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Black Box Warning
WARNING
See full prescribing information for complete Boxed Warning.
SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber .
levomilnacipran hydrochloride is not approved for use in pediatric patients
Levomilnacipran hydrochloride , a serotonin and norepinephrine reuptake inhibitor (SNRI) is indicated for the treatment of major depressive disorder (MDD). The efficacy of levomilnacipran hydrochloride was established in three 8-week, randomized, double-blind, placebo-controlled studies in adult patients with a diagnosis of MDD .
Limitation of Use: levomilnacipran hydrochloride is not approved for the management of fibromyalgia. The efficacy and safety of levomilnacipran hydrochloride for the management of fibromyalgia have not been established.
Dosing Information
General Instruction for Use
The recommended dose range for levomilnacipran hydrochloride is 40 mg to 120 mg once daily, with or without food. Levomilnacipran hydrochloride should be initiated at 20 mg once daily for 2 days and then increased to 40 mg once daily. Based on efficacy and tolerability, levomilnacipran hydrochloride may then be increased in increments of 40 mg at intervals of 2 or more days. The maximum recommended dose is 120 mg once daily.
Levomilnacipran hydrochloride should be taken at approximately the same time each day. levomilnacipran hydrochloride should be swallowed whole. Do not open, chew or crush the capsule.
Maintenance/Continuation/Extended Treatment
It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Patients should be reassessed periodically to determine the need for maintenance treatment and the appropriate dose for treatment. The efficacy of levomilnacipran hydrochloride has not been established beyond 8 weeks.
Special Populations
Renal Impairment: Dose adjustment is not recommended in patients with mild renal impairment (creatinine clearance of 60-89 mL/min). For patients with moderate renal impairment (creatinine clearance of 30-59 mL/min), the maintenance dose should not exceed 80 mg once daily. For patients with severe renal impairment (creatinine clearance of 15-29 mL/min), the maintenance dose should not exceed 40 mg once daily. levomilnacipran hydrochloride is not recommended for patients with end stage renal disease.
Discontinuing Treatment
Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as levomilnacipran hydrochloride . Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing levomilnacipran hydrochloride . If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate .
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with levomilnacipran hydrochloride . Conversely, at least 7 days should be allowed after stopping levomilnacipran hydrochloride before starting an MAOI antidepressant .
Use of levomilnacipran hydrochloride with Other MAOIs such as Linezolid or Methylene Blue
Do not start levomilnacipran hydrochloride in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.
In some cases, a patient already receiving levomilnacipran hydrochloride therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, levomilnacipran hydrochloride should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with levomilnacipran hydrochloride may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue .
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with levomilnacipran hydrochloride is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use .
Use of levomilnacipran hydrochloride with Strong Inhibitors of Cytochrome P450 (CYP3A4) Enzyme
The use of MAOIs intended to treat psychiatric disorders with levomilnacipran hydrochloride or within 7 days of stopping treatment with levomilnacipran hydrochloride is contraindicated because of an increased risk of serotonin syndrome. The use of levomilnacipran hydrochloride within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated
Starting levomilnacipran hydrochloride in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome
Warnings
WARNING
See full prescribing information for complete Boxed Warning.
SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber .
levomilnacipran hydrochloride is not approved for use in pediatric patients
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phase of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in TABLE 1
This image is provided by the National Library of Medicine.
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms 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.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for levomilnacipran hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Screening patients for bipolar disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that levomilnacipran hydrochloride is not approved for use in treating bipolar depression.
The concomitant use of levomilnacipran hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated. Levomilnacipran hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking levomilnacipran hydrochloride . Levomilnacipran hydrochloride should be discontinued before initiating treatment with the MAOI
Treatment with levomilnacipran hydrochloride and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Elevated Blood Pressure
SNRIs, including levomilnacipran hydrochloride , have been associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically throughout levomilnacipran hydrochloride treatment. Pre-existing hypertension should be controlled before initiating treatment with levomilnacipran hydrochloride . Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. For patients who experience a sustained increase in blood pressure while receiving levomilnacipran hydrochloride , discontinuation or other appropriate medical intervention should be considered.
TABLE 2 shows the mean changes in blood pressure, sustained hypertension, and upward shifts in hypertensive status that were observed in levomilnacipran hydrochloride -treated patients in the short-term placebo-controlled studies.
This image is provided by the National Library of Medicine.
In the short-term, placebo-controlled MDD studies, the mean increase from initiation of treatment in systolic BP was 3 mm Hg and diastolic BP was 3.2 mm Hg, as compared to no change in the placebo group. There were no dose-related changes in systolic and diastolic blood pressure observed.
In patients exposed to one-year, open-label treatment of levomilnacipran hydrochloride (doses range from 40-120 mg once daily), the mean change from initiation of treatment in systolic BP was 3.9 mm Hg and diastolic BP was 3.1 mm Hg.
In the short-term, placebo-controlled studies, 11.6 % of patients met orthostatic hypotension criteria (SBP or DBP) in the levomilnacipran hydrochloride group compared to 9.7% in the placebo group. Orthostatic reductions of blood pressure ≥ 10 mm Hg in DBP occurred in 5.8%, 6.1% and 9.8% of levomilnacipran hydrochloride -treated patients with doses of 40, 80 and 120 mg/day respectively, compared to 6.2% of placebo-treated patients.
Concomitant use of levomilnacipran hydrochloride with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. Effects of levomilnacipran hydrochloride on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. levomilnacipran hydrochloride should be used with caution in these patients.
Elevated Heart Rate
SNRIs including levomilnacipran hydrochloride have been associated with increased heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout levomilnacipran hydrochloride treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with levomilnacipran hydrochloride . For patients who experience a sustained increase in heart rate while receiving levomilnacipran hydrochloride , discontinuation or other appropriate medical intervention should be considered.
In short-term clinical studies, levomilnacipran hydrochloride treatment was associated with a mean increase in heart rate of 7.4 beats per minute (bpm) compared to a mean decrease of 0.3 bpm in placebo-treated patients. Heart rate increase in levomilnacipran hydrochloride -treated patients receiving doses of 40 mg, 80 mg and 120 mg was 7.2, 7.2, and 9.1 bpm.
levomilnacipran hydrochloride has not been systematically evaluated in patients with a cardiac rhythm disorder.
Abnormal Bleeding
SSRIs and SNRIs, including levomilnacipran hydrochloride , may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of levomilnacipran hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
Angle Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including levomilnacipran hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Urinary Hesitation or Retention
The noradrenergic effect of SNRIs including levomilnacipran hydrochloride , can affect urethral resistance. In the controlled short-term studies, urinary hesitation occurred in 4%, 5% and 6% of levomilnacipran hydrochloride -treated patients receiving doses of 40, 80 and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised in the use of levomilnacipran hydrochloride in patients prone to obstructive urinary disorders. If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with levomilnacipran hydrochloride , consideration should be given to the possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered.
Activation of Mania/Hypomania
Symptoms of mania/hypomania were reported in 0.2% of levomilnacipran hydrochloride -treated patients and 0.2% of placebo-treated patients in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other antidepressants. As with all antidepressants, use levomilnacipran hydrochloride cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.
Seizures
levomilnacipran hydrochloride has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. levomilnacipran hydrochloride should be prescribed with caution in patients with a seizure disorder. One case of seizure has been reported in pre-marketing clinical studies with levomilnacipran hydrochloride .
Monitor patients for these symptoms when discontinuing levomilnacipran hydrochloride . Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate.
Hyponatremia
Although no adverse events of hyponatremia were reported for levomilnacipran hydrochloride -treated patients in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. levomilnacipran hydrochloride should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Adverse Reactions
Clinical Trials Experience
The following adverse reactions are discussed in greater detail in other sections of the label.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Patient exposure
The safety of levomilnacipran hydrochloride was evaluated in 2,673 patients (18-78 years of age) diagnosed with MDD who participated in clinical studies, representing 942 patient-years of exposure. Among the 2,673 levomilnacipran hydrochloride -treated patients, 1,583 were exposed to levomilnacipran hydrochloride in short-term, placebo-controlled studies. There were 825 patients who continued from short-term studies into a one-year, open-label extension study.
Of the 2,673 patients exposed to at least one dose of levomilnacipran hydrochloride , 737 patients were exposed to levomilnacipran hydrochloride for at least 6 months and 367 were exposed for one year. In these studies levomilnacipran hydrochloride was given at doses ranging from 40-120 mg once daily and was given without regard to food.
Adverse reactions reported as reasons for discontinuation of treatment
In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who received levomilnacipran hydrochloride (40-120 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,040 placebo-treated patients in those studies. The most common adverse reaction leading to discontinuation in at least 1% of the levomilnacipran hydrochloride -treated patients in the short-term placebo-controlled studies was nausea (1.5%).
Common adverse reactions in placebo-controlled MDD studies
TABLE 3 shows the incidence of adverse reactions that occurred in ≥ 2% of levomilnacipran hydrochloride -treated MDD patients and at least twice the rate of placebo in the placebo-controlled studies.
In pooled data from the short-term placebo-controlled fixed-dose studies, there were no dose-related adverse reactions (greater than 2% overall incidence) in patients treated with levomilnacipran hydrochloride across the dose range 40-120 mg once daily, with the exception of erectile dysfunction and urinary hesitation (seeTABLE 4).
This image is provided by the National Library of Medicine.
There is limited information regarding Postmarketing Experience of Levomilnacipran in the drug label.
Drug Interactions
Other than CYP3A4 drug interactions, levomilnacipran hydrochloride is predicted, based on in vitro studies, to have a low potential to be involved in clinically significant pharmacokinetic drug interactions.
Monoamine Oxidase Inhibitors (MAOIs)
Serotonergic Drugs
Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when levomilnacipran hydrochloride is initiated or discontinued .
Potential for Other Drugs to Affect levomilnacipran hydrochloride
Dose adjustment is recommended when levomilnacipran hydrochloride is co-administered with strong inhibitors of CYP3A4 (e.g. ketoconazole) . An in vivo study showed a clinically meaningful increase in levomilnacipran exposure when levomilnacipran hydrochloride was co-administered with the CYP3A4 inhibitor ketoconazole (see FIGURE 1).
No dose adjustment of levomilnacipran hydrochloride is needed when co-administered with a CYP3A4 inducer or substrate.In vivo studies showed no clinically meaningful change in levomilnacipran exposure when co-administered with the CYP3A4 inducer carbamazepine or the CYP3A4 substrate alprazolam (seeFIGURE 1).
No dose adjustment of levomilnacipran hydrochloride is needed when co-administered with inhibitors of CYP2C8 , CYP2C19, CYP2D6, CYP2J2, P-glycoprotein, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. In vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimal contributions to metabolism of levomilnacipran. In addition, levomilnacipran is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 and is a weak substrate of P-gp.
This image is provided by the National Library of Medicine.
Potential for levomilnacipran hydrochloride to Affect Other Drugs
No dose adjustment of the concomitant medication is recommended when levomilnacipran hydrochloride is administered with a substrate of CYP3A4, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. In vitro studies have shown that levomilnacipran is not an inhibitor of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Concomitant use of levomilnacipran hydrochloride with alprazolam or carbamazepine, substrates of CYP3A4, had no significant effect on alprazolam or carbamazepine plasma concentrations (see FIGURE 1).
Central Nervous System (CNS)-Active Agents
The risk of using levomilnacipran hydrochloride in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when levomilnacipran hydrochloride is prescribed in combination with other CNS-active drugs, including those with a similar mechanism of action.
Alcohol
In an in vitro study, alcohol interacted with the extended-release properties of levomilnacipran hydrochloride . If levomilnacipran hydrochloride is taken with alcohol, a pronounced accelerated drug release may occur. It is recommended that levomilnacipran hydrochloride extended-release capsules not be taken with alcohol.
There are no adequate and well-controlled studies of levomilnacipran hydrochloride in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as levomilnacipran hydrochloride ), or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery. Levomilnacipran was not teratogenic in rats or rabbits when given 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, respectively. However, an increase in early post natal rat pup mortality was seen at a dose equivalent to 5 times the MRHD given during pregnancy and lactation. levomilnacipran hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome
A prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
Animal Data
No teratogenic effects were observed when levomilnacipran was administered to pregnant rats or rabbits during the period of organogenesis at oral doses up to 100 mg/kg/day. This dose is 8 and 16 times (in rats and rabbits, respectively) the maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis. Fetal body weights were reduced in rats, and skeletal ossification was delayed in both rats and rabbits at this dose; these effects were not observed in either species at doses up to 30 mg/kg/day, 2.4 times the MRHD in rats or 5 times the MRHD in rabbits.
When levomilnacipran was administered to pregnant rats at an oral dose of 60 mg/kg/day, 5 times the MRHD, during organogenesis and throughout pregnancy and lactation, there was an increase in early postnatal pup mortality; no pup mortality was seen at 20 mg/kg/day, 1.6 times the MRHD. Among the surviving pups, pre- and post-weaning pup weight gain was reduced up to at least 8 weeks of age; however, physical and functional development, including reproductive performance of the progeny, was not affected. The effects on body weight gain were not seen at 7 mg/kg/day, 0.6 times the MRHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Levomilnacipran in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Levomilnacipran during labor and delivery.
Nursing Mothers
It is not known if levomilnacipran hydrochloride is present in human milk. Studies have shown that levomilnacipran is present in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from levomilnacipran hydrochloride , a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Clinical studies on the use of levomilnacipran hydrochloride in pediatric patients have not been conducted; therefore, the safety and effectiveness of levomilnacipran hydrochloride in the pediatric population have not been established. levomilnacipran hydrochloride is not approved for use in pediatric patients
Geriatic Use
No dose adjustment is recommended on the basis of age (see FIGURE 2). In a multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had a slightly higher exposure (Cmax by 24% and AUC by 26%) of levomilnacipran than younger subjects (18-45 years).
Of the total number of subjects in clinical studies of levomilnacipran hydrochloride , 2.8% of patients were age 65 or older.
Because levomilnacipran is predominately excreted by the kidney, renal clearance of levomilnacipran should be considered when determining the dose [see Dosage and Administration (2.3)].
SSRIs and SNRIs, including levomilnacipran hydrochloride , have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event
Gender
There is no FDA guidance on the use of Levomilnacipran with respect to specific gender populations.
Race
There is no FDA guidance on the use of Levomilnacipran with respect to specific racial populations.
Renal Impairment
Renal excretion plays a predominant role in the elimination of levomilnacipran. Dose adjustment is not recommended for patients with mild (creatinine clearance of 60-89 ml/min) renal impairment. Dosing adjustment is recommended for patients with moderate (creatinine clearance of 30-59 ml/min) or severe (creatinine clearance of 15-29 ml/min) renal impairment (see FIGURE 2). levomilnacipran hydrochloride is not recommended for patients with end stage renal disease
Hepatic Impairment
Hepatic elimination of levomilnacipran is low. Dose adjustment is not recommended in subjects 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
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Levomilnacipran in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Levomilnacipran in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
There is limited information regarding Monitoring of Levomilnacipran in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Levomilnacipran in the drug label.
Overdosage
Human Experience
There is limited clinical experience with levomilnacipran hydrochloride overdose in humans. In clinical studies, cases of ingestions up to 360 mg daily were reported with none being fatal.
Management of Overdose
No specific antidotes for levomilnacipran hydrochloride are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in reducing levomilnacipran plasma concentrations.
Pharmacology
There is limited information regarding Levomilnacipran Pharmacology in the drug label.
Mechanism of Action
The exact mechanism of the antidepressant action of levomilnacipran is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of reuptake at serotonin and norepinephrine transporters. Non-clinical studies have shown that levomilnacipran is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).
Structure
The active ingredient of levomilnacipran hydrochloride is levomilnacipran, which is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). The chemical name of levomilnacipran is (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride; its empirical formula is C15H23ClN2O and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial US approval: 2013) is the 1S,2R-enantiomer of milnacipran. The chemical structure is:
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levomilnacipran hydrochloride capsules are intended for oral administration only. Each levomilnacipran hydrochloride capsule contains extended-release beads with 23.0, 45.9, 91.8, or 137.8 mg of levomilnacipran hydrochloride equivalent to 20, 40, 80, or 120 mg of levomilnacipran, respectively. Inactive ingredients include sugar spheres, ethylcellulose, talc, povidone, triethyl citrate, hypromellose, and titanium dioxide. Inactive ingredients also include shellac glaze, black iron oxide, yellow iron oxide (20 mg and 40 mg capsules only), and red iron oxide (80 mg and 120 mg capsules only).
Pharmacodynamics
Levomilnacipran binds with high affinity to the human serotonin (5-HT) and norepinephrine (NE) transporters (Ki = 11 and 91 nM, respectively) and potently inhibits 5-HT and NE reuptake (IC50 = 16-19 and 11 nM, respectively). Levomilnacipran lacks significant affinity for any other receptors, ion channels or transporters tested in vitro, including serotonergic (5HT1-7), α- and β- adrenergic, muscarinic, or histaminergic receptors and Ca2+, Na+, K+ or Cl- channels. Levomilnacipran did not inhibit monoamine oxidase (MAO).
Cardiovascular Electrophysiology
At a dose 2.5 times the maximum recommended dose, levomilnacipran does not prolong QTc to any clinically relevant extent.
Pharmacokinetics
The concentration of levomilnacipran at steady state is proportional to dose when administered from 25 to 300 mg once daily. Following an oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h. Steady-state concentrations of levomilnacipran are predictable from single-dose data. The apparent terminal elimination half-life of levomilnacipran is approximately 12 hours. After daily dosing of levomilnacipran hydrochloride 120 mg, the mean Cmax value is 341 ng/mL, and the mean steady-state AUC value is 5196 ng·h/mL. Interconversion between levomilnacipran and its stereoisomer does not occur in humans.
Absorption
The relative bioavailability of levomilnacipran after administration of levomilnacipran hydrochloride ER was 92% when compared to oral solution. Levomilnacipran concentration was not significantly affected when levomilnacipran hydrochloride was administered with food.
The median time to peak concentration (Tmax) of levomilnacipran is 6-8 hours after oral administration.
Distribution
Levomilnacipran is widely distributed with an apparent volume of distribution of 387-473 L; plasma protein binding is 22% over concentration range of 10 to 1000 ng/mL.
Metabolism
Levomilnacipran undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran. Both oxidative metabolites undergo further conjugation with glucuronide to form conjugates. The desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2 [see Drug Interactions (7.4, 7.5)].
Elimination/Excretion
Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose. Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%). The metabolites are inactive
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Levomilnacipran administered by oral gavage to rats for 2 years and Tg.rasH2 mice for 6 months did not increase the incidence of tumors in either study.
Rats received levomilnacipran at doses up to 90/70 mg/kg/day (the dose was lowered in males after 45 weeks of dosing). The 90 mg/kg/day dose is 7 times the maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis.
Tg.rasH2 mice received levomilnacipran at doses up to 150 mg/kg/day. This dose is 6 times the MRHD.
Mutagenesis
Levomilnacipran was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vivo micronucleus assay in rats. Additionally, levomilnacipran was not genotoxic in the in vitro mouse lymphoma (L5178Y TK+/-) cell forward mutation assay.
Impairment of Fertility
When levomilnacipran was administered orally to male and female rats before mating, through mating and up to Day 7 of gestation at doses up to 100 mg/kg/day, no effects were observed on fertility. This dose is 8 times the MRHD.
Clinical Studies
Treatment of Major Depressive Disorder
The efficacy of levomilnacipran hydrochloride for the treatment of major depressive disorder (MDD) was established in three 8-week randomized, double-blind, placebo-controlled studies (at doses 40-120 mg once daily) in adult (18 - 78 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. Two of the studies were fixed dose (Study 1 and Study 2) and one study was flexible dose (Study 3).
In Study 1, patients received 40 mg (n = 178), 80 mg (n = 179), or 120 mg (n = 180) of levomilnacipran hydrochloride once daily, or placebo (n = 176). In Study 2, patients received either 40 mg (n = 188) or 80 mg (n = 188) of levomilnacipran hydrochloride once daily, or placebo (n = 186). In the flexible-dose study (Study 3), patients received 40 to 120 mg (n = 217) of levomilnacipran hydrochloride once daily, or placebo (n = 217) with 21%, 34%, and 44% of levomilnacipran hydrochloride patients on 40 mg, 80 mg, and 120 mg, respectively at the end of their treatment.
In all three studies, levomilnacipran hydrochloride demonstrated superiority over placebo in the improvement of depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) total score (seeTABLE 5). levomilnacipran hydrochloride also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale (SDS) functional impairment total score.
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How Supplied
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
All package configurations: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature].
Storage
There is limited information regarding Levomilnacipran Storage in the drug label.
Images
Drug Images
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Advise patients, their families, and their caregivers about the benefits and risks associated with treatment with levomilnacipran hydrochloride and counsel them on its appropriate use. Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.
Suicide Risk
Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down
Dosing and Administration
Advise patients that levomilnacipran hydrochloride should be swallowed whole and should not be chewed, crushed or opened.
Advise patients that levomilnacipran hydrochloride can be taken with or without food. levomilnacipran hydrochloride should be initiated with a dose of 20 mg once daily for 2 days and then increased to 40 mg once daily. Based on efficacy and tolerability, levomilnacipran hydrochloride may then be increased in increments of 40 mg at intervals of 2 or more days. The maximum recommended dose is 120 mg once daily.
Instruct patients if they miss a dose, to take the missed dose as soon as they remember. If it is almost time for the next dose, instruct them to skip the missed dose and take their next dose at the regular time. Advise them not to take two doses of levomilnacipran hydrochloride at the same time.
Concomitant Medication
Instruct patients not to take levomilnacipran hydrochloride with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping levomilnacipran hydrochloride before starting an MAOI .
Serotonin Syndrome
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of levomilnacipran hydrochloride and triptans, tramadol, tryptophan supplements, other serotonergic agents, or antipsychotic drugs .
Effect on Blood Pressure and Heart Rate
Advise patients that they should have regular monitoring of blood pressure and heart rate when taking levomilnacipran hydrochloride [see Warnings and Precautions (5.3, 5.4)].
Abnormal Bleeding
Caution patients about the concomitant use of levomilnacipran hydrochloride and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding [see Warnings and Precautions (5.5)].
Angle Closure Glaucoma
Patients should be advised that taking levomilnacipran hydrochloride can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible .
Urinary Hesitation or Retention
Caution patients about the risk of urinary hesitation and retention while taking levomilnacipran hydrochloride , particularly in patients prone to obstructive urinary disorders
Activation of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania.
Caution patients about using levomilnacipran hydrochloride if they have a history of a seizure disorder . Patients with a history of seizures were excluded from clinical studies.
Discontinuation Syndrome
Advise patients not to stop taking levomilnacipran hydrochloride without first talking with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping levomilnacipran hydrochloride.
Hyponatremia
Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking levomilnacipran hydrochloride.
Alcohol
Advise patients to avoid consumption of alcohol while taking levomilnacipran hydrochloride [see Drug Interactions (7.6)].
Allergic Reactions
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.
Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with levomilnacipran hydrochloride .
Nursing Mothers
Advise patients to notify their healthcare provider if they are breastfeeding an infant and would like to continue or start levomilnacipran hydrochloride .
Interference with Cognitive and Motor Performance
Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that levomilnacipran hydrochloride therapy does not adversely affect their ability to engage in such activities.
Precautions with Alcohol
Alcohol-Levomilnacipran interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Fetzima
Fetzima Titration Pack
Look-Alike Drug Names
There is limited information regarding Levomilnacipran Look-Alike Drug Names in the drug label.
