Levomilnacipran by is a Prescription medication manufactured, distributed, or labeled by Amneal Pharmaceuticals LLC. Drug facts, warnings, and ingredients follow.
Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of Major Depressive Disorder (MDD) (1).
Limitation of Use: Levomilnacipran extended-release capsules are not approved for the management of fibromyalgia. The efficacy and safety of levomilnacipran extended-release capsules for the management of fibromyalgia have not been established (1).
The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) are: nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, tachycardia, vomiting, and palpitations (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 2/2019
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 [see Warnings and Precautions (5.1)].
Levomilnacipran is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].
Levomilnacipran, a serotonin and norepinephrine reuptake inhibitor (SNRI) is indicated for the treatment of major depressive disorder (MDD). The efficacy of levomilnacipran extended-release capsules was established in three 8-week, randomized, double-blind, placebo-controlled studies in adult patients with a diagnosis of MDD [see Clinical Studies (14)].
Limitation of Use: Levomilnacipran extended-release capsules are not approved for the management of fibromyalgia. The efficacy and safety of levomilnacipran extended-release capsules for the management of fibromyalgia have not been established.
The recommended dose range for levomilnacipran extended-release capsules is 40 mg to 120 mg once daily, with or without food. Levomilnacipran extended-release capsules 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 extended-release capsules 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 extended-release capsules should be taken at approximately the same time each day. Levomilnacipran extended-release capsules should be swallowed whole. Do not open, chew or crush the capsule.
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 extended-release capsules has not been established beyond 8 weeks.
Renal Impairment: Dose adjustment is not recommended in patients with mild renal impairment (creatinine clearance of 60 to 89 mL/min). For patients with moderate renal impairment (creatinine clearance of 30 to 59 mL/min), the maintenance dose should not exceed 80 mg once daily. For patients with severe renal impairment (creatinine clearance of 15 to 29 mL/min), the maintenance dose should not exceed 40 mg once daily. Levomilnacipran extended-release capsules are not recommended for patients with end stage renal disease [see Use in Specific Populations (8.7)].
Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as levomilnacipran extended-release capsules. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing levomilnacipran extended-release capsules. 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 [see Warnings and Precautions (5.10)].
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with levomilnacipran extended-release capsules. Conversely, at least 7 days should be allowed after stopping levomilnacipran extended-release capsules before starting an MAOI antidepressant [see Contraindications (4)].
Do not start levomilnacipran extended-release capsules 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 [see Contraindications (4)].
In some cases, a patient already receiving levomilnacipran extended-release capsules 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 extended-release capsules 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 extended-release capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].
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 extended-release capsules are unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].
The dose of levomilnacipran extended-release capsules should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir) [see Drug Interactions (7.4)].
Levomilnacipran extended-release capsules are available as 20 mg, 40 mg, 80 mg and 120 mg extended-release capsules.
Levomilnacipran extended-release capsules, 20 mg are supplied as size ‘4’ capsules, imprinted with “AN” on yellow cap and “411” on white body of the capsules with black ink, filled with off-white to pale yellow pellets.
Levomilnacipran extended-release capsules, 40 mg are supplied as size ‘3’ capsules, imprinted with “AN” on yellow cap and “414” on yellow body of the capsules with black ink, filled with off-white to pale yellow pellets.
Levomilnacipran extended-release capsules, 80 mg are supplied as size ‘2’ capsules, imprinted with “AN” on pink cap and “437” on white body of the capsules with black ink, filled with off-white to pale yellow pellets.
Levomilnacipran extended-release capsules, 120 mg are supplied as size ‘1’ capsules, imprinted with “AN” on pink cap and “455” on pink body of the capsules with black ink, filled with off-white to pale yellow pellets.
Starting levomilnacipran 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 [see Dosage and Administration (2.6) and Warnings and Precautions (5.2)].
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 to 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 4,400 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 1,000 patients treated) are provided in Table 1.
Table 1:
Age Range |
Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
Increases Compared to Placebo |
|
<18 |
14 additional cases |
18 to 24 |
5 additional cases |
Decreases Compared to Placebo |
|
25 to 64 |
1 fewer case |
≥65 |
6 fewer cases |
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 [see Dosage and Administration (2.4) and Warnings and Precautions (5.10) for a description of the risks of discontinuation of levomilnacipran].
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 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 is not approved for use in treating bipolar depression.
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of levomilnacipran with MAOIs intended to treat psychiatric disorders is contraindicated. Levomilnacipran 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. Levomilnacipran should be discontinued before initiating treatment with the MAOI [see Dosage and Administration (2.5, 2.6) and Contraindications (4)].
If concomitant use of levomilnacipran with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with levomilnacipran and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
SNRIs, including levomilnacipran, have been associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically throughout levomilnacipran treatment. Pre-existing hypertension should be controlled before initiating treatment with levomilnacipran. 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, 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-treated patients in the short-term placebo-controlled studies.
Table 2: Blood Pressure Mean Changes, Sustained Hypertension, and Upward Shifts in Hypertensive Status
Placebo |
Levomilnacipran 40 to 120 mg/day |
|
Mean change from baseline to end of treatment, mm Hg |
||
Systolic blood pressure (SBP) |
-0.4 |
3.0 |
Diastolic blood pressure (DBP) |
-0.0 |
3.2 |
Sustained Hypertension, % of patients |
||
Broad Criteria: SBP ≥ 140 mm Hg and an increase ≥15 mm Hg OR DBP ≥ 90 mm Hg and an increase ≥10 mm Hg for at least 3 consecutive visits |
1.2 |
1.8 |
Strict Criteria: SBP ≥ 140 mm Hg and an increase ≥15 mm Hg AND DBP ≥ 90 mm Hg and an increase ≥10 mm Hg for at least 3 consecutive visits |
0.1 |
0.3 |
Upward Shifts in Hypertensive Statusa, % of patients |
||
Normal/ Pre-hypertensive → Stage I/ Stage II |
7.1 |
10.4 |
a Normal Blood Pressure: SBP < 120 mm Hg and DBP < 80 mm Hg Pre-hypertension: SBP ≥ 120 mm Hg and ≤ 139 mm Hg or DBP ≥ 80 mm Hg and ≤ 89 mm Hg Stage I hypertension: SBP ≥ 140 mm Hg and ≤ 159 mm Hg or DBP ≥ 90 mm Hg and ≤ 99 mm Hg Stage II hypertension: SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg |
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 (doses range from 40 to 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 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-treated patients with doses of 40, 80 and 120 mg/day respectively, compared to 6.2% of placebo-treated patients.
Concomitant use of levomilnacipran with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. Effects of levomilnacipran on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Levomilnacipran should be used with caution in these patients.
SNRIs including levomilnacipran have been associated with increased heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout levomilnacipran treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with levomilnacipran. For patients who experience a sustained increase in heart rate while receiving levomilnacipran, discontinuation or other appropriate medical intervention should be considered.
In short-term clinical studies, levomilnacipran 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-treated patients receiving doses of 40 mg, 80 mg and 120 mg was 7.2, 7.2, and 9.1 bpm.
Levomilnacipran has not been systematically evaluated in patients with a cardiac rhythm disorder.
SSRIs and SNRIs, including levomilnacipran, 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 and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
The pupillary dilation that occurs following use of many antidepressant drugs including levomilnacipran may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
The noradrenergic effect of SNRIs including levomilnacipran, can affect urethral resistance. In the controlled short-term studies, urinary hesitation occurred in 4%, 5% and 6% of levomilnacipran-treated patients receiving doses of 40 mg, 80 mg and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised in the use of levomilnacipran in patients prone to obstructive urinary disorders. If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with levomilnacipran, consideration should be given to the possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered.
Symptoms of mania/hypomania were reported in 0.2% of levomilnacipran-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 cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.
Levomilnacipran has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Levomilnacipran 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.
There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Monitor patients for these symptoms when discontinuing levomilnacipran. 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 [see Dosage and Administration (2.4)].
Although no adverse events of hyponatremia were reported for levomilnacipran-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 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.
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 was evaluated in 2,673 patients (18 to 78 years of age) diagnosed with MDD who participated in clinical studies, representing 942 patient-years of exposure. Among the 2,673 levomilnacipran-treated patients, 1,583 were exposed to levomilnacipran 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, 737 patients were exposed to levomilnacipran for at least 6 months and 367 were exposed for one year. In these studies levomilnacipran was given at doses ranging from 40 mg to 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 (40 mg to 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-treated patients in the short-term placebo-controlled studies was nausea (1.5%).
Common adverse reactions in placebo-controlled MDD studies
The most commonly observed adverse events in levomilnacipran-treated MDD patients in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were: nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, tachycardia, vomiting, and palpitations.
Table 3 shows the incidence of adverse reactions that occurred in ≥ 2% of levomilnacipran-treated MDD patients and at least twice the rate of placebo in the placebo-controlled studies.
Table 3: Adverse Reactions Occurring in ≥ 2% of Levomilnacipran-treated Patients and at Least Twice the rate of Placebo-treated Patients
System Organ Class Preferred Term |
Placebo |
Levomilnacipran |
Gastrointestinal disorders |
||
Nausea |
6 |
17 |
Constipation |
3 |
9 |
Vomiting |
1 |
5 |
Cardiac disorders |
||
Tachycardiaa |
2 |
6 |
Palpitations |
1 |
5 |
Reproductive system and breast disordersb |
||
Erectile dysfunctionc |
1 |
6 |
Testicular paind |
<1 |
4 |
Ejaculation disordere |
<1 |
5 |
Investigations |
||
Heart rate increasedf |
1 |
6 |
Blood pressure increasedg |
1 |
3 |
Renal and urinary disorders |
||
Urinary hesitation |
0 |
4 |
Skin and subcutaneous tissue disorders |
||
Hyperhidrosis |
2 |
9 |
Rashh |
0 |
2 |
Vascular disorders |
||
Hot flush |
1 |
3 |
Hypotensioni |
1 |
3 |
Hypertensionj |
1 |
3 |
Metabolism and nutrition disorders |
||
Decreased appetite |
1 |
3 |
a Tachycardia also includes: sinus tachycardia and postural orthostatic tachycardia syndrome b Percentage is relative to the number of patients in the associated demographic sex category. Fewer than 2% of levomilnacipran-treated MDD female patients in placebo-controlled clinical studies reported adverse events related to sexual function. c erectile dysfunction includes: erectile dysfunction, organic erectile dysfunction and psychogenic erectile dysfunction d testicular pain includes: testicular pain, epididymitis, and seminal vesiculitis e ejaculation disorder includes: ejaculation disorder, ejaculation delayed, ejaculation failure, and premature ejaculation f Heart rate increased also includes: orthostatic heart rate response increased g Blood pressure increased also includes: blood pressure systolic increased, blood pressure diastolic increased and blood pressure orthostatic increased h Rash also includes: rash generalized, rash maculo-papular, rash erythematous and rash macular i Hypotension also includes: orthostatic hypotension and dizziness postural j Hypertension also includes: labile hypertension N = number of patients in the Safety Population |
Dose-related adverse reactions
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 across the dose range 40 mg to 120 mg once daily, with the exception of erectile dysfunction and urinary hesitation (see Table 4).
Table 4: Dose-Related Adverse Reactions
System Organ Class Preferred Term |
Placebo |
Levomilnacipran |
||
40 mg/d |
80 mg/d |
120 mg/d |
||
Urinary hesitation |
0 |
4 |
5 |
6 |
Erectile dysfunctiona |
2 |
6 |
8 |
10 |
aPercentage is relative to the number of male patients. N = number of patients in the Safety Population |
Other adverse reactions observed in clinical studies
Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with levomilnacipran were:
Cardiac disorders: Angina pectoris; Supraventricular and Ventricular extrasystoles
Eye disorders: Dry eye; Vision blurred; Conjunctival hemorrhage
General disorders: Chest pain; Thirst
Gastrointestinal disorders: Abdominal pain; Flatulence
Investigations disorders: Blood cholesterol increased; Liver function test abnormal
Nervous System disorders: Migraine; Paraesthesia; Syncope; Extrapyramidal disorder
Psychiatric disorders: Agitation; Anger; Bruxism; Panic attack; Tension; Aggression
Renal and Urinary disorder: Pollakiuria; Hematuria; Proteinuria
Respiratory, thoracic and mediastinal disorders: Yawning
Skin and subcutaneous tissue disorders: Dry skin; Pruritus; Urticaria
Besides these reactions reported under treatment with levomilnacipran, other potentially severe adverse events have been reported from the post-marketing experience with milnacipran. Since levomilnacipran is the principal pharmacologically active component of milnacipran, one should take into account the fact that the following adverse event could also potentially occur under treatment with levomilnacipran.
This adverse reaction includes: Takotsubo cardiomyopathy.
Other than CYP3A4 drug interactions, levomilnacipran is predicted, based on in vitro studies, to have a low potential to be involved in clinically significant pharmacokinetic drug interactions.
[see Dosage and Administration (2.5, 2.6), Contraindications (4), and Warnings and Precautions (5.2)]
[see Dosage and Administration (2.5, 2.6), Contraindications (4), and Warnings and Precautions (5.2)]
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 is initiated or discontinued [see Warnings and Precautions (5.5)].
Dose adjustment is recommended when levomilnacipran is co-administered with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Dosage and Administration (2.7)]. An in vivo study showed a clinically meaningful increase in levomilnacipran exposure when levomilnacipran was co-administered with the CYP3A4 inhibitor ketoconazole (see Figure 1).
No dose adjustment of levomilnacipran 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 (see Figure 1).
No dose adjustment of levomilnacipran 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.
Figure 1: PK Interactions between Levomilnacipran (LVM) and Other Drugs
No dose adjustment of the concomitant medication is recommended when levomilnacipran 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 with alprazolam or carbamazepine, substrates of CYP3A4, had no significant effect on alprazolam or carbamazepine plasma concentrations (see Figure 1).
The risk of using levomilnacipran in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when levomilnacipran 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. If levomilnacipran is taken with alcohol, a pronounced accelerated drug release may occur. It is recommended that levomilnacipran extended-release capsules not be taken with alcohol.
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies of levomilnacipran in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as levomilnacipran), 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 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 [see Warnings and Precautions (5.2)].
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.
It is not known if levomilnacipran 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, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
Clinical studies on the use of levomilnacipran in pediatric patients have not been conducted; therefore, the safety and effectiveness of levomilnacipran in the pediatric population have not been established. Levomilnacipran is not approved for use in pediatric patients [see Boxed Warning and Warnings and Precautions (5.1)].
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 to 45 years).
Of the total number of subjects in clinical studies of levomilnacipran, 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, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.11)].
Hepatic elimination of levomilnacipran is low. Dose adjustment is not recommended in subjects with mild (Child-Pugh score of 1 to 6), moderate (Child-Pugh score of 7 to 9), or severe (Child-Pugh score of 10 to 13) hepatic impairment (see Figure 2).
Renal excretion plays a predominant role in the elimination of levomilnacipran. Dose adjustment is not recommended for patients with mild (creatinine clearance of 60 to 89 ml/min) renal impairment. Dosing adjustment is recommended for patients with moderate (creatinine clearance of 30 to 59 ml/min) or severe (creatinine clearance of 15 to 29 ml/min) renal impairment (see Figure 2). Levomilnacipran is not recommended for patients with end stage renal disease [see Dosage and Administration (2.3)].
Levomilnacipran has not been systematically studied in animals or humans for its potential for abuse. There was no evidence suggestive of drug-seeking behavior in the clinical studies. It is not possible to predict on the basis of clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of levomilnacipran (e.g., development of tolerance or drug-seeking behavior).
There is limited clinical experience with levomilnacipran overdose in humans. In clinical studies, cases of ingestions up to 360 mg daily were reported with none being fatal.
No specific antidotes for levomilnacipran 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.
The active ingredient of levomilnacipran extended-release, capsules 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 molecular 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:
Levomilnacipran extended-release capsules are intended for oral administration only. Each levomilnacipran extended-release capsule contains extended-release beads with 23, 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 ethylcellulose, hypromellose, povidone, red iron oxide (80 mg and 120 mg), sugar sphere [sucrose, starch (Biological source: maize) and purified water], talc, triethyl citrate, titanium dioxide and yellow iron oxide (20 mg and 40 mg).
Each capsule is imprinted with black pharmaceutical ink which contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.
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).
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 to 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.
The concentration of levomilnacipran at steady-state is proportional to dose when administered from 25 mg to 300 mg once daily. Following an oral administration, the mean apparent total clearance of levomilnacipran is 21 to 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 120 mg, the mean Cmax value is 341 ng/mL, and the mean steady-state AUC value is 5,196 ng·h/mL. Interconversion between levomilnacipran and its stereoisomer does not occur in humans.
Absorption
The relative bioavailability of levomilnacipran after administration of levomilnacipran extended-release capsules was 92% when compared to oral solution. Levomilnacipran concentration was not significantly affected when levomilnacipran was administered with food.
The median time to peak concentration (Tmax) of levomilnacipran is 6 to 8 hours after oral administration.
Distribution
Levomilnacipran is widely distributed with an apparent volume of distribution of 387 to 473 L; plasma protein binding is 22% over concentration range of 10 to 1,000 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 [see Dosage and Administration (2.3)].
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.
The efficacy of levomilnacipran for the treatment of major depressive disorder (MDD) was established in three 8-week randomized, double-blind, placebo-controlled studies (at doses 40 mg to 120 mg once daily) in adult (18 to 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 once daily, or placebo (n = 176). In Study 2, patients received either 40 mg (n = 188) or 80 mg (n = 188) of levomilnacipran once daily, or placebo (n = 186). In the flexible-dose study (Study 3), patients received 40 to 120 mg (n = 217) of levomilnacipran once daily, or placebo (n = 217) with 21%, 34%, and 44% of levomilnacipran patients on 40 mg, 80 mg, and 120 mg, respectively at the end of their treatment.
In all three studies, levomilnacipran demonstrated superiority over placebo in the improvement of depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) total score (see Table 5). Levomilnacipran also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale (SDS) functional impairment total score.
Table 5: Summary of Results for the Primary Efficacy Endpoint MADRS
Study Number |
Treatment Group |
Mean Baseline Score (SD) |
LS Mean Change from Baseline (SE) |
Placebo-subtracted Differencea (95% CI) |
Study 1 (fixed dose) |
Levomilnacipran (extended-release capsules 40 mg/day)* |
36.0 (4.1) |
-14.8 (1.0) |
-3.2 (-5.9, -0.5) |
Levomilnacipran (extended-release capsules 80 mg/day)* |
36.1 (3.9) |
-15.6 (1.0) |
-4.0 (-6.7, -1.3) |
|
Levomilnacipran (extended-release capsules 120 mg/day)* |
36.0 (3.9) |
-16.5 (1.0) |
-4.9 (-7.6, -2.1) |
|
Placebo |
35.6 (4.5) |
-11.6 (1.0) |
- |
|
Study 2 (fixed-dose) |
Levomilnacipran (extended-release capsules 40 mg/day)* |
30.8 (3.4) |
-14.6 (0.8) |
-3.3 (-5.5, -1.1) |
Levomilnacipran (extended-release capsules 80 mg/day)* |
31.2 (3.5) |
-14.4 (0.8) |
-3.1 (-5.3, -1.0) |
|
Placebo |
31.0 (3.8) |
-11.3 (0.8) |
- |
|
Study 3 (flexible-dose) |
Levomilnacipran (extended-release capsules 40 to 120 mg/day)* |
35.0 (3.6) |
-15.3 (0.8) |
-3.1 (-5.3, -0.9) |
Placebo |
35.2 (3.8) |
-12.2 (0.8) |
- |
|
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval unadjusted for multiplicity. a Difference (drug minus placebo) in least-squares mean change from baseline to endpoint (Week 8). * Doses statistically significantly superior to placebo. |
Post-hoc analyses of the relationships between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
Levomilnacipran extended-release capsules are supplied in the following configurations:
Levomilnacipran Extended-release Capsules, 20 mg are supplied as size ‘4’ capsules, imprinted with “AN” on yellow cap and “411” on white body of the capsules with black ink, filled with off-white to pale yellow pellets.
They are available as follows:
Bottles of 30: NDC: 65162-411-03
Levomilnacipran Extended-release Capsules, 40 mg are supplied as size ‘3’ capsules, imprinted with “AN” on yellow cap and “414” on yellow body of the capsules with black ink, filled with off-white to pale yellow pellets.
They are available as follows:
Bottles of 30: NDC: 65162-960-03
Levomilnacipran Extended-release Capsules, 80 mg are supplied as size ‘2’ capsules, imprinted with “AN” on pink cap and “437” on white body of the capsules with black ink, filled with off-white to pale yellow pellets.
They are available as follows:
Bottles of 30: NDC: 65162-437-03
Levomilnacipran Extended-release Capsules, 120 mg are supplied as size ‘1’ capsules, imprinted with “AN” on pink cap and “455” on pink body of the capsules with black ink, filled with off-white to pale yellow pellets.
They are available as follows:
Bottles of 30: NDC: 65162-455-03
Storage and Handling
All package configurations: Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
See FDA-approved patient labeling (Medication Guide).
Information for Patients
Advise patients, their families, and their caregivers about the benefits and risks associated with treatment with levomilnacipran 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 [see Box Warning and Warnings and Precautions (5.1)].
Dosing and Administration
Advise patients that levomilnacipran extended-release capsules should be swallowed whole and should not be chewed, crushed or opened.
Advise patients that levomilnacipran extended-release capsules can be taken with or without food. Levomilnacipran 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 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 at the same time.
Concomitant Medication
Instruct patients not to take levomilnacipran with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping levomilnacipran before starting an MAOI [see Contraindications (4)].
Serotonin Syndrome
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of levomilnacipran and triptans, tramadol, amphetamines, tryptophan supplements, other serotonergic agents, or antipsychotic drugs [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].
Effect on Blood Pressure and Heart Rate
Advise patients that they should have regular monitoring of blood pressure and heart rate when taking levomilnacipran [see Warnings and Precautions (5.3, 5.4)].
Abnormal Bleeding
Caution patients about the concomitant use of levomilnacipran 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 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 [see Warnings and Precautions (5.6)].
Urinary Hesitation or Retention
Caution patients about the risk of urinary hesitation and retention while taking levomilnacipran, particularly in patients prone to obstructive urinary disorders [see Warnings and Precautions (5.7)].
Activation of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania [see Warnings and Precautions (5.8)].
Seizures
Caution patients about using levomilnacipran if they have a history of a seizure disorder [see Warnings and Precautions (5.9)]. Patients with a history of seizures were excluded from clinical studies.
Discontinuation Syndrome
Advise patients not to stop taking levomilnacipran without first talking with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping levomilnacipran [see Warnings and Precautions (5.10)].
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 [see Warnings and Precautions (5.11)].
Alcohol
Advise patients to avoid consumption of alcohol while taking levomilnacipran [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 [see Use in Specific Populations (8.1)].
Nursing Mothers
Advise patients to notify their healthcare provider if they are breastfeeding an infant and would like to continue or start levomilnacipran [see Use in Specific Populations (8.3)].
Interference with Cognitive and Motor Performance
Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that levomilnacipran therapy does not adversely affect their ability to engage in such activities.
Manufactured by:
Amneal Pharmaceuticals Pvt. Ltd.
Ahmedabad 382220, INDIA
Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807
Rev. 02-2018-00
Levomilnacipran (lee" voe mil na' si pran) Extended-Release Capsules
Read this Medication Guide before you start taking levomilnacipran extended-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Talk to your healthcare provider about:
What is the most important information I should know about depression, antidepressant medicines, other serious mental illnesses, suicidal thoughts or actions and serotonin syndrome?
Levomilnacipran extended-release capsules and other antidepressant medicines may cause serious side effects.
Levomilnacipran extended-release capsules are not approved for use in children. Talk to your child’s healthcare provider for more information.
Call your healthcare provider right away if you have any of the following symptoms or feelings, especially if they are new, worse, or worry you:
4. Serotonin syndrome: A rare, but potentially life-threatening condition called serotonin syndrome can happen when medicines such as levomilnacipran extended-release capsules are taken with certain other medicines. Serotonin syndrome can cause serious changes in how your brain, muscles, heart and blood vessels, and digestive system work.
Symptoms of serotonin syndrome may include:
What else do I need to know about antidepressant medicines?
What are levomilnacipran extended-release capsules?
Levomilnacipran extended-release capsules are a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD). Levomilnacipran extended-release capsule belongs to a class of medicines known as SNRIs (or serotonin-norepinephrine reuptake inhibitors).
Who should not take levomilnacipran extended-release capsules?
Do not take levomilnacipran extended-release capsules if you:
What should I tell my healthcare provider before taking levomilnacipran extended-release capsules? Before you take levomilnacipran extended-release capsules, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Especially tell your healthcare provider if you take:
Ask your healthcare provider if you are not sure if you are taking any of these medicines.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get new medicine.
Levomilnacipran extended-release capsules and some medicines may affect each other, may not work as well, or may cause serious side effects when taken together.
How should I take levomilnacipran extended-release capsules?
What should I avoid while taking levomilnacipran extended-release capsules?
What are the possible side effects of levomilnacipran extended-release capsules?
Levomilnacipran extended-release capsules may cause serious side effects, including:
Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.
The most common side effects of levomilnacipran extended-release capsules include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of levomilnacipran extended-release capsules. For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store levomilnacipran extended-release capsules?
Store levomilnacipran extended-release capsules at 20° to 25°C (68° to 77°F) ); excursions permitted between 15° to 30°C (59° to 86°F).
Keep levomilnacipran extended-release capsules and all medicines out of the reach of children.
General information about the safe and effective use of levomilnacipran extended-release capsules.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levomilnacipran extended-release capsules for a condition for which it was not prescribed. Do not give levomilnacipran extended-release capsules to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about levomilnacipran extended-release capsules. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about levomilnacipran extended-release capsules that is written for healthcare professionals.
For more information, go to www.amneal.com or call 1-877-835-5472.
What are the ingredients in levomilnacipran extended-release capsules?
Active ingredient: levomilnacipran hydrochloride
Inactive ingredients: ethylcellulose, hypromellose, povidone , red iron oxide (80 mg and 120 mg), sugar sphere [sucrose, starch (Biological source: maize) and purified water], talc, triethyl citrate, titanium dioxide and yellow iron oxide (20 mg and 40 mg).
Each capsule is imprinted with black pharmaceutical ink which contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
*All trademarks are the property of their respective owner.
Manufactured by:
Amneal Pharmaceuticals Pvt. Ltd.
Ahmedabad 382220, INDIA
Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807
Rev. 02-2018-00
NDC: 65162-411-03
Levomilnacipran Extended-Release Capsules, 20 mg
Rx only
30 Capsules
Amneal Pharmaceuticals LLC
NDC: 65162-960-03
Levomilnacipran Extended-Release Capsules, 40 mg
Rx only
30 Capsules
Amneal Pharmaceuticals LLC
NDC: 65162-437-03
Levomilnacipran Extended-Release Capsules, 80 mg
Rx only
30 Capsules
Amneal Pharmaceuticals LLC
NDC: 65162-455-03
Levomilnacipran Extended-Release Capsules, 120 mg
Rx only
30 Capsules
Amneal Pharmaceuticals LLC
LEVOMILNACIPRAN
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LEVOMILNACIPRAN
levomilnacipran capsule, extended release |
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Labeler - Amneal Pharmaceuticals LLC (123797875) |