AHFS Class:

• Selective Serotonin- and Norepinephrine-reuptake Inhibitors 28:16.04.16

Generic Name(s):

• Levomilnacipran Hydrochloride

Levomilnacipran hydrochloride, the 1 S , 2 R -enantiomer of racemic milnacipran hydrochloride, is a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) and an antidepressant.1,2,3,4,5,7,8,9,10,21

Major Depressive Disorder

Levomilnacipran hydrochloride is used for the treatment of major depressive disorder in adults.1

The manufacturer states that levomilnacipran is not approved for use in the treatment of fibromyalgia; efficacy and safety have not been established for this use.1

Clinical Experience

The efficacy of levomilnacipran in the treatment of major depressive disorder was mainly established in 3 multicenter, randomized, double-blind, placebo-controlled studies of 8 weeks' duration enrolling a total of 1709 adult outpatients who met DSM-IV-TR criteria for major depressive disorder.1,2,3,4 Two of the studies (Study 1 and Study 2) compared multiple fixed doses of levomilnacipran (40, 80, or 120 mg once daily; 40 or 80 mg once daily) and the third (Study 3) was flexible dose in design (initiating treatment at 20 mg, titrating up to a maximum of 120 mg once daily based on patient response).1,2,3,4 The primary outcome for all 3 trials was change from baseline to 8 weeks in Montgomery-Asberg Depression Rating Scale (MADRS); the key secondary endpoint was change in Sheehan Disability Scale (SDS) total score.2,3,4

In all 3 of these studies, levomilnacipran (40-120 mg once daily) was found to be more effective than placebo in improving depressive symptoms as measured by the mean change from baseline to week 8 in the MADRS total score.1 In Study 1, the difference in least squares (LS) mean change in MADRS score from placebo was -3.2, -4, or -4.9 for levomilnacipran 40, 80, or 120 mg, respectively.1 For Study 2, the difference in LS mean change in MADRS score from placebo was -3.3 or -3.1 for levomilnacipran 40 or 80 mg, respectively.1 Change in MADRS score in Study 3 for flexible dosing of levomilnacipran was also substantially different from placebo, with a LS mean difference of -3.1.1 Levomilnacipran was also found to be more effective than placebo in improving SDS total score in all 3 studies.1,2,3,4

Study 4 was a randomized, double-blind, placebo-controlled maintenance study evaluating prevention of relapse among patients with major depressive disorder who were treated with levomilnacipran.1,50 The study consisted of 3 phases.50 Patients completed an initial 8-week, open-label, run-in phase during which the dosage of levomilnacipran was titrated up to a maximum of 120 mg once daily based on patient response and tolerability.50 Patients considered responders (MADRS score ≤12) continued in a 12-week stabilization phase, followed by a final randomized, double-blind, 26-week, treatment phase.50 A total of 324 patients were randomized to treatment with either placebo or levomilnacipran in the randomized, double-blind phase.50 The primary outcome was time to first relapse after randomization in the double-blind phase.1 Relapse was defined as a ≥2 point increase in Clinical Global Impressions-Severity (CGI-S) score, risk of suicide, need for hospitalization due to depression, need for alternative antidepressant therapy, or a MADRS total score ≥18 at 2 consecutive visits.50 Time to relapse was substantially longer in patients who continued levomilnacipran compared with patients on placebo.50 Relapse occurred in 14.5 or 24.5% of patients treated with levomilnacipran or placebo, respectively, with a hazard ratio of 0.56 in favor of levomilnacipran.50

In another long-term (24-week), double-blind, relapse prevention study comparing fixed-dose extended-release levomilnacipran (40, 80, or 120 mg once daily) with placebo in 342 adults with major depressive disorder, time to relapse was not substantially longer with levomilnacipran versus placebo.30 The relapse rate for levomilnacipran (13.9%) was lower than that for placebo (20.5%), but the difference was not statistically significant (possibly because of lower than predicted relapse rates).30 In this study, relapse was defined as a MADRS total score ≥22 at 2 consecutive visits, Clinical Global Impressions-Improvement (CGI-I) score increase of ≥2 at 2 consecutive visits, discontinuation due to insufficient response, or a MADRS item 10 score ≥4.30

Clinical Perspective

Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.29,51,52,53 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.29,51,52,53 In general, these drugs have shown similar effectiveness; therefore, treatment is guided by specific patient and drug-related factors.29,52,53

A legacy practice guideline from the American Psychiatric Association (APA) states that the effectiveness of antidepressants in the treatment of major depressive disorder is generally comparable between and within classes of these medications, including selective serotonin reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), MAOIs, and other antidepressants (e.g., bupropion, mirtazapine, trazodone).29 Therefore, the initial selection of an antidepressant can be based mainly 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 (e.g., half-life, actions on cytochrome P-450 [CYP] isoenzymes, other drug interactions); and cost.29

The Department of Veterans Affairs and Department of Defense have developed guidelines for management of major depressive disorder.51 Treatment of uncomplicated major depressive disorder can be initiated with either psychotherapy (e.g., cognitive behavioral therapy) or pharmacotherapy, depending on patient preference; for patients with severe, persistent, or recurrent major depressive disorder, a combination of pharmacotherapy and psychotherapy is suggested.51 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, an SSRI, SNRI, trazodone, vilazodone, or vortioxetine is suggested.51 No evidence is available to suggest superiority of one agent over another.51 The guidelines recommend against using esketamine, ketamine, MAOIs, nefazodone, or TCAs as initial therapy.51 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAOIs or TCAs), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic.51

General

Pretreatment Screening

• Screen patients for a personal or family history of bipolar disorder, mania, or hypomania.1
• Monitor blood pressure and heart rate.1
• Control preexisting hypertension.1
• Treat preexisting tachyarrhythmias and other cardiac disease.1
• Inquire about baseline sexual function.1

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.1
• Monitor blood pressure and heart rate periodically during therapy.1
• Monitor for the emergence of serotonin syndrome during therapy.1
• Monitor for withdrawal symptoms when discontinuing levomilnacipran.1
• Inquire about changes in sexual function during treatment with levomilnacipran.1
• Monitor for signs and symptoms of bleeding, particularly in patients also taking aspirin, non-steroidal anti-inflammatory agents (NSAIAs), warfarin, or other anticoagulants.1
• Monitor for new or increased urinary hesitation or retention.1

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.33

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.1 Conversely, if switching from levomilnacipran to an MAOI, allow 7 days to elapse between discontinuation of levomilnacipran and initiation of the MAOI.1
• When discontinuing therapy, reduce dosage gradually and monitor for possible withdrawal symptoms; avoid abrupt discontinuance whenever possible.1 If intolerable symptoms occur following dosage reduction or discontinuance of therapy, consider resuming levomilnacipran therapy at the previous dosage and decreasing the dosage at a more gradual rate.1

Administration

Levomilnacipran hydrochloride is administered orally; it is commercially available as extended-release capsules containing 20 mg, 40 mg, 80 mg, or 120 mg of levomilnacipran.1

Administer the capsules orally once daily, with or without food, at approximately the same time each day.1 Swallow the capsules whole; do not open, chew, or crush.1

If a dose of levomilnacipran is missed, instruct patients to take the dose as soon as it is remembered, unless it is almost time for the next scheduled dose.1 If 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.1 Advise patients not to take 2 doses at the same time.1

Store levomilnacipran capsules at 25°C (excursions permitted between 15-30°C).1

Dosage

Dosage of levomilnacipran hydrochloride is expressed in terms of levomilnacipran.1

Adults

Major Depressive Disorder

For the management of major depressive disorder in adults, the recommended initial dosage of levomilnacipran is 20 mg once daily for 2 days, followed by an increase to 40 mg once daily.1 Depending on clinical response and tolerability, the daily dosage of levomilnacipran may be increased in increments of 40 mg at intervals of 2 or more days.1 The maximum recommended dosage of the drug is 120 mg once daily.1

Dosage Modification for Concomitant Use with CYP3A4 Inhibitors

The maximum recommended dosage of levomilnacipran should not exceed 80 mg once daily when used concurrently with strong cytochrome P-450 (CYP) 3A4 inhibitors.1

Special Populations

Hepatic Impairment

Dosage adjustment is 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.1

Renal Impairment

Dosage adjustment is not necessary in patients with mild renal impairment (creatinine clearance of 60-89 mL/minute).1

In patients with moderate renal impairment (creatinine clearance of 30-59 mL/minute), the dosage of levomilnacipran should not exceed 80 mg once daily.1

In patients with severe renal impairment (creatinine clearance of 15-29 mL/minute), the dosage of levomilnacipran should not exceed 40 mg once daily.1

Levomilnacipran is not recommended for use in patients with end-stage renal disease.1

Geriatric Patients

Routine dosage adjustment is not necessary in geriatric patients; however, consider the renal clearance of levomilnacipran when determining the dosage in such patients.1

Contraindications

• Known hypersensitivity to levomilnacipran hydrochloride, milnacipran hydrochloride, or any ingredient in the formulation.1
• Concurrent or recent (i.e., within 14 days) therapy with a monoamine oxidase inhibitor (MAOI) intended to treat psychiatric disorders.1 Use of an MAOI intended to treat psychiatric disorders within 7 days of levomilnacipran discontinuance.1
• Initiation of levomilnacipran therapy in patients receiving MAOIs such as linezolid or IV methylene blue.1

Warnings/Precautions

Warnings

Suicidal Thoughts and Behaviors

A boxed warning on the increased risk of suicidal thoughts and behavior in adolescent and young adult patients taking antidepressants is included in the prescribing information for levomilnacipran.1 In pooled analyses of placebo-controlled trials of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other drug classes) that included approximately 77,000 adult patients and 4500 pediatric patients, the incidence of suicidal thoughts and behaviors was greater in patients ≤24 years of age treated with an antidepressant compared to those treated with placebo.1 The incidence of suicidal thoughts and behaviors varied across different antidepressants and indications; however, the risk was increased in young patients for most studied drugs, with the highest incidence in patients with major depressive disorder.1 A reduced risk of suicidal thoughts and behaviors was observed with antidepressants compared with placebo in adults 24-65 years of age and ≥65 years of age.1 Whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use (i.e., >4 months) is unknown.1 However, data from placebo-controlled maintenance trials in adults with major depressive disorder demonstrate that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.1

Monitor all patients treated with antidepressants for any indication of 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.1 Counsel families and caregivers to monitor for changes in the patient's behavior, and to report such symptoms to a clinician.1 Consider changing the therapeutic regimen or discontinuing levomilnacipran in patients whose depression is persistently worse or in patients experiencing emergent suicidal thoughts or behaviors.1

Other Warnings and Precautions

Serotonin Syndrome

Selective serotonin- and norepinephrine- reuptake inhibitors (SNRIs) such as levomilnacipran can precipitate serotonin syndrome, a potentially life-threatening condition.1 Serotonin syndrome can occur when these drugs are used alone, but the risk is increased with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”], tricyclic antidepressants [TCAs], buspirone, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, amphetamines, and St. John's wort [ Hypericum perforatum ]) and with drugs that impair the metabolism of serotonin (i.e., MAOIs).1

Manifestations of serotonin syndrome 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).1

Concurrent or recent (i.e., within 14 days) use of MAOIs with levomilnacipran is contraindicated.1 Do not initiate levomilnacipran in patients who are being treated with MAOIs such as linezolid or IV methylene blue.1 If it is necessary to initiate treatment with an MAOI such as linezolid or IV methylene blue in a patient treated with levomilnacipran, discontinue levomilnacipran before initiating the MAOI.1

Monitor patients receiving levomilnacipran for the development of serotonin syndrome.1 If manifestations of serotonin syndrome occur, discontinue treatment with levomilnacipran and any concurrently administered serotonergic agents immediately, and initiate supportive symptomatic treatment.1

If concurrent therapy with levomilnacipran and other serotonergic drugs is clinically warranted, inform patients of the potential increased risk for serotonin syndrome and monitor for symptoms.1

Elevated Blood Pressure

SNRIs, including levomilnacipran, have been associated with increases in blood pressure.1 In short-term controlled studies in adults, mean increases in systolic and diastolic blood pressure from initiation of treatment to end of treatment were 3 and 3.2 mm Hg, respectively, in levomilnacipran-treated patients compared with no change in the placebo group.1 In adult patients receiving long-term (1 year), open-label treatment with levomilnacipran (40-120 mg once daily), the mean increase in systolic blood pressure was 3.9 mm Hg and mean increase in diastolic blood pressure was 3.1 mm Hg.1

In short-term, placebo-controlled studies in adults, 11.6% of patients receiving levomilnacipran met orthostatic hypotension criteria (systolic or diastolic blood pressure) compared with 9.7% of patients receiving placebo.1 Orthostatic reductions in diastolic blood pressure of 10 mm Hg or greater occurred in 5.8, 6.1, and 9.8% of patients receiving 40, 80, and 120 mg daily of levomilnacipran, respectively, compared with 6.2% of those receiving placebo.1

In short-term, placebo- and active-controlled studies in pediatric patients 7 to <18 years of age with major depressive disorder, new-onset hypertension (2 systolic and/or diastolic blood pressure measurements in the stage I hypertension range and/or 1 measurement in the stage II range) occurred in 36.2% of patients receiving levomilnacipran, compared with 20.7% of patients receiving placebo.1 Elevations in either systolic or diastolic blood pressure leading to measures at or above the stage II hypertension threshold occurred in 12.1% of pediatric patients receiving levomilnacipran, compared to 7.5% of patients receiving placebo.1 Sustained hypertension (≥3 consecutive systolic or diastolic blood pressure measurements at or above the stage I hypertension threshold) occurred in 15% of pediatric patients receiving levomilnacipran, compared to 4% of patients receiving placebo.1 The safety and effectiveness of levomilnacipran have not been established in pediatric patients.1

Concurrent use of levomilnacipran with other drugs that increase blood pressure and heart rate has not been evaluated, and the manufacturer recommends that such combinations be used with caution.1 Effects of levomilnacipran on blood pressure in patients with clinically important hypertension or cardiovascular disease have not been systematically evaluated; the drug should be used with caution in such patients.1

Measure blood pressure prior to initiating levomilnacipran and periodically throughout treatment.1 Control preexisting hypertension before initiating levomilnacipran therapy.1 Exercise caution in treating patients with preexisting hypertension, cardiovascular conditions, or cerebrovascular conditions that might be compromised by increases in blood pressure.1 Consider drug discontinuance or other appropriate medical intervention in patients who experience a sustained increase in blood pressure during levomilnacipran therapy.1

Elevated Heart Rate

SNRIs, including levomilnacipran, have been associated with increases in heart rate.1 In short-term clinical trials, levomilnacipran was associated with a mean increase in heart rate of 7.4 beats per minute compared with a mean decrease of 0.3 beats per minute with placebo.1 The heart rate increase was 7.2, 7.2, and 9.1 beats per minute in patients receiving 40, 80, and 120 mg of levomilnacipran daily, respectively.1

Concurrent use of levomilnacipran with other drugs that increase blood pressure and heart rate has not been evaluated, and the manufacturer recommends that such combinations be used with caution.1

Levomilnacipran has not been systematically evaluated in patients with cardiac rhythm disorders.1

Measure heart rate prior to initiating levomilnacipran and periodically during therapy with the drug.1 Treat preexisting tachyarrhythmias and other cardiovascular disease before initiating levomilnacipran therapy.1 Consider drug discontinuance or other appropriate medical intervention in patients who experience a sustained increase in heart rate during levomilnacipran therapy.1

Increased Bleeding Risk

Drugs that interfere with serotonin reuptake, including levomilnacipran, may increase the risk of bleeding events.1 Concurrent use of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, and other anticoagulants may add to this risk.1 Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding.1 In observational studies, exposure to SNRIs, particularly during the month before delivery, has been associated with a <2-fold increase in the risk of postpartum hemorrhage.1 Bleeding events related to SNRI and SSRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1

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.1

Angle-closure Glaucoma

The pupillary dilation (mydriasis) that occurs following the use of many antidepressant agents, including levomilnacipran, 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.1

Avoid treatment with antidepressants, including levomilnacipran, in patients with anatomically narrow angles.1

Urinary Hesitation and Retention

Because of their noradrenergic effect, SNRIs, including levomilnacipran, may affect urethral resistance.1 In controlled short-term trials, urinary hesitation occurred in 4, 5, and 6% of patients receiving levomilnacipran daily dosages of 40, 80, and 120 mg, respectively, compared with none of those receiving placebo.1

Exercise caution if levomilnacipran is used in patients prone to obstructive urinary disorders.1 If a patient develops symptoms of urinary hesitation, urinary retention, or dysuria during levomilnacipran therapy, consider the possibility that such effects may be drug-related; in such cases, consider discontinuance of the drug or other appropriate medical intervention.1

Activation of Mania/Hypomania

Symptoms of mania or hypomania were reported in 0.2% of patients receiving levomilnacipran and in 0.2% of patients receiving placebo in clinical studies.1 Activation of mania and hypomania also have been reported in a small proportion of patients with mood disorders who were treated with other antidepressants.1

Prior to initiating levomilnacipran, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.1

Seizures

One case of seizure has been reported during premarketing clinical trials with levomilnacipran.1 Levomilnacipran has not been systematically evaluated in patients with seizure disorders; patients with a history of seizures were excluded from clinical trials.1 Prescribe levomilnacipran with caution in patients with a history of seizure disorder.1

Discontinuation Syndrome

Adverse effects have been reported following discontinuance of serotonergic antidepressants, particularly when discontinuance was abrupt.1 These withdrawal effects include dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.1 While these events generally are self-limiting, there have been serious discontinuance symptoms.1

Monitor patients for possible withdrawal symptoms when discontinuing levomilnacipran therapy.1 Reduce levomilnacipran dosage gradually whenever possible.1 If intolerable symptoms occur following dosage reduction or discontinuance of levomilnacipran, consider resuming the previously prescribed dosage and decreasing the dosage at a more gradual rate.1

Hyponatremia

Hyponatremia may occur with use of SSRIs and SNRIs, including levomilnacipran.1 In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).1 Cases with serum sodium concentrations <110 mmol/L have been reported.1 Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia.1 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death.1

Discontinue levomilnacipran in patients with symptomatic hyponatremia, and initiate appropriate medical intervention.1

Sexual Dysfunction

SNRIs, including levomilnacipran, may cause symptoms of sexual dysfunction.1 SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction in males; in females, SNRI use can cause decreased libido and delayed or absent orgasm.1

Prescribers should inquire about sexual function prior to initiating levomilnacipran therapy.1 Prescribers should also inquire specifically about changes in sexual function during therapy, since patients may not spontaneously report sexual function.1 Obtain a detailed history (including timing of symptom onset) when assessing changes in sexual function, since sexual symptoms may have other causes, including the underlying psychiatric disorder.1 Discuss potential management strategies to support patients in making informed treatment decisions.1

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to antidepressants during pregnancy.1 Advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or by visiting [Web].1

Available data on levomilnacipran use in pregnant women are insufficient to assess for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 There are risks associated with untreated depression in pregnancy as well as with exposure to SNRIs, including levomilnacipran, during pregnancy.1

In observational studies, exposure to SNRIs, particularly during the month before delivery, has been associated with a <2-fold increase in the risk of postpartum hemorrhage.1 Neonates exposed to SNRIs or SSRIs, including levomilnacipran, late in the third trimester of pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.1 Clinical findings reported to date in neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.1 These findings appear to be consistent with either a direct toxic effect of SNRIs or SSRIs or, possibly, a drug withdrawal syndrome.1 In some cases, the clinical picture was consistent with serotonin syndrome.1

In animal reproduction studies, no malformations were observed when levomilnacipran was administered during the period of organogenesis at doses up to 8 or 16 times the maximum recommended human dose (MRHD) of 120 mg on a mg/m² basis in rats and rabbits, respectively.1 However, an increase in early post-natal rat pup mortality was observed at a dose equivalent to 5 times the MRHD given during pregnancy and lactation.1

There are risks associated with untreated depression in pregnancy.1 In a prospective longitudinal study, women who discontinued antidepressant therapy during pregnancy were more likely to experience a relapse of major depressive disorder than women who continued antidepressants.1 Consider the risk of untreated depression when discontinuing or changing antidepressants during pregnancy and postpartum.1

Lactation

It is unknown whether levomilnacipran is distributed into human milk; however, racemic milnacipran is present in human milk.1 The effects of levomilnacipran or milnacipran on the breast-fed infant or on milk production are also unknown.1

There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to SSRIs or SNRIs through breast milk.1 Monitor infants exposed to levomilnacipran for these effects.1

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for levomilnacipran and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal conditions.1

Pediatric Use

The safety and effectiveness of levomilnacipran in pediatric patients for the treatment of major depressive disorder have not been established; levomilnacipran is not approved for use in pediatric patients.1 In 2 randomized, double-blind, placebo- and active-controlled trials in pediatric patients (7-17 years of age) with major depressive disorder, levomilnacipran was not superior to placebo in terms of change from baseline to week 8 in the Children's Depression Rating Scale-Revised (CDRS-R) total score.1

An increased risk of suicidal thoughts and behaviors was observed in pediatric patients treated with antidepressants.1 Additionally, pediatric patients receiving levomilnacipran were more likely to develop new-onset and sustained hypertension compared to adults in clinical trials.1

Geriatric Use

In the 8-week clinical trials with levomilnacipran, 2.8% of patients were ≥65 years of age.1

According to the manufacturer, no dosage adjustment is recommended on the basis of age.1 However, because levomilnacipran is primarily eliminated by renal excretion, consider the renal clearance of levomilnacipran when determining the dosage in geriatric patients.1

SNRIs, including levomilnacipran, have been associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.1

Hepatic Impairment

Dosage adjustment of levomilnacipran is 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.1

Renal Impairment

Levomilnacipran is primarily eliminated by renal excretion.1 Dosage adjustment is not necessary in patients with mild renal impairment (creatinine clearance of 60-89 mL/minute).1 However, dosage adjustment is recommended in patients with moderate (creatinine clearance of 30-59 mL/minute) or severe renal impairment (creatinine clearance of 15-29 mL/minute).1 Levomilnacipran use is not recommended in patients with end-stage renal disease.1 Because of the large volume of distribution of levomilnacipran, hemodialysis is not expected to reduce plasma concentrations of the drug.1

Common Adverse Effects

Adverse effects reported in ≥5% of patients with major depressive disorder receiving levomilnacipran and at an incidence of at least twice that reported with placebo in controlled studies include nausea, constipation, hyperhidrosis, increased heart rate, erectile dysfunction, ejaculation disorder, tachycardia, vomiting, and palpitations.1

Levomilnacipran is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4 with minor contributions by CYP isoenzymes 2C8, 2C19, 2D6, and 2J2.1 In vitro studies demonstrate that levomilnacipran does not inhibit CYP isoenzymes 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, or 2E1.1

Levomilnacipran is a weak substrate of P-glycoprotein (P-gp), but is 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 3.1 In vitro studies demonstrate that levomilnacipran does not inhibit OATP1B1, OATP1B3, OCT2, OAT1, OAT3, or P-gp.1

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A4 Inhibitors

Concomitant use of levomilnacipran with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, itraconazole) increases levomilnacipran exposure.1

The dosage of levomilnacipran should not exceed 80 mg once daily if administered concomitantly with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir).1

Drugs Affecting Hemostasis

Concomitant use of levomilnacipran with an antiplatelet or anticoagulant drug (e.g., an nonsteroidal anti-inflammatory agent [NSAIA], aspirin, warfarin) may potentiate the risk of bleeding; this may be due to the effect of levomilnacipran on the release of serotonin by platelets.1

Closely monitor for bleeding in patients receiving an antiplatelet or anticoagulant drug when levomilnacipran is initiated or discontinued.1

Drugs that Increase Blood Pressure and Heart Rate

Concurrent use of levomilnacipran with other drugs that increase blood pressure and heart rate has not been evaluated; use such combinations with caution.1

Alcohol

Concomitant use of levomilnacipran with alcohol may cause an accelerated release of the drug.1

In vitro, levomilnacipran release from the extended-release capsules (20, 40, 80, and 120 mg) at 2 hours increased by approximately 9.5, 23, and 56% in the presence of 5, 20, and 40% (v/v) alcohol, respectively.1 The effect of 40% alcohol resulted in nearly complete drug release in 4 hours.1 No in vivo study has evaluated the effect of alcohol on drug exposure to date.1

Avoid concomitant use of levomilnacipran and alcohol.1

Diuretics

Concomitant use of levomilnacipran and diuretics may increase the risk of hyponatremia.1

Monoamine Oxidase Inhibitors

Concomitant use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs; e.g., levomilnacipran) with MAOIs (e.g., selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue) increases the risk of serotonin syndrome.1

Concomitant use of levomilnacipran with MAOIs intended to treat psychiatric disorders is contraindicated.1 Concomitant use of an MAOI intended to treat psychiatric disorders within 7 days of stopping levomilnacipran is contraindicated; use of levomilnacipran within 14 days after stopping an MAOI intended to treat psychiatric disorders is also contraindicated.1

Concomitant use of levomilnacipran with linezolid or IV methylene blue is contraindicated.1

Serotonergic Drugs

Concomitant use of levomilnacipran and other serotonergic drugs (e.g., SSRIs, SNRIs, tricyclic antidepressants [TCAs], 5-hydroxytryptamine type 1 receptor agonists [“triptans”], opioids [e.g., fentanyl, tramadol, meperidine, methadone], amphetamines, lithium, buspirone, tryptophan, St. John's wort [ Hypericum perforatum ]) increases the risk of serotonin syndrome.1

If concomitant use of levomilnacipran with another serotonergic drug is warranted, advise patients of the increased risk for serotonin syndrome and monitor for symptoms.1 If manifestations of serotonin syndrome occur, discontinue levomilnacipran and/or the concomitant serotonergic drug immediately, and initiate supportive symptomatic treatment.1

Description

Levomilnacipran hydrochloride is a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI).1,9,10,21 Levomilnacipran is the more active 1 S , 2 R enantiomer of the SNRI milnacipran, which is a racemic mixture of the 1 S , 2 R and 1 R , 2 S enantiomers that is used in the management of fibromyalgia.8,9,21 The precise mechanism of the antidepressant effect of levomilnacipran is not fully understood, but is thought to be related to potentiation of serotonin and norepinephrine activity in the CNS through selective inhibition of serotonin and norepinephrine reuptake.1

Levomilnacipran potently and selectively inhibits the reuptake of serotonin and norepinephrine, with preferential activity at the norepinephrine transporters.1,9,21 Levomilnacipran demonstrated a 2-fold preference for norepinephrine- over serotonin-reuptake inhibition in vitro.9,21 In in vitro studies, the drug lacked substantial affinity for other receptors, ion channels, or transporters tested, including serotonergic (5-HT_1-7), α- and β-adrenergic, muscarinic, and histaminergic receptors, and calcium, sodium, potassium, and chloride channels.1 Levomilnacipran does not inhibit monoamine oxidase (MAO).1,9

The concentration of levomilnacipran at steady state is dose-proportional over the dosage range of 25—300 mg (2.5 times the maximum recommended dosage) once daily.1 Interconversion between levomilnacipran and its stereoisomer does not appear to occur in humans.1

Relative oral bioavailability of levomilnacipran hydrochloride extended-release capsules is 92% compared with the oral solution.1 The median time to achieve peak plasma concentrations of levomilnacipran is 6-8 hours following oral administration of the drug.1 Administration of the drug with food did not substantially affect levomilnacipran concentrations.1

Levomilnacipran is widely distributed and 22% protein bound.1 The elimination half-life of the drug is approximately 12 hours.1 Levomilnacipran undergoes desethylation, which is catalyzed primarily by cytochrome P-450 (CYP) isoenzyme 3A4 with minor contributions by CYP isoenzymes 2C8, 2C19, 2D6, and 2J2, to form desethyl levomilnacipran; the drug also undergoes hydroxylation to form p -hydroxy-levomilnacipran.1 Both of these oxidative metabolites further undergo glucuronide conjugation.1

Following oral administration of a single radiolabeled dose of levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged drug.1 The principal metabolite excreted in urine is N -desethyl levomilnacipran, which accounted for approximately 18% of the dose; other metabolites excreted in urine include levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p -hydroxy levomilnacipran glucuronide (1%), and p -hydroxy levomilnacipran (1%).1 All of these metabolites are inactive.1

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).3
• 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.1 Instruct patients and caregivers to report such symptoms to their clinician.1
• Inform patients that levomilnacipran can be taken with or without food.1 Advise patients to swallow levomilnacipran extended-release capsules whole and not to chew, crush, or open the capsules.1
• If a dose of levomilnacipran is missed, instruct patients to take the dose as soon as they remember.1 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.1 Advise patients not to take 2 doses of the drug at the same time.1
• Instruct patients not to take levomilnacipran with or within 14 days of discontinuing a monoamine oxidase inhibitor (MAOI) and to allow 7 days after discontinuing levomilnacipran before initiating an MAOI.1
• 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).1
• 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).1 Instruct patients to contact their clinician or report to the emergency room immediately if signs and symptoms of serotonin syndrome develop.1
• Advise patients of the risk of increased blood pressure and heart rate with levomilnacipran.1 Advise patients that their blood pressure and heart rate should be measured periodically during therapy.1
• Advise patients about the increased risk of bleeding associated with concomitant use of levomilnacipran with aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, or other drugs that affect coagulation.1 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.1
• Advise patients that levomilnacipran can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals.1
• Advise patients about the risk of urinary hesitation or retention while taking levomilnacipran, particularly in patients prone to obstructive urinary disorders.1 Instruct patients to consult with their clinician if they develop any problems with urine flow.1
• Advise patients and their caregivers to look for signs of activation of mania/hypomania.1
• Caution patients about use of levomilnacipran if they have a history of a seizure disorder.1
• Advise patients not to abruptly stop taking levomilnacipran without first talking with their clinician.1 Inform patients that withdrawal symptoms may occur when suddenly stopping levomilnacipran, and they should monitor for withdrawal symptoms.1
• Advise patients that hyponatremia may occur due to levomilnacipran therapy.1 Advise patients of the signs and symptoms of hyponatremia.1
• Advise patients that levomilnacipran may cause symptoms of sexual dysfunction in both males and females.1 Advise patients to discuss any changes in sexual function and potential management strategies with their clinician.1
• Advise patients to avoid alcohol consumption during levomilnacipran therapy.1
• Advise patients of the risk of cognitive and motor impairment.1 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.1
• 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.1
• Advise patients to inform their clinician if they are or plan to become pregnant during levomilnacipran therapy.1 Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to levomilnacipran during pregnancy.1 Advise patients that levomilnacipran may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.1
• Advise patients to inform their clinician if they plan to breast-feed.1 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.1
• Advise patients of other important precautionary information.1

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.

1. AbbVie, Inc. Fetzima^® (levomilnacipran hydrochloride) extended-release capsules prescribing information. North Chicago, IL; 2024 Apr.

2. Asnis GM, Bose A, Gommoll CP et al. Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized, double-blind, placebo-controlled study. J Clin Psychiatry . 2013; 74:242-8. [PubMed 23561229]

3. Bakish D, Bose A, Gommoll C et al. Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study. J Psychiatry Neurosci . 2014; 39(1):40-49.

4. Sambunaris A, Bose A, Gommoll CP et al. A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder. J Clin Psychopharmacol . 2014; :34(1):47-56.

5. Mago R, Forero G, Greenberg WM et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig . 2013; 33:761-71. [PubMed 23999912]

7. Montgomery SA, Mansuy L, Ruth A et al. Efficacy and safety of levomilnacipran sustained release in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry . 2013; 74:363-9. [PubMed 23656841]

8. Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?. Int J Clin Pract . 2013; 67:1089-104. [PubMed 24016209]

9. Auclair AL, Martel JC, Assié MB et al. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology . 2013; 70:338-47. [PubMed 23499664]

10. Anon. Levomilnacipran (Fetzima): a new SNRI for depression. Med Lett Drugs Ther . 2013; 55:101-2. [PubMed 24419243]

21. Mago R, Mahajan R, Thase ME. Levomilnacipran: a newly approved drug for treatment of major depressive disorder. Expert Rev Clin Pharmacol . 2014; 7:137-45. [PubMed 24524592]

29. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry . 2010; 167(suppl) [Web]

30. Shiovitz T, Greenberg W, Chen C, et al. A randomized, double-blind, placebo-controlled trial of the effiacy and safety of levomilnacipran ER 40-120 mg/day for prevention of relapse in patients with major depressive disorder. Innov Clin Neurosci . 2014;11(1-2):10-22.

33. Institute for Safe Medication Practices (ISMP). ISMP list of confused drug names. ISMP; 2023.

50. Durgam S, Chen C, Migliore R, et al. Relapse prevention with levomilnacipran ER in adults with major depressive disorder: A multicenter, randomized, double-blind, placebo-controlled study. Depress Anxiety . 2019;36:225-234.

51. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder, 2022. [Web]

52. American Psychological Association. (2019). Clinical practice guideline for the treatment of depression across three age cohorts. Retrieved from http://www.apa.org/depression-guideline

53. Drugs for depression. Med Lett Drugs Ther. 2023 Dec 11;65(1691):193-200. doi: 10.58347/tml.2023.1691a. PMID: 38133585.