levomilnacipran (Rx)

Brand and Other Names:Fetzima
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Dosing & Uses


Dosage Forms & Strengths

capsule, extended-release

  • 20mg
  • 40mg
  • 80mg
  • 120mg

titration packs

  • Contains two 20mg capsules and twenty-six 40mg capsules

Major Depressive Disorders

SNRI indicated for major depressive disorders in adults

20 mg PO qDay x2 days initially; THEN

Increase to 40 mg PO qDay

Based on efficacy and tolerability, increase dose in increments of 40 mg/day at intervals of 2 or more days; not to exceed 120 mg/day

Dosage range: 40-120 mg/day

Dosage Modifications

Strong CYP3A4 inhibitors: Not to exceed 80 mg/day levomilnacipran maintenance dose

Hepatic impairment: Hepatic elimination is low, no dosage adjustment required with mild, moderate, or severe hepatic impairment

Renal impairment

  • Mild (CrCl 60-89 mL/min): No dosage adjustment required
  • Moderate (CrCl 30-59 mL/min): Not to exceed 80 mg/day maintenance dose
  • Severe (CrCl 15-29 mL/min): Not to exceed 40 mg/day maintenance dose
  • End-stage renal disease: Not recommended

Dosing Considerations

Not approved for the management of fibromyalgia

Screen for personal or family history of bipolar disorder, mania, or hypomania before initiating antidepressants

Safety and efficacy not established



Interaction Checker

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            Adverse Effects


            Nausea (17%)


            Erectile dysfunction, dose-related (6-10%)

            Constipation (9%)

            Tachycardia (6%)

            Urinary hesitation, dose-related (4-6%)

            Palpitations (5%)

            Vomiting (5%)

            Hyperhidrosis (2%)

            Increased heart rate (1%)

            Increased blood pressure (1%)

            Hot flush (1%)

            Hypotension (1%)

            Decreased appetite (1%)


            Testicular pain

            Ejaculation disorder

            Postmarketing Results

            Takotsubo cardiomyopathy



            Black Box Warnings

            In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 yr of age) taking antidepressants for major depressive disorders and other psychiatric illnesses

            This increase was not seen in patients aged >24 years; a slight decrease in suicidal thinking was seen in adults >65 years

            In children and young adults, risks must be weighed against the benefits of taking antidepressants

            Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; this should be done during initial 1-2 months of therapy and dosage adjustments

            The patient’s family should communicate any abrupt changes in behavior to the healthcare provider

            Worsening behavior and suicidal tendencies that are not part of the presenting symptoms may require discontinuation of therapy

            This drug is not approved for use in pediatric patients




            • Do not use MAOIs intended to treat psychiatric disorders with levomilnacipran or within 7 days of stopping levomilnacipran due to an increased risk of serotonin syndrome
            • Do not initiate levomilnacipran within 14 days of stopping an MAOI
            • Starting in a patient who is being treated with MAOIs such as linezolid or IV methylene blue is also contraindicated due to an increased risk of serotonin syndrome
            • If methylene blue or linezolid must be administered for an urgent condition to a patient currently taking a serotonergic drug, stop serotonergic drug immediately and monitor for CNS toxicity; serotonergic therapy may be resumed 24 hr after the last dose of methylene blue, or after 2 weeks of monitoring, whichever comes first


            All patients being treated with antidepressants should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment and when increasing or decreasing the dose

            Potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs both when taken alone, but especially when coadministered with other serotonergic agents; thoroughly review patient medications for other serotonergic drugs (eg, tryptophan supplements, tramadol, 5-HT agonists [triptans], MAOIs, TCAs, SSRIs)

            May increase blood pressure BP or heart rate (HR); BP should be controlled before initiating; monitor BP and HR while patient taking drug

            SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and GI hemorrhage to life-threatening hemorrhage; concomitant use of other drugs that inhibit platelets or anticoagulants may increase this risk

            Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy

            Can affect urinary hesitation or retention; caution with obstructive urinary disorders and discontinue is symptoms present

            May activate mania/hypomania in patients with bipolar disorder; screen patients for bipolar disorder prior to initiating

            Caution with seizure disorders

            Discontinuation symptoms (some serious) reported with abrupt withdrawal of serotonergic antidepressants; gradual dose reduction recommended

            Risk of hyponatremia in association with SIADH, particularly in patients taking diuretics or are otherwise volume depleted, or are elderly; discontinue if symptomatic hyponatremia occurs

            Drug interaction overview

            • Contraindicated with an MAOI (or within 14 days of stopping an MAOI) intended to treat psychiatric disorders or within 7 days of stopping treatment with levomilnacipran; it is also contraindicated in patients treated with linezolid or IV methylene blue
            • Coadministration with strong CYP3A4 inhibitors may increase levomilnacipran levels; see Dosage Modifications
            • Avoid alcohol with levomilnacipran; concomitant use may result in accelerated release of levomilnacipran from the extended-release capsules
            • SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events; coadministration with other antiplatelet drug or anticoagulants may cause additive risk
            • Coadministration with other serotonergic drugs may increase risk of serotonin syndrome

            Pregnancy & Lactation


            There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy; healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants

            Available data on pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; there are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs during pregnancy

            Clinical considerations

            • Women who discontinued antidepressants during pregnancy were more likely to experience relapse of major depression than women who continued antidepressants; consider risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum
            • Use of SNRIs in late pregnancy may be associated with an increased risk of postpartum hemorrhage

            Fetal/neonatal effects

            • Neonates exposed to SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; such complications can arise immediately upon delivery
            • Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

            Animal data

            • In animal reproduction studies, drug was not associated with malformations in rats or rabbits when given during the period of organogenesis at doses up to 8 or 16 times maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis, respectively
            • However, an increase in early post-natal rat pup mortality was seen at a dose equivalent to 5 times the MRHD given during pregnancy and lactation


            There are no available data on presence of drug in human milk; however, racemic milnacipran is present in human milk; there are no reports on effects of drug or milnacipran on breastfed infant or effects on milk production; however, there are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to SSRIs or SNRIs through breast milk

            The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal conditions

            Clinical considerations

            • Infants exposed to drug should be monitored for agitation, irritability, poor feeding and poor weight gain

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.



            Mechanism of Action

            Active enantiomer milnacipran; potent inhibitor of neuronal serotonin and norepinephrine reuptake (SNRI); inhibits norepinephrine uptake with ~3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters


            Bioavailability: 92%

            Peak plasma time: 6-8 hr

            Peak plasma concentration: 341 ng/mL

            AUC: 5196 ng•h/mL


            Protein bound: 22%

            Vd: 387-473 L


            Undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran; both oxidative metabolites undergo further conjugation with glucuronide to form conjugates and are inactive

            Desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2


            Half-life, terminal: 12 hr

            Total clearance: 21-29 L/hr

            Excretion: 58% unchanged in urine; 18% N-desethyl metabolite in urine



            Oral Administration

            May take with or without food

            Take at approximately the same time each day

            Swallow capsules whole; do not open, chew, or crush

            Discontinuing drug

            • Avoid abrupt discontinuation if possible; gradual dose reduction recommended to avoid discontinuation symptoms associated with serotonergic drugs




            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.