Levomilnacipran Hydrochloride (Monograph)

Brand name: Fetzima
Drug class: Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

Introduction

Antidepressant; selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) and 1S, 2R-enantiomer of racemic milnacipran.

Uses for Levomilnacipran Hydrochloride

Major Depressive Disorder

Treatment of major depressive disorder in adults.

Guidelines from the American Psychiatric Association and the Department of Veterans Affairs/Department of Defense state that there is no evidence to suggest superiority of one first-line antidepressant over another. Recommended first-line agents for initial treatment of major depressive disorder include bupropion, mirtazapine, an SSRI, an SNRI, trazodone, vilazodone, or vortioxetine. Select an initial antidepressant for treatment based on the following factors: patient preference; nature of prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication; and cost.

Manufacturer states levomilnacipran is not approved for use in the treatment of fibromyalgia.

Levomilnacipran Hydrochloride Dosage and Administration

General

Pretreatment Screening

• Screen patients for a personal or family history of bipolar disorder, mania, or hypomania.

• Monitor blood pressure and heart rate.

• Control preexisting hypertension.

• Treat preexisting tachyarrhythmias and other cardiac disease.

• Inquire about baseline sexual function.

Patient Monitoring

• Closely monitor for clinical worsening or emergence of suicidal thoughts and behavior, especially during the first few months of therapy and at times of dosage changes.

• Monitor blood pressure and heart rate periodically during therapy.

• Monitor for the emergence of serotonin syndrome during therapy.

• Monitor for withdrawal symptoms when discontinuing levomilnacipran.

• Inquire about changes in sexual function during treatment with levomilnacipran.

• Monitor for signs and symptoms of bleeding, particularly in patients also taking aspirin, NSAIAs, warfarin, or other anticoagulants.

• Monitor for new or increased urinary hesitation or retention.

Dispensing and Administration Precautions

• To avoid medication errors, the Institute for Safe Medication Practices (ISMP) recommends that prescribers communicate both the brand and generic names for levomilnacipran (Fetzima) on the prescription order form.

Other General Considerations

• If switching to levomilnacipran from a monoamine oxidase inhibitor (MAOI) intended to treat psychiatric disorders, allow 14 days to elapse between discontinuation of the MAOI and initiation of levomilnacipran. Conversely, if switching from levomilnacipran to an MAOI, allow 7 days to elapse between discontinuation of levomilnacipran and initiation of the MAOI.

• When discontinuing therapy, reduce dosage gradually and monitor for possible withdrawal symptoms; avoid abrupt discontinuance whenever possible. If intolerable symptoms occur following dosage reduction or upon discontinuance of therapy, consider resuming levomilnacipran therapy at the previous dosage and decreasing the dosage at a more gradual rate.

Administration

Oral Administration

Available as extended-release capsules containing 20 mg, 40 mg, 80 mg, or 120 mg of levomilnacipran.

Administer capsules orally once daily, with or without food, at approximately the same time each day. Swallow capsules whole; do not open, chew, or crush.

If dose is missed, take dose as soon as it is remembered, unless it is almost time for next dose. If it is almost time for next dose, skip the missed dose and take next dose at the regularly scheduled time. Do not take 2 doses at the same time.

Dosage

Available as levomilnacipran hydrochloride; dosage expressed in terms of levomilnacipran.

Adults

Major Depressive Disorder

Oral

Initially, 20 mg once daily for 2 days, followed by an increase to 40 mg once daily. Depending on clinical response and tolerability, may increase daily dosage in 40-mg increments at intervals of ≥2 days to a maximum of 120 mg once daily.

Dosage Modification for Concomitant Use with CYP3A4 Inhibitors

Maximum recommended dosage when used concomitantly with strong CYP3A4 inhibitors is 80 mg once daily.

Special Populations

Hepatic Impairment

Mild (Child-Pugh score of 1–6), moderate (Child-Pugh score of 7–9), or severe (Child-Pugh score of 10–13) hepatic impairment: Dosage adjustment not necessary.

Renal Impairment

Mild renal impairment (Cl_cr 60–89 mL/minute): Dosage adjustment not necessary.

Moderate renal impairment (Cl_cr 30–59 mL/minute): Dosage should not exceed 80 mg once daily.

Severe renal impairment (Cl_cr 15–29 mL/minute): Dosage should not exceed 40 mg once daily.

End-stage renal disease: Use not recommended.

Geriatric Patients

Routine dosage adjustment not necessary; however, consider renal clearance of levomilnacipran when determining dosage.

Cautions for Levomilnacipran Hydrochloride

Contraindications

• Known hypersensitivity to levomilnacipran hydrochloride, milnacipran hydrochloride, or any ingredient in the formulation.

• Concurrent or recent (i.e., within 14 days) therapy with a monoamine oxidase inhibitor (MAOI) intended to treat psychiatric disorders. Use of an MAOI intended to treat psychiatric disorders within 7 days of levomilnacipran discontinuance.

• Initiation of levomilnacipran therapy in patients receiving MAOIs such as linezolid or IV methylene blue.

Warnings/Precautions

Warnings

Suicidal Thoughts and Behaviors

Increased risk of suicidal thoughts and behavior observed in adolescent and young adult patients taking antidepressants. (see Boxed Warning.) Depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor patients for clinical worsening or emergence of suicidal thoughts and behaviors, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.

Counsel families and caregivers to monitor for changes in the patient’s behavior, and to report such symptoms to a clinician.

Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emergent suicidal thoughts or behaviors.

Other Warnings and Precautions

Serotonin Syndrome

SNRIs can precipitate serotonin syndrome; potentially life-threatening. Increased risk with concurrent use of other serotonergic drugs (e.g., serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”], tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, amphetamines, St. John's wort [Hypericum perforatum]) and with drugs that impair serotonin metabolism (MAOIs).

Symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).

Concurrent or recent (i.e., within 14 days) therapy with MAOIs intended to treat psychiatric disorders is contraindicated. Do not initiate levomilnacipran in patients treated with other MAOIs such as linezolid or IV methylene blue. If MAOI is necessary, discontinue levomilnacipran before initiating the MAOI.

Monitor patients for serotonin syndrome. If manifestations occur, immediately discontinue levomilnacipran and any concurrently administered serotonergic agents, and initiate supportive symptomatic treatment.

Elevated Blood Pressure

Possible increased blood pressure. Orthostatic hypotension also reported.

Concurrent use with other drugs that increase blood pressure and heart rate not evaluated; use with caution.

Patients with clinically important hypertension or cardiovascular disease not evaluated; use with caution.

Monitor blood pressure prior to initiating levomilnacipran and periodically during treatment. Control preexisting hypertension before initiating levomilnacipran. Use caution in treating patients with preexisting hypertension, cardiovascular conditions, or cerebrovascular conditions that might be compromised by blood pressure increases.

If sustained increase in blood pressure occurs during therapy, consider levomilnacipran discontinuance or other appropriate medical intervention.

Elevated Heart Rate

Increased heart rate reported. Use in patients with cardiac rhythm disorders not systematically evaluated.

Concurrent use with other drugs that increase blood pressure and heart rate not evaluated; use with caution.

Monitor heart rate prior to initiating levomilnacipran and periodically during therapy. Treat preexisting tachyarrhythmias and other cardiovascular disease before initiating levomilnacipran. If sustained increase in heart rate occurs during therapy, consider levomilnacipran discontinuance or other appropriate medical intervention.

Increased Bleeding Risk

Possible increased risk of bleeding (e.g., ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages). Concurrent use of aspirin, NSAIAs, warfarin, or other anticoagulants may increase risk.

Inform patients of the increased risk of bleeding associated with concomitant use of levomilnacipran and aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.

Angle-closure Glaucoma

Pupillary dilation (mydriasis) occurs with many antidepressants, including levomilnacipran, and may trigger an acute attack of angle-closure glaucoma (narrow-angle glaucoma) in patients with anatomically narrow angles who do not have a patent iridectomy.

Avoid treatment with antidepressants, including levomilnacipran, in patients with anatomically narrow angles.

Urinary Hesitation and Retention

SNRIs may affect urethral resistance. Use with caution in patients prone to obstructive urinary disorders.

If symptoms of urinary hesitation, urinary retention, or dysuria develop, consider possibility of drug-related effects. Also consider drug discontinuance or other appropriate medical intervention.

Activation of Mania/Hypomania

Activation of mania and hypomania reported with levomilnacipran and other antidepressants. Screen patients for any personal or family history of bipolar disorder, mania, or hypomania prior to initiating levomilnacipran.

Seizures

Seizures reported. Not systematically evaluated in patients with seizure disorders; use with caution in patients with a history of seizure disorder.

Discontinuation Syndrome

Withdrawal effects (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances [e.g., paresthesias, such as electric shock sensations], anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, seizures) reported following discontinuance of serotonergic antidepressants, particularly when discontinuance was abrupt. Events generally self-limiting, but serious cases reported.

Monitor patients for withdrawal symptoms when discontinuing therapy. Taper dosage gradually whenever possible. If intolerable symptoms occur following dosage reduction or discontinuance, consider resuming previous dosage and decreasing dosage at a more gradual rate.

Hyponatremia/SIADH

SSRIs and SNRIs, including levomilnacipran, may cause hyponatremia; in many cases, SIADH is apparent cause. Increased risk in geriatric patients, and in patients taking diuretics or otherwise volume-depleted.

Discontinue levomilnacipran and institute appropriate medical intervention in patients with symptomatic hyponatremia.

Sexual Dysfunction

SNRIs may cause symptoms of sexual dysfunction. Manifestations include ejaculatory delay or failure, decreased libido, and erectile dysfunction in males, and decreased libido and delayed or absent orgasm in females.

Inquire about sexual function prior to initiating levomilnacipran. Inquire specifically about changes in sexual function during therapy. Obtain a detailed history (including timing of symptom onset) when assessing changes in sexual function. Discuss potential management strategies to support patients in making informed treatment decisions.

Specific Populations

Pregnancy

Pregnancy exposure registry; advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or by visiting [Web].

Available data in pregnant women insufficient to assess for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Risks are associated with untreated depression in pregnancy as well as with exposure to SNRIs, including levomilnacipran, during pregnancy.

Use in the month before delivery may be associated with increased risk of postpartum hemorrhage.

Complications requiring prolonged hospitalization, respiratory support, and tube feeding observed in neonates exposed to SSRIs or SNRIs (including levomilnacipran) late in the third trimester.

Discontinuing antidepressant therapy during pregnancy may increase risk of major depressive disorder relapse. Consider risk of untreated depression when discontinuing or changing antidepressants during pregnancy and postpartum.

Lactation

Unknown whether distributed into human milk; racemic milnacipran present in human milk. Effects of levomilnacipran or milnacipran on breast-fed infant or on milk production unknown.

Agitation, irritability, poor feeding, and poor weight gain reported in infants exposed to SSRIs or SNRIs through breast milk. Monitor infants for these effects.

Consider developmental and health benefits of breast-feeding along with mother’s clinical need for levomilnacipran and any potential adverse effects on breast-fed child from drug or underlying maternal conditions.

Pediatric Use

Safety and efficacy not established; not approved for use in pediatric patients.

Increased risk of suicidal thoughts and behaviors observed in pediatric patients treated with antidepressants. Development of new-onset and sustained hypertension with levomilnacipran therapy more common in pediatric patients compared with adults.

Geriatric Use

No dosage adjustment recommended based on age; however, because levomilnacipran eliminated principally by renal excretion, consider renal function when determining dosage in geriatric patients.

SNRIs, including levomilnacipran, associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.

Hepatic Impairment

Dosage adjustment not necessary in patients with mild (Child-Pugh score of 1–6), moderate (Child-Pugh score of 7–9), or severe (Child-Pugh score of 10–13) hepatic impairment.

Renal Impairment

Levomilnacipran primarily eliminated by renal excretion.

Dosage adjustment not necessary in mild (Cl_cr60-89 mL/minute) renal impairment. However, dosage adjustment recommended in moderate (Cl_cr 30-59 mL/minute) or severe (Cl_cr 15-29 mL/minute) renal impairment.

Use not recommended in patients with end-stage renal disease.

Because of large volume of distribution, hemodialysis not expected to reduce levomilnacipran plasma concentrations.

Pharmacogenomic Considerations

Genetic variations in CYP2D6, CYP2C19, CYP2B6, SLC6A4(gene encoding serotonin transporter), and HTR2A (gene encoding postsynaptic serotonin-2A receptor) can influence metabolism, efficacy, and adverse effect profile of serotonin reuptake inhibitor antidepressants.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed guidelines for dosing or selection of these antidepressants based on genotype testing.

Levomilnacipran is predominantly metabolized by CYP3A4, with minor contributions by CYP2D6 and CYP2C19; therefore, altered metabolism of CYP2D6 and CYP2C19 is not expected to significantly affect levomilnacipran.

There is insufficient evidence to support any clinical recommendations based on SLC6A4and HTR2A genotypes.

Common Adverse Effects

Adverse effects (≥5%): nausea, constipation, hyperhidrosis, increased heart rate, erectile dysfunction, ejaculation disorder, tachycardia, vomiting, palpitations.

Drug Interactions

Primarily metabolized by CYP isoenzyme 3A4 with minor contributions by CYP isoenzymes 2C8, 2C19, 2D6, and 2J2. Does not inhibit CYP isoenzymes 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, or 2E1 in vitro.

Weak substrate of P-glycoprotein (P-gp). Not a substrate of breast cancer resistance protein (BCRP), organic anion-transporting polypeptides (OATP) 1B1 and 1B3, organic cation transporter (OCT) 2, and organic anion transporters (OAT) 1 and 3. Does not inhibit OATP1B1, OATP1B3, OCT2, OAT1, OAT3, or P-gp in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors: Concomitant use with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, itraconazole) increases levomilnacipran exposure.

Levomilnacipran dosage should not exceed 80 mg once daily if administered concomitantly with strong CYP3A4 inhibitors.

Drugs that Increase Blood Pressure and Heart Rate

Concurrent use with other drugs that increase blood pressure and heart rate not evaluated; use with caution.

Specific Drugs

Levomilnacipran Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Relative oral bioavailability of levomilnacipran extended-release capsules is 92% compared with oral solution.

Median time to achieve peak plasma concentrations is 6–8 hours after oral administration.

Concentration at steady state dose-proportional over dosage range of 25—300 mg once daily.

Interconversion between levomilnacipran and its stereoisomer does not appear to occur in humans.

Food

Administration with food does not substantially affect levomilnacipran concentrations.

Special Populations

Exposure increases with increasing severity of renal impairment.

Distribution

Extent

Widely distributed.

Unknown whether distributed into human milk; racemic milnacipran present in human milk.

Plasma Protein Binding

22%.

Elimination

Metabolism

Undergoes desethylation, catalyzed primarily by CYP3A4 with minor contributions by CYP isoenzymes 2C8, 2C19, 2D6, and 2J2, to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran. Both of these oxidative metabolites further undergo glucuronide conjugation.

Elimination Route

Levomilnacipran and metabolites primarily eliminated by renal excretion. Approximately 58% excreted in urine as unchanged drug. Approximately 18% excreted in urine as N-desethyl levomilnacipran, the principal metabolite. Other metabolites excreted in urine include levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%). All metabolites are inactive.

Half-life

Approximately 12 hours.

Special Populations

Pharmacokinetics not substantially affected by mild, moderate, or severe hepatic impairment.

Because of large volume of distribution, hemodialysis not expected to reduce plasma concentrations.

Stability

Storage

Oral

Capsules, extended-release

25°C (excursions permitted between 15–30°C).

Actions

• An SNRI antidepressant; levomilnacipran is the more active 1S, 2R enantiomer of the SNRI milnacipran, which is a racemic mixture of the 1S, 2R and 1R, 2S enantiomers used in the management of fibromyalgia.

• Precise mechanism of antidepressant action not fully elucidated, but thought to be related to potentiation of serotonin and norepinephrine activity in the CNS through selective inhibition of serotonin and norepinephrine reuptake.

• Potently and selectively inhibits reuptake of serotonin and norepinephrine, with preferential activity at norepinephrine transporters. Demonstrated a 2-fold preference for norepinephrine- over serotonin-reuptake inhibition in vitro.

• Lacks substantial affinity for other receptors, ion channels, or transporters tested, including serotonergic (5HT_1–7), α- and β-adrenergic, muscarinic, and histaminergic receptors and calcium, sodium, potassium, and chloride channels in vitro.

• Does not inhibit MAO.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Advise patients and caregivers to monitor for the emergence of suicidal thoughts and behaviors, especially during the first few months of therapy or during periods of dosage adjustment. Instruct patients and caregivers to report such symptoms to their clinician.

• Inform patients that levomilnacipran can be taken with or without food. Advise patients to swallow levomilnacipran extended-release capsules whole and not to chew, crush, or open the capsules.

• If a dose of levomilnacipran is missed, instruct patients to take the dose as soon as they remember. However, if a dose is missed and it is almost time for the next scheduled dose, instruct patients to skip the missed dose and take the next dose at the regularly scheduled time. Advise patients not to take 2 doses of the drug at the same time.

• Instruct patients not to take levomilnacipran with or within 14 days of discontinuing an MAOI and to allow 7 days after discontinuing levomilnacipran before initiating an MAOI.

• Advise patients to notify their clinician if any signs or symptoms of an allergic reaction develop during levomilnacipran therapy (e.g., rash, hives, swelling, difficulty breathing).

• Inform patients of the potential risk of serotonin syndrome, particularly with concurrent use of levomilnacipran and other serotonergic agents (e.g., 5-HT1 receptor agonists [also called triptans], tricyclic antidepressants, opioids, lithium, amphetamines, tryptophan, buspirone, St. John’s Wort). Instruct patients to contact their clinician or report to the emergency room immediately if signs and symptoms of serotonin syndrome develop.

• Advise patients of the risk of increased blood pressure and heart rate with levomilnacipran. Advise patients that their blood pressure and heart rate should be measured periodically during therapy.

• Advise patients about the increased risk of bleeding associated with concomitant use of levomilnacipran with aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation. Advise patients to inform their clinician if they are taking or planning to take any prescription or OTC drugs that increase the risk of bleeding.

• Advise patients that levomilnacipran can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals.

• Advise patients about the risk of urinary hesitation or retention while taking levomilnacipran, particularly in patients prone to obstructive urinary disorders. Instruct patients to consult with their clinician if they develop any problems with urine flow.

• Advise patients and their caregivers to look for signs of activation of mania/hypomania.

• Caution patients about use of levomilnacipran if they have a history of a seizure disorder.

• Advise patients not to abruptly stop taking levomilnacipran without first talking with their clinician. Inform patients that withdrawal symptoms may occur when suddenly stopping levomilnacipran, and they should monitor for withdrawal symptoms.

• Advise patients that hyponatremia may occur due to levomilnacipran therapy. Advise patients of the signs and symptoms of hyponatremia.

• Advise patients that levomilnacipran may cause symptoms of sexual dysfunction in both males and females. Advise patients to discuss any changes in sexual function and potential management strategies with their clinician.

• Advise patients to avoid alcohol consumption during levomilnacipran therapy.

• Advise patients of the risk of cognitive and motor impairment. Advise patients to exercise caution while operating hazardous machinery, including driving a motor vehicle, until they are reasonably certain that levomilnacipran therapy does not adversely affect their ability to engage in such activities.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.

• Advise patients to inform their clinician if they are or plan to become pregnant during levomilnacipran therapy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to levomilnacipran during pregnancy. Advise patients that levomilnacipran may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.

• Advise patients to inform their clinician if they plan to breast-feed. Advise breast-feeding patients receiving levomilnacipran to monitor infants for sedation, agitation, irritability, poor feeding, and poor weight gain and to seek medical care if such signs occur.

• Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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Frequently asked questions

• Does Fetzima cause weight loss or weight gain?
• Does Fetzima cause hair loss?

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