difficulty breathing).1

  • Importance of advising patients, their families, and caregivers to watch for signs of activation of mania/hypomania.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., bipolar disorder, seizure disorder) 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 levomilnacipran with aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.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.

Levomilnacipran Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

20 mg (of levomilnacipran)

Fetzima

Forest

40 mg (of levomilnacipran)

Fetzima

Forest

80 mg (of levomilnacipran)

Fetzima

Forest

120 mg (of levomilnacipran)

Fetzima

Forest

Titration Pack

2 Capsules, extended-release, Levomilnacipran Hydrochloride 20 mg (of levomilnacipran; Fetzima)

26 Capsules, extended-release, Levomilnacipran Hydrochloride 40 mg (of levomilnacipran; Fetzima)

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

Forest

AHFS DI Essentials. © Copyright 2016, Selected Revisions May 29, 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

1. Forest Pharmaceuticals. Fetzima (levomilnacipran hydrochloride) extended-release capsules prescribing information. St. Louis, MO; 2014 Jul.

2. Asnis GM, Bose A, Gommoll CP et al. Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013; 74:242-8. [PubMed 23561229]

3. Bakish D, Bose A, Gommoll C et al. Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study. J Psychiatry Neurosci. 2013; 38:130040. [PubMed 24144196]

4. Sambunaris A, Bose A, Gommoll CP et al. A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder. J Clin Psychopharmacol. 2013; :. [PubMed 24172209]

5. Mago R, Forero G, Greenberg WM et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig. 2013; 33:761-71. [PubMed 23999912]

6. Montgomery SA, Mansuy L, Ruth AC et al. The efficacy of extended-release levomilnacipran in moderate to severe major depressive disorder: secondary and post-hoc analyses from a randomized, double-blind, placebo-controlled study. Int Clin Psychopharmacol. 2013; :. [PubMed 24172160]

7. Montgomery SA, Mansuy L, Ruth A et al. Efficacy and safety of levomilnacipran sustained release in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2013; 74:363-9. [PubMed 23656841]

8. Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?. Int J Clin Pract. 2013; 67:1089-104. [PubMed 24016209]

9. Auclair AL, Martel JC, Assié MB et al. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology. 2013; 70:338-47. [PubMed 23499664]

10. Anon. Levomilnacipran (Fetzima): a new SNRI for depression. Med Lett Drugs Ther. 2013; 55:101-2.

11. Forest Pharmaceuticals, Inc. Savella (milnacipran hydrochloride) film-coated tablets prescribing information. St. Louis, MO; 2013 Nov.

12. US 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 website.

13. Park SH, Wackernah RC, Stimmel GL. Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants?. J Pharm Sci. 2014; 77:71-8.

14. US Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA website.

15. US 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 website.

16. US Food and Drug Administration. Drug Safety Communication: Serious CNS reactions possible when linezolid (Zyvox) is given to patients taking certain psychiatric medications. 2011 Jul 26. From FDA website.

17. US Food and Drug Administration. Drug Safety Communication: Updated information about the drug interaction between linezolid (Zyvox) and serotonergic psychiatric medications. 2011 Oct 20. From FDA website.

18. US 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.

19. Food and Drug Administration. Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. 2011 Jul 26. From FDA website.

20. Food and Drug Administration. Drug Safety Communication: Updated information about the drug interaction between methylene blue (methylthioninium chloride) and serotonergic psychiatric medications. 2011 Oct 20. From FDA website.

21. Mago R, Mahajan R, Thase ME. Levomilnacipran: a newly approved drug for treatment of major depressive disorder. Expert Rev Clin Pharmacol. 2014; 7:137-45.

22. 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.

23. 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.

24. 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; 292:2372-85.

25. 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]

26. 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]

27. Dahl ML, Olhager E, Ahlner J. Paroxetine withdrawal syndrome in a neonate. Br J Psychiatr. 1997; 171:391-2.

28. Bridge JA, Iyengar S, Salary CB. 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]

29. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry. 2010; 167(suppl)

30. Shiovitz T, Bose A, Greenberg W et al. The efficacy and safety of levomilnacipran SR in the prevention of relapse in major depressive disorder: results from a phase III clinical trial. Poster presented at the US Psychiatric and Mental Health Congress 25th annual meeting. San Diego, CA: 2012 Nov 8-11.

31. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005; 352:1112-20. [PubMed 15784664]

32. Yonkers KA, Wisner KL, Stewart DE et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol. 2009; 114:703-13. [PubMed 19701065]

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