levomilnacipran

General Information

Levomilnacipran (brand Fetzima) is a serotonin-norepinephrine reuptake inhibitor (SNRI) indicated for major depressive disorder in adults (label).

It is the active enantiomer of milnacipran and is described as having relatively greater norepinephrine reuptake inhibition than some other SNRIs, which can translate to a more “activating” clinical feel in some patients (mechanism/clinical).

Clinically important adverse-effect themes include nausea, sweating, increased heart rate and blood pressure, and urinary hesitation or retention—considerations that can matter when anxiety, insomnia, or baseline urinary obstruction risk is present (label/clinical).

Because renal excretion is predominant and a substantial fraction is excreted unchanged, dosing requires renal adjustments (label).

The compare view, levomilnacipran evidence feed, and print page support shared decision-making around activation, blood pressure monitoring, and taper planning.

Levomilnacipran is selected similarly to other SNRIs after SSRI nonresponse, with additional attention to blood pressure/heart rate and urinary retention risk. Renal dosing constraints often drive selection when chronic kidney disease is present.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Inhibits serotonin (SERT) and norepinephrine (NET) transporters, with relatively greater NET inhibition than many SSRIs and some other SNRIs (mechanism/class).

Minimal direct muscarinic, histamine, or α1 receptor antagonism, so anticholinergic burden is typically lower than TCAs; autonomic effects (BP/HR, sweating) reflect SNRI pharmacology (class).

• SERT and NET inhibition (SNRI).

Metabolism and Pharmacokinetics

• Apparent terminal elimination half-life is ~12 hours; mean clearance 21–29 L/h (label).
• Predominantly renally eliminated. After oral radiolabeled dosing, ~58% is excreted in urine as unchanged levomilnacipran; additional metabolites are eliminated in urine (label).
• Metabolism: desethylation is catalyzed primarily by CYP3A4 with minor contributions by CYP2C8/2C19/2D6/2J2; strong inhibitors can increase exposure (label).
• Renal impairment increases exposure and requires labeled dose caps; this is a key selection factor in older adults and chronic kidney disease (label/clinical).

Dosing and Administration

• Label initiation: 20 mg once daily for 2 days, then 40 mg once daily. The recommended dose range is 40–120 mg once daily, with or without food (label).
• Renal impairment: labeling sets maximum daily doses (e.g., 80 mg/day in moderate impairment; 40 mg/day in severe impairment) (label).
• Capsules are swallowed whole; crushing or opening can alter extended release and tolerability (label).
• Discontinuation symptoms can occur; tapering is commonly used when stopping after longer courses (label/clinical).

Monitoring & Labs

• Blood pressure and heart rate at baseline and after titrations; ongoing monitoring is emphasized in labeling (label).
• Renal function review for long-term therapy so dosing remains aligned with kidney function changes over time (label/clinical).
• Screening for urinary obstruction risk and follow-up if urinary hesitation/retention symptoms emerge (label/clinical).
• Suicidality and mood switching surveillance early in treatment and after dose changes, especially in young adults and bipolar-spectrum illness (label/clinical).

Monitoring is typically centered on BP/HR effects and urinary retention risk, with renal dosing constraints tracked over time.

Adverse Effects

Interactions

• MAOIs are contraindicated; washout periods are used to reduce risk of serotonin syndrome and severe reactions (label).
• Strong CYP3A4 inhibitors can increase exposure; dosing and tolerability are commonly reassessed when potent inhibitors are started or stopped (label/clinical).
• Additive serotonergic burden with SSRIs/SNRIs, linezolid, triptans, and tramadol increases serotonin syndrome risk (label/class).
• Agents that raise blood pressure or heart rate (stimulants, decongestants) can compound autonomic effects; OTC products are a common source of unintentionally stacked exposure (clinical).

Other Useful Information

• Selection among SNRIs often hinges on activation profile, blood pressure tolerance, and renal function; levomilnacipran is typically avoided or dose-limited in significant renal impairment (label/clinical).
• When depressive symptoms occur in bipolar disorder, antidepressants are commonly paired with a mood stabilizer and monitored for mood switching; see the bipolar disorder hub for longitudinal care pathways.
• If urinary retention or problematic hypertension emerges, clinicians commonly reassess alternatives rather than escalating dose (clinical).

References

1. Fetzima (levomilnacipran) Extended Release Capsules Prescribing Information — DailyMed (2025)
2. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)
3. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
4. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018)