Fetzima (Levomilnacipran)
levomilnacipran hydrochloride extended-release capsules
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major Depressive Disorder (MDD) | Adults (18+) | Monotherapy | FDA Approved |
Levomilnacipran is the active 1S,2R-enantiomer of milnacipran and was approved by the FDA in July 2013 for the treatment of MDD in adults. Its efficacy was established in three 8-week, randomized, double-blind, placebo-controlled studies (two fixed-dose and one flexible-dose) at doses of 40 to 120 mg once daily. The drug is explicitly not approved for fibromyalgia management, despite its parent compound milnacipran holding that indication. Levomilnacipran is distinguished from other SNRIs by its preferential norepinephrine reuptake inhibition (NE:5-HT selectivity ratio of approximately 2:1), which may confer benefits for fatigue and motivational symptoms in depression.
Fibromyalgia: Despite milnacipran’s approval for fibromyalgia, levomilnacipran has not been studied for this indication, and the FDA PI explicitly states it is not approved for fibromyalgia. Evidence quality: Very low.
Fatigue-predominant depression: Mechanism-based rationale from its noradrenergic profile; limited direct clinical evidence beyond post-hoc analyses of pivotal MDD trials. Evidence quality: Low.
Anxiety disorders: No dedicated trials; limited evidence from pooled analyses of anxious depression subgroups. Evidence quality: Very low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDD — new diagnosis, standard patient | 20 mg daily × 2 days, then 40 mg daily | 40–120 mg once daily | 120 mg/day | Titrate in 40 mg increments every ≥2 days based on response and tolerability Titration pack available: two 20 mg + twenty-six 40 mg capsules |
| MDD — moderate renal impairment (CrCl 30–59 mL/min) | 20 mg daily × 2 days, then 40 mg daily | 40–80 mg once daily | 80 mg/day | Do not exceed 80 mg/day |
| MDD — severe renal impairment (CrCl 15–29 mL/min) | 20 mg daily × 2 days, then 40 mg daily | 40 mg once daily | 40 mg/day | Do not exceed 40 mg/day Half-life prolonged to ~27.7 h in severe impairment |
| MDD — end-stage renal disease (ESRD) | Not recommended | Dialysis unlikely to reduce plasma concentrations due to large Vd | ||
| MDD — hepatic impairment (any severity) | 20 mg daily × 2 days, then 40 mg daily | 40–120 mg once daily | 120 mg/day | No dose adjustment needed; hepatic elimination is low Applies to mild, moderate, and severe hepatic impairment (Child-Pugh 1–13) |
| MDD — concurrent strong CYP3A4 inhibitor | 20 mg daily × 2 days, then 40 mg daily | 40–80 mg once daily | 80 mg/day | Do not exceed 80 mg/day with ketoconazole, itraconazole, clarithromycin, etc. Ketoconazole increases levomilnacipran AUC by ~57% |
| MDD — elderly (65+) | 20 mg daily × 2 days, then 40 mg daily | 40–120 mg once daily | 120 mg/day | No age-based adjustment; modestly higher exposure (Cmax +24%, AUC +26%) Monitor for hyponatremia; limited data (<3% of trial patients were 65+) |
| MDD — discontinuation / tapering | Gradual dose reduction recommended | No specific taper schedule in PI; reduce dose gradually whenever possible to minimize discontinuation symptoms | ||
Unlike desvenlafaxine (which starts at target dose), levomilnacipran requires a 2-day lead-in at 20 mg followed by titration. The therapeutic range is 40–120 mg, offering dose flexibility. Its preferential norepinephrine reuptake inhibition across all therapeutic doses distinguishes it from venlafaxine and duloxetine, which achieve meaningful noradrenergic activity only at higher doses. This makes levomilnacipran particularly worth considering for patients whose depression features prominent fatigue, low energy, or psychomotor slowing. Capsules must be swallowed whole and must not be opened, chewed, or crushed.
Alcohol disrupts the extended-release mechanism of levomilnacipran capsules. In vitro data show that 40% alcohol causes nearly complete drug release within 4 hours, creating a dose-dumping risk. Patients must be counselled to avoid alcohol while taking levomilnacipran. This interaction is unique to levomilnacipran among the SNRIs.
Pharmacology
Mechanism of Action
Levomilnacipran is the more pharmacologically active 1S,2R-enantiomer of the racemic SNRI milnacipran. It inhibits both serotonin (SERT) and norepinephrine (NET) reuptake transporters, but with a distinctive selectivity profile: levomilnacipran is approximately 2-fold more potent at inhibiting norepinephrine reuptake than serotonin reuptake. This contrasts sharply with other marketed SNRIs (venlafaxine, desvenlafaxine, duloxetine), all of which preferentially inhibit serotonin reuptake. Importantly, levomilnacipran achieves simultaneous serotonin and norepinephrine reuptake inhibition across its full dose range (40–120 mg), unlike venlafaxine, which requires higher doses to engage the norepinephrine transporter. Levomilnacipran has no clinically meaningful affinity for muscarinic, histaminergic, or adrenergic receptors, which accounts for its relatively clean side-effect profile outside of its expected monoaminergic effects.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | 92% bioavailability (ER capsule vs solution); Tmax 6–8 h; food does not significantly affect concentration | Can be given with or without food; steady state within ~3 days at once-daily dosing; no interconversion between enantiomers |
| Distribution | Vd = 387–473 L; protein binding 22% (non-saturable, 10–1000 ng/mL) | Very wide tissue distribution; dialysis ineffective for overdose; low protein binding minimizes displacement interactions |
| Metabolism | Primary: CYP3A4 (desethylation to N-desethyl levomilnacipran); minor: CYP2C8, 2C19, 2D6, 2J2; also UGT glucuronidation | Strong CYP3A4 inhibitors require dose cap at 80 mg/day; does not significantly inhibit or induce CYP enzymes; weak P-gp substrate |
| Elimination | t½ ~12 h; clearance 21–29 L/h; 58% unchanged in urine; 18% as N-desethyl metabolite; all metabolites inactive | Primarily renal elimination of parent drug; dose reduction in moderate and severe renal impairment; not recommended in ESRD |
Side Effects
| Adverse Effect | Incidence (40–120 mg) | Clinical Note |
|---|---|---|
| Nausea | 17% (placebo 6%) | Most common adverse effect; tends to occur early and is often transient; only cause of discontinuation in ≥1% of patients (1.5%) |
| Adverse Effect | Incidence (40–120 mg) | Clinical Note |
|---|---|---|
| Constipation | 9% (placebo 3%) | Likely noradrenergic effect; increase fiber, fluids; osmotic laxative if persistent |
| Hyperhidrosis | 9% (placebo 2%) | Related to noradrenergic activation; breathable clothing, clinical antiperspirants |
| Heart rate increased | 6% (placebo 1%) | Noradrenergic class effect; mean increase ~7 bpm; monitor in patients with cardiac disease |
| Tachycardia | 6% (placebo 2%) | Includes sinus tachycardia and postural orthostatic tachycardia syndrome |
| Erectile dysfunction (men) | 6% (placebo 1%) | Dose-related: 6% at 40 mg, 8% at 80 mg, 10% at 120 mg; inquire proactively |
| Ejaculation disorder (men) | 5% (placebo <1%) | Includes delayed ejaculation, ejaculation failure, and premature ejaculation |
| Palpitations | 5% (placebo 1%) | Noradrenergic effect; often benign but evaluate if persistent or symptomatic |
| Vomiting | 5% (placebo 1%) | Usually early and self-limiting; taking with food may help |
| Urinary hesitation | 4% (placebo 0%) | Dose-related: 4%/5%/6% at 40/80/120 mg; more prominent in males; evaluate for urinary retention |
| Testicular pain (men) | 4% (placebo <1%) | Includes epididymitis and seminal vesiculitis; unique among SNRIs |
| Hot flush | 3% (placebo 1%) | Noradrenergic mediated vasomotor effect |
| Blood pressure increased | 3% (placebo 1%) | Includes systolic, diastolic, and orthostatic BP increases; control hypertension before starting |
| Hypertension | 3% (placebo 1%) | Includes labile hypertension; regular monitoring essential |
| Hypotension | 3% (placebo 1%) | Includes orthostatic hypotension and postural dizziness; advise rising slowly |
| Decreased appetite | 3% (placebo 1%) | Weight-neutral in short-term and long-term studies |
| Rash | 2% (placebo 0%) | Includes generalized, maculopapular, erythematous, and macular rash |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Suicidal ideation (age <25) | Uncommon | First weeks or dose changes | Close monitoring; consider discontinuation if worsening; FDA Black Box Warning |
| Serotonin syndrome | Rare | Hours to days after dose increase or serotonergic co-medication | Immediate discontinuation; supportive care; cyproheptadine if severe |
| Sustained hypertension | Uncommon | Weeks to months | Regular BP monitoring; control pre-existing hypertension before initiation; consider dose reduction or discontinuation |
| Urinary retention | Uncommon | Variable; dose-related | Discontinue or reduce dose; evaluate for BPH; may require catheterization in acute cases |
| Hyponatremia / SIADH | Rare | First weeks; higher risk in elderly | Check serum sodium; discontinue if symptomatic; fluid restriction |
| Mania / hypomania activation | Rare | First weeks | Discontinue; evaluate for bipolar disorder; initiate mood stabilizer |
| Abnormal bleeding | Uncommon | Any time, especially with concurrent anticoagulants/NSAIDs | Monitor for bruising, GI bleeding; adjust anticoagulation as needed |
| Seizures | Rare | Any time | Discontinue; use cautiously in patients with seizure disorders |
| Angle-closure glaucoma | Rare | Any time | Avoid in untreated anatomically narrow angles; urgent ophthalmology referral if acute symptoms |
| Takotsubo cardiomyopathy | Very rare (post-marketing) | Variable | Discontinue; cardiology referral; supportive care |
The noradrenergic potency of levomilnacipran produces clinically significant cardiovascular effects more prominently than other SNRIs. Heart rate increases (mean ~7 bpm), tachycardia, palpitations, and blood pressure elevation are all more common than with placebo. Pre-existing hypertension must be controlled before initiation. Routine heart rate and blood pressure monitoring throughout treatment is essential. These effects may limit levomilnacipran’s suitability for patients with significant cardiovascular disease, tachyarrhythmias, or uncontrolled hypertension.
Drug Interactions
Levomilnacipran is primarily metabolized by CYP3A4, making strong CYP3A4 inhibitors the main pharmacokinetic interaction concern. Unlike desvenlafaxine (UGT-metabolized) and duloxetine (CYP1A2/2D6-metabolized), levomilnacipran does not significantly inhibit or induce any CYP enzymes. Its low protein binding (22%) further reduces displacement interaction risk. The most important interactions are pharmacodynamic: serotonergic combinations and the unique alcohol-induced dose-dumping effect on the extended-release formulation.
Monitoring
- Blood PressureBaseline, then regularly
RoutineControl pre-existing hypertension before initiation. Monitor for sustained BP increases. Noradrenergic potency of levomilnacipran makes this particularly important compared to serotonin-preferential SNRIs. - Heart RateBaseline, then regularly
RoutineMean increase ~7 bpm; monitor for tachycardia (6% incidence) and palpitations (5%). Pre-existing tachyarrhythmias and other cardiac disease should be treated before initiation. - Suicidality AssessmentWeekly for first 4 weeks, then at each visit
RoutineEspecially important in patients under 25. Monitor for clinical worsening, agitation, irritability, and suicidal ideation. - Urinary FunctionEach visit
RoutineInquire about urinary hesitation or difficulty voiding at each follow-up; dose-related (4–6%). Particularly relevant in males and patients with prostatic hypertrophy. Discontinue if urinary retention develops. - Sexual FunctionBaseline, then periodically
RoutineInquire proactively; erectile dysfunction (6%, dose-related up to 10% at 120 mg), ejaculation disorder (5%), and testicular pain (4%) are notable. Female sexual dysfunction was <2% in trials. - Serum SodiumAs indicated
Trigger-basedCheck if symptoms of hyponatremia develop. Elderly patients and those on diuretics are at highest risk. - Renal FunctionBaseline
RoutineCreatinine clearance determines dosing caps. 58% of drug excreted renally unchanged. - Intraocular PressureBaseline in at-risk patients
Trigger-basedMydriasis from SNRIs may trigger angle-closure glaucoma in patients with untreated anatomically narrow angles.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to levomilnacipran, milnacipran HCl, or any excipient in the formulation
- Concurrent MAOI use or use within 14 days of MAOI discontinuation
- Initiation in patients receiving linezolid or IV methylene blue
Relative Contraindications (Specialist Input Recommended)
- Uncontrolled hypertension: Blood pressure must be adequately managed before starting levomilnacipran; noradrenergic potency amplifies BP effects
- Significant cardiac disease or tachyarrhythmias: Pre-existing cardiac conditions should be treated before initiation; heart rate increases of ~7 bpm are expected
- Urinary obstruction or severe BPH: Dose-dependent urinary hesitation and retention risk; alternative antidepressant may be preferable
- Untreated narrow-angle glaucoma: Mydriasis may precipitate acute angle-closure attack
- End-stage renal disease: Not recommended; drug accumulates and dialysis is ineffective
Use with Caution
- Seizure disorders: Seizures have been reported rarely
- Moderate-severe renal impairment: Dose cap required (80 mg or 40 mg depending on severity)
- Bipolar disorder: Screen before initiation; risk of mania/hypomania activation
- Elderly patients (65+): Increased hyponatremia risk; limited clinical trial data in this age group
- Patients at bleeding risk: Concurrent anticoagulant or NSAID use increases bleeding risk
- Third trimester pregnancy: Neonatal adaptation syndrome reported with SNRI exposure
Antidepressants increased the risk of suicidal thinking and behavior in pediatric and young adult patients in short-term studies. Closely monitor all patients for clinical worsening and emergence of suicidal thoughts and behaviors. Levomilnacipran is not approved for use in pediatric patients. Two randomized, placebo- and active-controlled 8-week trials in pediatric patients (7–17 years) with MDD did not establish efficacy, and an increased risk of blood pressure elevation was observed in this population.
Patient Counselling
Purpose of Therapy
Levomilnacipran is prescribed to treat major depression by increasing the availability of both serotonin and norepinephrine in the brain. Improvement in mood and energy levels typically begins within 2 to 4 weeks, with full therapeutic benefit developing over 6 to 8 weeks. It is important to continue taking the medication as prescribed even after symptoms improve, to prevent relapse.
How to Take
Take one capsule at approximately the same time each day, with or without food. Swallow the capsule whole; do not open, chew, or crush it, as this will damage the extended-release mechanism. The starting dose is 20 mg for the first 2 days, after which your prescriber will increase and adjust the dose based on how you respond.
Sources
- Fetzima (levomilnacipran) Extended-Release Capsules. Full Prescribing Information. AbbVie Inc. Revised April 2024. dailymed.nlm.nih.govPrimary source for all dosing, contraindications, adverse reaction incidence rates, and pharmacokinetic parameters cited in this monograph.
- Fetzima (levomilnacipran) FDA label. August 2023 revision (Warnings and Precautions update). accessdata.fda.govMost current FDA label PDF including 2023 warnings updates on serotonin syndrome and bleeding risk.
- Asnis GM, Bose A, Gommoll CP, Chen C, Greenberg WM. 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(3):242-248. doi:10.4088/JCP.12m08197Pivotal fixed-dose Study 1 establishing efficacy of levomilnacipran 40, 80, and 120 mg for MDD.
- 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. 2014;39(1):40-49. doi:10.1503/jpn.130040Fixed-dose Study 2 confirming efficacy of 40 mg and 80 mg doses with MADRS primary endpoint.
- 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. 2014;34(1):47-56. doi:10.1097/JCP.0000000000000060Flexible-dose Study 3 (40–120 mg) supporting clinical flexibility in dosing.
- Shiovitz T, Greenberg WM, Chen C, Forero G, Gommoll CP. A randomized, double-blind, placebo-controlled trial of the efficacy and safety of levomilnacipran ER 40-120 mg/day for prevention of relapse in patients with major depressive disorder. Innov Clin Neurosci. 2014;11(1-2):10-22.Relapse prevention trial establishing longer-term efficacy of levomilnacipran for MDD maintenance treatment.
- Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults. Can J Psychiatry. 2024;69(9):641-687. doi:10.1177/07067437241245384Current Canadian guideline listing levomilnacipran as a first-line antidepressant option for MDD.
- Auclair AL, Bhardwaj SK, Bhougal A, et al. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in neurochemical and behavioral models of antidepressant activity. Neuropharmacology. 2013;70:338-347. doi:10.1016/j.neuropharm.2013.02.024Characterizes the preferential noradrenergic selectivity profile of levomilnacipran (NE:5-HT ~2:1).
- Stahl SM, Grady MM, Moret C, Briley M. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 2005;10(9):732-747. doi:10.1017/S1092852900019726Comparative review of SNRI pharmacology placing milnacipran/levomilnacipran in the context of the SNRI class.
- Brunner E, Gommoll C, Engel C, et al. Disposition and metabolism of [14C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats. Drug Des Devel Ther. 2015;9:3199-3215. doi:10.2147/DDDT.S82505Comprehensive mass-balance and metabolite identification study establishing renal excretion of 58% unchanged drug and CYP3A4-mediated desethylation pathway.
- Asnis GM, Henderson MA. Levomilnacipran for the treatment of major depressive disorder: a review. Neuropsychiatr Dis Treat. 2015;11:125-135. doi:10.2147/NDT.S54710Comprehensive review of efficacy, safety, tolerability, and PK profile from pivotal and long-term studies.
- Gautam M, Kaur M, Jagtap P, Krayem B. Levomilnacipran: more of the same? Prim Care Companion CNS Disord. 2019;21(5):27423. doi:10.4088/PCC.19nr02521Narrative review analyzing the unique noradrenergic profile of levomilnacipran and its potential for fatigue-predominant depression.