Levomilnacipran Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

In a nutshell

Levomilnacipran is the most noradrenergic SNRI, making it particularly suitable for patients with fatigue-predominant depression. Its clean receptor profile and minimal drug interactions are advantages. However, cardiac and urinary effects require monitoring in high-risk populations, especially those with cardiovascular disease or BPH.

• Choosing levomilnacipran over other SNRIs:
  • Preferred for patients with predominant fatigue and low energy symptoms
  • Highest norepinephrine-to-serotonin selectivity (2:1 ratio)
  • Simultaneous serotonin and norepinephrine effects without the need for dose escalation
  • Minimal drug interactions and weight-neutral profile
  • Consider alternative SNRIs in patients with:
    • Unstable cardiovascular conditions requiring strict BP control
    • History of urinary obstruction or retention
    • Need for established efficacy in anxiety or pain conditions

Pharmacodynamics and mechanism of action

• Potent and selective serotonin and norepinephrine reuptake inhibition (SNRI), by blocking SERT and NET.
• Greater potency for norepinephrine reuptake inhibition than serotonin (5HT: NE=1:2) ^[1].
• Serotonergic effects:
  • Levomilnacipran inhibits both serotonin and norepinephrine reuptake simultaneously across all doses, unlike venlafaxine and duloxetine, which have sequential effects ^[2].
• Noradrenergic effects:
  • Most noradrenergic of all SNRIs
  • Potential efficacy in alleviating the fatigue symptom cluster in MDD, though further research is needed ^[3].
  • Better functional outcomes in patients with low baseline energy ^[4].
  • Males may show greater improvement in work/activities and somatic symptoms, while younger women in retardation and somatic symptoms ^[5].
• Levomilnacipran shows no meaningful interaction with muscarinic, histaminergic receptors, or ion channels ^[6].

Pharmacokinetics

Metabolism

• Primarily metabolized via CYP3A4.
• Minor contribution by CYP2C8, 2C19, 2D6, and 2J2.
• Drug interactions:
  • Contraindicated with MAOIs.
    • Allow 14 days after stopping MAOI before starting levomilnacipran.
    • Allow 7 days after stopping levomilnacipran before starting MAOI.
  • Levomilnacipran levels potentially increased by:
    • Strong CYP3A4 inhibitors (e.g., ketoconazole)
    • Maximum dose should not exceed 80 mg/day ^[6].
  • Alcohol
    • The extended-release properties of levomilnacipran are disrupted by alcohol, risking rapid drug release. Concurrent use should be avoided ^[6].

Half-life

• Levomilnacipran’s half-life is approximately 12 hours.

Dosage forms

• Capsules:
  • 20 mg, 40 mg, 80 mg, 120 mg.
  • Fetzima.
• Capsules (Titration Pack):
  • 20 mg & 40 mg.
  • Fetzima Titration.
• Formulation considerations:
  • Levomilnacipran is only available as extended-release capsules.
  • Extended-release capsules should be taken once daily, with or without food.
  • Capsules should be swallowed whole, not split, crushed, or chewed.

Indications

FDA-Approved Indications

Major Depressive Disorder

• First-line treatment option for major depression ^[7]
• No head-to-head comparisons with other antidepressants. Efficacy comparable to other second-generation antidepressants in network meta-analyses ^[8].
• May be particularly effective for patients with fatigue and low energy due to its higher noradrenergic potency compared to other SNRIs.
• Dosing:
  • Initial: 20 mg once daily for 2 days
  • Increase to 40 mg once daily
  • May increase in increments of 40 mg at intervals of 2 or more days
  • Target dose: 40-120 mg once daily
  • Maximum dose: 120 mg once daily

Off-label Uses

• Off-label uses of levomilnacipran are primarily based on mechanism of action inferences as an SNRI, with limited direct clinical evidence.

Fibromyalgia

• Not FDA-approved for fibromyalgia management, despite its parent compound milnacipran having this indication ^[6].

Anxiety Disorders

• Limited evidence available for use in anxiety disorders.
• Improves depression-related anxiety in trials ^[9].
• No clinical trials have specifically evaluated levomilnacipran for anxiety disorders.

Vasomotor Symptoms of Menopause

• Limited evidence available; other SNRIs (venlafaxine, desvenlafaxine) have stronger evidence base for this indication ^[10].

Diabetic Peripheral Neuropathy

• Limited evidence available;duloxetine, has FDA approval and a stronger evidence base for this indication ^[11].

Chronic Musculoskeletal Pain

• Limited evidence available duloxetinehas FDA approval and a stronger evidence base for this indication ^[12].

Side Effects

Most common side effects

Gastrointestinal

• Nausea (17% incidence, most common adverse effect) ^[6]
  • Leading cause of discontinuation (1.5%)
  • Less common than with venlafaxine
  • More severe early in treatment
  • Requires slow titration for tolerance development
• Dry mouth (10% incidence)
• Constipation (9% incidence)
  • Recommend increasing fluid and fiber intake ^[13,14].
• Vomiting (5% incidence)
• Decreased appetite (3% incidence)
  • Weight neutral in short-term: -0.5 kg vs placebo +0.1 kg at 8 weeks ^[15–18]
  • Maintains weight neutrality long-term: -0.5 to -0.55 kg weight loss over 24-48 weeks ^[19,20]

Other common side effects

• Cardiovascular effects
  • Tachycardia (6% incidence) ^[6]
  • Elevated blood pressure
    • Although levominacipran can cause BP elevations, hypertension is uncommon (1.8% vs 1.2% with placebo) ^[21].
      • 10.4% of patients progressed from normal/pre-hypertensive to Stage I/II hypertension (vs 7.1% with placebo)
    • Monitor BP and HR at baseline and throughout treatment.
    • Discontinue levomilnacipran if sustained hypertension develops.
  • Orthostatic hypotension: 11.6% (vs 9.7% placebo)
• Urinary hesitation (4-6% incidence) ^[21]
  • Dose-dependent risk. Higher in patients prone to obstructive urinary disorders.
  • Advise patients to report any difficulty urinating.  
  • If symptoms develop, consider discontinuing levomilnacipran or reducing the dose.
• Antidepressant-induced sexual dysfunction ^[21]
  • Dose-dependent.
  • More common in males.
    • Erectile dysfunction (6-10% incidence)
    • Ejaculatory disorder (5% incidence)
    • Testicular pain (4% incidence)
  • Incidence was <2% in female patients ^[6].
  • Ranking of risk: SSRIs and venlafaxine > tricyclics > other SNRIs ^[22]
  • Consider reducing the dose, or switching to an antidepressant with a lower risk of sexual dysfunction, such as bupropion or mirtazapine.
• Sweating (9 % incidence)
  • Consider switching to an SSRI
  • Terazosin and oxybutynin have shown efficacy in reducing ADIES ^[23,24].
• Discontinuation syndrome
  • Increased incidence at higher dosages, possibly related to noradrenergic effects.
  • SNRIs, paroxetine, and mirtazapine have the highest risk among antidepressants ^[25].
  • Taper the dose over two to four weeks to reduce discontinuation emergent adverse events ^[26].
• Dizziness (8% incidence)
• Insomnia (5% incidence)
  • Less frequent than with other SNRIs

Severe side effects

• Serotonin syndrome
  • Risk increases with MAOIs and other serotonergic drugs.
  • Life-threatening risk has been reported with SNRIs alone or with serotonergic drugs/MAOIs; monitor for mental changes, autonomic instability, hyperreflexia, and GI symptoms.
  • Avoid tryptophan and watch triptans carefully ^[6].
• Ocular effects
  • Acute angle closure glaucoma reported ^[27]
  • Higher risk in females >50y, Asians/Inuit, hyperopia, family history.
  • Mechanism likely serotonergic/adrenergic effects on pupil/pressure ^[28]
• Bleeding risk
  • The absolute risk remains low in most patients, but is significantly elevated when combined with NSAIDs, antiplatelet agents, or anticoagulants ^[29].
    • Data quality remains low due to the absence of randomized trials and potential confounding by depression.
  • Monitor closely during initial months of combined antidepressant-anticoagulant therapy, particularly in patients with a history of intracranial or GI hemorrhage ^[30].
• Hyponatremia
  • No hyponatremia cases reported with levomilnacipran in trials, but SNRIs can cause SIADH-related hyponatremia ^[6].
  • Ranking of risk ^[31]:
    • MAOIs > SNRIs > SSRIs > TCAs > Mirtazapine
  • Special caution in elderly patients, patients taking diuretics or who are otherwise volume-depleted.

Use in special populations

Pregnancy

• No data are available on human pregnancy outcomes with levomilnacipran.
• Levomilnacipran did not increase congenital malformations in rats (up to 8x human dose) or rabbits (16x human dose) ^[6].
• Antidepressant use during pregnancy was associated with a 32% increased risk of postpartum hemorrhage (RR = 1.32, 95% CI: 1.17–1.48) ^[32].
  • SNRIs higher risk than SSRIs (RR 1.62, 95% CI 1.41-1.85)

Breastfeeding

• No specific data exist for levomilnacipran in breast milk.
• Evidence from milnacipran (parent compound):
  • Low milk levels (relative infant dose 2.8% of maternal dose)
  • Suggests minimal infant exposure
• Breastfed infants should be monitored for:
  • Sedation
  • Poor feeding patterns
  • Weight gain adequacy
• For treatment-naive breastfeeding patients, antidepressants other than SNRI are generally preferred ^[33].

Hepatic impairment

• Levomilnacipran undergoes minimal hepatic elimination. No dose adjustments are required for patients with hepatic impairment, regardless of severity (Child-Pugh scores 1-13) ^[6].

Renal impairment

• CrCl ≥60 mL/minute:
  • No dosage adjustment necessary
• CrCl 30 to 59 mL/minute:
  • Maximum dose: 80 mg
• CrCl 15 to 29 mL/minute:
  • Maximum dose: 40 mg
• End-stage renal disease (ESRD):
  • Use is not recommended

Elderly

• No age-based dose adjustment is required for levomilnacipran, despite elderly patients (>65 years) showing modestly increased exposure compared to younger adults ^[6].
• Clinicians should monitor elderly patients for hyponatremia, a known risk with SNRIs and SSRIs.

Brand names

* US: Fetzima, Fetzima Titration  – Canada: Fetzima  – Other countries/regions: Cipran, Levomil, Fetzima.

References

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