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Uses

Major Depressive Disorder

Levomilnacipran hydrochloride is used for the treatment of major depressive disorder in adults. The short-term antidepressant efficacy of levomilnacipran was mainly established in 3 multicenter, randomized, double-blind, placebo-controlled studies of 8 weeks' duration in 1709 adult outpatients who met DSM-IV-TR criteria for major depressive disorder. Two of the studies compared multiple fixed doses of levomilnacipran and the third was flexible dose in design. In all 3 of these studies, levomilnacipran (40-120 mg once daily given as extended-release capsules) was found to be more effective than placebo in improving depressive symptoms as measured by the mean change from baseline to week 8 on the Montgomery-Asberg Depression Rating Scale (MADRS) total score (the primary efficacy end point). Levomilnacipran was also found to be more effective than placebo in improving the Sheehan Disability Scale (SDS) functional impairment total score (the secondary efficacy end point) in these studies. In the flexible-dose study, 21, 34, and 44% of the levomilnacipran-treated patients were receiving 40, 80, or 120 mg once daily of the drug, respectively, at the end of the treatment; the mean daily dosage was approximately 73 mg. No age-, race-, or gender-related differences in efficacy were noted in these studies.

In a long-term (24-week), double-blind relapse prevention study comparing fixed-dose extended-release levomilnacipran (40, 80, or 120 mg daily) with placebo in 345 adults with major depressive disorder, the relapse rate for levomilnacipran (14%) was lower than that for placebo (21%), but the difference did not achieve statistical significance (possibly because of lower than predicted relapse rates). In a longer-term (48-week), multicenter, open-label, flexible-dose study, extended-release levomilnacipran (40-120 mg daily) was found to be generally well tolerated in adults with major depressive disorder. Most of the adverse effects were mild or moderate in severity and similar to those reported in the short-term studies; in addition, levomilnacipran did not appear to be associated with weight gain during long-term use.

The manufacturer states that the efficacy of levomilnacipran for long-term use (i.e., exceeding 8 weeks) has not been established. If the drug is used for extended periods, the need for continued therapy and the appropriate dosage should be reassessed periodically.

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), serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and other antidepressants (e.g., bupropion, mirtazapine, trazodone). 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. For most patients, an SSRI, SNRI, mirtazapine, or bupropion is considered optimal based on these considerations. Clinicians may consult APA's Practice Guidelines for the Treatment of Patients with Major Depressive Disorder (at http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx) for additional information.

Fibromyalgia

Levomilnacipran is the more active 1S,2R-enantiomer of racemic milnacipran (Savella), which is labeled by the US Food and Drug Administration (FDA) for the management of fibromyalgia.(See Description.) However, the manufacturer states that levomilnacipran (Fetzima) is not approved for the management of fibromyalgia, and that the efficacy and safety of the drug for the management of this condition have not been established.

Dosage and Administration

Administration

Levomilnacipran hydrochloride is commercially available as extended-release capsules, which are administered orally once daily, with or without food, at approximately the same time each day. Extended-release capsules of the drug should be swallowed whole and should not be opened, chewed, cut, or crushed.

Patients receiving levomilnacipran should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

The manufacturer states that at least 2 weeks must elapse between discontinuance of a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders and initiation of levomilnacipran therapy and that at least 7 days should elapse between discontinuance of levomilnacipran and initiation of MAO inhibitor therapy. (See Contraindications, Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions, and Drug Interactions: Monoamine Oxidase Inhibitors.)

Dosage

Dosage of levomilnacipran hydrochloride is expressed in terms of levomilnacipran.

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. Depending on efficacy and tolerability, the daily dosage of levomilnacipran may be increased in increments of 40 mg at intervals of 2 or more days. The maximum recommended dosage of the drug is 120 mg once daily. In a short-term, flexible-dose clinical study of levomilnacipran in major depressive disorder, 21, 34, and 44% of the patients were receiving 40, 80, or 120 mg of the drug once daily, respectively, at the end of the treatment; the mean daily dosage was approximately 73 mg. A titration pack of levomilnacipran hydrochloride (Fetzima) capsules is commercially available for the initial 1-month dosage titration period.

The dosage of levomilnacipran should not exceed 80 mg once daily when used concurrently with potent CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir).(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

While the optimum duration of levomilnacipran therapy has not been established, it generally is agreed that acute depressive episodes require several months or longer of sustained antidepressant therapy. In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with chronic and recurrent major depressive disorder). The manufacturer states that the efficacy of levomilnacipran for long-term use (i.e., exceeding 8 weeks) has not been established. If levomilnacipran is used for extended periods, the need for continued maintenance therapy and the appropriate dosage of the drug should be reassessed periodically.

Discontinuance of Therapy

Because withdrawal effects may occur with discontinuance of serotonergic drugs such as levomilnacipran, abrupt discontinuance should be avoided whenever possible. When levomilnacipran therapy is discontinued, the dosage should be reduced gradually and the patient monitored for possible withdrawal symptoms. If intolerable symptoms occur following dosage reduction or upon discontinuance of therapy, reinstitution of levomilnacipran therapy at the previously prescribed dosage may be considered until symptoms abate. The clinician may resume dosage reduction at that time, but at a more gradual rate.(See Withdrawal of Therapy under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Special Populations

Dosage adjustment is not necessary in patients with mild renal impairment (creatinine clearance of 60-89 mL/minute). In patients with moderate renal impairment (creatinine clearance of 30-59 mL/minute), the maintenance dosage of levomilnacipran should not exceed 80 mg once daily. In patients with severe renal impairment (creatinine clearance of 15-29 mL/minute), the maintenance dosage should not exceed 40 mg once daily. Levomilnacipran is not recommended for use in patients with end-stage renal disease.

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.

Routine dosage adjustment is not necessary in geriatric patients; however, the renal clearance of levomilnacipran should be considered when determining the dosage in such patients.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment based on gender is not recommended.

Cautions

Contraindications

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

Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders. Use of an MAO inhibitor intended to treat psychiatric disorders within 7 days of levomilnacipran discontinuance.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautionsand also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Initiation of levomilnacipran therapy in patients receiving MAO inhibitors such as linezolid or IV methylene blue.(See Drug Interactions: Linezolidand also see Drug Interactions: Methylene Blue.)

Warnings/Precautions

Warnings

Worsening of Depression and Suicidality Risk

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If a decision is made to discontinue therapy, levomilnacipran dosage should be tapered as rapidly as is feasible but consideration should be given to the risks of abrupt discontinuance. FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.

Other Warnings and Precautions

Serotonin Syndrome

Potentially life-threatening serotonin syndrome has been reported with SSRIs and SNRIs alone, but particularly with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [''triptans''], tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort [Hypericum perforatum]) and with drugs that impair the metabolism of serotonin (particularly MAO inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue). 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). Patients receiving levomilnacipran should be monitored for the development of serotonin syndrome.

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated. (See Contraindicationsand also see Drug Interactions: Monoamine Oxidase Inhibitors.) Levomilnacipran also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue.(See Drug Interactions: Linezolidand also see Drug Interactions: Methylene Blue.)

If concurrent therapy with levomilnacipran and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased.(See Drug Interactions.)

If manifestations of serotonin syndrome occur, treatment with levomilnacipran and any concurrently administered serotonergic agents should be immediately discontinued and supportive and symptomatic treatment initiated.

For further information on serotonin syndrome, including manifestations and treatment,

Elevated Blood Pressure

SNRIs, including levomilnacipran, have been associated with increases in blood pressure. In short-term controlled studies, 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. In patients receiving long-term (1 year), open-label treatment with levomilnacipran (40-120 mg once daily), the mean increase from initiation of treatment in systolic blood pressure was 3.9 mm Hg and diastolic blood pressure was 3.1 mm Hg.

In short-term, placebo-controlled studies, 11.6% of patients receiving levomilnacipran met orthostatic hypotension criteria (systolic or diastolic blood pressure) compared with 9.7% of patients receiving placebo. 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.

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.(See Drug Interactions: Drugs that Increase Blood Pressure and Heart Rate.)

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.

The manufacturer states that preexisting hypertension should be controlled before initiating levomilnacipran therapy. In addition, blood pressure should be measured prior to initiating levomilnacipran and then monitored periodically throughout treatment. Caution should be used in treating patients with preexisting hypertension, cardiovascular conditions, or cerebrovascular conditions that might be compromised by increases in blood pressure.

Drug discontinuance or other appropriate medical intervention should be considered in patients who experience a sustained increase in blood pressure during levomilnacipran therapy.

Elevated Heart Rate

SNRIs, including levomilnacipran, have been associated with increases in heart rate. 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. 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.

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.(See Drug Interactions: Drugs that Increase Blood Pressure and Heart Rate.)

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

The manufacturer states that preexisting tachyarrhythmias and other cardiovascular disease should be treated before initiating levomilnacipran therapy. In addition, heart rate should be measured prior to initiating levomilnacipran and periodically during therapy with the drug.

Drug discontinuance or other appropriate medical intervention should be considered in patients who experience a sustained increase in heart rate during levomilnacipran therapy.

Abnormal Bleeding

SNRIs and SSRIs, including levomilnacipran, may increase the risk of bleeding events. Concurrent use of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, and other anticoagulants may add to this risk. 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. Bleeding events related to SNRI and SSRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. The manufacturer recommends that patients be advised of the risk of bleeding associated with the concomitant use of levomilnacipran and aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.(See Drug Interactions: Drugs Affecting Hemostasis.)

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.(See Advice to Patients.)

Urinary Hesitation and Retention

Because of their noradrenergic effect, SNRIs, including levomilnacipran, may affect urethral resistance. 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.

The manufacturer recommends exercising caution if levomilnacipran is used in patients prone to obstructive urinary disorders. If a patient develops symptoms of urinary hesitation, urinary retention, or dysuria during levomilnacipran therapy, the possibility that such effects might be drug-related should be considered; in such cases, discontinuance of the drug or other appropriate medical intervention should be considered.

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. Activation of mania and hypomania also have been reported in a small proportion of patients with mood disorders who were treated with other antidepressants. Levomilnacipran should therefore be used with caution in patients with a personal or family history of bipolar disorder, mania, or hypomania.

Seizures

Levomilnacipran has not been systematically evaluated in patients with seizure disorders; patients with a history of seizures were excluded from clinical trials. One case of seizure has been reported during premarketing clinical trials with the drug. Levomilnacipran therapy should be used with caution in patients with a history of a seizure disorder.

Withdrawal of Therapy

Adverse effects have been reported following discontinuance of serotonergic antidepressants, particularly when discontinuance was abrupt. 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. While these events generally are self-limiting, there have been serious discontinuance symptoms.

Patients should be monitored for possible withdrawal symptoms when discontinuing levomilnacipran therapy. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following dosage reduction or discontinuance of levomilnacipran, the previously prescribed dosage should be reinstituted until symptoms abate; dosage reductions may then be resumed at a more gradual rate.(See Dosage and Administration: Dosage.)

Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion

Although no cases of hyponatremia were reported in levomilnacipran-treated patients in the main clinical trials, treatment with SSRIs and SNRIs may result in hyponatremia. In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium concentrations lower than 110 mmol/L have been reported. Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia. 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. Levomilnacipran should be discontinued and appropriate medical intervention should be instituted in patients with symptomatic hyponatremia.

Specific Populations

Pregnancy

Category C.

Some neonates exposed to SNRIs or SSRIs late in the third trimester of pregnancy have developed complications, which have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries. Such complications may arise immediately upon delivery and usually last several days or up to 2-4 weeks. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying. These clinical features appear to be consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug withdrawal syndrome. In some cases, the clinical picture was consistent with serotonin syndrome (see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions).

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, clinicians may consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103063/pdf/nihms293836.pdf).

Lactation

It is not known whether levomilnacipran is distributed into human milk. Levomilnacipran is distributed into milk in rats. Because of the potential for serious adverse reactions to levomilnacipran in nursing infants, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Clinical studies of levomilnacipran in pediatric patients have not been conducted; therefore, the safety and effectiveness of the drug in pediatric patients have not been established.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants). However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or ideation. No suicides occurred in these pediatric trials. These findings should be carefully considered when assessing potential benefits and risks of levomilnacipran in a child or adolescent for any clinical use.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

The manufacturer states that levomilnacipran is not approved for use in pediatric patients.

Geriatric Use

In clinical trials with levomilnacipran, 2.8% of patients were 65 years of age or older.

In a multiple-dose clinical pharmacokinetic study, individuals older than 65 years of age had slightly higher exposure to levomilnacipran (peak plasma concentration increased by 24% and area under the concentration-time curve [AUC] increased by 26%) than younger individuals (18-45 years of age).

Because levomilnacipran is primarily eliminated by renal excretion, renal clearance of levomilnacipran should be considered when determining the dosage in geriatric patients.

SSRIs and SNRIs, including levomilnacipran, have been associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.(See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Hepatic Impairment

Hepatic elimination of levomilnacipran is low, and the pharmacokinetics of the drug are not substantially affected by hepatic impairment. Therefore, 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.

Renal Impairment

Levomilnacipran is primarily eliminated by renal excretion.

Dosage adjustment is not necessary in patients with mild renal impairment (creatinine clearance of 60-89 mL/minute). 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). Levomilnacipran use is not recommended in patients with end-stage renal disease.(See Dosage and Administration: Special Populations.)

Because of levomilnacipran's large volume of distribution, hemodialysis is not expected to reduce plasma concentrations of the drug.

Common Adverse Effects

Adverse effects reported in at least 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, tachycardia (including sinus tachycardia and postural orthostatic tachycardia syndrome), vomiting, and palpitations. The incidence of erectile dysfunction was dose related in a pooled analysis of these studies.

Drug Interactions

Levomilnacipran is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4 with minor contributions by CYP isoenzymes 2C8, 2C19, 2D6, and 2J2. In vitro studies demonstrate that levomilnacipran does not inhibit CYP isoenzymes 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, or 2E1. Other than CYP3A4-mediated drug interactions, levomilnacipran has a low potential to be involved in clinically important pharmacokinetic drug interactions.

Levomilnacipran is not a substrate or inhibitor 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. No dosage adjustment is necessary when levomilnacipran is used concomitantly with a substrate or inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

Drugs Affecting Hepatic Microsomal Enzymes

Ketoconazole and Other Potent CYP3A4 Inhibitors

Concomitant administration of levomilnacipran and ketoconazole substantially increased levomilnacipran exposure in an in vivo study.

The manufacturer states that the dosage of levomilnacipran should not exceed 80 mg once daily if administered concomitantly with potent CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir).

Inhibitors of Other CYP Isoenzymes

In vitro studies suggest that CYP isoenzymes 2C8, 2C19, 2D6, and 2J2 have minimal contributions to the metabolism of levomilnacipran; therefore, no dosage adjustment of levomilnacipran is necessary when the drug is used concomitantly with inhibitors of these isoenzymes.

Carbamazepine and Other CYP3A4 Inducers

No clinically important changes in levomilnacipran exposure occurred when the drug was administered concomitantly with carbamazepine (a CYP3A4 inducer) in vivo. The manufacturer of levomilnacipran states that dosage adjustment of the drug is not necessary when used concomitantly with a CYP3A4 inducer.

Drugs Metabolized by Hepatic Microsomal Enzymes

Alprazolam and Other CYP3A4 Substrates

No clinically important changes in levomilnacipran exposure occurred when the drug was administered concomitantly with alprazolam (a CYP3A4 substrate) in vivo; alprazolam exposure also was not substantially changed by levomilnacipran (also a CYP3A4 substrate). The manufacturer states that no dosage adjustment of levomilnacipran is necessary when the drug is used concomitantly with a CYP3A4 substrate.

Substrates of Other CYP Isoenzymes

In vitro studies have shown that levomilnacipran does not inhibit CYP isoenzymes 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, or 2E1. No dosage adjustment of concomitantly administered substrates of these isoenzymes is recommended in patients receiving levomilnacipran.

Drugs Affecting P-glycoprotein Transport

Levomilnacipran is a weak substrate of P-glycoprotein (P-gp), but did not inhibit P-gp in in vitro studies. No dosage adjustment of concomitantly administered P-gp substrates is recommended in patients receiving levomilnacipran.

Drugs Affecting Hemostasis

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs were administered concurrently with warfarin or other anticoagulants. The manufacturer of levomilnacipran recommends carefully monitoring patients receiving warfarin during initiation and discontinuance of levomilnacipran therapy.

The risk of bleeding may be increased if levomilnacipran is used concurrently with aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs); levomilnacipran and drugs that affect hemostasis should be used concomitantly with caution.

Monoamine Oxidase Inhibitors

Concomitant use of SSRIs and SNRIs (e.g., levomilnacipran) and monoamine oxidase (MAO) inhibitors is associated with a risk of serious, sometimes fatal, serotonin syndrome. Concomitant use of MAO inhibitors intended to treat psychiatric disorders with levomilnacipran is contraindicated. In addition, at least 2 weeks should elapse between discontinuance of an MAO inhibitor and initiation of levomilnacipran and at least 7 days should elapse between discontinuance of levomilnacipran and initiation of MAO inhibitor therapy. (See Contraindicationsand also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Linezolid

Linezolid, an anti-infective agent that is also a reversible MAO inhibitor, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs and SNRIs. Because of this potential risk, linezolid generally should not be used in patients receiving levomilnacipran. However, the manufacturer and the US Food and Drug Administration (FDA) state that certain life-threatening or urgent situations may necessitate immediate linezolid treatment in a patient receiving a serotonergic drug such as levomilnacipran. In such emergency situations, the availability of alternative anti-infectives should be considered and the benefits of linezolid should be weighed against the risk of serotonin syndrome. If linezolid is indicated in such emergency situations, levomilnacipran must be immediately discontinued and the patient monitored for symptoms of CNS toxicity for 2 weeks or until 24 hours after the last linezolid dose, whichever comes first. Treatment with levomilnacipran may be resumed 24 hours after the last linezolid dose.

If nonemergency use of linezolid is being planned for a patient receiving levomilnacipran, levomilnacipran should be withheld for at least 2 weeks prior to initiating linezolid.

Treatment with levomilnacipran should not be initiated in a patient receiving linezolid. In patients who require more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. Levomilnacipran may be started 24 hours after the last linezolid dose. (See Contraindicationsand also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Methylene Blue

Methylene blue, a potent and reversible inhibitor of MAO-A, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs and SNRIs. Most of these cases occurred when methylene blue was used as a diagnostic (visualizing) dye (1-8 mg/kg IV) during parathyroid surgery; it is unclear whether there is a risk of serotonin syndrome when methylene blue is administered by other routes or in lower IV doses in patients receiving serotonergic drugs. Because of this potential risk, methylene blue generally should not be used in patients receiving levomilnacipran. However, the manufacturer and the FDA state that certain life-threatening or urgent situations may necessitate immediate IV methylene blue treatment in a patient receiving a serotonergic drug such as levomilnacipran. In such emergency situations, the availability of alternative interventions should be considered and the benefits of methylene blue should be weighed against the risk of serotonin syndrome. If methylene blue is indicated in such emergency situations, levomilnacipran must be immediately discontinued and the patient monitored for symptoms of CNS toxicity for 2 weeks or until 24 hours after the last methylene blue dose, whichever comes first. Treatment with levomilnacipran may be resumed 24 hours after the last methylene blue dose.

If nonemergency use of methylene blue is being planned for a patient receiving levomilnacipran, levomilnacipran should be withheld for at least 2 weeks prior to initiating methylene blue treatment.

Treatment with levomilnacipran should not be initiated in a patient receiving IV methylene blue. In patients who require more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. Levomilnacipran may be started 24 hours after the last IV methylene blue dose. (See Contraindicationsand also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

The manufacturer of levomilnacipran states that the risk of administering methylene blue by non-IV routes (e.g., oral tablets, local injection) or in IV doses much lower than 1 mg/kg in patients receiving levomilnacipran is unclear. Clinicians should be aware of the possibility of the emergent symptoms of serotonin syndrome with concomitant use.

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Concomitant use of levomilnacipran and a selective serotonin-reuptake inhibitor (SSRI) or another selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and an SSRI or another SNRI is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran and the concurrently administered SSRI or SNRI should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Tricyclic Antidepressants

Concomitant use of levomilnacipran and a tricyclic antidepressant is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and tricyclic antidepressants is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran, the tricyclic antidepressant, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

5-HT1 Receptor Agonists (''Triptans'')

Concomitant use of levomilnacipran and a triptan is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and triptans is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran, the triptan, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Tryptophan

Concomitant use of levomilnacipran and tryptophan is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and tryptophan is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran, tryptophan, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Serotonergic Drugs

Concomitant use of levomilnacipran and other serotonergic drugs is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and other serotonergic drugs is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

CNS-active Drugs

The risk of concurrent use of levomilnacipran and other CNS-active drugs has not been systematically evaluated. The manufacturer of levomilnacipran recommends using caution when the drug is used in combination with other centrally-acting drugs, including those with a similar mechanism of action.(See Drug Interactions: Alcohol.)

Alcohol

In an in vitro study, alcohol interacted with the extended-release properties of levomilnacipran. If levomilnacipran is taken with alcohol, a pronounced accelerated release of the drug may occur. The manufacturer therefore recommends that levomilnacipran extended-release capsules not be taken with alcohol. (See Drug Interactions: CNS-active Drugs and also see Advice to Patients.)

Buspirone

Concomitant use of levomilnacipran and buspirone is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and buspirone is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran, buspirone, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Diuretics

Concomitant use of levomilnacipran and diuretics may increase the risk of hyponatremia.(See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Fentanyl

Concomitant use of levomilnacipran and fentanyl is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and fentanyl is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran, fentanyl, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Lithium

Concomitant use of levomilnacipran and lithium is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and lithium is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran, lithium, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

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; such combinations should be used with caution.

Tramadol

Concomitant use of levomilnacipran and tramadol is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and tramadol is clinically warranted, caution should be exercised and patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran, tramadol, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

St. John's Wort

Concomitant use of levomilnacipran and St. John's wort (Hypericum perforatum) is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of levomilnacipran and St. John's wort is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with levomilnacipran, St. John's wort, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

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