LEVOMILNACIPRAN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for LEVOMILNACIPRAN (LEVOMILNACIPRAN).

How it works

Serotonin-norepinephrine reuptake inhibitor (SNRI); increases extracellular levels of serotonin and norepinephrine by inhibiting their reuptake into presynaptic neurons.

What the body does with it

Metabolism	Primarily via CYP3A4; minor contribution from other CYP enzymes; undergoes glucuronidation.
Excretion	Primarily renal excretion: ~58% of the dose excreted unchanged in urine. Minor biliary/fecal elimination: ~18% recovered in feces.
Half-life	Terminal elimination half-life is approximately 12 hours (range 9–13 hours), supporting once-daily dosing.
Protein binding	Approximately 22% bound to plasma proteins (primarily albumin).
Volume of Distribution	Apparent volume of distribution ranges from 0.7–1.1 L/kg, indicating distribution into total body water and some tissue binding.
Bioavailability	Oral bioavailability is approximately 92%, with minimal first-pass metabolism.
Onset of Action	Oral: Clinical improvement may be observed within 1–2 weeks, but full therapeutic benefit often requires 4–8 weeks.
Duration of Action	After a single oral dose, effects persist for about 24 hours due to once-daily dosing; sustained action with steady-state levels achieved within 3–5 days.

Classification & Brands

Dosing & administration

20 mg orally twice daily, with or without food; may increase to 40 mg twice daily after 7 days based on tolerability.

Dosage form	CAPSULE, EXTENDED RELEASE
Renal impairment	eGFR 30-59 mL/min: 20 mg once daily; eGFR 15-29 mL/min: 20 mg every other day; eGFR <15 mL/min: not recommended.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: 20 mg once daily, maximum 20 mg twice daily; Child-Pugh C: not recommended.
Pediatric use	Not established; safety and efficacy in pediatric patients (<18 years) have not been evaluated.
Geriatric use	Start at 20 mg once daily; maximum 40 mg total daily. Monitor for hyponatremia and serotonin syndrome.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for LEVOMILNACIPRAN (LEVOMILNACIPRAN).

Breastfeeding	Levomilnacipran is excreted into breast milk in low amounts; relative infant dose estimated at <2% of maternal weight-adjusted dose. M/P ratio not reported. Caution recommended due to potential adverse effects on infant neurodevelopment, though no confirmed harm. Consider benefits of breastfeeding vs. risk of drug exposure.
Teratogenic Risk	First trimester: Limited human data; animal studies show increased fetal malformations at doses equivalent to human therapeutic exposure. Second and third trimesters: Risk of persistent pulmonary hypertension of the newborn (PPHN) and neonatal withdrawal syndrome (irritability, feeding difficulties, respiratory distress) with late third trimester use.

Warnings & precautions

■ FDA Black Box Warning

Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Monitor closely for clinical worsening and emergence of suicidality.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Concomitant use with MAOIs or within 14 days of MAOI discontinuation.","Severe hepatic impairment (Child-Pugh class C).","Uncontrolled narrow-angle glaucoma.","Hypersensitivity to levomilnacipran or any component of the formulation."]

Clinical Precautions

Precautions

["Suicidal thoughts and behaviors; monitor for worsening of depression and suicidality.","Serotonin syndrome: risk especially with concomitant serotonergic drugs.","Elevated blood pressure and heart rate: monitor blood pressure regularly.","Activation of mania/hypomania: screen for bipolar disorder prior to treatment.","Angle-closure glaucoma: may precipitate an attack.","Discontinuation syndrome: taper dose gradually to avoid withdrawal symptoms.","Hyponatremia: risk in elderly or volume-depleted patients.","Hepatic impairment: reduce dose in moderate impairment; contraindicated in severe impairment.","Renal impairment: reduce dose in moderate/severe impairment.","Use with MAOIs: contraindicated; risk of serotonin syndrome."]

Clinical Tips & Counseling

Drug interactions

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LEVOMILNACIPRAN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for LEVOMILNACIPRAN (LEVOMILNACIPRAN).

How it works

Serotonin-norepinephrine reuptake inhibitor (SNRI); increases extracellular levels of serotonin and norepinephrine by inhibiting their reuptake into presynaptic neurons.

What the body does with it

Metabolism	Primarily via CYP3A4; minor contribution from other CYP enzymes; undergoes glucuronidation.
Excretion	Primarily renal excretion: ~58% of the dose excreted unchanged in urine. Minor biliary/fecal elimination: ~18% recovered in feces.
Half-life	Terminal elimination half-life is approximately 12 hours (range 9–13 hours), supporting once-daily dosing.
Protein binding	Approximately 22% bound to plasma proteins (primarily albumin).
Volume of Distribution	Apparent volume of distribution ranges from 0.7–1.1 L/kg, indicating distribution into total body water and some tissue binding.
Bioavailability	Oral bioavailability is approximately 92%, with minimal first-pass metabolism.
Onset of Action	Oral: Clinical improvement may be observed within 1–2 weeks, but full therapeutic benefit often requires 4–8 weeks.
Duration of Action	After a single oral dose, effects persist for about 24 hours due to once-daily dosing; sustained action with steady-state levels achieved within 3–5 days.

Classification & Brands

Dosing & administration

20 mg orally twice daily, with or without food; may increase to 40 mg twice daily after 7 days based on tolerability.

Dosage form	CAPSULE, EXTENDED RELEASE
Renal impairment	eGFR 30-59 mL/min: 20 mg once daily; eGFR 15-29 mL/min: 20 mg every other day; eGFR <15 mL/min: not recommended.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: 20 mg once daily, maximum 20 mg twice daily; Child-Pugh C: not recommended.
Pediatric use	Not established; safety and efficacy in pediatric patients (<18 years) have not been evaluated.
Geriatric use	Start at 20 mg once daily; maximum 40 mg total daily. Monitor for hyponatremia and serotonin syndrome.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for LEVOMILNACIPRAN (LEVOMILNACIPRAN).

Breastfeeding	Levomilnacipran is excreted into breast milk in low amounts; relative infant dose estimated at <2% of maternal weight-adjusted dose. M/P ratio not reported. Caution recommended due to potential adverse effects on infant neurodevelopment, though no confirmed harm. Consider benefits of breastfeeding vs. risk of drug exposure.
Teratogenic Risk	First trimester: Limited human data; animal studies show increased fetal malformations at doses equivalent to human therapeutic exposure. Second and third trimesters: Risk of persistent pulmonary hypertension of the newborn (PPHN) and neonatal withdrawal syndrome (irritability, feeding difficulties, respiratory distress) with late third trimester use.

Warnings & precautions

■ FDA Black Box Warning

Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Monitor closely for clinical worsening and emergence of suicidality.