FETZIMA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FETZIMA (FETZIMA).
Fetzima (levomilnacipran) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It inhibits the reuptake of serotonin and norepinephrine, with approximately 2-fold higher potency for norepinephrine reuptake inhibition, which enhances neurotransmission in the central nervous system.
| Metabolism | Primarily metabolized via CYP3A4 to desethyllevomilnacipran (major active metabolite) and other minor metabolites. Minor involvement of CYP2C8, CYP2C19, and CYP2D6. Not a significant inhibitor or inducer of CYP enzymes at therapeutic concentrations. |
| Excretion | Primarily renal (approximately 65% as unchanged levomilnacipran and 25% as N-desmethyllevomilnacipran); fecal excretion accounts for ~8%. |
| Half-life | Terminal elimination half-life is approximately 12 hours for levomilnacipran; at steady state, half-life supports once-daily dosing without extensive accumulation. |
| Protein binding | 22% bound to plasma proteins (primarily albumin) in a concentration-independent manner. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 387 L (~5.5 L/kg based on 70 kg), indicating extensive tissue distribution. |
| Bioavailability | Absolute oral bioavailability is approximately 92% (not significantly affected by food, although a high-fat meal delays Tmax by ~2 hours). |
| Onset of Action | Clinical effect (antidepressant) typically observed within 1–2 weeks of oral administration; full therapeutic benefit may require 4–8 weeks. |
| Duration of Action | Duration of clinical effect is approximately 24 hours with once-daily dosing; steady-state concentrations are achieved within 4–5 days. |
| Molecular Weight | 246.3 |
20 mg orally once daily for 2 days, then 40 mg once daily for 2 days, then 80 mg once daily for 2 days, then 120 mg once daily; maximum dose 120 mg/day.
| Dosage form | CAPSULE, EXTENDED RELEASE |
| Renal impairment | eGFR 30-59 mL/min: maximum dose 80 mg/day; eGFR 15-29 mL/min: maximum dose 40 mg/day; eGFR <15 mL/min or on dialysis: not recommended. |
| Liver impairment | Child-Pugh A or B: no adjustment; Child-Pugh C: not studied, use with caution. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | Maximum recommended dose 80 mg/day in patients >65 years. |
| 1st trimester | Risk of persistent pulmonary hypertension of the newborn (PPHN) and congenital malformations based on limited data. Use only if potential benefit justifies risk. |
| 2nd trimester | Monitor for maternal adverse effects and fetal growth restriction. Insufficient data to rule out risk. |
| 3rd trimester | Risk of neonatal adaptation syndrome including respiratory distress, feeding difficulties, irritability. Consider tapering before delivery. |
Clinical note
Comprehensive clinical and safety monograph for FETZIMA (FETZIMA).
| Placental transfer | Likely crosses the placenta based on molecular weight and lipophilicity; however, specific data limited. |
| Breastfeeding | Levomilnacipran is excreted into breast milk in low concentrations; however, no adverse effects in breastfed infants have been reported. Caution is advised, especially in preterm infants or those with compromised renal function. |
■ FDA Black Box Warning
Suicidality and Antidepressant Drugs: Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults. Fetzima is not approved for use in pediatric patients.
| Serious Effects |
Concomitant use with MAOIs or within 14 days of discontinuing MAOI therapyAngle-closure glaucomaSevere hypertension or uncontrolled hypertensionKnown hypersensitivity to levomilnacipran or any excipientConcomitant use with linezolid or intravenous methylene blue
| Precautions | Suicidal thoughts and behaviors in pediatric and young adult patients, Serotonin syndrome or neuroleptic malignant syndrome-like reactions, Elevated blood pressure and heart rate, Activation of mania/hypomania in patients with bipolar disorder, Angle-closure glaucoma, Urinary hesitancy/retention (especially in men with prostatic disorders), Increased bleeding risk (especially with NSAIDs, aspirin, anticoagulants), Seizures, Discontinuation syndrome upon abrupt discontinuation |
| Food/Dietary | Take with food to reduce gastrointestinal side effects. No specific dietary restrictions; avoid excessive alcohol intake. |
Loading safety data…
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | FETZIMA (levomilnacipran) is a serotonin-norepinephrine reuptake inhibitor (SNRI). In animal studies, no teratogenicity was observed at clinically relevant doses. Human data are limited; however, SNRIs in general are associated with a small increased risk of cardiac malformations when used in the first trimester. Third trimester use may result in persistent pulmonary hypertension of the newborn (PPHN) and neonatal adaptation syndrome (e.g., respiratory distress, feeding difficulties, irritability). The risk of poor neonatal adaptation increases with exposure near term. Overall, the absolute risk is low, but the drug should be used during pregnancy only if the potential benefit justifies the potential fetal risk. |
| Fetal Monitoring | Monitor pregnant individuals for worsening depression or anxiety. For neonates, monitor for symptoms of neonatal adaptation syndrome, including poor feeding, respiratory distress, jitteriness, irritability, and constant crying, especially if exposure occurred in the third trimester. In cases of late third-trimester exposure, a pediatric mental health consultation is recommended. No specific fetal monitoring beyond standard prenatal care is required; however, consider growth and well-being assessments as clinically indicated. |
| Fertility Effects | FETZIMA may reduce fertility in males and females based on animal studies. In rats, oral administration resulted in decreased pregnancy rates and increased preimplantation loss. In humans, no specific fertility studies have been conducted. Whether the effect is reversible in humans is unknown. Caution is advised when prescribed to individuals planning to conceive. |
| Clinical Pearls | FETZIMA (levomilnacipran) is a serotonin-norepinephrine reuptake inhibitor (SNRI) with preferential inhibition of norepinephrine reuptake, making it useful for fatigue and low energy in major depressive disorder (MDD). Dose adjustment is required in renal impairment; contraindicated in severe renal impairment (CrCl < 30 mL/min). Monitor blood pressure regularly due to dose-dependent increases. Avoid abrupt discontinuation; taper to prevent withdrawal symptoms. Onset of therapeutic effect may take 2–4 weeks. |
| Patient Advice | Take FETZIMA with food to improve tolerability and reduce nausea. · Swallow capsules whole; do not crush or chew. · Do not stop taking FETZIMA abruptly; consult your doctor for a gradual taper. · Avoid driving or operating machinery until you know how FETZIMA affects you. · Report any signs of suicidal thoughts, worsening depression, or unusual behavioral changes. · Monitor for increased blood pressure; have it checked regularly. · Avoid alcohol while taking FETZIMA. |