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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for FETZIMA (FETZIMA).
| Breastfeeding | Levomilnacipran is excreted into human breast milk. The infant dose via breast milk is estimated to be approximately 2-4% of the maternal weight-adjusted dose. The milk-to-plasma (M/P) ratio is not well established but is likely low. A study of three mother-infant pairs reported an M/P ratio of approximately 1.0 based on limited data. Monitor the infant for signs of lethargy, poor feeding, and irritability. The American Academy of Pediatrics considers SNRIs to be compatible with breastfeeding, but caution is advised. The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for FETZIMA. |
| 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. |
■ 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 |
["Hypersensitivity to levomilnacipran or any excipient","Concomitant use of MAOIs or within 14 days of MAOI discontinuation","Use of linezolid or intravenous methylene blue due to risk of serotonin syndrome"]
| 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"] |
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| 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. |